Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications and Formulations

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Delivery System Handbook for Personal Care and Cosmetic Products Technology, Applications, and Formulations Edited by

Meyer R. Rosen Interactive Consulting, Inc. East Norwich, New York

Copyright © 2005 by William Andrew, Inc. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the Publisher. Cover art by Brent Beckley ISBN: 0-8155-1504-9 Library of Congress Cataloging-in-Publication Data Rosen, Meyer R. Delivery system handbook for personal care and cosmetic products: technology, applications, and formulations / edited by Meyer R. Rosen. p. cm. Includes index. ISBN 0-8155-1504-9 (0-8155) 1. Cosmetic delivery systems—Handbooks, manuals, etc. 2. Advertising—Cosmetics—Handbooks, manuals, etc. 3. Cosmetics—Handbooks, manuals, etc. 4. Hygiene products—Handbooks, manuals, etc. I. Title. TP983.3.R67 2005 668'.55—dc22 2005023020 Printed in the United States of America. This book is printed on acid-free paper. 10 9 8 7 6 5 4 3 2 1 Published in the United States by William Andrew, Inc. 13 Eaton Avenue Norwich, NY 13815 1-800-932-7045 www.williamandrew.com

NOTICE To the best of our knowledge the information in this publication is accurate; however the Publisher does not assume any responsibility or liability for the accuracy or completeness of, or consequences arising from, such information. This book is intended for informational purposes only. Mention of trade names or commercial products does not constitute endorsement or recommendation for use by the Publisher. Final determination of the suitability of any information or product for any use, and the manner of that use, is the sole responsibility of the user. Anyone intending to rely upon any recommendation of materials or procedures mentioned in this publication should be independently satisfied as to such suitability, and must meet all applicable safety and health standards.

Dedication To my Father and Mother, Philip and Jeanne Rosen, who provided their son with the opportunity of an extraordinary education and thereby laid the foundation for me to contribute to our Industry and to my Fellow Travellers in this Process we call Life. To my loving wife Selma, the wind beneath my wings. Soul Mate Extraodinaire Loved beyond the power of mere words to express. She who has supported me in all things and under all circumstances. When it was time to grow from the Corporate World into the All-in-One role of Consultant, it was Selma who taught me to listen to what was wanted and needed and then, to provide it. To Selma, who taught me: “When you change the way you look at things, …the things you look at change”.

Contributing Authors

Aikens, Patricia – Chapter 41 Patricia Aikens received a B.S. in chemistry from Rensselaer Polytechnic Institute in Troy, NY and a Ph.D. in organic chemistry from Emory University in Atlanta, GA. She has worked in research and development mainly for the cosmetic industry over the past 10 years at ICI and Dragoco. She is currently the Technical Group Leader for Skin-Care and Sunscreens for BASF Corp. in Ledgewood, NJ. BASF Corp 1705 Rte. 46 W. #4, Ledgewood, NJ 07852 Tel: 973-448-5306 E-mail: [email protected] Al-Khalili, Mohammad – Chapter 3 Mohammad Al-Khalili, Iomai Corp., Gaithersburg, Maryland, is a visiting scientist in the Drug Delivery Laboratory at the New Jersey Center for Biomaterials. He received his PhD in pharmaceutics from the University of South Carolina, where he performed research into the diverse aspects of transdermal drug delivery. Iomai Corporation 20 Firstfield Road, Suite 250 Gaithersburg, MD 20878 Tel: 301-556-4535, Fax: 301-556-4501 E-mail: [email protected] Ansaldi, Anthony – Chapter 15 Anthony Ansaldi, Presperse Inc., Somerset, New Jersey, is marketing director for Presperse, Inc.

He is currently working on new approaches to market development and new product management. Mr. Ansaldi holds seven patents and has published papers on various topics in the field of cosmetics. Presperse Inc. 635 Pierce Street, Somerset, NJ 08873 Tel: 732-356-5200, Fax: 732-356-3533 E-mail: [email protected] Artmann, Carl W. – Chapter 18 Carl W. Artmann, PhaCos GmbH, Munich, Germany, is head of Research & Development for PhaCos, an institute for cosmetic and clinical testing. He focuses on combining university research in pharmacology, especially with respect to cosmetic applications, with the requirements set by the industry. His main interests are in efficient management of clinical and cosmetic studies for the pharmaceutical and cosmetic industries. Dr. Artmann’s investigations contributed to the development of new transdermal delivery systems. He has been a consultant involved in the conception and realization for new product lines for several global companies. PhaCos GmbH Gesellschaft für Pharmazie und Kosmetik Grubmühlerfeldstr. 54 D 82131 Gauting b. München Tel: +49 089 893057-25, Fax: +49 089 893057-26 Email: [email protected] Ciba Specialty Chemicals Inc. Basel, Switzerland

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Aust, Duncan T. – Chapter 21 Duncan T. Aust, DPT Laboratories, San Antonio, Texas, has been instrumental in the development of many new product ideas and technologies in various aspects of cosmetic products. He is currently vice president of Research & Development at DPT Laboratories. He has presented papers at many industry conferences and authored several patents covering delivery systems, formulation systems, preservatives, and sunscreen systems. He received a PhD in biotechnology from King’s College at the University of London. DPT Laboratories 318 McCullough, San Antonio, TX 78232 Tel: 210-228-3515 E-mail: [email protected] Baschong, Werner – Chapter 18 Werner Baschong, Ciba Specialty Chemicals, Inc., Basel, Switzerland, is head of Scientific Liaisons and Biological Testing for Home & Personal Care. His interests include evidence-based transport of cosmetic actives and mechanisms of action in light- and age-induced changes in Caucasian and non-Caucasian skin. Dr. Baschong is a fellow of the European Cell Biology Organization and several other associations. He regularly presents at international congresses on cosmetic science, dermatology, and photobiology, and publishes in scientific journals. He pursues his own research at the University of Basel in repair and engineering of skin, cartilage, and bone. His PhD is in chemistry of natural products. Ciba Specialty Chemicals, Inc. Klybeckstrasse 141, CH-4056 Basel, Switzerland Tel: +41 61 636 51 45 E-mail: [email protected] Bell, Andrew – Chapter 11 Andrew Bell, Ciba Specialty Chemicals, Inc., Bradford, England, is project leader in the New Applications Section, Water and Paper Treatment Segment. He previously worked in the Encapsulation Design department for about 10 years, where he contributed to many of the encapsulation core competencies associated with Ciba.

Ciba Specialty Chemicals, Water & Paper Treatment P.O. Box 38, Low Moor Bradford, England, BD12 OJZ E-mail: [email protected] Ciba Specialty Chemicals Inc. Basel, Switzerland Boucher, Julie – Chapter 34 Julie Boucher, Wacker Chemical Corp., Adrian, Michigan, is sales manager, responsible for the sales from the Wacker Silicones Division to the personal care industry. She is an active member of the Society of Cosmetic Chemists. Wacker Chemical Corp. Silicones Division 3301 Sutton Road, Adrian, MI 49221 Tel: 001 517 918 6080, Fax: 001 517 264 8101 E mail: [email protected] Brockway, Barbara – Chapter 21 Barbara Brockway is currently with Optima Chemicals, U.K. She was formerly technical manager of personal care at Huntsman LLC in Austin, TX. Prior to that she worked at The Collaborative Group in Stony Brook, New York. She received a PhD in biochemistry from the University of Kent, Canterbury, U.K. Optima Chemicals Unit 17, Chiltern Business Village, Arundel Road Uxbridge, Middlesex, London UB8 2SN Tel: 44-1895-231-231 Fax: 44-1895-231-789 E-mail: [email protected] Buffa, Charles W. – Chapter 31 Charles W. Buffa, Biosil Technologies, Inc., Paterson, New Jersey, is founder and president of Biosil. Biosil specializes in the design and marketing of products based on emerging silicone, ester, and biotechnology resources useful in the personal care market. Biosil Technologies Inc. 510 East 31St Street Paterson, NJ 07504 Tel: 973-684-2000, Fax: 973-742-9048 E-mail: [email protected].

CONTRIBUTING AUTHORS

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Byers, Blaine H. – Chapter 26

Dayan, Nava – Chapters 4 & 9

Blaine H. Byers, Stepan Company, Northfield, Illinois, is senior manager of Global Personal Care Product Development. He is responsible for new technology screening, development, commercialization, and promotional literature as well as customer support for personal care product development at Stepan. He has been active in guiding development of new emulsification and emollient technologies for personal care applications. Dr. Byers is a member of the Society of Cosmetic Chemists, American Oil Chemists Society, and American Chemical Society. He received a PhD in inorganic/organometallic chemistry from the University of Illinois, UrbanaChampaign.

Nava Dayan, Lipo Chemicals, Inc., Paterson, New Jersey, specializes in the design and development of innovative raw materials, delivery systems, and formulations for cosmetic, personal care, and topical applications. She has authored more than 50 papers and presentations. Dr. Dayan is one of the founders of the Israeli Society of Cosmetic Chemists and is a member of the American Association of Pharmaceutical Scientists, the International Controlled Release Society, and the US Society of Cosmetic Chemists. She received her PhD in pharmaceutics.

Stepan Company 22 W. Frontage Road, Northfield, IL 60093 Tel: 847-501-2442, Fax: 847-501-2466 E-mail: [email protected]

Lipo Chemicals Inc. 207 19th Ave., Paterson, NJ 07504 Tel: 973-345-8600 ext. 3899, Fax: 973-345-8365 E-mail: [email protected] Delvaux, Myriam – Chapter 45

Cattaneo, Maurizio – Chapter 12 Maurizio Cattaneo, IVREA Laboratories, Inc., Quincy, Massachusetts, is founder of IVREA and its president and chief scientific advisor. Dr. Cattaneo has served as an adjunct professor and lecturer in the Department of Chemical Engineering at Northeastern University in Boston, Massachusetts. He received a PhD in chemical engineering at McGill University in Canada. IVREA Laboratories Inc. 216 Ricciuti Drive, Quincy, MA 02169 Tel: 617-376-2491, Fax: 617-376-0696 E-mail: [email protected] Coste, Rosemarie L. – Chapter 5 Rosemarie L. Coste, Elsom Research Co., Inc., San Antonio, Texas, is vice president and director of planning at Elsom. She is managing editor of the Journal of Topical Formulations. Her interests include identifying traditional and new uses for plant material. 4510 Black Hickory Woods San Antonio, TX, 78249-1402 Tel: 210-493-5225, Fax: 210-493-8949 E-mail: [email protected]

Myriam Delvaux, Dow Corning, Brussels, Belgium, is marketing manager for new business development in the Life Sciences Industries Group at Dow Corning’s European headquarters. She has been global market leader for both skin care and hair care markets, and European market leader at Dow Corning. Dow Corning Corp Parc Industrial B-7820 Seneffe, Brussels, Belgium Tel: 32-64-888773 E-mail: [email protected] Dow, Peter – Chapter 17 Peter Dow, Arch Personal Care, South Plainfield, New Jersey, works in the Research & Development Group where he is active in developing new functional ingredients for personal care. He has recently been involved in the transfer of technology from medical delivery to cosmetic delivery systems. Arch Personal Care South Plainfield, NJ Tel: 908-412-6184

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Elder, Todd – Chapter 11 Todd Elder, Ciba Specialty Chemicals, Tarrytown, New York, is director, delivery effects, for the Home & Personal Care Segment of Ciba. He is responsible for the creation of a new global center focused on the development of novel technologies for the delivery of useful actives in home and personal care products. His primary interests are in polymeric, or biologically derived encapsulation. Dr. Elder holds a number of patents relating to the personal care industry. He received a PhD in pharmaceutical sciences from the University of Kentucky. Ciba Specialty Chemicals 540 White Plains Road., Tarrytown, NY 10591-9005 Tel: 914-785-2328, Fax: 914-785-2779 E-mail: [email protected] Freers, Susan O. – Chapter 35 Susan O. Freers, Grain Processing Corp., Muscatine, Iowa, is technical manager, pharmaceutical/personal care, involved in developing applications for new and novel ingredients for the pharmaceutical and personal care industries. She has developed numerous formulations and products for these industries. Ms. Freers holds one patent and has another pending for use of novel ingredients in selected applications. She has written several articles or editorials for journals such as Cosmetic & Toiletries Worldwide and Pharmaceutical Technology. Grain Processing Corporation 1600 Oregon Street, Muscatine, IA 52761 Tel: 563-264-4542; Fax: 563-264-4289 E-mail: [email protected]

at Dow/Amerchol Corporation. He also worked as Hair Care Manager for Firmenich, Inc. Presently he is a Senior Research Scientist at Ciba Chemical Specialties. He is the author of numerous publications on hair physical properties, hair damage and delivery of actives from shampoos. He directs the course on Hair Product Development for the Center for Professional Advancement. In 2000 Dr. Gamez-Garcia received the SCC award for the best published paper from the Society of Cosmetic Chemists for his work on hair damage. Ciba Specialty Chemicals Corp. 540 White Plains Road PO Box 2005, Tarrytown, NY 10591 Tel: 914-785-2000 E-mail: [email protected] Green, Barbara A. – Chapter 43 Barbara A. Green, NeoStrata Co., Inc., Princeton, New Jersey, is executive director, Technical and Consumer Affairs. She provides clinical and technical support for NeoStrata’s product lines and emerging ingredient technologies, and participates in new business development. She has published articles in various cosmetic and dermatology journals and is frequently interviewed by trade and consumer beauty magazines. Ms. Green is a registered pharmacist in New Jersey. Barbara A. Green NeoStrata Co. 307 College Road East, Princeton, NJ 08540 Tel: 609-520-0715 E-mail: [email protected] Greenberg, Stephen – Chapter 9

Gamez-Garcia, Manuel – Chapter 23 Manuel Gamez-Garcia received his Master’s degree in Electrochemistry from the Tokyo Institute of Technology in Japan, and his PhD in Engineering Physics in the field of Polymers from the University of Montreal in Canada. He worked for two years for Pirelli Corporation in the field of physical and chemical properties of polymers. Following that he held the positions of Manager of Claim Substantiation for Hair Care at Croda, Inc. and Applications Manager for Hair Care

Stephen Greenberg, Lipo Chemicals, Inc., Paterson, New Jersey, is senior vice president-business development. He is a member of the Society of Cosmetic Chemists and has held the position of IFSCC President. Dr. Greenberg holds two patents. He received his PhD in chemistry from the University of Virginia. Lipo Chemicals, Inc. 207 19th Ave., Patterson, NJ 07504 Tel: 973-345-8600 E-mail: [email protected]

CONTRIBUTING AUTHORS Gruber, James (Vince) – Chapter 17 James (Vince) Gruber, Arch Personal Care, South Plainfield, New Jersey , is director of Research and Market Development, responsible for developing new technologies and products for both skin and hair care applications. He is investigating active botanical extracts based on nitrogen fixation symbiosome extracts, as well as the use of single nucleotide polymorphism analysis for oxidative stress. He has authored book chapters as well as several journal papers. Dr. Gruber has authored a number of patents and patent applications on polymers, encapsulation, and natural extracts. He is a member of several professional organizations. James (Vince) Gruber Arch Personal Care South Plainfield, NJ Tel: 908-412-6184 E-mail: [email protected] Guyard, Geraldine – Chapter 9 Geraldine Guyard, is currently at L’Oreal. She was previously performing scientific studies to learn the behavior of new raw materials in formulations, developing new formulations for skin care, hair care, and color cosmetics. She is a member of the Society of Cosmetic Chemists, the Dermal Clinical Evaluation Society, and the New Jersey Pharmaceutical Association for Science and Technology. She received the doctor of pharmacy at the University of Paris XI, France. L’Oreal USA 30 Teminal Avenue Clark, NJ 07066 Tel: 732-680-5783 E-mail: [email protected] Hart, Janice – Chapter 37 Janice Hart, Coletica, Inc., Northport, New York, is vice president of sales and marketing for the United States subsidiary of Coletica, S.A., based in Lyon, France. She was co-owner of Advanced Scientific Imaging, a company dedicated to the study of skin microtopography through image analysis. Ms. Hart has published numerous papers and other publications. She is active in, and has held many positions in the Society of Cosmetic Chemists.

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Coletica Inc. 541 5th Ave., Suite 1108, New York, NY 10017 Tel: 212-450-8280 E-mail: [email protected] Hawkins, John – Chapter 25 John Hawkins, Huntsman Performance Products, Austin, Texas, is senior project leader, Surface Sciences Division. Huntsman Performance Products 10003 Woodloch Forest Drive, The Woodlands, TX 77380 Hawkins, Scott – Chapter 9 Scott Hawkins, Lipo Technologies, Inc., Vandalia, Ohio, is director of business operations. His field of expertise is in aqueous and solvent-based microencapsulation techniques, including fluid bed processing/granulators. He has designed and developed taste-masked and sustained release pharmaceutical, encapsulated water insoluble materials for cosmetic and fragrance industries, and industrial applications. 800 Scholz Drive, Vandalia, OH 45377 Tel: 937-264-1222, Fax: 937-264-1225 E-mail: [email protected] Healy, Lin Lu – Chapter 30 Lin Lu Healy, Penreco, Houston, Texas, is senior research associate in the Research & Development Department. She has been involved in research and development of a variety of cosmetic and personal care products and has published articles in several trade journals and given presentations at international conferences. Penreco 910 Louisana St., Suite 400, Houston, TX 77002 Tel: 281-362-3150 E-mail: [email protected] Herzog, Bernd – Chapter 18 Bernd Herzog, Ciba Specialty Chemicals, Grenzach Wyhlen, Germany is head of application UV-absorbers in Research and Development of the Home & Personal Care Segment. His main

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interests are the physical chemistry and characterization of colloidal systems in general, and more specifically particle sizing and optical properties of particulate UV absorbers. He has published 16 papers and holds 12 patents. Köchlinstrasse 1, D-79639 Grenzach Wyhlen, Germany Tel: +49) 7624 122817 E-mail: [email protected] Hoath, Steven – Chapter 29 Steven Hoath, University of Cincinnati, Cincinnati, Ohio, is professor of pediatrics at the University of Cincinnati and medical director of the Skin Sciences Institute at the Cincinnati Children’s Hospital Medical Center. He is an expert in newborn intensive care and the biology of vernix caseosa, epidermal barrier development, and the application of skin-based sensing systems for noninvasive biomedical monitoring and measurement. University of Cincinnati Cincinnati, OH E-mail: [email protected] Jentzsch, Axel – Chapter 41 Axel Jentzsch studied biology and chemistry and received his doctoral degree in biological chemistry from the University of Hohenheim. He worked in the research group at Hoffmann-La Roche in Basel and then joined BASF headquarters in Ludwigshafen. He was responsible for the development of new active ingredients for skin care for four years. He is currently the Technical Marketing Manager for Cosmetic Ingredients in the Business Unit “Regional Marketing Europe.” BASF AG 38 Carl-Bosche-Strasse Ludwigshafen Rheinland-Pfalz D-67056, Germany Tel: +49 621 60 76978 [email protected] Kanouni, Mouhcine – Chapter 22 Mouhcine Kanouni, Ciba Specialty Chemicals, Tarrytown, New York, has authored papers on multiple emulsions, microemulsions, and polymer stabi-

lization, and is co-inventor on a patent for phase stable multiple emulsion compositions. He received the J. Whittam Science Award from the City College of New York and the Bayer & BP S. Thames Award at the International Waterborne, High Solids Coatings Symposium. Dr. Kanouni is a member of the Federation of Societies for Coating Technology and has offered seminars on stabilization of coatings. He received his PhD in physical chemistry from the City University of New York. Faculty Natural Science Dept. Hostos Community College 500 Grand Concourse, Bronx, NY 10451 Tel: 718-518-4130 Email:[email protected] Kantner, Steve – Chapter 39 Steve Kantner, 3M, Saint Paul, Minnesota, is a division scientist. He has worked as a synthetic polymer chemist in a variety of research and product development positions, recently focusing on novel cosmetic ingredients. He is co-author on 16 publications and co-inventor on 38 patents. Dr. Kantner received a PhD in physical organic chemistry at the University of Wisconsin, Madison. Steve Kantner 3M Company Bldg. 230-3F-08 Saint Paul, Minnesota 55144-100 Tel: 651-736-5190 E-mail: [email protected] Kulkarni, Vitthal – Chapters 13 & 21 Vitthal S. Kulkarni, DPT Laboratories, Ltd., San Antonio, Texas, is principal research scientist, responsible for preformulation and characterization of skin care pharmaceutical products. His research interests include the field of lipids and liposomes. Dr. Kulkarni has published more than 20 research papers and two book chapters. He received a PhD from the University of Pune, Pune, India, studying the monomolecular films of fatty alcohols and polymers spread at the air/water interface. DPT Laboratories 318 McCullough, San Antonio, TX 78215 Tel: 210-228-3542, Fax: 210-227-7782 E-mail: [email protected]

CONTRIBUTING AUTHORS

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Kvitnitsky, Emma – Chapter 10

Lidert, Zev – Chapter 8

Emma Kvitnitsky, Tagra Biotechnologies, Ltd., Netanya, Israel, is production development manager. At MIGAL Galilee Technological Center, she manages the Chemistry Plant Extracts Laboratory. She is responsible for the development of extraction technology, isolation of specific materials, and development of analytical methods for quality control and product certification. She has extensive knowledge of the regulations, laboratory controls, and process validation requirements relevant to the cosmetic, pharmaceutical, and food supplement industries.

Zev Lidert, Paragon Chemicals, Inc., Dresher, Pennsylvania, is research director at Paragon. The company identifies targets for technology acquisition, develops manufacturing cost information, furnishes experimental samples, and delivers commercial volumes to customers in the chemical industry. Dr. Lidert previously worked on developing safe herbicides and plant biotechnology products development. He received a PhD from Lund University, Sweden.

Tagra Biotechnologies, Ltd. Netanya, Israel Tel: 972-9-865-6454, Fax: 972-9-865-4278 E-mail: [email protected]

Paragon Chemicals. Inc. 269 Westwind Way, Dresher, PA 19025 Tel: 215-345-8756 E-mail: [email protected] Lupia, Joseph – Chapter 18

Lefebvre, Michel S. – Chapter 19 Michel S. Lefebvre, University of NSW, Sydney, Australia, is visiting professor, and also a director of Steripak Pty Ltd. Dr. Lefebvre has participated in major technological developments in medical engineering, membrane technology, and organic chemistry. He has received international prizes, including the Grand Prix des Ingenieurs Civils de France, as well as technical excellence awards in both the United States and France. He founded research and development companies OPISA, Memtec Research laboratories Pty Ltd, and Syrinx Research Institute. Steripak Pty. PO Box 152 Kurrajong Sydney, New South Wales, Australia Fax: 61-245-677-580 E-mail: [email protected]

Joe Lupia received his B.S. degree in Biochemistry from the University of Scranton and a Ph.D. in Synthetic Organic Chemistry from Seton Hall University. He is currently located in Basel Switzerland and is a Global Marketing Manager for Ciba Specialty Chemicals. He has global responsibility for Protection, Hair Dyes, Moisturizers and Delivery Systems as well as introduction of new Research & Development activities in the product development and launch of new technologies in his areas of the Personal Care industry. Mr. Lupia has over 20 presentations, patents, and papers in the area of stabilization in industrial as well as personal care areas. Ciba Specialty Chemicals Protection and Hair Dyes CH-4002 Basel, Switzerland Tel: +41 61 636 25 89, Fax: +41 61 636 31 83 E-mail: [email protected]

Lerner, Natalya – Chapter 10 Natalya Lerner, Tagra Biotechnologies, Ltd., Netanya, Israel, is an expert in biochemistry and physiology of fodder plants in arid regions. She has recently been involved in the studies of stability of capsulated and non-capsulated vitamins in various formulations. Dr. Lerner has published 33 papers. She received a PhD degree from Rostov-on-Don State University. Tagra Biotechnologies, Ltd. Netanya, Israel E-mail: [email protected]

Lynch, Matthew – Chapter 29 Matthew L. Lynch, Procter & Gamble Company, Ross, Ohio, is senior research scientist in the Colloid and Surfactant Group of the Corporate Research Division. He has authored numerous publications and has filed patents in the areas of colloids, nanoparticles, liquid crystalline systems, solidstate behavior of soaps, and non-linear optics of surfaces. Dr. Lynch is an adjunct assistant professor of chemistry at the University of Cincinnati, and a member of the American Chemical Society, American

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Institute of Chemical Engineers, and American Association for the Advancement of Science. He has a PhD in chemistry. Procter & Gamble Company Ross, OH Tel: 513-627-0392, Fax: 513-627-1233 E-mail: [email protected]

He is the author of more than 80 publications and 15 patents in the fields of polymer and colloid science and biophysical chemistry. Dr. Meier received a PhD in polymer chemistry at the University of Freiburg, Switzerland. University of Basel Department of Chemistry Klingelbergstr. 80 CH, Switzerland [email protected]

Majeed, Muhammed – Chapter 7 Muhammed Majeed, Sabinsa Corporation, Piscataway, New Jersey, is founder and chief executive officer of Sabinsa. Dr. Majeed combines his expertise in the area of phytopharmaceuticals with his broad knowledge of botanicals from Ayurveda, the traditional system of medicine in India. He pioneered the introduction of over 50 innovative phytonutrients to global markets for use as nutraceuticals and cosmeceuticals. He has numerous patents and publications to his credit, and was awarded the Ellis Island Medal of Honor. He received a PhD in industrial pharmacy from St. John’s University, New York. Sabinsa Co. Piscataway, NJ Tel: 732-777-1111, Fax: 732-777-1443 E-mail: [email protected] Meidan, Victor – Chapter 3 Victor Meidan, UMDNJ-New Jersey Medical School, Newark, New Jersey, is a research fellow investigating identification and development of synergistic combination strategies for enhancing drug permeation through human skin. He received a PhD in pharmaceutical sciences from Aston University, U.K. Department of Pharmacology and Physiology UMDNJ-New Jersey Medical School Lab for Drug Delivery 111 Lock Street, Newark NJ 07103-2714 Tel: 973-972-9728, Fax: 973-972-9726 E-mail: [email protected] Meier, Wolfgang – Chapter 28 Wolfgang Meier, University of Basel, Switzerland, is professor in the Department of Chemistry.

Mendrok, Christine – Chapter 18 Christine Mendrok Ciba Specialty Chemicals, Grenzach Wyhlen, Germany, studied food chemistry and environmental toxicology at the University of Kaiserslautern, Germany. She has been working in the field of cosmetics at global companies, focusing on formulating actives and UV absorbers in skin care. She is a fellow of the German Association of Applied Cosmetics. Ciba Specialty Chemicals Grenzach Wyhlen, Germany Michniak-Kohn, Bozena B. – Chapter 3 Bozena B. Michniak-Kohn, UMDNJ-New Jersey Medical School, Newark, New Jersey, is a graduate faculty member at the College of Pharmacy, State University of NJ-Rutgers, and the director of the Drug Delivery Laboratory of the New Jersey Center for Biomaterials. Her research involves the design and testing of novel dermal penetration enhancers, iontophoretic drug delivery systems, and bioengineered human skin analogs that can be used to screen the transdermal delivery profiles of drugs. Dr. Michniak-Kohn is U.S. editor of The Controlled Release Society Newsletter and member of several professional organizations. She received a PhD in pharmacology from Leicester Polytechnic, U.K. Department of Pharmacology and Physiology UMDNJ-New Jersey Medical School Lab for Drug Delivery 111 Lock Street, Newark, NJ 07103-2714 Tel: 973-972-9720, Fax: 973-972-9726 E-mail: [email protected]

CONTRIBUTING AUTHORS Milora, David J. – Chapter 43 David J. Milora, NeoStrata Co., Inc., Princeton, New Jersey, is project manager responsible for the formulation development of cosmetics and over-thecounter drugs containing patented AHA and polyhydroxy acid technology. He is also involved in formulation and technical support for NeoStrata joint ventures. His work has resulted in five patents. NeoStrata Company 307 College Road East, Princeton, NJ 08540 Tel: 609-520-6401 [email protected] Mongiat, Sébastien – Chapter 18 Sebastien Mongiat, Ciba Specialty Chemicals, Grenzach Wyhlen, Germany, is head of Formulation Research & Development in the Personal Care business. He is in charge of formulation support for R&D projects in UV absorbers, hygiene effects, and skin actives. Ciba Specialty Chemicals Att: S.Mongiat Geb. 0001-2-04 Köchlinstrasse 1 D-79639 Grenzach Wyhlen, Germany Tel: +49 7624 122849, Fax: +49 7624 122888 E-mail: [email protected] Murphy, Betty J. – Chapters 24, 38, & 40 Betty J. Murphy, ReGenesis, LLC, Montclair, New Jersey, is president and managing member of ReGenesis. She was previously co-founder and president of CPR, where she was co-inventor on many of the company’s patents. ReGenesis LLC 31 South Fullerton Avenue, Montclair, NJ 07042 Tel: 973-233-1064, Fax: 973-233-1481 E-mail: [email protected]

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Nacht is a member of several professional societies, has co-authored more than 50 scientific papers and book chapters, and holds 14 patents. He received a PhD in biological chemistry in Argentina. Riley-Nacht, LLC 10375 Designata Avenue, Las Vegas, NV 89135 Tel: 702-547-1611, Fax: 702-531-6432 E-mail: [email protected] Newton, Joanna – Chapter 33 Joanna Newton, Dow Corning, Seneffe, Belgium, is leading a technical innovation team within the Life Sciences Business Group. Their main project is searching for new silicones in hair, skin, and household care applications. She received a PhD from the University of Manchester, U.K. Dow Corning S.A. Parc Industriel Zone C, B-7180 Seneffe, Belgium Tel: 32 (0) 64-888-834 E-mail: [email protected] O’Lenick, Anthony, J. – Chapter 31 Anthony J. O’Lenick, Siltech LLC, Dacula Georgia, is president of Siltech, a silicone and surfactant specialty company. He has published over 25 technical papers, contributed chapters to three books, written a book on surfactants, and is inventor on over 200 patents. Mr. O’Lenick has received a number of awards for his work in silicone chemistry, including the Samuel Rosen Award from the American Oil Chemists’ Society and the Innovative Use of Fatty Acids Award from the Soap and Detergents Association. 2170 Luke Edwards Road, Dacula, GA 30019 Tel: 678-442-0210, Fax: 678-442-9624 E-mail: [email protected]. Perrier, Eric – Chapter 37

Nacht, Sergio – Chapter 16 Sergio Nacht, Riley-Nacht, Las Vegas, Nevada, is co-founder of Riley-Nacht, LLC, Global Skin Ventures, a consulting, product development, and international distribution company. He has conducted extensive research in dermatology and developed numerous skin care and dermatological products. Dr.

Eric Perrier, Coletica, S.A., Lyon, France, is vice president and scientific director of Coletica.. He is author of several scientific publications and has filed more than 20 families of international patents on such subjects as micro- and nanoencapsulation technologies, UV-sensitive micro spheres, and plant SOD and plant albumin. He has participated in interna-

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tional research programs, as well as international cooperation developments. Coletica Inc. Lyon, France E-mail: [email protected] Perry, Robert J. – Chapter 32 Robert J. Perry, GE Global Research Center, Niskayuna, New York, is senior research chemist. His research activities have emphasized novel organo-functional siloxanes and processes. Dr. Perry received a PhD in chemistry from Colorado State University. GE Global Research Center, Polymer & Specialty Chemical Technologies One Research Circle K-1, 5B2A, Niskayuna, NY 12309 Tel: 518-387-6062; Fax: 518-387-7403 E-mail: [email protected] Pollock, David – Chapter 6 David Pollock, Clinical Results, Inc., St. Petersburg, Florida, is founder and president of the company, a product development laboratory. He is responsible for developing a number of innovative products. Mr. Pollock writes for several trade publications and has been a keynote speaker at a number of national conferences. He has served on the board of directors for the Florida Cosmetics & Pharmaceutical Association. Clinical Results, Inc. 5900 Central Avenue, St. Petersburg, FL 33707 Tel: 727-344-0519, Fax: 727-344-3920 E-mail: [email protected] Postiaux, Stéphanie – Chapter 33 Stephanie Postiaux, Dow Corning, S.A., Seneffe, Belgium, is with the Global Innovation Team for Life Sciences. Her responsibilities include evaluation of novel silicone technologies for cosmetic applications, and the development of new testing capabilities to support technical evaluation. Dow Corning S.A. Parc Industriel Zone C, B-7180 Seneffe, Belgium

Prakash, Lakshmi – Chapter 7 Lakshmi Prakash, Sabinsa Corporation, Piscataway, New Jersey, is director of technical services. She has participated in research and formulation development and has authored several publications and patents on nutraceuticals and cosmeceuticals. Dr. Prakash received a PhD in food science from Rutgers University. Sabinsa Corporation 70 Ethel Road West, Unit 6, Piscataway, NJ 08854 Tel: 732-777-1111 Fax: 732-777-1443 E-mail: [email protected] Punto, Louis – Chapter 17 Louis Punto, Arch Personal Care, South Plainfield, New Jersey, is director of product applications. He guides research and development of totally new, innovative personal care products. These products highlight the newest active ingredients developed by Arch Chemicals. His goals are to advance the science of hair and skin technology by incorporating new ingredients and technology developed by Arch into novel treatment products. Mr. Punto holds several patents, including the first selftanning product in spray form. Arch Personal Care South Plainfield, New Jersey Tel: 908-412-6184 E-mail: [email protected] Rerek, Mark E. – Chapter 27 Mark E. Rerek, International Specialty Products, Corp., Wayne, New Jersey, is director of skin care R&D. He is responsible for the development and scale-up of novel materials with demonstrated beneficial skin care biophysical properties. He is also visiting professor at Rutgers University and works on investigating the molecular structure and organization of skin lipids through vibrational spectroscopy and imaging techniques. Dr. Rarek is the author of 25 papers and holds 11 patents. He received his PhD from Northwestern University. ISP Corporation 1361 Alps Road, Wayne, NJ 07470 Tel: 973-872-4307, Fax: 973-628-3401 E-mail: [email protected]

CONTRIBUTING AUTHORS Reheis, Inc. Berkeley Heights, NJ E-mail: [email protected]

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Cardinal Health, Topical Technologies 27 School House Road, Somerset, NJ 08873 Tel: 732-537-6544, Fax: 732-302-3047 E-mail: [email protected]

Rosano, Henri L. – Chapter 22 Henri L. Rosano is emeritus professor of chemistry at City College of the City University of New York. He is the author or co-author of over 100 scientific papers and holds several patents, including one covering the recent research in the preparations of multiple emulsions. Dr. Rosano served as a consultant to several chemical companies and has conducted many symposia on surface and colloid chemistry. An active member of several professional societies, he is a senior grade member of the American Chemical Society. City College of the City University of New York New York, New York Ryklin, Irma – Chapter 26 Irma Ryklin, Stepan Company, Northfield, Illinois, is a senior product specialist in the Personal Care Department. She is responsible for developing and commercializing new technologies in hair, skin, and sun care areas. Ms. Ryklin has extensive experience in formulating micro-emulsion, emulsion/suspension, and isotropic consumer products. She is the author of four papers and holds nine patents.

Schlosser, Arndt – Chapter 34 Arndt Schlosser, Wacker Chemical Corp., Adrian, Michigan, is program manager, cosmetics. He is a member of the Society of Cosmetic Chemists and of the Bunsengesellschaft for Physical Chemistry in Germany, and has written papers and lectured at many professional meetings. His main areas of interest are volatile linear silicone fluids and silicone film formers for achieving long lasting effects in color cosmetics, for which he has developed several different concepts and application tests. Dr. Schlosser received a PhD in physical chemistry from Justus-Liebig University, Giessen, Germany. Wacker Chemical Corp., Silicones Division 3301 Sutton Road, Adrian, MI 49221, USA Tel: 517-264 8390, Fax: 517-264 8101 E-mail: [email protected] Schreiber, Jörg – Chapter 28

Stepan Company 22 W. Frontage Road, Northfield, IL 60093 Tel: 847-501-2128, Fax: 847-501-2466 E-mail: [email protected]

Jörg Schreiber, Beiersdorf AG, Hamburg, Germany, has done product development and research projects for several well-known brands. He is an expert on cosmetic actives such as antimicrobials, preservatives, and skin care actives. Dr Schreiber has contributed to several books and journals and holds 40 patents concerning new delivery systems and cosmetic actives.

Saxena, Subhash – Chapter 16

Beiersdorf AG Hamburg, Germany E-mail: [email protected]

Subhash Saxena, Cardinal Health, Somerset, New Jersey, is senior vice president, head of Research & Development, for Cardinal Health, Topical Technologies. He is the holder of several patents and the author of numerous publications in the fields of drug metabolism, analytical chemistry, and various drug delivery systems. Dr. Saxena received a PhD in pharmaceutical chemistry/pharmacologytoxicology from the School of Pharmacy, University of Louisiana, Monroe.

Schwarzwaelder, Claudius – Chapter 34 Claudius Schwarzwaelder, Wacker-Chemie GmbH, Burghausen, Germany, is technical service manager. He has been responsible for the development and application of silicones (fluids, resins, and emulsions) in hair care products for the cosmetic industry. Previously, Dr. Schwarzwaelder conducted research and development in the area of new delivery systems for skin care products.

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Wacker-Chemie GmbH Johannes Hess Straße 24, 84489 Burghausen, Germany Tel: +49 (0)8677-83-8389, Fax: +49 (0)8677-83-3131 [email protected]

ReGenesis LLC 31 South Fullerton Avenue, Montclair, NJ 07042 Tel: 973-233-1064, Fax: 973-233-1481 E-mail: [email protected] Spicer, Pat – Chapter 29

Shapiro, Yury E. – Chapter 10 Yury E. Shapiro, Tagra Biotechnologies, Ltd., Netanya, Israel, is professor of biochemistry at Bar-Ilan University and a consultant at Tagra. His research interests are folding and dynamics of proteins, micro- and nanoencapsulation, liquid crystals and hydrogels, micellar enzymology, self-assembly, receptor binding and receptor mimetic systems, biological membranes, and theoretical conformational analysis. Dr. Shapiro has published more than 200 technical papers. He received a D.Sc degree from the Institute of Macromolecular Chemistry, Ukrainian Academy of Sciences, Kiev.

Patrick T. Spicer, Procter & Gamble Corp., West Chester, Ohio, is adjunct assistant professor of chemical engineering at the University of Cincinnati, and technology leader in the Complex Fluids Group at Procter & Gamble. His work involves scale-up and scale-down of complex fluid processes when colloidal and surfactant transformations play a critical role in product quality and stability. A member of several professional associations, Dr. Spicer received the AIChE’s Best PhD in Particle Technology Award and was a participant in the National Academy of Engineering’s Frontiers of Engineering Program.

Tagra Biotechnologies, Ltd. Netanya, Israel E-mail: [email protected]

Procter & Gamble Corp. 8256 Union Centre Blvd., West Chester, OH 45069 Tel: 513-634-9628 E-mail: Spicer.ptpg.com

Smadi, Raeda M. – Chapter 25

Stoller, Catherine – Chapter 33

Raeda M. Smadi, formerly senior chemist at Huntsman Performance Products, Austin Texas, is now a chemist with Johnson and Johnson Consumer Products. Johnson and Johnson Consumer Products 199 Grandview Road, Skillman NJ 08558 Tel: 908-874-2364 E-mail: [email protected]

Catherine Stoller, Dow Corning S.A., Seneffe, Belgium, is a project chemist at Dow Corning Personal Care. Her current responsibilities include the assessment of new emerging opportunities for life sciences with particular attention to technology transfer issues to enable effective identification and development across multiple market lines. Dr. Stoller received a PhD in chemistry from the University of Brussels, Belgium.

Smith, James A. – Chapters 24, 38, & 40

Dow Corning S.A. Parc Industriel Zone C, B-7180 Seneffe, Belgium

James A. Smith, ReGenesis LLC, Montclair, New Jersey, is co-founder, chairman, and managing member of ReGenesis. He has been involved in formulation and marketing of several major brands of household products. He is noted for his ability to transfer technology from unrelated areas, thereby creating novel patent platforms, applications, and new markets. Mr. Smith has been granted over 50 patents in the household, personal care, and topical drug delivery areas.

Thau, Paul – Chapter 42 Paul Thau, PaCar Tech, Berkeley Heights, New Jersey, is president of PaCar, a cosmetic consulting company. He works in the areas of innovative product development, new cosmetic raw materials, technology transfer, and technology acquisition. Mr. Thau is a fellow of the Society of Cosmetic Chemists, and has held several offices in that organization. He holds 11 patents.

CONTRIBUTING AUTHORS PaCar Tech 181 Dogwood Lane, Berkeley Heights, NJ 07922 Tel: 908-771-0866 E-mail: [email protected] Tonucci, David – Chapter 44 David Tonucci, Interactive Consulting Inc., East Norwich, New York, is director of product safety, as well as an independent consultant in toxicology. He has broad experience in clinical program design and product safety assurance. Dr. Tonucci has a PhD in pharmacology and toxicology from the State University of New York, Buffalo. Interactive Consulting Inc. East Norwich, NY 11732 Tel: 516-922-2167, Fax: 516-922-3830 E-mail: [email protected] Vincent, Anne-Marie – Chapter 33 Anne-Marie Vincent, Dow Corning S.A., Seneffe, Belgium, is currently with the Global Innovation Team for Life Sciences. She has worked in the area of silicone modified organic products, and is now focusing on new market and technology opportunities Dow Corning S.A. Parc Industriel Zone C, B-7180 Seneffe, Belgium Visscher, Marty – Chapter 29 Marty Visscher, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, is executive director of the Skin Sciences Institute. She is an expert on the effects of the environment and skin treatment products on the skin as a function of age, race, skin condition, and skin disease. Recently, she has focused on infant skin development and adaptation immediately after birth. Dr. Visscher has pioneered the development and use of psychomotor techniques to measure relevant skin effects of ingredients and skin care products. Cincinnati Children’s Hospital Medical Center Cincinnati, OH E-mail: [email protected]

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Wertz, Philip W. – Chapter 3 Philip W. Wertz, University of Iowa, Iowa City, is professor in the Department of Oral Pathology, Radiology, and Medicine. His research focus is on lipids and barrier function in skin and oral muscosa. Dr. Wertz is a member of several professional organizations. He received a PhD in biochemistry from the University of Wisconsin. N450 DSB, Dows Institute University of Iowa, Iowa City IA 52242 Tel: 319-335-7409, Fax: 319-335-8895 E-mail: [email protected] Wiechers, Johann – Chapter 20 Johann W. Wiechers, Uniqema, Gouda, The Netherlands, is Skin R&D manager, with global responsibility for that function. His main interests are cosmetic claim substantiation, non-invasive skin bioengineering, skin sensory techniques, clinical trial design, skin penetration, and biostatistics. Dr. Wiechers is a member of several scientific organizations and boards. He has published over 185 papers and presentations in the fields of topical drug delivery and cosmetic science, and is regularly invited to speak at both scientific and commercial conferences. He received his PhD from the University of Groningen, The Netherlands, in the subject of skin penetration enhancement. Uniquema, Gouda The Netherlands Tel: +31 182-542 780, Fax: +31 182-542-747 E-mail: [email protected] Wille, John J. – Chapter 36 John J.Wille, Bioderm Technologies, Inc., Trenton, New Jersey, is president of Bioderm. His current work involves the development of novel plantderived anti-aging and anti-irritant actives for topical delivery to skin. He has developed a novel topical delivery system designed for hydrophobic actives. Dr. Wille serves as consultant to Fortune 500 pharmaceutical and cosmetic companies. He is board member and founder of Hygene Biomedical Corp. and vice president for R&D of Sarva Bio Remed, LLC. He is active in several professional societies.

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He received a PhD in cell biology/genetics from Indiana University. Bioderm Technologies Inc. 36 South Broad Street, Trenton, NJ 08608 Tel: 609-656-0784, Fax: 609-396-8603 E-mail: [email protected] Wilmott, Jim – Chapter 21 James M. Wilmott, Chanel, Inc, Piscataway, New Jersey, is executive director of skin care and fragrance development. He is responsible for the development of regional and global new products as well as the identification of new performance and unique aesthetic agents. Mr. Wilmott is knowledgeable about current and emerging marketing and technology trends around the world, and has written several articles on the subject. He has received many patents for the introduction of innovative technology into the personal care market. 4 Ridgefield Drive, Shoreham, New York 11786 Tel: 516-380-1493, Fax: 631-821-7776 E-mail: [email protected] Chanel, Inc./ Englehardt Corp. 876 Centennial Avenue, Piscataway, NJ 08855 Tel: 732-980-2189 E-mail: [email protected] Wolf, Mike – Chapter 9 Mike Wolf, Lipo Technologies, Inc., Vandalia, Ohio, is research and development manager. His interests include micro-encapsulation and entrapment of water-insoluble actives using a variety of innovative methods. He is inventor or co-inventor on over 30 U.S. patents and even more foreign patents.

Lipo Technologies, Inc. 800 Scholz Drive, Vandalia, OH 45377 Tel: 937-264-1222, Fax: 937-264-1225 E-mail: [email protected] Yeboah, Hubert – Chapter 33 Hubert Yeboah, Wacker Chemical Corp., Adrian, Michigan, holds the position of cosmetic chemist. He is a member of the Society of Cosmetic Chemists. Wacker Chemical Corp., Silicones Division 3301 Sutton Road, Adrian, MI 49221, USA Tel: 517-264-8229, Fax: 517-264-8101 E-mail: [email protected] Yechiel, Elishalom – Chapters 5 & 14 Elishalom Yechiel, Elsom Research Co.,Inc., San Antonio, Texas, is founder, president, and director of research. He is also scientific editor of the Journal of Topical Formulations. His research interests are in membrane structure and the aging process, and in using nanotechnology to develop new emulsification techniques. Dr. Yechiel developed intra-dermal and trans-dermal vehicles for delivery via skin of actives and drugs in cosmetic and OTC applications. He is currently working on a topical anticancer drug for melanoma, based on a vehicle and transporter he developed. He received a PhD in biochemistry from Hebrew University. Elsom Research Co.,Inc. 4510 Black Hickory Wood San Antonio, TX, 78249-1402 Tel: 210-493-5225, Fax: 210-493-8949 E-mail: [email protected]

Contributing Companies and Universities Amerchol Corporation P.O. Box 4051, 136 Talmadge Road Edison, New Jersey 08818-4051 Tel: 732-248-6000, Fax: 732-287-4186 The Amerchol Corporation, a subsidiary of The Dow Chemical Company, is a global manufacturer and marketer of performance chemicals for use in personal care applications. These products are primarily emollients, moisturizers, and conditioners; and they find the majority of their uses in consumer skin care and hair care products. The Amerchol Corporation is also known for its dedicated service to the personal care industry. Amerchol offers world-class technical support services that make formulators jobs easier and more efficient. Amerchol operates a worldwide distribution system that deliver the products needed, when and where they are needed. Arch Personal Care 70 Tyler Place South Plainfield, New Jersey 07080 Tel: 908-561-5200 www.archchemicals.com/Fed/PC [email protected] Arch Personal Care Products is a leading specialty chemical company providing cosmetic ingredients and ideas to the personal care and cosmetics industries. Arch Personal Care Products’ ingredients are unique in their functionality and offer new marketing opportunities and concepts.

Arch Personal Care is on the forefront of the industry, with a wide range of biotechnological active ingredients, delivery systems, proteins, botanicals, functional ingredients, anti-dandruff actives, and preservation systems. They are committed to the development of novel products such as “biotechnological active ingredients” in which yeastderived products have become the mainstays of Arch Personal Care Products. They have created protein complexed vitamins, yeast complexed minerals, and respiratory factors. They have also developed active lipids and liposomes delivery systems to increase activity of ingredients, as well as active botanicals from natural sources that provide efficacy in cosmetic preparations. BASF Corporation, Nutrition and Cosmetics 3000 Continental Drive North Mount Olive, New Jersey 07828 Tel: 973-426-2600, 800-426-8709 Fax: 973-426-5369, 973-426-2610 www.basf.com, www.cosmetic.basf.com, www.basf.com/usa BASF is a leading global chemical company, offering its customers a range of high-performance products, including chemicals, plastics, performance products, agricultural products, and fine chemicals, as well as crude oil and natural gas. In 2002, BASF had sales of $34 billion and employed more than 89,000 people worldwide. BASF Corporation is the North American affiliate of BASF AG, Ludwigshafen, Germany.

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Beiersdorf AG Unnastrasse 48, 20245 Hamburg, Germany Tel: +49(0)40-4909-0, Fax: +49(0)40-4909-3434 www.Beiersdorf.com, www.Nivea.com As a leading international company, Beiersdorf concentrates on the care of a limited number of global consumer brands including their development, manufacture, and marketing. These brands are: NIVEA, 8 x 4, atrix, Eucerin, Labello, la prairie, JUVENA, FUTURO, tesa, and the plaster brands Hansaplast and Elastoplast. Bioderm Technologies, Inc. 36 Broad Street Trenton, New Jersey 08608 www.bioderminc.com Bioderm Technologies, Inc. is a skin and wound care R&D and consulting company. It is located in the Trenton Business and Technology Center in Trenton, N.J. Dr. John J. Wille is its founder and President. The company operates a research facility and conducts sponsored research projects. The laboratory houses a fully equipped tissue culture and microbiology laboratory, as well as a separate wet chemistry laboratory. Bioderm Technologies, Inc., has provided professional consulting and research services to Fortune 500 pharmaceutical companies and to several biotechnological companies. Areas of expertise include: topical drug delivery systems, cosmetic formulations, discovery and development of novel anti-irritant plant derived “actives,” and development of customized tissue culture media recipes. Biosil Technologies Inc. 510 East 31st Street Paterson, New Jersey 07504 Tel: 973-684-2000, Fax: 973-742-9048 www.biosiltech.com Biosil Technologies is a specialty chemical company that specializes in silicone and biological compounds for the personal care market.

Cardinal Health Topical Technologies 301 Laser Lane Lafayette, Louisiana 70507 Tel: 800-261-8032, Fax: 800-458-8493 Cardinal Health Topical Technologies is a premier global provider of novel topical delivery products and technologies. Among its innovations are patented technologies such as Microsponge®, Polytrap®, and DelPouch®. Cardinal is also an important knowledge center for the dermatological industry, providing information and consultation services to manufacturers who are interested in pursuing difference-making topical applications for their molecules, compounds, or products. Chanel, Inc. 876 Centennial Avenue Piscataway, New Jersey 08855 Tel: 731-980-2189 www.chanelusa.com Children’s Hospital Medical Center University of Cincinnati Cincinnati, Ohio 45221 Ciba Specialty Chemicals Inc. Home & Personal Care Segment Klybeckstrasse 141, CH-4002 Basel, Switzerland Tel: +41 61 636 24 14, Fax: +41 61 636 31 83 [email protected], www.cibasc.com/ homeandpersonalcare Ciba Specialty Chemicals has a balanced global presence, with nearly 20,000 employees around the world and sales in 120 countries. It operates 64 production sites in 25 countries, and maintains 16 research centers in 9 countries. The company is comprised of five business segments: Home & Personal Care (supporting the Home & Fabric Care, Personal Care industries), Plastic Additives (Plastics and Lubricants), Water & Paper Treatment (Water, Paper, and Pollution Control), Coating Effects (Paints, Imaging & Inks, Electronics, and Plastics), and Textile Effects (Textiles).

CONTRIBUTING COMPANIES AND UNIVERSITIES Ciba Specialty Chemicals Corporation North America (Canada, USA) 4090 Premier Drive High Point, North Carolina 27261-2444 Tel: 1-336-801-2126, Fax: 1-336-801-2057 [email protected] Ciba Specialty Chemicals is a leading company dedicated to producing high-value effects for our customers’ products. Ciba’s specialty chemicals improve the quality of life by providing performance, protection, strength and color. The company’s products: protect people and materials from damaging UV radiation, fire and degradation; enhance health and beauty; provide antimicrobial protection; enhance durability against heat, corrosion and wear; provide color that differentiates and decorates plastics, paper, textiles, metal, etc; and add functionality and efficiency for products and processes. City College of New York New York, New York 10031

Clinical Results, Inc. 5900 Central Avenue St. Petersburg, Florida 33707 Tel: 727-344-0519, Fax: 727-344-3920 www.ClinicalResults.com Clinical Results, Inc. is a contract product development laboratory employing cutting-edge technologies and developing formulations of cosmeceutical and personal care treatment products. Company clients include dermatologists, plastic surgeons, multi-level marketers, and some of the most prestigious names in the personal care industry. Coletica Inc. 260 Main St. Northport, New York 11768 Tel: 631-262-1222, Fax: 631-262-9526 [email protected] Coletica Inc., R&D and Production 32 Rue Saint Jean de Dieu 69007 Lyon France

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Tel: 33 (4)72-76-60-00, Fax: 33 (4)78-58-09-71 [email protected] Coletica S.A. Commercial Department 83 rue de Villiers 92200 Neuilly Sur Seine France Tel: 33 (1) 47-45-35-00 Coletica is an industry leader in providing technology to the cosmetic industry. Coletica’s business is supported by three technology platforms that are protected by 53 families of International Patents. These platforms act as a veritable “toolbox” for the cosmetic chemist to design novel and effective ingredients. This “toolbox” allows Coletica to have a distinct competitive advantage by providing one product for each project of each client. Coletica specializes in the following types of technologies: tissue engineering, active compounds, optimization technologies, encapsulation, molecular coupling, and coating. Today Coletica has one of the best teams in the world in its sector of research. The company has 30 scientists devoted to research and development. In 2001, 19% of Coletica’s sales were reinvested into research. The scientific expertise of Coletica was recognized in 1999 and 2000 by being awarded the first place prize for technological innovation at the In Cosmetics Awards. Coletica has also been awarded the 2000 trophy for innovation by The French National Institute for Industrial Property. Dow Corning Corporation P.O. Box 0994, 2200 West Salzburg Rd. Midland, Michigan 48686 Tel: 517-496-6000, 989-496-6000, 800-248-2481 Fax: 517-496-6974, 989-496-8026 www.dowcorning.com Dow Corning was established in 1943 as a joint venture between Corning Glass Works and Dow Chemical Co. specifically to explore the potential of silicones. It employs more than 7500 people at 40 manufacturing and service locations worldwide. Dow Corning Life Sciences group offers more than 60 silicon-based products to improve the per-

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formance of personal care formulations. Dow Corning is a global leader in silicon-based technology and innovation, offering more than 7,000 products and services, and provides performance-enhancing solutions to serve the diverse needs of more than 25,000 customers worldwide.

sions; additional formulation technologies and new combinations of existing technologies are being developed, as are new applications for liposomes as carriers of beneficial materials. Elsom Research manufactures and markets several lines of cosmeceuticals, dermaceuticals, and theraceuticals.

DPT Laboratories 318 McCullough San Antonio, Texas 78215 Tel: 210-476-8150 or 866-CALLDPT (866-225-5378) www.dptlabs.com

Engelhard Corporation Corporate Headquarters 101 Wood Avenue Iselin, New Jersey 08830-0770 Tel: (732) 205-5000, Fax: (732) 321-1161

DPT, a DFB Pharmaceuticals, Inc. company, provides outsourcing services to the pharmaceutical, biotechnology, and consumer healthcare industries. A reputation for quality, expertise, leading-edge technologies, and an excellent regulatory compliance record is why DPT is the market leader in semisolid and liquid contract services. Headquartered in San Antonio, TX, DPT has facilities there and in Lakewood, NJ, with approximately 1 million square feet of state-of-the-art manufacturing, packaging, and distribution space. Over 1,400 DPT employees provide customers confidence in full-service, turnkey, or stand-alone development, production, packaging, and worldwide distribution services for a variety of semi-solid and liquid, Rx, biopharmaceutical, and consumer products. Recognized for unparalleled technical expertise and, as one of the fastest growing R & D groups, DPT employs over 100 of the industry’s top scientists and has developed a niche in offering R & D services for two of the newest specialty drug delivery methods – aerosol foam and intra-nasal. Elsom Research Co., Inc. 4510 Black Hickory Woods San Antonio, Texas 78249-1402 www.elsomresearch.com Elsom Research Co., Inc. specializes in custom small/medium size batch topical formulations, creatively combining nanotechnology and botanical ingredients, vitamins, and other actives. Nanotechnologies currently available for use in custom manufacturing include Nanosomes™, nanoencapsulation, nanoemulsions, and double emul-

As a market-driven, surface and materials science company, Engelhard enjoys the double duty of forecasting trends and developing the effect pigments and personal care materials that bring life to those trends. Engelhard provides a complete line of effect and color-enhancing pigments as well as performance minerals for cosmetic and personal care products. The company’s line of pigments provides luster, complex color, dimensionality, and other visual effects. Its performance minerals enhance tactile qualities, wear, absorption, and other essential properties. Engelhard’s performance personal care materials provide important performance attributes to cosmetics and personal care products. These include moisturization, sun/environmental protection, and anti-aging properties, among other benefits. The company has trend forecasting and extensive R&D capabilities that enable it to help customers create a diverse range of effects for all consumer groups. To accompany trend presentations, it develops sample formulations that cover a variety of products, including lip, eye and nail colors, face and body makeup, bath products, and hair and skin care products. Engelhard technologies can create new and exciting products through changes in applications and formulations. GE Silicones 260 Hudson River Rd. Waterford, New York 12188 Tel: 518-233-3330, Fax: 518-233-2367 www.gesilicones.com GE Silicones, an operating division of GE Specialty Materials, is a global manufacturer of silicone

CONTRIBUTING COMPANIES AND UNIVERSITIES

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products. The global GE Silicones business includes GE Silicones Americas, GE Sealants & Adhesives, GE Bayer Silicones, and GE Toshiba Silicones. It has 3,500 employees and manufactures over 4,000 products for the automotive, aviation, consumer, electronics, healthcare, and personal care industries.

Interactive Consulting, Inc. P.O. Box 66, 7 Deusenberg Drive East Norwich, New York 11732 Tel: 516-922-2167, Fax: 516-922-3830 www.chemicalconsult.com See company description in “Series Editor Preface”

Grain Processing Corporation 1600 Oregon Street Muscatine, Iowa 52761 Tel: 563-264-4265, 800-448-4472 Fax: 563-264-4289 www.grainprocessing.com, [email protected]

International Specialty Products ISP Corporation 1361 Alps Road Wayne, New Jersey 07470 Tel: 973-628-4000, Fax: 973-628-3311 www.ispcorp.com

For more than 50 years, Grain Processing Corporation (GPC) has produced and marketed ingredients to customers worldwide. GPC’s dedication to the personal care/cosmetic industry is illustrated by the creation of new and novel ingredients for the industry, assisting customers in introducing new products, improving quality, and optimizing process efficiency with functional ingredients. GPC’s multiple lines of ingredients offer the personal care industry a wide range of selective functionality. Examples include PURE-DENT maltodextrins and corn and MALTRIN QD starches, MALTRIN ZeinaTM, and PURE-GEL superabsorbent polymers, and natural ethylsyrup solids, and WATER LOCK alcohol. Huntsman Surface Sciences European Technical Center Trinity Street, Oldbury West Midlands, UK B69 4XB Tel: +44(0)121 429 6700 Fax: +44(0)121 420 5700 Huntsman Performance Products Division comprises the surface sciences (surfactants, linear alkylbenzene, oxides, and glycols), performance chemicals (amines, carbonates, and gas-treating chemicals), and maleic anhydride businesses. Huntsman Surface Sciences is a leading global supplier of surface effect chemicals and their intermediates. Regional operating groups headquartered in the United States, Australia, and the United Kingdom employ 14 plant sites and three research and development facilities to offer one of the most diverse lines of surfactants and related products in the industry.

International Specialty Products (ISP) is a leading manufacturer of specialty chemicals, fine chemicals, and mineral products. The company produces more than 325 specialty chemicals, which are used in a broad range of applications in such markets as pharmaceuticals, food and beverage, hair and skin care, plastics, agriculture, coatings, and adhesives. ISP has approximately 2,700 dedicated professionals at more than fifty locations worldwide including manufacturing facilities, research laboratories, sales, and technical service offices. International Specialty Products is committed to a strong thrust in R&D with over 200 people worldwide in application development centers in the USA, UK, Turkey, Singapore, Brazil, China, and India. Approximately 130 scientists, with over half of them holding doctorate degrees, are employed at the 32,800 sq. ft. corporate research facility in Wayne, New Jersey. Core strengths of the company are in synthetic chemistry, polymer science, process engineering, and analytical characterization. ISP meets and exceeds customers’ expectations through innovative technology, performance enhancing products, and exceptional service. IVREA Inc. 8 Kendrick Road #3 Wareham, Massachusetts 02571 Tel: 508-295-2795, Fax: 508-291-2024 www.ivrea.biz IVREA Inc. is a privately held skin care company and leader in providing topical delivery systems based on advanced-biopolymer research. IVREA’s mission includes, but is not limited to, the

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licensing of selected areas of technology. This is accomplished largely by means of technology transfer based on product development technology and its applications to specialized product lines. IVREA’s resources include laboratory, manufacturing, and packaging facilities. These resources allow complete customization from product concept to finished product. Lipo Chemicals, Inc. 207 19th Avenue Paterson, New Jersey 07504 Tel: 973-345-8600, Fax: 973-345-8365, 973-289-8481 www.lipochemicals.com Lipo Chemicals, Inc. has been supplying the cosmetic and personal care industries with specialty raw materials since 1962. With a unique marketing approach and a focus on new technologies, Lipo offers a wide array of specialty, basic, and naturally derived ingredients. Active in 50 countries, Lipo offers complete technical support, formulation expertise, and innovative product solutions. Expanded laboratory, manufacturing, and research facilities affirm their commitment to technical excellence. Lipo’s unique delivery systems provide opportunities to combine incompatible materials into a single formulated product, convert liquids to solids, and release components upon demand. Lipo has been at the forefront of technological innovations, including the first microencapsulation of liquid crystals, microspheres, and the development of fragrance sampling systems. Lipo Technologies Inc., (distributed by Lipo Chemicals Inc.) 800 Scholz Drive Vandalia, Ohio 45377 Tel: 937-264-1222 www.lipotechnologies.com NeoStrata Company, Inc. 307 College Road East Princeton, New Jersey 08540 Tel: 609-520-0715, Fax: 609-520-0849 www.neostrata.com

NeoStrata Company, Inc. is a research-based, dermatological company dedicated to the advancement of skin care and skin disease treatment. NeoStrata is internationally recognized by the medical community for its development of alphahydroxyacid technology and formulations. The company markets a comprehensive line of professional and consumer skin care products based on its exclusive, advanced AHA technology. Pa Car Tech 181 Dogwood Lane, Berkeley Heights, New Jersey 07922 Tel: 908-771-0866, Fax: 908-771-0867 Pa Car Tech specializes in the areas of innovative product development, new cosmetic raw materials, technology transfer, and technology acquisition. Paragon Chemicals, Inc. 269 Westwind Way Dresher, Pennsylvania 19025 Tel: 215-444-9818, Fax: 215-444-9932 www.paragonchemicals.com Paragon Chemicals Inc. is a Pennsylvania based company. With access to cost-effective process development and manufacturing in China, Paragon Chemicals identifies targets for technology acquisition, develops manufacturing cost information, furnishes experimental samples, and delivers commercial volumes to customers in the chemical industry. Penreco 8701 New Trails Dr., Ste 175 The Woodlands, Texas 77381 Tel: 281-362-3150, Fax: 281-362-3168 www.penreco.com Penreco is a joint venture between Conoco and M.E. Zukerman Energy Investors. Penreco is a major producer of specialty hydrocarbon products. Its product slate includes highly refined white oils, petrolatums, specialty solvents, ink oils, petroleum sulfonates, and a line of gelled products. Penreco markets its products to a variety of industries, including cosmetics, pharmaceuticals, agriculture, aerosols, textiles, drilling, ore floatation, printing, paint manufacturing, baking, and candlemaking.

CONTRIBUTING COMPANIES AND UNIVERSITIES PhaCos GmbH Grubmuhlerfeldstr. 54 für Pharmazie und Kosmetik, D82131 Gauting/Germany Tel: (+49) 089 893057 25, Fax: 089 893057 26 [email protected] PhaCos GmbH evolved as an independent company from the Grosshadern Hospital of the LudwigMaximilian University Munich, Germany. PhaCos coordinates the proper resources of the cooperating clinics for the cosmetic and pharmaceutical industry. Our coworkers are those of the cooperating laboratories and clinics. They are enrolled for specific projects and do otherwise appropriate basic and clinical research. The direct involvement of clinical research insures clinical experience, the use of up-todate techniques, and cutting-edge knowledge. PhaCos coordinates cosmetic and clinical research at different facilities located in the larger area of Munich. It operates according to the national and international guidelines required for a specific project. PhaCos strengths: Examinations in DermatoCosmetics; customer-tailored designs; in vitro and in vivo pharmocokinetics; clinical studies phase I–IV; biometry; project coordination; consultancy for new products in cosmetic and medicine; and in vitro and in vivo screening of product-ideas. PhaCos facilities: Grosshadern Hospital and Dermatological Clinic and Polyclinic LMU, Munich, University of Regensburg, Department of Dermatology, and Pettenkofer Institute of the LMU, Munich. Key industry partners: Bayer, Boehringer Ingelheim, Ciba Specialty Chemicals, CotyLancaster, Novartis, Ratiopharm, and Roche – Symrise. Presperse Inc. 635 Pierce Street Somerset, New Jersey 08873 Tel: 732-356-5200, Fax: 732-356-3533, [email protected], www.presperse.com Presperse, Inc. is an international organization specializing in servicing the cosmetic and personal care industries with unique specialty raw materials. Presperse offers over 200 diverse raw materials.

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Presperse’s strength is based on its ability to locate and supply innovative specialty raw materials from worldwide sources. The company currently represents a diverse list of suppliers worldwide, as well as having a group of dedicated global service partners whose aim is to provide our customers with the best possible service on a global basis. Procter & Gamble Co. Ross, Ohio www.pg.com Two billion times a day, P&G brands touch the lives of people around the world. Our company has one of the largest and strongest portfolios of trusted, quality brands, including Pampers, Tide, Ariel, Always, Whisper, Pantene, Bounty, Pringles, Folgers, Charmin, Downy, Lenor, Iams, Crest, Actonel, Olay, and Clairol Nice-n-Easy. The P&G community consists of nearly 98,000 employees working in almost 80 countries worldwide. P&G embraces the principles of personal integrity, respect for the individual, and doing what’s right for the long term. We recognize our consumers, brands, and employees as the pillars of our business. ReGenesis LLC 31 South Fullerton Avenue, Montclair, New Jersey 07042 Tel: 973-233-1064, Fax: 973-233-1481 [email protected] ReGenesis LLC invents, formulates, patents, and consumer tests its own innovative household, personal care, and topical dermatological products. The company’s current focus is concentrated on developing highly innovative personal care products. Riley-Nacht LLC 10375 Designata Avenue Las Vegas, Nevada 89135 Tel: 702-547-1611, Fax: 702-531-6432 www.riley-nacht.com Riley-Nacht, LLC, is a global brand development consulting company that focuses on the skincare industry. Founded and managed by an executive team with a combined experience of over 70 years in the

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skin and healthcare industry, Riley-Nacht brings unparalleled expertise to all stages of brand development for its clients.

Scribionics San Antonio, Texas www.scribionics.com

The Company provides a large range of services, including: product formulation, formulation enhancement, safety and stability testing, clinical protocols, clinical testing, technology licensing, brand image development, package development, contract manufacturing, market planning, physician and university endorsements, international product registration, worldwide distribution, and infomercial product development.

Scribionics Katvah, is a technical communications company specializing in educational, scientific, and literary projects. Scribionics designs, creates, and edits a variety of publications including websites, electronic journals, business correspondence, training material, catalogs, product safety inserts, and packaging.

Riley-Nacht enjoys preferred customer relationships with many of the leading contract manufacturers and suppliers in the United States and abroad. Additionally, Riley-Nacht has developed a global distribution network for skin and healthcare products for the retail, pharmacy, direct response, department store, salon, and physician channels. Riley-Nacht can develop global marketing materials, manage registration of products, trademarks and patents, contract with international distributors, and manage the distribution process. Sabinsa Corporation 121 Ethel Road West Unit 6 Piscataway, New Jersey 08854 Tel: 732-777-1111, Fax: 732-777-1443, [email protected], www.sabinsa.com Sabinsa Corporation is committed and dedicated to the principles of tradition, innovation, and research. Founded on the application-oriented manufacture of standardized phytonutrient ingredients, specialty chemicals, and organic intermediates for the pharmaceutical, food, and nutritional industries, Sabinsa has also established itself as a manufacturer and supplier of high-quality cosmeceutical ingredients. The cosmeceuticals line includes botanical extracts, specialty chemicals, and botanical essential oils, with versatile applications in cosmetic formulations. The company’s state-of-the-art manufacturing and R & D facilities in India are equipped to handle a wide range of products and production requirements. Capabilities to effect claims substantiation studies, in vitro toxicological evaluation, and clinical testing are also available.

Scribionics’ current activities focus on presenting scientific information in a way that makes it usable by non-scientists. Projects include contributing to and publishing the on-line Journal of Topical Formulations (http://www.topicalformulations.com/) and moderating its forums, as well as assisting clients with scholarly articles and technical and non-technical presentations. To contact Scribionics, send a note to [email protected]. Siltech LLC 2170 Luke Edwards Road Dacula, Georgia 30019 Tel: 678-442-0210, Fax: 678-442-9624 www.Siltechllc.com Siltech is a specialty chemical company that provides develops, manufactures, and markets a wide range of silicone compounds for industrial and personal care markets. Siltech is basic in hydrosilylation technology, a unit operation in which vinyl containing compounds are reacted with silanic hydrogen compounds to make organo-functional products. This technique allows for the creation of new products previously unavailable to the personal care formulation chemist Stepan Company 22 West Frontage Road Northfield, Illinois 60093 Tel: 847-446-7500, 800-745-7837, Fax: 847-501-2100, 847-501-2443 www.stepan.com Stepan Company is a major global manufacturer of specialty and intermediate chemicals including sur-

CONTRIBUTING COMPANIES AND UNIVERSITIES factants. With manufacturing and marketing facilities around the world, Stepan sells products primarily to consumer and industrial product companies that use them to make finished products. Steripak Pty Ltd. P.O. Box 152, Kurrajong, NSW, 2572 Australia Sydney Office: Level 5, 5 Elizabeth Street, Sydney, NSW, 2000, Tel: +61 292 217 020, Fax: +61 292 217 080 [email protected] Steripak Pty Ltd. is a scientific consultancy firm and a producer of specialty chemicals. Tagra Biotechnologies, Ltd. 8 Hamlacha Street, P.O. Box 8213, South Ind. Area, Netanya, Israel 42293 Tel: 972-9-865-6454, Fax: 972-9-865-4278 [email protected], www.tagra.com Tagra’s mission is to allow pharmaceutical and cosmetic manufacturers and, more importantly, their customers, to optimally benefit from the potential functionality of active ingredients when applied on human skin. Tagra has designed and developed innovative and unique delivery systems ideally protecting unstable substances that would otherwise be in danger of losing their activity, as proven ideal candidates for effective complexes and formulations for both the pharmaceutical and cosmeceutical industries. Tagra’s delivery systems, backed by its four patents, focus on the microencapsulation of non-water soluble ingredients, including but not limited to: antibiotics and other active pharmaceutical ingredients for dermal application (presently under development); vitamins; natural oils; fragrances; and pigments. Tagra’s products are already selling in over 15 countries including the USA, France, Spain, Italy, Japan, and other countries. Over 20 finished formulations containing Tagra’s ingredients are sold in drug stores, department stores, and alike.

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3M Personal Care & Related Products Division 3M Center, Building 220-9W-08 Saint Paul, Minnesota 55144-1000 Tel: 651-737-9709 www.3M.com/personalcare 3M is an $18 billion diversified technology company with leading positions in consumer and office; display and graphics; electro and communications; health care; industrial; safety, security, and protection services; and transportation and other businesses. The company has operations in more than 60 countries and serves customers in nearly 200 countries. 3M is one of the 30 stocks that make up the Dow Jones Industrial Average and also is a component of the Standard & Poor’s 500 Index. In addition to the 3M™ HydroElegance Technology, 3M offers other finished goods and several ingredients to formulators in the cosmetic industry. Uniqema 1000 Uniqema Boulevard New Castle, Delaware 19720-2790 Tel: 302-574-5000, 888-424-3696, Fax: 302-574-3525 www.uniqema.com Uniqema Americas 3411 Silverside Road P.O.Box 15391 Wilmington, Delaware 19850 Tel: 302-887-3000 (Ext. 3507), Fax: 302-887-3525 Uniqema is a global leader in the creation of ingredient technologies that deliver sensory and functional effects in personal care products. They continuously develop their expertise in the application of these ingredients, such as specialized emulsion systems, emulsifiers, high performing mild specialty surfactants, conditioning ingredients, inorganic sunscreens, emollients, and skin tone evening ingredients. Recent innovations include low level emulsification, alkanolamide replacements, and highly active inorganic sunscreen agents. Uniqema is known for innovation and the new ideas they bring to their customers.

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University of Basel Basel, Switzerland University of Iowa Dows Institute Iowa City, Iowa 52242-1316 University of Medicine and Dentistry of New Jersey, Department of Physiology and Pharmacology, Van Dyk Division Newark, New Jersey 07103 Wacker Chemical Corporation 3301 Sutton Road Adrian, Michigan 49221 Tel: 800-248-0063, Fax: 517-264-8101

[email protected], http://www.wacker.com,http:// www.wackersilicones.com Wacker Silicones, one of four operating divisions of Wacker-Chemie, GmbH, Munich, Germany, is a leading global manufacturer of a broad range of silicone-based additives for the cosmetics, health, human care, and other major industries. Wacker-Belsil® offers a comprehensive range of silicone-based additives for virtually limitless applications. These range from bath, cleansing, and sunscreen products for treating skin and hair, to deodorants and most forms of cosmetics, and to makeup. Foam-control, conditioning, and thixotropic control are just three typical applications that they offer.

Series Editor’s Preface Breakthroughs in Personal Care and Cosmetic Technology is a series of books dedicated to providing a wide range of science and technology related to novel product and process development, testing and manufacturing. The focus of this series is at the cutting edge of the personal care, cosmetics, pharmaceutical, and food industries. This series acknowledges the similarities of technology used in each of these areas and highlights the value of technology transfer among them. The definition of a “Breakthrough,” as used in the title of this series, is a new idea, product, innovation, or shift in viewpoint that changes the course of the industry and what it does. The “Breakthrough” series will also include overviews of the way things are done, their evolution, and sometimes revolution, that results from technology enhancements, be they optimization, or step function in nature, as well as shifts in consumer needs or regulatory requirements around the world. The series will provide practical information, of course; but in a larger context, the volumes are designed to expand current awareness of technology push and market pull forces. It seeks to mentor, educate, and act as a catalyst for the generation of the new ideas and applications yet to come. The range of subjects in the series is intended to be of interest to both the R&D and manufacturing communities as well as technical marketing and business management. Taken as a whole, this series is designed to be a unifying resource to facilitate enhanced communication among all parties responsible for new product generation. It is a goal of this series to acknowledge and facilitate effective, synergistic interaction among the widely differing points of view that are typically required to produce commercially successful products.

The intent of the series is to cover a range of technology, formulations, ingredients, labeling, manufacturing equipment, processing technology, quality control, packaging, legal/regulatory, and testing topics. The volumes will balance practical and theoretical aspects with a clear emphasis on the practical. Ample references will be provided in each volume. The range of topics will include, but not be limited to: delivery systems, fermentation process, biocides, emulsifying agents, surfactants, rheological behavior, naturals and botanicals, fragrances, bioengineering, cosmeceuticals, “cosmetic-drugs” and overthe-counter pharmaceuticals. Since such a series is most effectively produced by means of an “additive” the editor would term “tincture-of-time,” it is anticipated that other areas will be added, as the industry evolves and consumer needs, on a global scale, continue to become ever more sophisticated and demanding. Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications, & Formulations is the first book in this series. It highlights over forty different approaches to incorporating functional actives into effective formulated products that make a real difference. It is internationally sourced from the critical thinking of more than 80 authors, almost 50 companies, and 9 countries. A unique feature of this Handbook is its “bookat-a-glance,” executive section which provides a Mind Map™ overview of the important key words and concepts in each chapter and how they are related to each other. This section has been specifically designed to empower decision making leading to the development of innovative new product differentiation in a global context.

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About the Editor

Week’s Global Beauty Congress, and moderator for the PCITX product development conferences.

Meyer R. Rosen is President of Interactive Consulting, Inc. (www.chemicalconsult.com). Among his many accomplishments, Mr. Rosen is a Fellow of the American Institute of ChemMeyer R. Rosen ists; a Fellow of the Royal Society of Chemistry (London) and a past Vice-President of the Association of Consulting Chemists and Chemical Engineers. He holds national certifications as both a Professional Chemist and Professional Chemical Engineer. Mr. Rosen is a Fellow of the American College of Forensic Examiners, a Board Certified Forensic Examiner, and a Diplomate of the American Board of Forensic Engineering and Technology. He has been a Technical Advisor and Moderator for the HBA Global Beauty Expo, Chemical

Mr. Rosen’s firm consults for many Fortune 500 companies. It provides management and technology solutions including, but not limited to: custom market research, ideation sessions, and market & applications development services. Product areas served include consumer, household, personal care, cosmetic, industrial, pharmaceutical, and medical. Mr. Rosen has published over 40 technical papers, holds over 20 patents, and has presented talks at numerous technical conferences. He has written articles for Chemical Market Reporter, DCI magazine, Global Cosmetic Industry, HAPPI magazine, and Specialty Chemicals (UK). Mr. Rosen is the coauthor of the Rheology Modifiers Handbook: Practical Use and Application from William Andrew Publishing.

Interactive Consulting, Inc.

supporting patent simplification and analysis, technology transfer, technical journalism, toxicology issues, technical sales training, and academic/industrial relationships. Interactive also provides support to companies and attorneys involved in technical product litigation, patent infringement, and trade secret issues. It also provides consulting services in areas of product formulation, optimization, characterization, and control.

www.chemicalconsult.com Interactive Consulting, Inc., is a technologybased, management consulting firm committed to creating and facilitating breakthroughs in market, product, and process development by empowering individuals and groups involved in technical, business, leadership, and culture issues. The company provides management and technology solutions internationally to specialty chemical and allied industries. Markets served include, but are not limited to: personal care, consumer and household products, industrial products and processes, and the food and pharmaceutical industries. Company specialties include: creative market and applications development support, strategic/tactical planning and ideation seminars, meeting facilitation, and custom market and technology research. As specialists in the Capture and Presentation of Complex Information, results of its Ideation for Action sessions are significantly enhanced by its use of sophisticated mind mapping technology. Interactive Consulting, Inc. conducts group training and development programs designed to empower “out of the box” strategic and tactical solutions for technology and business issues. It provides services

Meyer R. Rosen

Aug. 2, 2005

Interactive Consulting’s staff has an extensive background and experience in a wide variety of the major technical and business needs of both specialty chemical and finished goods companies. The company provides technology and applications development support based on core technical strengths in: polymers and surfactants, surface and interfacial chemistry, delivery systems, rheology modifiers, and water soluble polymers such as poly (ethylene oxide) and poly (acrylamide). Other core strengths include: toxicology and testing issues, organosilicones, films, flocculants, coagulants, clays, binders, detergents, lubricants, gels, foams, and emulsions. Interactive Consulting, Inc. can be contacted by phone: 516-922-2167, FAX: 516-922-3830, or mail at P.O. Box 66, East Norwich, New York 11732, USA. An overview of Interactive Consulting is available on the web at www.chemicalconsult.com.

Preface BEFORE you merely glance at this Preface and move on without reading it, as I have done so many times with other books, I invite you to slow down and read it carefully. I request this because the Preface has many insights that I would like to share with you about motivations and technology and the “way things work” that have culminated in the book you hold in your hands.

One Editor’s Journey

as the personal care and pharmaceutical industries as well as academia.

A year after I became the Editor-in Residence of this book, I met someone who said to me, “Oh, I see, you let others do the work and you get your name on the front.” I laughed, for unless you have lived through the process of becoming an Editor, just by your own say so, you will not understand the journey. Having made that journey, I would like to share some of it with you. This is my way of letting you in, so to speak, on the behind-the-scenes evolution of what many of us would like others to know—that once, we too, passed this way and made a difference.

The process continued with identifying and contacting senior management in the Personal Care and Pharmaceutical industries, as well as in academia, and asking them what they thought of my idea. I spoke to about 150 companies in the almost three years of acquiring chapters and inviting many people to participate and share the value I saw for them and my vision of making a difference in the industry.

In a nutshell, the process began with finding a subject of wide, and expanding, interest that I expected would continue for many years to come. This was followed by generating a vision for the book that touched, moved, and inspired me. That vision was to facilitate and empower the origination, design, and communication emanating from a text that not only described technology and its origins, but pointed to actual products based on that technology, their applications and starting formulations. I had the idea to put together an unusual sort of book that would be useful not only to technologists, but to their marketing and business counterparts, in areas as diverse

There were follow-ups too numerous to mention; finding people saying yes and meaning yes, as well as finding others saying yes, and meaning no. It included the seemingly endless experience of reading and rereading; questioning authors that knew far more about their subject than I did. Many times I was glad to be uneducated in some aspects since I expected the readers to also be relatively uneducated, but wanting to learn about the subject without having to plough through fields of unexplained jargon. I had to find enough authors and chapter topics to meet the page target set by the publisher and then design the subject matter in accordance with my vision. My responsibilities included wrestling with getting what I wanted, not getting some of what I wanted and, finally, just staying open and taking what

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I did get. All of this searching was held in the context of leaving no stone unturned; and going the last quarter-inch with every possibility. My journey involved being committed and being unstoppable in having my vision manifested by the right people, the right companies, and the right subjects. It concluded with something like the wellknown Lays potato chip commercial sound bite, “Bet you can’t just eat one.” What I mean by that is I had to put myself in the mode of finding authors for several years, and then stop finding them. I found the latter part quite challenging since potential authors seemed to be everywhere I looked. The longer I looked, and even when I wasn’t looking, they were there before me. And so, inevitably, I came to what you hold in your hands right now. I hope my old English teacher at the Polytechnic Institute of Brooklyn, Professor Louis Zukovsky, will forgive me, wherever he is, for starting the latter sentence with an “And.” Inevitably, I came to a point in time called NOW, where I declared the work complete as well as declaring the incompletions complete. I learned that this work represents but a snapshot in time, and there will always be more to come since the field, and life itself, evolves with the certainty of time’s arrow, entropy. The chapters before you have been collected, nurtured, and read over and over with numerous edits. Putting the book together is reminiscent of how the brick patio in my backyard was once put together. I recall watching the bricklayer, in awe, as he steadily worked on the project, each brick having to be fit in exactly right, laying precisely horizontal on the foundation he had first built so carefully. I couldn’t help but ask him how he kept going. I still remember his face as he said, thoughtfully, “One brick at a time; just one brick at a time.” And so it goes, with all things…

Eureka! The Origins of this Book I thought you would like to know how the idea for this book first came into being. As President of Interactive Consulting, Inc., I frequently attend trade shows to see what is new in our industry. As a Consultant, and President of our consulting firm, this practice is critical to our being effective with clients, and

being knowledgable in the technical journalism process that I am so fond of participating in. Talking with exhibitors and attendees of such conferences provides me with a sense of what is going on in the industry. I also use such endeavors to gather ideas and market research for the trade press articles I write as well as the confidential reports we prepare for our clients. In 2001, during my visits to several trade shows including HBA Global Expo, where I was the Technical Conference Advisor, Society of Cosmetic Chemists (SCC) Suppliers Day(s), and the SCC Educational Conference in Texas, I saw a pattern emerging. The pattern was a plethora of technologies focused on novel ways to deliver useful actives in personal care products. I became aware of a whole new vista of surface and interfacial science, some of it focused on the selforganization of molecules into wondrous “containers” of various sorts. These “containers,” were being used by many to “hold” their favorite functional chemical, cosmeceutical, or active. The “containers” not only hold these materials , but were being designed to “deliver” them slowly, in a targeted manner, to selected parts of the skin. I was so moved by the many different approaches I saw that I wrote a two-part article on the subject for Global Cosmetic Industry Magazine. These were published in September and October of 2001. Not long after the articles appeared, interest seemed to be expanding in this area and I was offered the opportunity to edit a book on the subject by William Andrew Publishing. I have grown much from the experience. I like to think of it as a transition from “Consultant, as Editor” to “Editor, as Consultant.” After all, with a threeyear immersion in the technology, on a global basis, and the opportunity to ask experts in their field to explain what they were saying, in writing, so that I could understand, the experience became the most significant long- term learning experience I have had since going to college. Having determined there was indeed much interest in such a book, I began to think of a possible title and finally came to Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications, Formulations. I asked the people who were developing these new delivery systems whether they would describe their “Eureka!”

PREFACE discovery moments as well as provide an in-depth technical discussion of their commercial technology. So often, we go to technical conferences and make an agreement not to do “commercials” for the products we have worked so hard to develop. The vision I transmitted to potential authors and their companies was to generate a world-class, unusual text that would become the foundation text for the industry. It would enable readers to really understand how the commercial technology worked as well as describe current and potential applications. It would provide introductory sections on the skin as a substrate, and complete with discussion of safety issues, and the distinctions of “cosmetic” and “drug.” The book would also provide marketers with a novel approach for choosing what they should recommend to their companies as the next likely successful product. It would also guide their Research and Development Departments as to what they should develop next. Of course, proprietary information was not included but I resolved to facilitate the generation of a text that was far beyond some mere technical advertising literature. It was to be not quite so in-depth as a fully detailed scientific treatise, and yet would fully acknowledge the commercial products and technology that the work was based upon. Finally, since the Publisher was well known in the industry to have many books consisting exclusively of Formulations, and knowing the power of having such formulations to jump-start formulators on their own path, I decided to have the book include both the technology and the formulations. I further resolved to have the function of each ingredient stated in all formulations in order to avoid the frustration I previously had over many years of seeing ingredients listed and not knowing what they were for. In the same period, I was offered, and accepted, a three-year appointment as co-organizer of the American Chemical Society Colloid and Surface Chemistry Division. I set up, at National meetings, sessions on Technology Transfer between Academia and Industry at the Personal Care-Pharmaceutical technology interface. I learned much from these sessions and some of this is intercalated within the chapters The results of this inquiry grew and grew into the book you now hold in your hands, or, perhaps,

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are reading parts on William Andrew Publication’s sister company’s www.knovel.com website.

The Roots of Delivery System Technology This book arises from an industry trend based on the development of novel actives that have beneficial effects on skin and hair. An ever-increasing search has been, and is, in progress for novel efficacious ingredients. This search ranges from the Rain Forests of Africa and Brazil to the development and application of new analytical techniques capable of identifying natural compounds that have high concentrations of chemical components clinically demonstrated to do some good on skin and hair. This book is designed to meet a market pull requiring the delivery of these actives, in a controlled manner, to an intended target, at an appropriate time. This pull is based upon a number of trends. First, there is a desire to reduce the irritation potential of useful ingredients. Second, in view of the high cost that accompanies many of the newer materials, the incorporation of such ingredients into delivery systems allows one to slow down and target their release. This process allows more cost effective use of such materials. Further, novel performance claims have grown out of the development of such sophisticated delivery system technology. I have observed that the use of delivery systems has availed itself of much synergistic technology transfer between the pharmaceutical, personal care, and food industries. This trend continues on a significant upswing as this book goes to press and is expected to continue for quite some time.

My Vision for this Book I like to think of the Delivery System Movement as a foundation and introduction to a powerful, intriguing, and emerging technology. This technology will, in my view, enable the use of sophisticated actives for skin and hair care. It points to a new era of possibility for the development of effective personal care products beyond anything that has ever

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

been produced before. Such products are required by an ever-more-sophisticated, demanding market that really needs and wants to look good and feel better. It is my Vision that this book will serve as a Foundation text of training and development in this field for years to come. In the last decade or so, there has emerged the now-familiar trend of globalization, mergers, acquisitions, and layoffs occurring in the specialty chemical industry. Considerable personnel movement has occurred, not only from one company to another but from one industry to another. Large and small companies alike have suffered from a loss of mentoring for incoming employees, be they students, new hires from other companies, or individuals with five to ten or more years’ experience in a particular field. For such individuals and companies, a need exists for training in the science and technology of formulating and, especially in understanding the rapidly growing field of delivery systems and how to formulate with them. This need goes far beyond standard academic training in fundamentals, and points to the full meaning of the word “experience.” It is one purpose of this book to provide a basic foundation in the newly emerging science and technology of delivery systems. My hope and wish is that it will serve as a valuable productivity tool enabling individuals to capture the essence and experience of others. I can also foresee implementation, in the Academic World, of introductory courses in this subject and invite those Professors interested in the expanding opportunity of combining technology from both the personal care, pharmaceutical and food industries, to take on the job of designing a course based on this text. As I have said earlier, the book will be useful to technologists, of course, but I have also designed it to be useful to Marketing and Business personnel as well. In my experience, there is much to be said for the creation of a safe clearing where Research and Development, Marketing, and Business leaders can meet to understand each others needs and objectives. This book is intended to facilitate the generation of that clearing and the effectiveness that is born of being within it. It is my intention that this work contributes to creating the next generation of novel personal care and pharmaceutical products.

The breadth of this work is extensive. It covers technology and critical thinking of 80 authors, from 48 companies, five Universities, three consultants, and nine countries. There are 45 chapters, each of which represents a different view of the subject at hand. Reading the varying points of view of these many talented people, on the subject of “Personal Care and Cosmetic Product Delivery Systems” is somewhat like the story I once heard of the three blind men who were asked to describe what was in front of them as they touched it for the first time. The first man described it as a huge, flat wall; the second one described it as a cylindrical, rigid pillar, and the third man described it as a skinny, flexible rope. What was in front of them was an Elephant! And so, too, as you look at the “Elephant,” Delivery System Handbook for Personal Care and Cosmetic Products, each author’s view will be as the view of one of the blind men. In the end, however, the “Truth,” if there is such a thing, of the “Whole” will emerge and provide you with a new place to stand in your chosen role as Developer, Marketer, Corporate Executive, or Academician interested in the Science and Technology of Personal Care and Cosmetic Delivery Systems. Beyond the Preface and Introduction, which I have written, the book continues with three overview chapters for both the uninitiated and the sophisticated reader. The first of these, “Skin Physiology and Penetration Pathways,” is intended to introduce the Skin as a substrate, and it delves quite deeply into skin physiology. This chapter provides a perspective of what a delivery system, or formulation containing a delivery system, will encounter as it is applied to the stratum corneum. A second introductory chapter has a comprehensive discussion entitled “Delivery System Design in Topically Applied Formulations,” and a third introductory chapter entitled “From Ancient Potions to Modern Lotions: A Technology Overview and Introduction to Topical Delivery Systems.” The main body of this work introduces a wide range of delivery system technologies useful to the personal care formulations chemists, pharmaceutical technologists and their associated marketing claims and regulatory strategists. Each chapter is written by one or more experts in the field. Many of these individuals have presented papers on their subject to peer groups at well-respected scientific meet-

PREFACE ings. Much of the work is protected by patents, as is custom and practice. The core of each technology is described in depth. Novel features, key ingredients, benefits, and potential claims are described. Although I would have liked to have all of the 150 companies I contacted during the three years it took to bring this book to a stage that it could be sent to the publisher, this has not been possible for a wide variety of reasons. However, what is included is covered in depth. It has been written, as I have said previously, by committed individuals seeking to make a difference and generate a world-class text. While the book does not cover all the subjects I would have liked to address, it does represent a beginning to the process of bringing order to this field and represents an opportunity for future contributors in later editions. As Editor, I have continually challenged the authors to provide explanations of concepts they knew so well that they frequently didn’t know that others didn’t know them. I have taken the 45 chapters and, as my good friend and associate David Braun once said, “arbitrarily, but thoughtfully, arranged them into “subject” sections. These are entitled: “Fundamentals,” “Crossing the Barrier,” “Encapsulation,” “Liposomes,” “Particles,” “Emulsions,” “Foams,” “Structured Systems,” “Silicones,” “Starch-Based,” “Activated Delivery,” “Substrate-Based,” and “Specific Ingredient Delivery,” “Efficacy and Safety,” and “Marketing by Design.” In each of the chapters on specific delivery system technologies, an extensive compendium of exemplar formulations is presented. These have been designed by supplier companies using their own delivery systems in order to demonstrate the usefulness of their technology in a wide variety of applications. They serve as a showcase of approaches for using their delivery systems as well as providing starting points for the design of new formulations. As I previously mentioned, one innovation I have incorporated into these formulations is to have the authors include the function of each ingredient. I have chosen to do this so the reader does not have to wander in the wilderness of not knowing why the ingredients are there. I can still remember how many times I asked people about the purpose of an ingredient in a formulation and hearing they didn’t know since it “was made before their time.”

LIX

The book concludes with one chapter that addresses safety and safety testing issues and another that introduces a powerful market pull analysis tool for individuals responsible for generating business and marketing directions for technologists. This approach is useful for characterizing the claims needed to generate products for the sophisticated and educated consumers who comprise the internet-savvy generation of today. Key company contacts and supplier lists round out the information presented. I refer you to the Table of Contents for a more detailed description of the chapters within in each of the technical sections. We’ve also provided contact information for the authors, as well as their companies, so you can get in touch with them easily and find out more about their products and ideas. I also call your attention to a special approach I have taken to present the Table of Contents and important key words and concepts. This approach is contained in the chapter pages of a “Rapid-Read,” Book-at-a-Glance, executive summary. To do this, I have employed a technology known as Mind Maps®. This novel approach for the Capture and Presentation of Complex Information is interesting, useful, and of service to both business and technical readers. It provide a rapid-read, organized approach for those with too much to do, in too little time, as they seek to understand and develop products in a global context. I have found this approach of extraordinary value in the many Ideation For Action sessions I have conducted for senior managers of specialty chemical companies. If this approach intrigues you regarding its simplicity and effectiveness at summarizing and organizing the large bodies of complex information you have to deal with, I invite you to contact Interactive Consulting, Inc., for further information on the design of training and development sessions for your own special needs. It is my intention, as Editor, to have provided a description of as many of the delivery system technologies as I could obtain agreement for having. I have presented them, in total, not only for their individual value; but also as a foundation for idea generation to move the industry to further breakthroughs. This book is useful for those faced with actives that are too expensive, look great but degrade too fast, or functional actives that work—but are irritating. An awareness of the range of delivery technology

LX

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

available is mandatory in today’s world. Each day, we may be faced with an image in the mirror of our own aging faces, or look at the faces of those we care about, whether young or older. And, each day we come face to face with the reality of the need, and yearning, for slowing the travails of time’s inevitable movement as it leaves its mark of wrinkled skin upon us all. This mark is the common ground that calls to us all as we seek to make a real difference by smoothing out some of these wrinkles and gouges in the road of life. We are an industry that can, is, wants to, and is committed to making a difference to one of the most compelling needs of human being; that of looking good. I believe the development of novel delivery systems which facilitate the use of “fountain of

youth” functional actives is an idea whose time has come. I assert this book is the beginning of the process to collect, record, describe, and teach the technology to those who need it and want it. I invite you to delve into the mysteries to come. Begin with the Introduction; please do not pass it by, for therein lies much in the way of interesting and informative perspectives I have gathered on this journey that has become a central part of my life’s commitment for these past four years. Meyer R. Rosen, Editor

August 2, 2005

Acknowledgments To David Braun, my old friend and colleague, for introducing me to the world of personal care, Suppliers’ day, and the wonders of the Society of Cosmetic Chemistry, and for his invitation to coauthor our book, Rheology Modifier Handbook: Practical Use & Application (William Andrew Publishing, Norwich, New York) and contribute my view of the practical application of rheology for problem solving. To my good friend and colleague, Jon Barb, who first introduced me to Mind Maps® and their power for the organization and representation of complex information. To my son, David Rosen, for saying, “Dad, you are much more than Mind Maps.” To my mother, Jeanne Rosen, who sent me to typing school, one summer, oh-so long ago. I acknowledge her commitment to enable me to quickly say what I wanted to, in writing, in the days long before I ever heard of such a thing as a computer, let alone that I might be sitting in front of one some day and letting what was in my mind flow out so easily, into your minds and hearts. To my father, Philip Rosen, who asked me to choose the best college so that I could really “have a trade;” and for sending me to that college, even though it cost him dearly. To my English teacher, Professor Louis Zukovsky, at the Polytechnic Institute of Brooklyn, who taught me never to use a long word, when a short one would do. My professor gave me an “A” in a course that most of my fellow students in our Engineering School never got and taught me that good technical ability was only half of the foundation for success in the world. The other half, he said, was to be able to write effectively about what I had thought about, or accomplished. He was so right!

To Dr. Frederick Eirich, Professor of Physical Chemistry and author of the well-known book Series on Rheology, who gave me a treasured “A” twice in his five-credit, blockbuster physical chemistry course. I had the privilege of acknowledging him on his 90th birthday at the Chemists Club in New York and finally told him how much it had meant to me that he let us write anything we wanted on one 8.5 x 11 inch of paper, and bring it into all the exams with us so “we wouldn’t have to struggle with remembering equations.” It was only then, he said, “that we could concentrate on learning the real joy of the science.” I believe that my interest and competence in mind mapping ® technology derives from this experience since I translated that practice in Dr. Eirich’s class into an ability to represent complex information on a single “page” and have brought these “summaries” to you for each chapter of this book. To William Andrew Publishing for the opportunity to learn to be an Editor, design a major book, and follow it through to completion. To Millicent Treloar, my Senior Acquisitions Editor at William Andrew Publishing, for her timely, thoughtful, knowledgeable support of me in my role as novice editor. To William Woishnis, CEO of William Andrew Publishing, for introducing me to the world of book publishing and its needs and for his certainty that I was an Editor-in-the-Making. To Martin Scrivener, Publisher, William Andrew Publishing, for inviting me to be Series Editor of Breakthoughs in Personal Care and Cosmetic Technology and for sharing his vision of what is yet to come. To the Contributors to this book, and their companies, or universities, who represent a broad spectrum of talents and specialties. Your commitment to

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

LXII

developing the technology and science described in this book, and communicating it to others, along with your willingness to review numerous edits in order to meet my vision of a truly world-class, global endeavor has taught me more than mere words can say. To my Teachers—the dedicated authors in this book, who formed a partnership with me and committed to producing a world class text. From you, I learned that teaching and learning are correlated like the front of the hand and the back of the hand. We taught and learned from each other. To the 150 companies, worldwide, that I contacted in the course of almost three years, who were involved in the development and/or application of delivery system technology in the Personal Care and Pharmaceutical fields. I acknowledge: • Those who Took the opportunity to present their business and technology information in a novel format and trusted that it would be worth their time and commitment. • Those who Wanted to write a chapter and didn’t because of other priorities. • Those who Continued on, in spite of job transitions, both willed and unexpected, amidst the uncertainty, self-searching and inevitable reinvention of themselves that such change can bring. • Those who Kept their commitment and provided drafts on time, or even earlier than promised. • Those who Had the technology almost in hand but decided it was just a bit to early and danced to the drummer of more data generation and the inevitable timely filing of patent applications. • Those who Contributed with the intention of training “Those-To-Come,” and for their wisdom in knowing that, inevitably, we all pass this way once and we have a duty to pass on our knowledge and discoveries. • Those who Saw this as a business opportunity for selling products and licensing technology and supporting the growth and reputations of their companies. • Those who Wrote on planes, on vacations, on weekends, at night when their children were finally asleep, in order to get the job done.

• Those who Enrolled their colleagues in writing parts of their chapters when it took more than one person to get the job done. • Those who Answered my seemingly endless questions in order to produce a book that was truly understandable, even if you knew very little about the subject when you began to read it. • Those who Said yes, when they meant no, and provided me with numerous opportunities to support them in turning their no into a real yes, and sometimes taking months or even years to commit and begin, or to finish. • Those who Said no, after due consideration, and taught me that I won’t always get what I want. • Those who Said yes, and dropped out of communication along the way. • My Self, as Editor, for Being willing to take on the job without knowing all of it’s impact on my life and family. – For creating the satisfaction I feel right now, as I realize, and acknowledge the privilege and opportunity of meeting so many talented, intelligent, creative and motivated people along the way. – I thank you all for this opportunity and am grateful to you for what you have taught me. • You, the Reader, Who I hope will take the time to capture, hold, and consider these acknowledgments rather than skipping them, as I usually have done in the past with other books. It is my wish that you know something of what it has taken to produce this Work and the commitment of the many people involved. I assert that, in total, the combined efforts of the many individuals and companies who have contributed to this book will provide you, the Reader with access to the New and Emerging Science and Technology of Personal Care Delivery Systems. May it serve you also as a Reference and Source of who and where to go to for years to come as the increasingly sophisticated needs and demands of our global community continue to expand. Meyer R. Rosen, Editor

August 2, 2005

Contents

Contributing Authors ....................................................................................................... xxix Contributing Companies and Universities ....................................................................... xLiii Series Editor’s Preface ...................................................................................................

Liii

About the Editor ..................................................................................................................

Liv

Interactive Consulting, Inc. ..................................................................................................

Liv

Preface ...........................................................................................................................

Lv

One Editor’s Journey ..........................................................................................................

Lv

Eureka! The Origins of This Book .......................................................................................

Lvi

The Roots of Delivery System Technology ......................................................................... Lvii My Vision for This Book ...................................................................................................... Lvii Acknowledgments ...............................................................................................................

Part I. 1.

2.

Introduction .................................................................................................

1

The Delivery System Movement .........................................................................................

3

1.1

Introduction .............................................................................................................

4

1.2

The “Eureka!” Moment ............................................................................................

5

1.3

The Birth of Ideas ....................................................................................................

6

1.4

What Is a Delivery System? .................................................................................... 1.4.1 Factors Affecting the Efficacy of a Delivery System .................................. 1.4.2 For What Application Areas Are Delivery Systems Useful? .......................

7 8 8

1.5

The Philosophy Behind This Book .......................................................................... 1.5.1 What You Should LOOK FOR as You Read ..............................................

9 9

1.6

Using the Mind Maps® .............................................................................................

10

Executive Summary: Book-at-a-Glance ..............................................................................

11

Part II. 3.

Lxi

Skin Fundamentals .....................................................................................

75

Skin: Physiology and Penetration Pathways .......................................................................

77

3.1

78 78 79 80 80

Biology of the Skin .................................................................................................. 3.1.1 Overall Structure ........................................................................................ 3.1.2 Cell Replication .......................................................................................... 3.1.3 The Differentiation Process ........................................................................ 3.1.4 The Desquamation Process .......................................................................

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v

vi

4.

Contents 3.2

Stratum Corneum .................................................................................................... 3.2.1 The Permeation Barrier .............................................................................. 3.2.2 Stratum Corneum Ultrastructure ................................................................ 3.2.3 Structural Proteins of the Stratum Corneum .............................................. 3.2.4 Stratum Corneum Lipids ............................................................................ 3.2.5 The Two-compartment Model .................................................................... 3.2.6 The Domain Mosaic Model ........................................................................ 3.2.7 The Single Gel Phase Model ..................................................................... 3.2.8 The Sandwich Model .................................................................................

81 81 82 83 84 85 85 86 86

3.3

Penetration Pathways into the Skin ........................................................................ 3.3.1 The Bulk Stratum Corneum ....................................................................... 3.3.2 The Appendages and Breaches Created in the Stratum Corneum ........... 3.3.3 Chemical Enhancement of Permeation ..................................................... 3.3.4 Physical Enhancement of Permeation ....................................................... 3.3.5 Effects of Skin Hydration ............................................................................ 3.3.6 Supersaturation of the Drug Solution .........................................................

87 87 88 89 90 93 93

3.4

Delivery System Factors ......................................................................................... 3.4.1 Molecular Weight of the Drug Molecule ..................................................... 3.4.2 Lipophilicity of the Active Molecule ............................................................ 3.4.3 Effect of the Delivery System on Permeation ............................................

94 94 95 95

3.5

Conclusions .............................................................................................................

95

References ..........................................................................................................................

96

Delivery System Design in Topically Applied Formulations: an Overview .......................... 101 4.1

Introduction ............................................................................................................. 102

4.2

Routes for Skin Penetration .................................................................................... 103 4.2.1 Skin Penetration Pathways ........................................................................ 104 4.2.2 Skin Penetration Enhancers ...................................................................... 106

4.3

Improvement of the Therapeutic Index ................................................................... 106

4.4

Design of Delivery Systems .................................................................................... 106

4.5

Examples of Delivery Systems ................................................................................ 4.5.1 Liposomes .................................................................................................. 4.5.2 Elastic Vesicles .......................................................................................... 4.5.3 Particulate Systems ................................................................................... 4.5.4 Molecular Systems: Dendrimers ................................................................

4.6

Determination of the Site of Action .......................................................................... 110 4.6.1 Intracellular Delivery .................................................................................. 110 4.6.2 Metabolism in the Epidermis ...................................................................... 110

4.7

Topical Applications: Examples .............................................................................. 112 4.7.1 Reduction of Melanin Synthesis by Inhibiting Tyrosinase Activity ............. 112 4.7.2 Reducing the Appearance of Wrinkles by Affecting the Collagen-elastin Network ...................................................................................................... 112 This page has been reformatted by Knovel to provide easier navigation.

107 107 107 108 109

Contents 4.7.3 4.7.4 4.8

vii

Improvement of Acne Condition and Intrafollicular Delivery ...................... 113 Improving the Appearance of Skin Imperfections and Superficial Delivery ...................................................................................................... 114

Summary and Future Challenges ........................................................................... 115

References .......................................................................................................................... 116 5.

From Ancient Potions to Modern Lotions: a Technology Overview and Introduction to Topical Delivery Systems .................................................................................................... 119 5.1

Introduction ............................................................................................................. 120

5.2

Origins of Delivery Systems .................................................................................... 5.2.1 Defining Delivery Systems ......................................................................... 5.2.2 Delivery Systems in Nature ........................................................................ 5.2.3 Nature-inspired Delivery Systems Technology ..........................................

120 120 121 122

5.3

Origins of Personal Care: When Medicine and Cosmetics Were One .................... 5.3.1 Ancient Medicine: Unifying Theories and Philosophical Aspects ............... 5.3.2 Traditional Medicine: Maintaining Balance ................................................ 5.3.3 Modern Medicine: Separation and Reunion of Medicine and Cosmetics ..................................................................................................

124 124 126 127

5.4

Foundations of Personal Care Technology ............................................................. 128 5.4.1 Technology in Ancient Formulae ............................................................... 128

5.5

New Technology for Personal Care: an Introduction to Delivery Vehicles .............. 5.5.1 Nanosomes™ ............................................................................................ 5.5.2 Nanoemulsions and Dispersicles™ ........................................................... 5.5.3 Nanoencapsulation ....................................................................................

5.6

Conclusions ............................................................................................................. 130

5.7

Formulations ........................................................................................................... 5.7.1 Acne Treatment (Traditional Chinese), Enhanced with Nanoencapsulation .................................................................................... 5.7.2 Oil of Anointing (Ancient Hebrew), Enhanced with Nanoemulsion ............ 5.7.3 Pain Relief Gel (Ayurvedic), Enhanced with Nanosomes™ ......................

130 130 130 130 131 131 131 132

References .......................................................................................................................... 132

Part III. 6.

Crossing the Barrier ................................................................................... 135

Crossing the Lipid Barrier with the Echo-Derm™ Delivery System (A Skin-mimicking, Lamellar Matrix System) ..................................................................................................... 137 6.1

What Is a Delivery System? .................................................................................... 137

6.2

Anatomy of a “Perfect Product” ............................................................................... 138

6.3

Skin’s Functions ...................................................................................................... 139 6.3.1 Background: Skin Structure ....................................................................... 139 6.3.2 Bricks-and-mortar Model ............................................................................ 139

6.4

Why Worry about Delivery ...................................................................................... 140

6.5

Delivery Options ...................................................................................................... 140 This page has been reformatted by Knovel to provide easier navigation.

viii

Contents 6.5.1 6.5.2 6.5.3 6.5.4

What Is a Liposome? ................................................................................. What Are Nanospheres? ............................................................................ Changing the Cosmeceutical Landscape .................................................. The Echo-Derm™ Delivery System ...........................................................

141 142 142 142

6.6

Formulating Guidelines ........................................................................................... 6.6.1 Preloading .................................................................................................. 6.6.2 Auto-loading ............................................................................................... 6.6.3 High End Dermal Hydro-cream ..................................................................

145 145 145 146

6.7

Sample Formulations .............................................................................................. 147

References .......................................................................................................................... 156 7.

Tetrahydropiperine: a Natural Topical Permeation Enhancer ............................................. 157 7.1

Introduction ............................................................................................................. 158

7.2

Historical Perspective .............................................................................................. 7.2.1 The Spice Route and Black Pepper ........................................................... 7.2.2 Use of Black Pepper in Folk Medicine ....................................................... 7.2.3 Discovery as a Delivery System ................................................................

158 158 159 159

7.3

Concept Development ............................................................................................. 7.3.1 Skin as a Delivery Conduit for Bioactives .................................................. 7.3.2 Black Pepper Extract as Bioavailability Enhancer for Nutraceuticals ......... 7.3.3 Tetrahydropiperine (THP): Unique Black Pepper Constituent Derived from Piperine .............................................................................................. 7.3.4 Mechanism of Action ..................................................................................

160 160 162 165 165

7.4

Scientific Basis for Efficacy ..................................................................................... 166 7.4.1 Chemistry of Tetrahydropiperine (THP) ..................................................... 166 7.4.2 Experimental Evidence for Topical Formation Enhancement Efficacy of THP ............................................................................................................ 168

7.5

Safety Profile ........................................................................................................... 172 7.5.1 THP: Low Skin Irritation Potential .............................................................. 172

7.6

Enhancing Topical Delivery of Bioactives with THP ................................................ 173 7.6.1 Potential Skin and Hair Care Applications ................................................. 173

7.7

Formulation Strategies ............................................................................................ 173 7.7.1 Skin Care ................................................................................................... 173 7.7.2 Hair Care .................................................................................................... 173

7.8

Summary ................................................................................................................. 174

7.9

Formulations ........................................................................................................... 174

References .......................................................................................................................... 176

Part IV. 8.

Encapsulation ............................................................................................. 179

Microencapsulation: an Overview of the Technology Landscape ....................................... 181 8.1

Background ............................................................................................................. 181 8.1.1 Definitions .................................................................................................. 182 This page has been reformatted by Knovel to provide easier navigation.

Contents

ix

8.2

Microencapsulation Technology Vectors ................................................................ 8.2.1 Scope and Market Size .............................................................................. 8.2.2 What Is Being Encapsulated Today? ......................................................... 8.2.3 Why Encapsulate? ..................................................................................... 8.2.4 Effects Desired ...........................................................................................

182 182 183 184 185

8.3

Bringing It All Together: the Encapsulation Technology Landscape ....................... 8.3.1 Non-chemical, Mechanical ......................................................................... 8.3.2 Non-chemical, Aqueous ............................................................................. 8.3.3 Chemical, Aqueous ....................................................................................

185 186 186 188

8.4

Microencapsulation Technology Challenges and Market Trends ............................ 188 8.4.1 Technology Challenges ............................................................................. 189 8.4.2 Market Trends ............................................................................................ 189

8.5

Conclusions ............................................................................................................. 189

References .......................................................................................................................... 190 9.

Microcapsules as a Delivery System .................................................................................. 191 9.1

Introduction ............................................................................................................. 192

9.2

Microcapsules ......................................................................................................... 9.2.1 Selecting an Appropriate Microencapsulation System ............................... 9.2.2 Coating Systems for Water-insoluble Actives ............................................ 9.2.3 Coating Systems for Water-soluble Actives ............................................... 9.2.4 Effect of Formulation Environment ............................................................. 9.2.5 Physical Forms of Microcapsules ..............................................................

9.3

Microcapsule Release Mechanisms ........................................................................ 195 9.3.1 Mechanical Rupture ................................................................................... 195 9.3.2 Controlled Release .................................................................................... 195

9.4

Encapsulation by in Situ Polymerization ................................................................. 198

9.5

Formulations: Features and Benefits ...................................................................... 203

9.6

Conclusions ............................................................................................................. 204

9.7

Formulations ........................................................................................................... 205

192 193 193 194 194 194

References .......................................................................................................................... 213 10.

Tagravit™ Microcapsules as Controlled Drug Delivery Devices and Their Formulations ....................................................................................................................... 215 10.1

Microencapsulation: a Delivery Method for Unstable Actives ................................. 216

10.2

Contemporary Microencapsulation Techniques ...................................................... 217

10.3

Preparation of Microcapsules for Skin Applications ................................................ 220

10.4

Microencapsulation of Unstable Lipophilic Actives ................................................. 221

10.5

Stability Determination of Microencapsulated Vitamins in Various Formulations ........................................................................................................... 223

10.6

Model Formulations Developed for Stability Testing of Tagravit™ Microencapsulated Products ................................................................................... 224 10.6.1 Stability Variables ...................................................................................... 224 This page has been reformatted by Knovel to provide easier navigation.

x

Contents 10.6.2 Effects of Stability Variables ...................................................................... 224 10.7

Effect of Formulation on Stability of Microencapsulated Vitamins ........................... 10.7.1 Increased Stability of Microencapsulated Retinol Palmitate ...................... 10.7.2 Increased Stability of Microencapsulated α-tocopherol ............................. 10.7.3 Increased Stability of Microencapsulated Vitamin F .................................. 10.7.4 Effect of Plasticizers in the Microcapsular Wall on Stability of Active ........ 10.7.5 Effect of Loaded Amount of Encapsulated Retinol Palmitate on Its Stability in Formulation ...............................................................................

226 226 226 228 228 230

10.8

Incorporation of Tagravit/Tagrol™ Microcapsules into Cosmetic Formulations ...... 231 10.8.1 Basic Principles .......................................................................................... 231 10.8.2 Application of Tagravit™/Tagrol™ Microcapsules ..................................... 233

10.9

Conclusions ............................................................................................................. 233

10.10 Model and Recommended Formulations ................................................................ 235 10.10.1 Model Formulations ................................................................................... 235 10.10.2 Recommended Formulations ..................................................................... 250 References .......................................................................................................................... 257 11.

Phase-change Materials: a Novel Microencapsulation Technique for Personal Care ........ 259 11.1

Introduction ............................................................................................................. 260

11.2

History of Ciba Encapsulation Technology ............................................................. 260

11.3

Review of Ciba Encapsulation Techniques ............................................................. 260 11.3.1 Capsule Particle Size ................................................................................. 261

11.4

Skin Temperature Regulation via Phase-change Materials .................................... 261 11.4.1 The “Eureka!” Moment ............................................................................... 262 11.4.2 Selection of Melting Point of Encapsulated Wax ....................................... 262

11.5

Phase-change Materials ......................................................................................... 11.5.1 Preparation of Encapsulated PCMs ........................................................... 11.5.2 Application of PCMs in Personal Care Formulations ................................. 11.5.3 Potential Applications ................................................................................. 11.5.4 Future Work ...............................................................................................

11.6

Conclusions ............................................................................................................. 265

11.7

Formulations ........................................................................................................... 267

263 263 265 265 265

Acknowledgments ............................................................................................................... 272 12.

Topical Delivery Systems Based on Polysaccharide Microspheres .................................... 273 12.1

Background ............................................................................................................. 273

12.2

Acceptable Cosmetic Delivery Systems .................................................................. 12.2.1 Good Skin Tolerance ................................................................................. 12.2.2 Stability of the Active Ingredient ................................................................. 12.2.3 No Ghosting ............................................................................................... 12.2.4 Biodegradability .........................................................................................

12.3

Chitosphere™ Topical Delivery Technology ........................................................... 279

12.4

Conclusions ............................................................................................................. 280 This page has been reformatted by Knovel to provide easier navigation.

274 274 277 278 279

Contents 12.5

xi

Formulation ............................................................................................................. 281

References .......................................................................................................................... 282

Part V. 13.

Liposomes ................................................................................................... 283

Liposomes in Personal Care Products ................................................................................ 285 13.1

Introduction ............................................................................................................. 285

13.2

The “Lip-O-somes” .................................................................................................. 286

13.3

Lipids and Their Self-assembly ............................................................................... 287

13.4

Liposomes: Production Methods ............................................................................. 288

13.5

Encapsulation/Loading of Actives in Liposomes ..................................................... 290

13.6

Characterization of Liposomes ................................................................................ 292

13.7

Formulating with Liposomes ................................................................................... 295

13.8

Liposomes: Applications in Personal Care Products ............................................... 297

13.9

Liposomes: Future Trends ...................................................................................... 298

References .......................................................................................................................... 299 14.

Interactive Vehicles in Synergistic Cosmeceuticals: Advances in Nanoencapsulation, Transportation, Transfer, and Targeting ............................................................................. 303 14.1

Introduction ............................................................................................................. 304

14.2

What Can Be Claimed? ........................................................................................... 304

14.3

What Can Be Named? ............................................................................................ 304

14.4

What Can Be Explained? ........................................................................................ 14.4.1 Vehicles for Overcoming Obstacles in Actives’ Performance .................... 14.4.2 Interactions, Mobilization, and Transport of Actives: Across the Barriers ...................................................................................................... 14.4.3 Drug Delivery Technology Rejuvenates Old Drugs and Gives Them New Applications ....................................................................................... 14.4.4 Topical and Injectable Vehicles ................................................................. 14.4.5 Synergistic Effects ..................................................................................... 14.4.6 Side Effects ................................................................................................ 14.4.7 Nanoemulsion-based Vehicles .................................................................. 14.4.8 Nanosomes™ and Double Emulsion-based Vehicle Technologies ........... 14.4.9 Intra-dermal and Trans-dermal Vehicles ....................................................

305 305 305 308 308 310 314 314 314 314

14.5

Formulations ........................................................................................................... 316 14.5.1 Moisturizing Wrinkle Cream with Green Tea and Vitamins ........................ 316 14.5.2 Face Cream with Jojoba, Aloe Vera, and Vitamin E .................................. 316

14.6

Conclusions ............................................................................................................. 316

References .......................................................................................................................... 319

Part VI. 15.

Particles ....................................................................................................... 321

Porous Entrapment Spheres as Delivery Vehicles ............................................................. 323 15.1

Introduction ............................................................................................................. 323 This page has been reformatted by Knovel to provide easier navigation.

xii

Contents 15.2

Before Cosmospheres ............................................................................................ 323 15.2.1 Microcapsules ............................................................................................ 323 15.2.2 Liposomes .................................................................................................. 325

15.3

Porous Entrapment System Technology ................................................................. 326 15.3.1 What Are Cosmospheres? ......................................................................... 326

15.4

Conclusion .............................................................................................................. 327

15.5

Formulations ........................................................................................................... 328

References .......................................................................................................................... 332 16.

Polymeric Porous Delivery Systems: Polytrap® and Microsponge®......................................... 333 16.1

Introduction ............................................................................................................. 334 16.1.1 Needs in Skin Care .................................................................................... 334 16.1.2 Entrapments: General Description ............................................................. 334

16.2

Polytrap® Technology .............................................................................................. 16.2.1 What Is a Polytrap Polymer? ..................................................................... 16.2.2 How Are Polytrap Polymers Made? ........................................................... 16.2.3 How Can They Be Loaded? ....................................................................... 16.2.4 Mode of Action ........................................................................................... 16.2.5 Main Applications ....................................................................................... 16.2.6 Strengths and Limitations ..........................................................................

334 334 335 335 335 335 337

16.3

Microsponge® Technology ...................................................................................... 16.3.1 What Is a Microsponge® Polymer? ............................................................ 16.3.2 How Are Microsponge® Polymers Made? .................................................. 16.3.3 How Are They Loaded? ............................................................................. 16.3.4 Mode of Action ........................................................................................... 16.3.5 Main Applications .......................................................................................

338 338 338 339 340 341

16.4

Summary and Conclusions ..................................................................................... 344

16.5

Formulations ........................................................................................................... 345

References .......................................................................................................................... 351 17.

Chronospheres®: Controlled Topical Actives Release Technology .................................... 353 17.1

Introduction ............................................................................................................. 353

17.2

Chemistry and Historical Development ................................................................... 354

17.3

Functional Properties .............................................................................................. 355

17.4

Formulary Guidelines .............................................................................................. 356

17.5

Manufacturing Process ........................................................................................... 357

17.6

Formulations ........................................................................................................... 358

Acknowledgements ............................................................................................................. 359 References .......................................................................................................................... 364 18.

Nanotopes™: a Novel Ultra-small Unilamellar Carrier System for Cosmetic Actives ......... 365 18.1

Introduction ............................................................................................................. 366 18.1.1 The Nanotopes™ System .......................................................................... 367 This page has been reformatted by Knovel to provide easier navigation.

Contents

xiii

18.1.2 Surfactant-stability of Nanotopes™ Particles ............................................. 368 18.2

Nanotopes™: Stability in Formulation ..................................................................... 368 18.2.1 Particle Stability in the Presence of Sodium Dodecyl Sulphate as Assessed by Dynamic Light Scattering (DLS) ........................................... 368 18.2.2 Stability of Nanotopes™ and Liposomes in the Presence of Various Surfactants, as Assessed by Turbidity Measurements .............................. 370

18.3

Nanotopes™: Performance ..................................................................................... 18.3.1 Influence of Nanotopes™ Encapsulation on Stability of Vitamin A Palmitate .................................................................................................... 18.3.2 In Vitro Performance of Aqueous Nanotopes™ Solutions on Human Skin ............................................................................................................ 18.3.3 In Vitro Performance on Human Skin of Nanotopes™ in Cosmetic Formulations .............................................................................................. 18.3.4 In Vivo Performance of Aqueous Nanotopes™ in Solutions ...................... 18.3.5 In Vivo Performance of Formulated Nanotopes™ .....................................

373 373 375 377 379 381

18.4

Conclusions ............................................................................................................. 382

18.5

Formulations ........................................................................................................... 383

Acknowledgements ............................................................................................................. 393 References .......................................................................................................................... 393 19.

Practical Application of Fractal Geometry for Ultra-high Surface Area Personal Care Delivery Systems ................................................................................................................ 395 19.1

Fractal Geometry, Fractal Polymers, and the Cosmetic Industry ............................ 396 19.1.1 Why Are Fractal Polymers Important for the Cosmetic Industry? .............. 396 19.1.2 The “Eureka!” Moment ............................................................................... 396

19.2

From Cantor Dust to Sierpinski-menger Sponge: the Fractal World ....................... 397 19.2.1 Applying the Fractal Concept to Personal Care Systems .......................... 398

19.3

Fractal Geometry: Statistics and Chemistry ............................................................ 399

19.4

Fractal Poly-epsilon Caprolactam (FPEC) .............................................................. 401 19.4.1 Description and Properties ......................................................................... 401 19.4.2 Cosmetic Applications ................................................................................ 403

19.5

Commercially Available Grades .............................................................................. 403 19.5.1 Nomenclature Used ................................................................................... 403 19.5.2 Examples of Fractal Polymer Grades Available ......................................... 404

19.6

Conclusion .............................................................................................................. 404

19.7

Formulations ........................................................................................................... 405

References .......................................................................................................................... 405

Part VII. 20.

Emulsions .................................................................................................... 407

Optimizing Skin Delivery of Active Ingredients from Emulsions: from Theory to Practice ............................................................................................................................... 409 20.1

Introduction ............................................................................................................. 410 This page has been reformatted by Knovel to provide easier navigation.

xiv

Contents 20.2

The Principles of Skin Delivery ............................................................................... 411

20.3

Measurement of Skin Penetration ........................................................................... 20.3.1 In-vitro Methods ......................................................................................... 20.3.2 In-vivo Methods .......................................................................................... 20.3.3 Animal Skin versus Human Skin ................................................................ 20.3.4 The Need for New Nondestructive Methods ..............................................

412 412 413 413 414

20.4

Formulation Mapping .............................................................................................. 20.4.1 Selecting the Right Model Penetrants ........................................................ 20.4.2 Test Formulations ...................................................................................... 20.4.3 Skin Preparation ........................................................................................ 20.4.4 Diffusion Cells ............................................................................................ 20.4.5 Application of Formulations ........................................................................ 20.4.6 Determination of Skin Penetration and Skin Distribution ........................... 20.4.7 Results .......................................................................................................

414 414 415 415 416 416 416 416

20.5

The Importance of Ingredient Selection in Formulations for Dermal and Transdermal Delivery .............................................................................................. 20.5.1 Theoretical Considerations ........................................................................ 20.5.2 The Relative Polarity Index (RPI) ............................................................... 20.5.3 An Example of Using the RPI Concept ...................................................... 20.5.4 The Influence of the Emulsifier ..................................................................

424 424 425 429 430

20.6

Conclusions ............................................................................................................. 431

20.7

Formulations ........................................................................................................... 433

Acknowledgments ............................................................................................................... 434 References .......................................................................................................................... 434 21.

The Delivery Systems’ Delivery System ............................................................................. 437 21.1

Introduction ............................................................................................................. 21.1.1 History of Cosmetics .................................................................................. 21.1.2 Contemporary Cosmetics .......................................................................... 21.1.3 The Future .................................................................................................

438 438 438 438

21.2

Current Vehicles for Delivery Systems .................................................................... 439

21.3

Issues with Emulsions ............................................................................................. 442 21.3.1 The “Eureka!” Moment ............................................................................... 446

21.4

Surfactant-free Lamellar Phase (Lα) Dispersions: an Alternative to the Conventional Emulsification Process ...................................................................... 446

21.5

Defining a Semiquantitative Aesthetic Scale ........................................................... 450

21.6

Formulating with Lα Dispersions – System 3™ ....................................................... 452

21.7

System 3™ Advantages .......................................................................................... 452

21.8

Conclusion .............................................................................................................. 454

21.9

Formulations ........................................................................................................... 455

References .......................................................................................................................... 472

This page has been reformatted by Knovel to provide easier navigation.

Contents 22.

xv

Preparation of Stable Multiple Emulsions as Delivery Vehicles for Consumer Care Products: Study of the Factors Affecting the Stability of the System (w1/o/w2) ................... 473 22.1

Introduction/Objectives ............................................................................................ 22.1.1 Uses and Application/Objectives ............................................................... 22.1.2 Multiple Emulsion Stability ......................................................................... 22.1.3 Other Factors Affecting Stability of Multiple Emulsions .............................

474 474 475 475

22.2

Materials/Methods ................................................................................................... 22.2.1 Materials .................................................................................................... 22.2.2 Methods ..................................................................................................... 22.2.3 Mechanical Equipment ............................................................................... 22.2.4 Evaluation Techniques ...............................................................................

475 475 476 476 476

22.3

Experiments ............................................................................................................ 22.3.1 Surface Isotherms ...................................................................................... 22.3.2 Particle Size Determination ........................................................................ 22.3.3 Pendant Drop Method to Measure Dynamic Interfacial Tension ...............

479 479 480 480

22.4

Results and Discussion ........................................................................................... 22.4.1 Monolayer Experiments – Study of the Primary Interface .......................... 22.4.2 Investigation of Polyglycerol Ester of Ricinoleic Acid ................................. 22.4.3 Interactions between the Low- and High-HLB Emulsifiers at the o/w2 Interface ..................................................................................................... 22.4.4 Determination of the Minimum Amount of Primary Surfactant to Be Used in the Preparation of the w1/o Emulsion ............................................ 22.4.5 Determination of the Optimum Amount of Solute Necessary to Stabilize the Primary w1/o Emulsion and the w1/o/w2 Multiple Emulsion .................. 22.4.6 Selection Criteria for the Water Soluble Polymeric Thickener ................... 22.4.7 Influence of the Concentration of the Betaine/Sodium Lauryl Ether Sulfate Mixture on the Rheological Properties of Xanthan Gum and the Resulting w1/o/w2 Stability .......................................................................... 22.4.8 Droplet Breakup in Double Emulsion Systems ..........................................

480 481 484 485 487 488 489

489 493

22.5

Measurement of the Dynamic Interfacial Tension Oil/Water Using the Pendant Drop Tensiometer Method ...................................................................................... 493 22.5.1 The Pendant Drop Technique .................................................................... 493 22.5.2 Equilibrium Adsorption Measurement and Discussion ............................... 494

22.6

Conclusion .............................................................................................................. 494

References .......................................................................................................................... 496

Part VIII. Foams .......................................................................................................... 499 23.

Coacervate Foam Delivery Systems ................................................................................... 501 23.1

Introduction ............................................................................................................. 501

23.2

Coacervate Foams .................................................................................................. 502

23.3

Analysis Methodology ............................................................................................. 502

23.4

Results .................................................................................................................... 503 This page has been reformatted by Knovel to provide easier navigation.

xvi

Contents 23.4.1 Formation of Coacervates .......................................................................... 503 23.4.2 Properties of Coacervate Foams ............................................................... 504 23.4.3 Application of Coacervate Foams .............................................................. 507 23.5

Conclusions ............................................................................................................. 510

References .......................................................................................................................... 511 24.

Soft Cell Approach to Personal Care: Hydrophilic Active-filled Polyurethane Delivery Systems .............................................................................................................................. 513 24.1

Forming Reactive Substrates Containing Actives ................................................... 514

24.2

“Eureka!” – Formulation Plus Applicator in-situ ....................................................... 514

24.3

Exploring Hydrophilic Polyurethane Technology ..................................................... 24.3.1 The Formulator as Chemical Artist ............................................................ 24.3.2 Limitations .................................................................................................. 24.3.3 Understanding Hydrophilic Polyurethane Stability .....................................

514 515 516 516

24.4

Hydrophilic Polyurethane Shaped or Molded Foams .............................................. 24.4.1 Types and Functional Characteristics for Skin Care Products ................... 24.4.2 Marketing Benefits versus Traditional Skin Care Products ........................ 24.4.3 Types and Functional Characteristics for Hair Care Products ................... 24.4.4 Marketing Benefits versus Traditional Hair Care Products ........................

517 517 519 519 521

24.5

Hydrophilic Polyurethane Foam Film Coatings ....................................................... 521 24.5.1 Types and Functional Characteristics for Skin and Hair Care ................... 521 24.5.2 Marketing Benefits of Foam Film Coatings ................................................ 523

24.6

Hydrophilic Polyurethane Foam Laminates (Cast Foam) ........................................ 523 24.6.1 Marketing Benefits – Foam Laminates ...................................................... 523

24.7

Manufacturing Techniques and Methods ................................................................ 24.7.1 Molding Foams .......................................................................................... 24.7.2 Casting Foams ........................................................................................... 24.7.3 Coating Foam Films ...................................................................................

24.8

Summary ................................................................................................................. 525

24.9

Formulations ........................................................................................................... 526 24.9.1 Patents ....................................................................................................... 532

Part IX. 25.

524 524 524 525

Structured Systems .................................................................................... 533

Sugar Structured Surfactant Systems (S4™) ..................................................................... 535 25.1

Sugar Structured Surfactant Delivery System (S4™) ............................................. 536

25.2

Conventional Structured Surfactant Systems ......................................................... 25.2.1 Dispersed Lamellar Systems ..................................................................... 25.2.2 Expanded Lamellar Systems ..................................................................... 25.2.3 Spherulitic Lamellar Systems ..................................................................... 25.2.4 Advantages of Conventional Structured Systems ...................................... 25.2.5 Drawbacks of Conventional Structured Systems for Personal Care Use ............................................................................................................. This page has been reformatted by Knovel to provide easier navigation.

536 536 536 537 537 537

Contents

xvii

25.3

Sugar Structured Surfactant Delivery System ......................................................... 25.3.1 Structurant ................................................................................................. 25.3.2 Role of Co-structurant ................................................................................ 25.3.3 Surfactant Types ........................................................................................ 25.3.4 Suspended Additives .................................................................................

538 538 539 539 540

25.4

Properties of S4™ ................................................................................................... 25.4.1 Optical Properties ...................................................................................... 25.4.2 Rheology .................................................................................................... 25.4.3 Thermal Stability ........................................................................................ 25.4.4 Preservative free ........................................................................................ 25.4.5 Performance ..............................................................................................

540 540 541 542 542 542

25.5

Applications of the S4™ .......................................................................................... 542

25.6

Conclusions ............................................................................................................. 545

25.7

Formulations ........................................................................................................... 545

References .......................................................................................................................... 546 26.

Shear-thinning Lamellar Gel Network Emulsions as Delivery Systems .............................. 547 26.1

Introduction ............................................................................................................. 548

26.2

The “Eureka!” Effect ................................................................................................ 548

26.3

Preparation of Lamellar Gel Network Emulsions .................................................... 549

26.4

Molecular Identification ........................................................................................... 26.4.1 Chemistry and Function ............................................................................. 26.4.2 Molecular Modeling of Sodium Stearyl Phthalamate ................................. 26.4.3 Interfacial Tension (IFT) .............................................................................

26.5

Identification and Characterization of Lamellar Gel Network Structure ................... 552 26.5.1 Conductivity Method .................................................................................. 552 26.5.2 Rheological Method ................................................................................... 554

26.6

Applications ............................................................................................................. 26.6.1 Skin Irritation .............................................................................................. 26.6.2 Moisturization Effect of RM1 in Creams and Lotions ................................. 26.6.3 SPF Enhancement in Sunscreen Formulations ......................................... 26.6.4 Formulating Sprayable Products ................................................................

26.7

Conclusion .............................................................................................................. 564

26.8

Formulations ........................................................................................................... 565

550 550 550 552

554 554 556 559 564

References .......................................................................................................................... 568 Acknowledgment ................................................................................................................. 568 27.

ProLipid® Skin-mimetic Lamellar Gel Carrier and Delivery Systems .................................. 569 27.1

Introduction ............................................................................................................. 27.1.1 Definition of Lamellar Gel Organization ..................................................... 27.1.2 Lamellar Gels and Skin Lipid Organization ................................................ 27.1.3 The “Eureka!” Moment ............................................................................... 27.1.4 Determining ProLipid® Lamellar Gel Structure ........................................... This page has been reformatted by Knovel to provide easier navigation.

570 570 571 571 571

xviii

Contents 27.1.5 Product Structuring with ProLipid® Lamellar Gels ...................................... 572 27.2

Formulating with ProLipid® Lamellar Gels ............................................................... 573 27.2.1 Selection of ProLipid® Lamellar Gel Systems ............................................ 573 27.2.2 Preparation of ProLipid® Lamellar Gel Emulsions ...................................... 573

27.3

Delivery of Functional Materials from ProLipid® Lamellar Gel Formulations ........... 27.3.1 Demonstration of Lamellar Gel Structure in ProLipid® Emulsions ............. 27.3.2 Long Lasting Moisturization ....................................................................... 27.3.3 Delivery and Substantivity of Sunscreen Agents ....................................... 27.3.4 Delivery and Substantivity of Ascorbic Acid ...............................................

27.4

Extended Insect Repellency with a ProLipid® 151 Lotion ........................................ 576

27.5

Extended Fragrance Release with ProLipid® Systems ........................................... 577

27.6

Conclusions ............................................................................................................. 577

27.7

Formulations ........................................................................................................... 578

574 574 574 575 576

References .......................................................................................................................... 586 28.

Intelligent Polymers and Self Organizing Liposome Gel Delivery Systems ........................ 587 28.1

Introduction ............................................................................................................. 588

28.2

Chemical Structure of Lipids ................................................................................... 588

28.3

Lamellar Phases ..................................................................................................... 588

28.4

Liposomes ............................................................................................................... 28.4.1 Liposomes and Human Skin ...................................................................... 28.4.2 Formation of Vesicles ................................................................................ 28.4.3 Current Technologies for Preparation of Vesicles .....................................

28.5

Spontaneous Formation of Liposomes from Lamellar Liquid Crystals .................... 591

28.6

New Product Delivery Vehicles Based on Fluid Liposomal Dispersions Obtained from Lamellar Phases .............................................................................. 592

28.7

Stability Issues with Liposomes .............................................................................. 28.7.1 Current Approaches to Stabilize Liposomes .............................................. 28.7.2 Traditional Liposomal Gels ........................................................................ 28.7.3 Current Liposomal Products with Enhanced Viscosity ...............................

28.8

New Liposomal Gels in the Presence of Intelligent Polymers ................................. 595 28.8.1 Polymers for Attachment to the Liposome Surface .................................... 596 28.8.2 Discussion of the New Liposome Gel Approach ........................................ 596

28.9

Summary ................................................................................................................. 598

588 590 590 590

593 593 594 594

28.10 Formulations ........................................................................................................... 599 References .......................................................................................................................... 602 29.

Cubosomes® and Self-assembled Bicontinuous Cubic Liquid Crystalline Phases ............. 603 29.1

Introduction ............................................................................................................. 604

29.2

The “Eureka!” Moment ............................................................................................ 605

29.3

Cubosome Applications .......................................................................................... 605

29.4

Liquid Precursor Process for Cubosome Manufacture ............................................ 606 This page has been reformatted by Knovel to provide easier navigation.

Contents

xix

29.5

Powdered Cubosome Precursors Using Spray-drying Technology and the Hydrotrope Method ................................................................................................. 607

29.6

Functionalized Cubic-phase Liquid Crystals ........................................................... 609

29.7

Clinical Evaluation of Skin Conditioning by Cubic-phase Liquid Crystals ............... 611

29.8

Clinical Study Results ............................................................................................. 611

29.9

Conclusions ............................................................................................................. 615

29.10 Formulations ........................................................................................................... 616 References .......................................................................................................................... 618 30.

Nonaqueous Delivery Systems with Controlled Rheological Behavior ............................... 621 30.1

Introduction ............................................................................................................. 621

30.2

Background ............................................................................................................. 622 30.2.1 Polymeric Rheological Additives for Nonaqueous Systems ...................... 623 30.2.2 Unique Characteristics of Thermoplastic Block Copolymers ..................... 624

30.3

Thermoplastic Block Copolymers as Rheological Modifiers .................................... 30.3.1 Mechanism ................................................................................................. 30.3.2 The “Eureka!” ............................................................................................. 30.3.3 Rheological Properties ............................................................................... 30.3.4 Primary Functions of Elastomeric Gels in Personal Care Applications ......

30.4

Formulating with Elastomeric Copolymers .............................................................. 628 30.4.1 Identify the Appropriate System ................................................................. 628 30.4.2 Incorporating the Gelling Copolymer ......................................................... 629

625 625 625 626 627

30.4.3 Prototype Formulation ............................................................................................. 630 References .......................................................................................................................... 631

Part X. 31.

Silicones ...................................................................................................... 633

Cationic Silicone Complexes as Delivery Systems ............................................................. 635 31.1

Introduction ............................................................................................................. 636

31.2

The “Eureka!” Moment ............................................................................................ 636

31.3

Group Opposites ..................................................................................................... 636

31.4

Silicone Compounds ............................................................................................... 637 31.4.1 Carboxy Silicone Polymers ........................................................................ 637

31.5

Fatty Quaternary Ammonium Compounds .............................................................. 639

31.6

Silicone Complex Improvements ............................................................................. 639 31.6.1 Organic Quats ............................................................................................ 639 31.6.2 Silicone Quat Complexes ........................................................................... 639

31.7

Desirable Properties of Cationic Silicone Complexes ............................................. 640 31.7.1 Compatibility with Anionic Surfactants ....................................................... 640 31.7.2 Compatibility with Anionic Surfactants Test ............................................... 640

31.8

Fatty Quaternary, Carboxy Silicone Conditioner ..................................................... 641 31.8.1 Test Method ............................................................................................... 641 31.8.2 Test Results ............................................................................................... 642 This page has been reformatted by Knovel to provide easier navigation.

xx

Contents 31.9

Recent Advancements ............................................................................................ 644

31.10 Conclusions ............................................................................................................. 644 31.11 Formulations ........................................................................................................... 645 References .......................................................................................................................... 666 32.

“Pro-fragrant” Silicone Delivery Polymers ........................................................................... 667 32.1

Introduction ............................................................................................................. 667

32.2

Silicone-based Molecular Release of Fragrances ................................................... 32.2.1 Hydrolytic Cleavage of Fragrant Silicone Copolymers ............................... 32.2.2 Axilla Bacteria (Enzyme) Triggers for Fragrance Release ......................... 32.2.3 Hydrolytically Cleavable Si-O Bonds as Fragrance Release Mechanism ................................................................................................. 32.2.4 Hydrolysis of Silicone-based Schiff Bases ................................................. 32.2.5 Hydrolysis of Fragrant Silicic-acid Esters ................................................... 32.2.6 Silicone Personal Care Active Delivery Polymers ......................................

668 668 668 669 671 671 675

32.3

Silicone-based Non-releasing Delivery Polymers ................................................... 675 32.3.1 Sunscreens ................................................................................................ 675

32.4

Summary ................................................................................................................. 677

32.5

Formulations ........................................................................................................... 678

References .......................................................................................................................... 682 33.

Silicone Technology as Delivery Systems for Personal Care Ingredients .......................... 683 33.1

Introduction ............................................................................................................. 684

33.2

Silicone as Delivery Systems .................................................................................. 686

33.3

Technology Review ................................................................................................. 33.3.1 Synergistic Effect: Silicones as Enhancers of Organic Ingredient Efficacy ...................................................................................................... 33.3.2 Silicone Elastomers: Entrapment and Controlled Release ........................ 33.3.3 Silicone Vesicles and Encapsulation .........................................................

33.4

33.5

Silicone-based Cosmetic Formulations as Delivery Systems ................................. 33.4.1 Non-aqueous Emulsions of Polyols in Silicone to Deliver StorageSensitive Personal Care Actives ................................................................ 33.4.2 Multiple-phase Emulsions .......................................................................... 33.4.3 Polyether Modified Silicone Elastomers for Multiple-phase Emulsions ...... 33.4.4 Polar Solvent-in-oil Emulsions and Multiple Emulsions .............................

687 687 693 695 699 700 700 702 703

Formulations ........................................................................................................... 704

References .......................................................................................................................... 714 34.

Linear Silicone Fluids for Controlled Volatility Delivery Systems ........................................ 715 34.1

The “Eureka!” Moment ............................................................................................ 716 34.1.1 Evaluation of Octamethylcyclotetrasiloxane (D4) ....................................... 716 34.1.2 The New VOC Rules .................................................................................. 716

34.2

Introduction to Silicone Technology ........................................................................ 717 34.2.1 Silicone Manufacture ................................................................................. 717 This page has been reformatted by Knovel to provide easier navigation.

Contents

xxi

34.2.2 Dimethicones or Linear Polydimethylsiloxanes .......................................... 719 34.3

Linear Volatile Silicone Fluids with Controlled Volatility .......................................... 34.3.1 What Is a Volatile? ..................................................................................... 34.3.2 What Volatile Silicones Have Been Known Previously? ............................ 34.3.3 The New Linear Volatile Silicone Fluids ..................................................... 34.3.4 What Are the Properties of the New Volatile Linear Dimethicones? .......... 34.3.5 How Linear Volatile Dimethicones Are Different from Other Volatiles ....... 34.3.6 How to Use the Linear Volatile Silicones ...................................................

719 719 721 722 723 723 724

34.4

Applications ............................................................................................................. 34.4.1 Hair Care .................................................................................................... 34.4.2 Skin Care and Sun Care ............................................................................ 34.4.3 Color Cosmetics ......................................................................................... 34.4.4 Antiperspirants, Deodorants, and Perfumes ..............................................

725 725 725 725 725

34.5

Conclusions ............................................................................................................. 726

34.6

Formulations ........................................................................................................... 727

References .......................................................................................................................... 738 Acknowledgements ............................................................................................................. 738

Part XI. 35.

Starch-based Systems ................................................................................ 739

Starch-based Delivery Systems .......................................................................................... 741 35.1

Background ............................................................................................................. 741 35.1.1 Starch Chemistry ....................................................................................... 742 35.1.2 Formulation History .................................................................................... 743

35.2

Trends ..................................................................................................................... 744 35.2.1 Ingredients from Natural/Botanical Resources .......................................... 744

35.3

Starch Modifications: Chemical and Physical ......................................................... 35.3.1 Modification Benefits .................................................................................. 35.3.2 Starch Modification Chemistry and Functionality ....................................... 35.3.3 Starch Granule Gelatinization .................................................................... 35.3.4 Functionality in Formulations .....................................................................

745 745 746 747 747

35.4

Novel Starch-based Delivery Systems .................................................................... 35.4.1 Introduction ................................................................................................ 35.4.2 Absorbent Starch Delivery Systems .......................................................... 35.4.3 Film-forming Starch Delivery Systems ....................................................... 35.4.4 Film-forming/Viscosifier Starch Delivery Systems ......................................

747 747 748 750 752

35.5

Future Innovation .................................................................................................... 754

35.6

Formulations ........................................................................................................... 754

References .......................................................................................................................... 760 36.

Thixogel™: Novel Topical Delivery Systems for Hydrophobic Plant Actives ...................... 761 36.1

Introduction ............................................................................................................. 762 36.1.1 Genesis of Concepts: the “Eureka!” Moment ............................................. 762 This page has been reformatted by Knovel to provide easier navigation.

xxii

Contents 36.1.2 Statement of the Problem .......................................................................... 763 36.1.3 Thixogel Technology .................................................................................. 763 36.2

Thixogel Formulations ............................................................................................. 763

36.3

Delivery System Technology ................................................................................... 36.3.1 Essential Elements of Thixogel Delivery System ....................................... 36.3.2 Thixogel Processing ................................................................................... 36.3.3 Surface Science and Interfacial Principles ................................................. 36.3.4 Emulsification Studies on Thixogel Formulations ...................................... 36.3.5 Role of Key Ingredients .............................................................................. 36.3.6 Key Formulating Factors ............................................................................

764 764 765 767 768 769 771

36.4

Thixogel Applications .............................................................................................. 36.4.1 Current Applications ................................................................................... 36.4.2 Skin Hydrating Thixogel Formulations ....................................................... 36.4.3 Skin Protecting Thixogel Formulations ...................................................... 36.4.4 Reversible Hydration Effects of Topically Applied Thixogels ..................... 36.4.5 Delivery of Oxygen from Thixogel .............................................................. 36.4.6 Antimicrobial Thixogel Formulations .......................................................... 36.4.7 Antioxidant and Antiirritant Hydrophobic Plant Actives .............................. 36.4.8 Hydro-alcoholic Extracts of Plants Rich in Flavonoids ............................... 36.4.9 Antioxidant Plant Extracts ..........................................................................

773 773 773 774 774 775 776 777 779 779

36.5

Summary ................................................................................................................. 779 36.5.1 Benefits to Formulators and Customers .................................................... 780

36.6

Formulations ........................................................................................................... 780

Acknowledgments ............................................................................................................... 793 References .......................................................................................................................... 793

Part XII. 37.

Activated Delivery Systems ....................................................................... 795

Smart Vectorization: Enzymatically Activated Encapsulation Technologies ....................... 797 37.1

Introduction ............................................................................................................. 798

37.2

The “Eureka!” Moment ............................................................................................ 799

37.3

Limits of Current Technologies ............................................................................... 799

37.4

Overview of Trigger Release Mechanisms ............................................................. 37.4.1 Release with Change in Pressure .............................................................. 37.4.2 Release with Change in Temperature ....................................................... 37.4.3 Release with pH Change ........................................................................... 37.4.4 Release by Osmotic Pressure ................................................................... 37.4.5 Molecular Encapsulation and Release ....................................................... 37.4.6 Release by Enzymatic Digestion ............................................................... 37.4.7 Enzymatic Release: an Exact Approach ....................................................

37.5

Encapsulation Technologies Applicable to Enzymatic Release .............................. 803 37.5.1 Formaldehyde- or Glutaraldehyde-based Techniques ............................... 803 This page has been reformatted by Knovel to provide easier navigation.

800 800 800 801 801 802 802 802

Contents

xxiii

37.5.2 Non-Formaldehyde- or Non-glutaraldehyde-based Techniques ................ 803 37.6

Micro- and Macrosized Particles for Enzymatically Activated Technologies ........... 37.6.1 Marine Collagen ......................................................................................... 37.6.2 Plant Proteins ............................................................................................. 37.6.3 Polysaccharide-based Encapsulation ........................................................ 37.6.4 Nanoencapsulation ....................................................................................

805 805 806 806 806

37.7

Properties and Performance of Micro- and Nanospheres and Capsules ................ 37.7.1 Enzymatic Digestion in Vitro ...................................................................... 37.7.2 Penetration vs. Storage ............................................................................. 37.7.3 Pharmacokinetic ........................................................................................ 37.7.4 In Vivo Results ........................................................................................... 37.7.5 Membrane Selection ..................................................................................

807 807 808 811 812 813

37.8

Perspectives and Conclusions ................................................................................ 813

37.9

Formulations ........................................................................................................... 814

References .......................................................................................................................... 816 38.

“Thinking Outside the Jars and Bottles”: Delivery Systems for Unit-dose Topical Delivery of Complementary and/or Incompatible Actives ................................................... 817 38.1

Simultaneous Delivery Systems .............................................................................. 38.1.1 Why Two Different Actives at the Same Time? ......................................... 38.1.2 Eureka! Keep Active Separate until Time of Use ....................................... 38.1.3 Packaging Descriptions and Functional Characteristics ............................ 38.1.4 Stability: Effective Solutions for Incompatibility .......................................... 38.1.5 Heightened Effectiveness Due to in Situ Mixing on Skin ........................... 38.1.6 Marketing Benefits ..................................................................................... 38.1.7 Patchless Patch – Sustained Release of Actives ...................................... 38.1.8 Formulation Combinations That Fulfill Consumer Needs .......................... 38.1.9 TanDerm™ and SnapPack Manufacturing ................................................ 38.1.10 Summary ....................................................................................................

818 818 818 818 822 822 822 823 823 824 825

38.2

Sequential Delivery Systems .................................................................................. 38.2.1 A Systems Approach to Skin Care ............................................................. 38.2.2 Eureka! Two Separate Products in a Back-to-Back Wipe .......................... 38.2.3 Advantages of Two Formulations Delivered in Sequence from a Single System ....................................................................................................... 38.2.4 TwinDerm™ Packette: Description and Function ...................................... 38.2.5 Marketing Benefits ..................................................................................... 38.2.6 Sequential Combinations That Fulfill Consumer Needs ............................ 38.2.7 Packette Manufacturing ............................................................................. 38.2.8 Summary ....................................................................................................

825 825 825

38.3

825 825 826 826 827 827

Simultaneous Delivery Formulations ....................................................................... 828

Patents ................................................................................................................................ 830 References .......................................................................................................................... 830 This page has been reformatted by Knovel to provide easier navigation.

xxiv

Contents

Part XIII. Substrate-based Systems .......................................................................... 831 39.

Water-soluble Adhesive Patch Delivery Systems for Personal Care Actives ..................... 833 39.1

Introduction ............................................................................................................. 834

39.2

Background ............................................................................................................. 834 39.2.1 The “Eureka!” Moment ............................................................................... 835

39.3

Features and Benefits ............................................................................................. 835

39.4

Suggested Uses and Applications .......................................................................... 39.4.1 Skin Care ................................................................................................... 39.4.2 Skin Decoration .......................................................................................... 39.4.3 Hair Treatment ........................................................................................... 39.4.4 Oral Care ................................................................................................... 39.4.5 Nail Care ....................................................................................................

837 837 837 837 838 838

39.5

Materials of Construction ........................................................................................ 39.5.1 The Carrier ................................................................................................. 39.5.2 The Adhesive ............................................................................................. 39.5.3 Active Agents ............................................................................................. 39.5.4 Support Layer ............................................................................................

838 838 840 841 842

39.6

Formulations ........................................................................................................... 39.6.1 Product and Safety Information ................................................................. 39.6.2 Notice ......................................................................................................... 39.6.3 Warranty Information .................................................................................

842 842 842 842

References .......................................................................................................................... 848 40.

“Dry & Deliver!”: Substrate-based, Water-activated, Anhydrous Delivery Systems ............ 849 40.1

Anhydrous Delivery Systems: an Overview ............................................................ 850

40.2

Eureka! Solid Lotion Coatings for Drying and Treating Wetted Skin ....................... 850

40.3

Functional Characteristics of Solid Anhydrous Formulations .................................. 40.3.1 Advantages of Solid Anhydrous Formulations ........................................... 40.3.2 Limitations .................................................................................................. 40.3.3 Stability Issues ...........................................................................................

40.4

Single or Multiple Active Coatings ........................................................................... 852

40.5

Selection of Substrate Carrier ................................................................................. 40.5.1 Paper Substrates ....................................................................................... 40.5.2 Nonwoven Substrates ................................................................................ 40.5.3 Urethane Foams ........................................................................................

40.6

Marketing Benefits .................................................................................................. 853

40.7

Skin Care Products ................................................................................................. 40.7.1 Cleansing ................................................................................................... 40.7.2 Treatment ................................................................................................... 40.7.3 Blemish Control .......................................................................................... 40.7.4 Organic Actives and Natural Ingredients ................................................... 40.7.5 Makeup Application .................................................................................... This page has been reformatted by Knovel to provide easier navigation.

850 851 851 851 852 852 853 853 853 853 854 854 854 854

Contents

xxv

40.7.6 Dermabrasion ............................................................................................ 855 40.7.7 Skin Lightening .......................................................................................... 855 40.8

Packaging ............................................................................................................... 855

40.9

Manufacturing Methods ........................................................................................... 855

40.10 Summary ................................................................................................................. 855 40.11 Formulations ........................................................................................................... 856 Reference ........................................................................................................................... 858

Part XIV. Specific Ingredient Delivery ....................................................................... 859 41.

RetiSTAR™ for Cosmetic Formulations: Stabilized Retinol ................................................ 861 41.1

Introduction ............................................................................................................. 861

41.2

Retinol: an Anti-aging Skin Care Ingredient ............................................................ 863

41.3

Formulating Skin Treatment Products with Retinol ................................................. 863

41.4

Advantages Over Prior Art Systems ....................................................................... 865 41.4.1 Use of Antioxidant Vitamins to Deliver Stabilized Retinol .......................... 865 41.4.2 Technical and Economic Advantages of RetiSTAR™ ............................... 866

41.5

Formulations ........................................................................................................... 867

References .......................................................................................................................... 871 42.

Controlled Delivery and Enhancement of Topical Activity of Salicylic Acid ......................... 873 42.1

Introduction ............................................................................................................. 873

42.2

Contemporary Technologies and Vehicles to Modify Delivery and Activity of Salicylic Acid ........................................................................................................... 42.2.1 Polymeric Complexation ............................................................................ 42.2.2 Liposome Delivery System ........................................................................ 42.2.3 Polymeric Entrapment and/or Encapsulation ............................................. 42.2.4 Acid pH Emulsion Systems ........................................................................ 42.2.5 Gel Delivery Vehicles ................................................................................. 42.2.6 Anti-irritant Compositions ...........................................................................

42.3

874 874 875 875 877 878 878

Conclusions ............................................................................................................. 878

References .......................................................................................................................... 879 43.

Controlled Delivery of Hydroxyacids ................................................................................... 881 43.1

Topical Use of AHAs ............................................................................................... 43.1.1 An AHA Has to Be Absorbed to Work ........................................................ 43.1.2 Why Stinging Is Important, but Not Essential ............................................. 43.1.3 The Case for Controlled-delivery of AHAs .................................................

43.2

Amphoteric Controlled-release Systems ................................................................. 883 43.2.1 Evidence of Amphoteric AHA Complexes .................................................. 884 43.2.2 Commercialization of Amphoteric AHAs .................................................... 887

43.3

Molecular Complexing Agents ................................................................................ 888 43.3.1 Selection of Molecular Complexing Agents ............................................... 888 43.3.2 Applications of AHA Molecular Complexing Agents .................................. 889 This page has been reformatted by Knovel to provide easier navigation.

881 882 882 882

xxvi

Contents 43.4

Summary ................................................................................................................. 889

43.5

Formulations ........................................................................................................... 890

References .......................................................................................................................... 907

Part XV. 44.

Efficacy and Safety ..................................................................................... 909

New and Emerging Testing Technology for Efficacy and Safety Evaluation of Personal Care Delivery Systems ....................................................................................................... 911 44.1

Introduction ............................................................................................................. 912

44.2

History of Clinical Testing ........................................................................................ 912

44.3

Regulatory Oversight .............................................................................................. 913 44.3.1 United States Food and Drug Administration (FDA) .................................. 913 44.3.2 European Union ......................................................................................... 914

44.4

Developing a Clinical Safety Plan ........................................................................... 915 44.4.1 Identifying the Target Population ............................................................... 915 44.4.2 Defining the Product Claims ...................................................................... 916

44.5

Preclinical Safety Data ............................................................................................ 44.5.1 Preclinical Animal Data .............................................................................. 44.5.2 In Vitro Data ............................................................................................... 44.5.3 Comparative Analysis ................................................................................

918 918 918 919

44.6

Safety Testing Protocols ......................................................................................... 44.6.1 Irritation Testing ......................................................................................... 44.6.2 Sensitization Testing .................................................................................. 44.6.3 Phototoxicity Testing .................................................................................. 44.6.4 Photoallergenicity (Photosensitization) Testing ......................................... 44.6.5 Safety-in-use Testing ................................................................................. 44.6.6 Systemic Exposure ....................................................................................

919 920 921 922 922 923 923

44.7

Product Testing Programs ...................................................................................... 44.7.1 Example 1: Evaluation of a New Delivery System ..................................... 44.7.2 Example 2: Clinical Testing of a New Delivery System ............................. 44.7.3 Example 3: Safety Testing for a New Delivery System ..............................

924 924 924 926

44.8

Post-market Surveillance ........................................................................................ 926

44.9

Conclusion .............................................................................................................. 927

References .......................................................................................................................... 928

Part XVI. Marketing by Design and Advertising Analysis ....................................... 931 45.

GraphiSenses: a New Methodology for Identifying Personal Care Opportunities .............. 933 45.1

Introduction ............................................................................................................. 934 45.1.1 How Does the GraphiSenses Approach Lead to New Products? .............. 934

45.2

Idea Generation ...................................................................................................... 935

45.3

First Step: Database of Print Advertisements ......................................................... 935 45.3.1 Database .................................................................................................... 935 This page has been reformatted by Knovel to provide easier navigation.

Contents 45.3.2 45.3.3 45.3.4 45.3.5 45.3.6 45.3.7 45.4

xxvii

Advertisement Analysis .............................................................................. Synthesis of Verbatim Responses: Definition of Key Words ..................... Definition of the Axes of Communication ................................................... Product Mapping ........................................................................................ Product Clustering ..................................................................................... Driver Definition .........................................................................................

936 936 936 937 937 937

Second Step: Sensory Evaluation of the Drivers .................................................... 45.4.1 Procedure .................................................................................................. 45.4.2 Results ....................................................................................................... 45.4.3 The Sensory Analysis Leads to a Kind of “Identity Card” That Qualifies Each Driver ................................................................................................

938 938 939 940

45.5

Formulations ........................................................................................................... 941 45.5.1 Formulation Philosophy ............................................................................. 941 45.5.2 Formulation Details .................................................................................... 941

45.6

Validation ................................................................................................................ 949 45.6.1 Validation by Sensory Evaluation .............................................................. 949 45.6.2 Validation by Consumer Testing ................................................................ 952

45.7

Conclusions ............................................................................................................. 952

Definitions and Methodology ............................................................................................... 954 Details on Sensory Analysis and Definitions ........................................................... 954 Methodology of Evaluation ...................................................................................... 955 References .......................................................................................................................... 956

Glossary ........................................................................................................................ 957 Suppliers/Vendors ........................................................................................................ 973 Trademarks ................................................................................................................... 983 Index .............................................................................................................................. 987

This page has been reformatted by Knovel to provide easier navigation.

Part I Introduction

The Delivery System Movement

INTRODUCTION

Book-at-a-Glance

1 The Delivery System Movement Meyer R. Rosen Interactive Consulting, Inc. East Norwich, New York

1.1 1.2 1.3 1.4

1.5 1.6

Introduction ....................................................................................... 4 The “Eureka!” Moment...................................................................... 5 The Birth of Ideas ............................................................................. 6 What is a Delivery System? ............................................................. 7 1.4.1 Factors Affecting the Efficacy of a Delivery System ............. 8 1.4.2 For What Application Areas are Delivery Systems Useful? .. 8 The Philosophy Behind This Book .................................................... 9 1.5.1 What You Should LOOK FOR As You Read ........................ 9 Using the “Maps” ............................................................................ 10

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 3–10 © 2005 William Andrew, Inc.

4

1.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Introduction

After about three years in the making, it is my pleasure and privilege to introduce you to what I assert will become the basic textbook defining the foundation of the Delivery System Movement. In the last several years, the personal care industry has recognized that it must go beyond the simple identification of useful actives that provide the basis for novel claims, features, and benefits. Further, the industry has come to recognize that a pinch of something good, mentioned on the label for its advertising value, or its good “story,” just doesn’t cut it any more with real people in the aging, baby boomer population. Further, having too low a level of a high profile ingredient is no longer appropriate for their smoother skinned offspring who want to do everything they can to avoid the wrinkled appearance of their elders. Some of the issues associated with the industry’s recognition of the need to move to a higher ground include providing protection of functional actives from processing, environmental, and formulation stressors. Fortunately, these needs are timely since they correspond with the emergence of a technology platform to provide solutions for these issues (i.e., the new “Science of Delivery Systems”). This science relies upon a whole range of new and existing technologies. These technologies are evolving at a rapid rate and address the need for novel approaches to carry actives within formulations and successfully deliver them to substrates like skin and hair. These methodologies provide technology that controls when the actives should be delivered, where they should be delivered, how they should be delivered, and enable their delivery at an optimal rate. Delivery onto, and into, the substrate at some useful concentration, in a timely fashion, under appropriate use and application conditions is of critical importance. Control of an active’s release, where and when it will do the most good, is indeed becoming a critical issue. Stimulation triggers like pH, temperature, shear, and enzymes are all under investigation to allow the formulation chemist more complete control of this area. This approach will significantly impact the design of future generations of personal care systems. The challenges described above are being broadly addressed by a wide range of supplier and

formulator companies. During the research phase of this book, I contacted over 150 companies doing work in this area. It became apparent that numerous opportunities for technology transfer exist at the interface among the Pharmaceutical (i.e., Drugs), Personal Care (i.e., Cosmeceuticals & Functional Actives), Food (i.e., Nutraceuticals) and the Industrial arenas. While the title of this book is Delivery System Handbook for Personal Care and Cosmetic Products, there is much of interest to those individuals responsible for research, marketing, and business in these other markets. I invite you to look for ideas in your area even though it may not specifically be Personal Care. There are many nuggets of gold just waiting to be transferred to areas outside of Personal Care, especially if you stay open as you read and take what you get. The best ideation emerges from a “silent synthesis” of what is on the page and what is in your mind. This is especially true if you read the book having put at stake your commitment to generate new ideas and applications in your own field. As with any complex issue, numerous technical approaches have evolved, and continue to evolve, to solve the emerging challenges. With each jump in technology, a range of new capabilities has become apparent. These capabilities represent an ever-widening choice of approaches for formulators as well as new opportunities for achieving truly effective, consumer-perceivable benefits. This book provides an overview of some of the major technologies now being developed and marketed for carrying and delivering functional personal care actives. The approach taken is based upon detailed descriptions of fundamental scientific and technological principles. It has been designed to provide a basic understanding of the physical and chemical phenomena associated with such systems. I have encouraged both the authors, and their companies, to describe the technology they have worked so hard to develop and protect, as well as point to starter formulations they have developed and demonstrated as being effective. This book was conceived as a vehicle for Supplier Companies to describe some of the underlying technology and critical thinking that has gone into the development of cutting edge products which have recently introduced, or will be introduced to the market place for use by formulators. It has also been

ROSEN: THE DELIVERY SYSTEM MOVEMENT designed to help sell their products, or technology. I have done this unabashedly for product sales are a need of the real world we live in. No one individual or company spends the considerable amount of money and time required in research and development without expecting an appropriate return on its investment. From my view of having consulted widely in the real world of personal care products, it is essential for communication to be upgraded to a new level among suppliers of active ingredients and delivery systems, as well as the finished goods houses they serve, be they small or large. Part of my consulting practice is deeply involved in providing solutions for this need. If this resource is of use to you, in your company, I invite you to contact me. Rather than describing the science only, or just writing a technical advertisement, I have asked the contributing companies to bring the whole “package” together for readers. Where possible, authors have described what I call the “Eureka!” moment; that moment where the idea for their novel invention, or approach, occurred. I have done this with the intention of letting students of the science, be they in industry or academia, know that the reality of breakthroughs does not usually follow a linear path. It is often the case that an idea from an entirely unrelated field causes a transformation in thinking within the field being explored. As you will see, this book has been designed to facilitate such technology transfer.

1.2

The “Eureka!” Moment

In our business, we are all looking for the next breakthrough. However, we really don’t know what we have to do to get it. In hindsight, and with the passage of time, we are able to recognize such breakthroughs. We delve deeply into the history of the breakthrough, hoping we will uncover the levers and dials of what worked; but, sadly, for the most part, even if we discover what worked THEN, it does not help us for the next time. I once read a book called “The Eureka Effect: The Art and Logic of Breakthrough Thinking.” It was written by David Perkins, a founding member

5 of the think tank “Project Zero” at the Harvard Graduate School of Education” (W. W. Norton Company, New York, 2000). The book inquired into the question, “Is there a science of breakthrough thinking?” In my view, this is required reading for those of you in search of new product ideas. It stimulated me to ask each of the authors to search their memories and see if they could come up with their own “Eureka!” moment of discovery. As you read the descriptions of the evolution of their technology as I have, one comes quickly to the conclusion that no one breakthrough is similar to another. And so, there is room for you to generate the story of your own breakthrough which may emerge as you read this book, or at some time later. It is funny to me that with all the setting of objectives, one year or five years in advance, as so many of us in the corporate world are prone to do, we don’t usually find what we set out to find in our, oh, so carefully written goals. It is more real for us to know that, while we must pay our dues, (i.e., we must know the literature and technology that came before us through our scientific gatekeepers), we must know the market needs and competitive challenges through our sales and marketing experts, and we must do the research and development—goals and all—still, with all this, the breakthrough we seek may come at a surprising moment. It may come, perhaps, even while we are sleeping and by association with another, entirely unrelated, set of information. I like to think of this route as the “Unconscious Technology Transfer Conduit.” It is this Conduit I invite you to tap into as you read the book. Certainly read for the information and the critical thinking; but also read between the lines. Let the material just sit in the back of your “mind,” and simmer. I promise you, there will come a day, perhaps many weeks or months later, that the novel idea you have been looking for will just show up for you. Write it down quickly! I find that when the “Eureka!” moment happens for me, if I don’t capture it in the kind of time called NOW (a concept I got from a fantastic course I took called “Mission Control”), it will be gone—forever. Thus is the mystery of the unconscious mind and the Unconscious Technology Transfer Conduit we all are in search of on the path to the next breakthrough.

6

1.3

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

The Birth of Ideas

I have always been interested in the process by which ideas are born. This interest arises from a “natural” talent I have for generating ideas when information is provided to, or gathered by, me. My company, Interactive Consulting, Inc., has conducted many useful brainstorming sessions for major corporations. One need that has become evident in running such sessions is the need to effectively capture ideas flowing at the speed of thought, and modulated only by the velocity of speech to speed them along to listening ears and judging minds. People often ask me to design sessions that go beyond ideas. Everyone had ideas, they said. Some companies said they had more ideas than their staffs could deal with. In these situations, they struggled with prioritizing the ideas. They also struggled with remembering the ideas after I had left. Some “light” would go out of the room after the Ideation Session as people went back to their cell phones, their yearly objectives, and the urgent call to action of the next key account emergency. I would be kidding myself if I thought that I was the “light” that left. No, it was something else that left. After years of considering this, it came to me that what was missing was recognizing and acknowledging that ideas generated during a brainstorming session were all connected in some way, in the minds of the people in the room. And, as I came to see it clearly, when a group worked together on an issue, there was a higher presence in the room. No, I am not going religious on you. What I mean is there was a “Group Mind” that was present, for the individuals played to each other and their speaking served as a foundation to build upon each other’s ideas. There is one other thing that emerges over and over again in the brainstorming sessions I run. People don’t want ideas only. They frequently have plenty of staff who are bright and creative and have already generated plenty of their own ideas. What they want are “Action and Results;” and they want them NOW. However, with all their strategic thinking and all their six-sigma, black-belt technology, somehow these did not really made the difference they thought they would. People want to come up with “what to do next,” and to go beyond the idea-generating stage.

After much thinking, experience, and experimenting, I came to design our Ideation-For-Action technology. This approach not only generates and supports the formulation of new ideas, but allows one to remember them far longer than one would ever think possible. In this way, seeds are planted within the unconscious mind of the players and, with the passage of time, and the darkness of night, they robustly entered the Unconscious Technology Transfer Conduit and produced the desired unexpected results (i.e., breakthroughs). The Ideation-For-Action technology involves the use of what one of our clients called “Directed Information Clustering,” and some have described as “knowledge-mapping” techniques. This approach has been extremely productive for solving technological/business related issues in both the group and individual coaching sessions I have conducted for senior and middle management of numerous specialty chemical companies. In this text, I have used part of this methodology to facilitate the “capture, holding, and consideration”* of these ideas for the design of an overview of this entire book, one chapter at a time. I recommend that you spend two minutes on each of these “maps.” You will soon see that you have captured a “picture” of the chapter, and of the authors “mind” on the subject. This exercise will lead you to places in the book you want to go to first. It will also lead you to begin the journey of selecting what you want to read and when you want to read it. I will also offer one other bit of coaching on using the mapped contents. I encourage you to copy the “maps” and make your notes on them as you read the book. You will find that you will then understand what you are reading at a much deeper level; that you will remember your ideas better; and that they will be integrated more effectively with other ideas and concepts within the book in a quite unexpectedly powerful manner that is far beyond what you have ever known. As I am typing this, quite spontaneously, and without notes, that little voice in the back of my head—the one we all have (you know, the one that just said “What is he talking about?” or “I don’t have

* Phrase coined by Dr. Olli Miettienen, Professor of Epidemiology, McGill University, Montreal, Canada.

ROSEN: THE DELIVERY SYSTEM MOVEMENT a little voice like that.”)—that voice—said to me, “Why are you telling them all this in the Introduction to this book. My answer is this. This book is not what it appears, alone. Sure, it is chock full of information. Some of it, you know; some of it, “you know you don’t know” and some of it lies in the realm of “you don’t know that you don’t know.” This range of the possibility of information and potential invention is a series of concepts I learned in a course called the “Landmark Forum,” which is a three-day training in the study of Ontology, or the Way of Being, of Human Beings. The course is given around the world by Landmark Education, the world’s largest University without walls. I assert that all of the text, when combined with the mind map representation of the various chapters, will find its way more effectively into your “Unconscious Technology Transfer Conduit” than anything you have ever encountered before. In a way, this approach to supporting your need to develop new products is itself a Delivery System. To paraphrase William Shakespeare, what these “Maps” represent is a delivery system within (a book) about delivery systems. And now that I have uncovered that idea for myself, and shared it with you, I feel complete. Let us now return to some of the specific details about this book. And so, to work…

1.4

What is a Delivery System?

Having attended numerous conferences and listened to the many “Voices of Delivery,” it seems clear that we will need to have some clarification of definitions in order to have this book become the cornerstone of the field that I intend it to be. An “active” is a substance that can provide beneficial properties to the skin or hair. In my view, a delivery system is simply a way of holding, carrying, and transporting an active to a substrate. It typically concentrates the active in a particular location within a formulation and alters the absorption and/or adsorption of actives into and/or onto a substrate. It may provide the benefit of a barrier system by forming a film on the substrate which then becomes the barrier. A delivery system can control the rate of release from a formulation as well as the rate of

7 active absorption. It can minimize the concentration of active in the epidermis and dermis and thereby minimize the potential for irritation. It can also maximize the concentration of active in a part of the substrate—a concept known as the “Reservoir” effect. There are some who say we are at the end of the time that cosmetics do not penetrate the skin. In some cases, you may want the active to go into, and perhaps through, the stratum corneum and into the viable layer beneath. This notion is certainly valid scientifically if one expects to continue to improve the quality and effectiveness of products used in our industry. As to the legal distinctions between “cosmetics” and “pharmaceuticals”—and the enlarging gray area between them, I leave these to others to discuss in detail. Suffice it to say that I believe the time is coming where a bridge must inevitably be built to connect the two legally defined areas of cosmetics and pharmaceuticals so the enormous potential of each can be used to benefit the other. We must continue the upward climb for the development of safe, effective products that we all want and need. The steel pegs in the mountain we climb to do this are the eventual, inevitable recognition that expansion of knowledge and application of the biochemistry of active function will bring us closer to the top of the mountain where we can really smooth out the wrinkles that time imposes upon us all. My definition of a delivery system includes many approaches you would not ordinarily think of as classical “delivery systems.” In my view, a delivery system does not have to be a fancy arrangement of molecules in space only. It can include fluids, or emulsions (both oil-in-water and water-in-oil), viscous solutions, surfactant-structured systems and many other forms as well. All of these systems can act as “carriers” since, inevitably, the carrier ends up on the substrate and is either absorbed, adsorbed, volatilized, or remains on the surface. All of these constitute “delivery systems” in the definition I have used in this book. My definition of a delivery system is useful in this context because it allows one to think far more broadly about putting an active into “something” and then putting that “something” into a finished formulation. This approach allows the active to be protected in the formulation, and enables it to come out when we want it to, where we want it to, and at the rate that we want it to.

8

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

A delivery system is any type of vehicle that makes an “active” available to a target site. An effective delivery system is one that reaches the target and creates a high concentration reservoir for the active. Delivery systems may provide sustained release, controlled release, or release, without release into the substrate. They concentrate the payload. The bulk concentration is low but the concentrated material is delivered to the intended site. The IDEAL delivery system would be nontoxic to skin or hair. It would actually carry the actives into the substrate, provide controlled release (if desired), penetrate deeply or superficially (as needed), improve formulation aesthetics, and allow easy handling of liquid or solid actives. For optimal penetration, the ideal delivery system has to be small enough to penetrate and be similar in polarity to target permeation paths of the skin. It has recently been demonstrated that carriers themselves can be designed to achieve optimal penetration. Each active has different requirements, and each type of application adds still other requirements to the active/delivery vehicle system. The industry is moving towards custom designed delivery systems and is already well on its way towards that goal for specific actives. Delivery systems may, or may not slow down the rate of actives’ delivery. They may or may not enhance penetration—and they can be designed to be delivered to different “depths” and to different locations. They generally protect sensitive actives from oxidation and attack by other formulation components or environmental stressors. Delivery systems include, but are not limited to, liquid/liquid dispersions such as oil-in-water or water-in-oil emulsions, microemulsions, or multiple emulsions. Some delivery systems allow the incorporation of oil soluble actives in water-based formulations while others enable the incorporation of water soluble actives in oil-based systems. Other forms of delivery systems include liquid/ solid systems such as dispersions of inorganic materials like zinc oxide and titanium dioxide for sunscreens. They can also be solid/solid systems such as freeze-dried liposomes, or be actives encapsulated in molecular or macromolecular matrices to provide a dry powder form.

1.4.1

Factors Affecting the Efficacy of a Delivery System

There are many factors that affect the efficacy of a delivery system. Some of these include the ability to penetrate, humectancy, polarity of the carrier system delivering the active, polarity of the active itself, electrical charge (if any), size of the active molecule, the nature of the delivery system vehicle, aging stability of actives in the system, and the final formulation into which the delivery system is placed.

1.4.2

For What Application Areas are Delivery Systems Useful?

Here are just a few examples of delivery system applications. In skin care, they are employed in sunscreens, anti-wrinkle products, skin whitening/ bleaching, antioxidant delivery, flavor and fragrance delivery, sensory markers (e.g., warming, cooling, tingling), and coloring. In hair care, some applications include nutrient delivery, antistatic agents, relaxing chemicals for ethnic hair, coloring/dyeing, conditioning agents, humectants, and deodorants. As to unfulfilled, or partially unfulfilled needs in this field, there is a strong interest in better methods of controlled and targeted release (site specific); a need to get inside the hair shaft and deliver functional actives; further enhancement of shelf life via delivery technology, and inclusion of sensory markers to convey a sense of immediacy to product performance from the consumer’s viewpoint. One key concept in delivery system technology is the distinction between delivery onto the skin (e.g., acne preparations and sunscreens) and delivery into the skin (e.g., skin lightening). In the latter category, as Johann Wiechers, Principal Scientist, and Skin R&D Manager of Uniqema (author of Ch. 20) likes to say, “we must also inquire as to how deeply into the skin we are talking about.” I believe that the technology of delivery systems for personal care products is very broad indeed. When viewed in total, this panorama is emerging as a critical major subject area. Formulators have moved beyond just finding and incorporating novel functional actives. Our industry has responded to consumer needs with a wide range of technical

ROSEN: THE DELIVERY SYSTEM MOVEMENT approaches and more are coming. As the time for publication of this book came nearer and nearer, I have had to resist the temptation for continuing to add new chapters, or I would never have gotten done! I have to admit, a few chapters were added quite close to our deadline, and these were completed in an incredibly short time. How could I resist making the book more and more complete? Inevitably, and with the emergence of new systems at practically every conference I went to, or their presence in almost every new edition of a trade or scientific journal, I had to stop somewhere and leave these newest ones for a second edition of this book at a later time. Johann Wiechers, in my view a brilliant man who likes to generate catchy titles and provocative words, recently noted that “we have had the decade of active ingredients. Now we are living in the decade of active’s delivery systems. This decade will last only five years, before we get to the decade of truly functional cosmetics.” With such flexibility becoming available, a whole new range of product distinctions are emerging. These distinctions will give rise to novel ways for formulators to invite marketers and consumers alike into an exciting new world of possibility to enhance beauty in ways not previously available.

1.5

The Philosophy Behind This Book

I believe that Personal Care Delivery Systems and formulations based upon them are the wave of the future. Used individually, and in combination, they provide pathways for innovation that have not previously been available. Our industry and the purchasing public are ready for more products with sophisticated, substantiated claims for both skin and hair products. As newer and more efficacious actives have been developed, a need has emerged to deliver such actives in a controlled manner to an intended target, and to demonstrate that they actually work. Some of this need is based on reducing irritation potential while other aspects include actually producing and extending a youthful image far longer than has previously been thought possible. Other consumer needs

9 include enhanced protection from the sun. Beyond simple sunscreens lies the brilliant marketing idea of putting sunscreens into non-sunscreen products such as makeup, and even hair styling systems, in this ozone-hole conscious world. With the familiar trend of globalization, mergers, acquisitions, and layoffs occurring in the specialty chemical industry, considerable personnel movement from one company to another and from one industry to another has occurred. Large and small companies alike have suffered from a loss of mentoring for incoming employees. Examples of such individuals include students, new hires from other companies, or individuals with five to ten years experience in a particular field. As a result, a part of the audience for this book are those with a need for training in the science and technology of formulating with such delivery systems. This need goes beyond standard academic training in fundamentals and points to the full meaning of the word “experience.” It is my intention that this book will serve as a valuable productivity tool— enabling individuals to capture the essence of the experience of others. It will also provide each supplier company a showcase for the use and application of “old standby” ingredients as well as new, cutting-edge products. The intended audience for this book goes far beyond the industrial scientists and market managers wanting to learn more of the technology. It is also intended for students in universities, and for their professors. So often, the graduate of the academic institution is faced with issues barely touched upon in school when they enter the industrial environment. Coping with complex issues, rather than simplified models, is a potential barrier for industrial success of the newly graduated. I am committed to producing a book that eases the transition of the graduating student into industrial environments where delivery technology is of critical importance.

1.5.1

What You Should LOOK FOR as You Read

LOOK FOR the story of where the idea came from and the role of the technology transfer process, especially across different technical and/or market areas. Many of these stories provide a taste of the real world.

10

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

LOOK FOR a discussion of the type of delivery system and a technical understanding of the concept: what it is, its essential elements, what makes it special or novel, and its value when used in a formulation. LOOK FOR a discussion of applications for the technology, both current and potential, and a description of the claims and value available both to the formulator and the consumer. LOOK FOR a description of the basic surface, interfacial and polymer principles important for understanding the use and application of each particular Delivery System Technology. LOOK FOR the function of each ingredient in the formulations. LOOK FOR a list at the end of each chapter for reference sources. LOOK FOR Contributors’ and Suppliers’ lists with key company contacts in the book’s Table of Contents. These will assist you in expediting use of the technology and in contacting a knowledgable resource to find out more about it. Finally, LOOK FOR an extensive compendium of exemplar formulations that demonstrate the value of each delivery system and hold the potential for generating commercial sales opportunities for your company. As Suellen Bennett, Global Product Manager, Cosmetics, of GE Advanced Materials, Quartz, taught me once, formulations are the work-product

of an extensive investment of corporate time, money, and intellectual property. They are the bottom-line result which informs a prospective customer how the delivery system can produce a marketable product with useful, and hopefully, consumer-perceivable claims and benefits. Such formulations are the starting point suggestions for you and your company—a foundation to branch off from and move on to more proprietary systems that make a difference. And now, to the details…

1.6

Using the Mind Maps®

We begin with the chapters in the “mind-map” form I have mentioned previously. Linger in this chapter to come. It will be worth it. You don’t have to study the pages in detail. The diagrams are laid out the way your mind works; like a neural network. Just let the information soak in, one page at a time. Let your eyes start at the center of each page. The center contains the central focus idea. Then, let your eyes move clockwise around (at first) to see the headings of the various branches. Each of these is associated with the central focus thought of each chapter. Finally, just let your eyes go where they want to on the page. Your mind will do the rest. I wish you a pleasant, informative, creative journey from who you are now to who you will become.

2 Executive Summary Book-at-a-Glance Meyer R. Rosen Interactive Consulting, Inc. East Norwich, New York

This entire book has been summarized by the editor in Mind form. These maps will significantly enhance your ability to rapidly capture, consider, and retain the ideas and information presented in each chapter. They will also serve as a foundation for generating new ideas for you, the reader, as well as provide a glimpse into the associations among keywords and concepts in the minds of the authors and editor. Enjoy!!

Map®

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 11–74 © 2005 William Andrew, Inc.

Index

I. Introduction

Suppliers & Trade Name Index

II. Skin Fundamentals

Glossary III. Crossing the Barrier XVI. Marketing by Design

IV. Encapsulation XV. Efficacy & Safety

Chapter 2 Book-at-a-Glance V. Liposomes XIV. Specific Ingredient Delivery

VI. Particles XIII. Substrate Based

VII. Emulsions XII. Activated Delivery VIII. Foams XI. Starch- Based

X. Silicones

IX. Structured Systems

The Delivery System Movement

Chapter 1 Meyer R. Rosen Interactive Consulting, Inc.

Part I INTRODUCTION

Chapter 2 Book-at-a-Glance Meyer R. Rosen Interactive Consulting, Inc.

Chapter 3 Skin: Physiology and Penetration Pathways

Michniak-Kohn, et al. UMDNJ-New Jersey Medical School Dow Institute New Jersey Center for Biomaterials: Laboratory for Drug Delivery

Part II SKIN FUNDAMENTALS

Chapter 5 Yechiel & Coste Elsom Research Co,. Inc.

From Ancient Potions to Modern Lotions: A Technology Overview and Introduction to Topical Delivery Systems

Delivery System Design in Topically Applied Formulations: An Overview

Chapter 4 Dayan Lipo Chemicals, Inc.

17

Overall structure Molecular weight Lipophilicity Effect on permeation Vehicle effects

Active molecules

DELIVERY SYSTEM FACTORS

Chalone Sphingosine Stem cells

Cell replication

Differentiation SKIN BIOLOGY

Processes

Isopeptide linkages Transglutaminase 1 Acylglucosylceramide Cornified envelopes

Desquamation Fundamentals Physiology Kerotinocytes Desmosomes Granules

Bulk stratum corneum Appendages & breaches

Liposomes Alcohols & glycols Accelerants Amines & amides Chemical Fatty acids & their esters Terpenes Metabolic or biochemical Microneedles Sonophoresis Supersaturation Iontophoresis Electroporation FITC Dextrans

Chapter 3 SKIN: PHYSIOLOGY & PENETRATION PATHWAYS Michniak-Kohn, et al.

Permeation Barrier Ultra Structure

Permeation enhancement

PENETRATION PATHWAYS

STRATUM CORNEUM

Disulfide linkages

Two compartment Domain Gel phase Mosaic domains Single gel phase Sandwich

Physical

Lipids

Drug solution

Linoleate chains Acylceramide

Structural Proteins

Models

Effects Occlusive

Lamellar Keratinohyalin

Skin hydration

6-hydroxysphingosine Phytosphingosine Bases Dihydrosphingosine Ceramides

Supersaturation

18

Intercellular Transcellular Pilosebaceous Ceramides Polymorphism Intercalate

Polar Pores More impactful claims Efficacy Safety

Improving Acne Intra-follicular delivery Keratolitic Salicylic acid Bacteriocidal Fungicidal

FUTURE CHALLENGES

SKIN PENETRATION

Pathways Stratum corneum

Delivery systems SKIN IMPERFECTIONS

INTERCELLULAR LIPID DOMAINS

Superficial delivery THERAPEUTIC INDEX

Stratum corneum-stratum granolosum interface Desquamation Process

Corneocytes

Epidermis Dermis

ENZYMATIC REACTIONS

Ceramides

Improvement Active Compounds

Long chain Polymorphorism

Alpha hydroxy acids Ceramides Hyaluronic acid

Design Epidermis First pass effect Enzymatic metabolism being digestied

Reduction Tyrosinase activity Inhibition Organelles Dendrites Endocytosed by keratinocytes Reduction Collagenelastin network

Liposomes METABOLISM

Chapter 4 DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW Dayan

Vesicles

Ultraflexible

Transferosomes

Elastic Porous microparticles Examples

Melanin Synthesis

Wrinkle Appearance

Particulate

COSMETIC APPLICATIONS

Molecular

DELIVERY SYSTEMS

Intracellular delivery Intra-follicular delivery Acne Follicle Keratolitic agent

Skin Penetration Enhancers

Determination

Macroparticles Nanoparticles Cellulosebased Natural Microsponges Dendrimers

Reduce barrier resistance Chemical Physical Enzymatic Liposomes Vesicular Niosomes Carriers Elastic vesicles

SITE OF ACTION

Active compound

Marine sponge collagen

Physical properties

Solubility Chemical stability Physical stability Acid Chemical form Base Salt

19

NEW TECHNOLOGY

Acne

Internal

Personal care Delivery systems

Chinese

External Annointing Oil of Holiness

Hebrew

Origins

Emulsification Summerian Salves clay tablets & filtrates Adding herbs to water

Extraction

Grinding materials Egyptian colored eye cosmetics Downsizing

Digestive process Reproductive process Infection process "To save, rescue, set free, release, rid, divest, unload, assist, disburden, speak, surrender, yield, abandon, recite, report, communicate, transfer" Outer layers of Overcome skin barriers Membrane surrounding a cell

Definition of Delivery Technology in Ancient Formulae

FORMULATIONS

DELIVERY SYSTEMS

Problems intended to be solved

Size reduction

Mammals soothe, cool & protect their skin Natural substances

Topical

Separation & reunion Separate information Separate regulation When medicine & cosmetics were one A trend towards reunion

Chapter 5 TOPICAL DELIVERY SYSTEMS Yechiel & Coste

Injectable

Oral

Medicine & cosmetics

Sharply pointed insect stingers & mouth parts

Outer coating of berries stripped away by bird during consumption & transported some distance away

MODERN MEDICINE

Cosmeceuticals

Separate regulations

NATUREINSPIRED

Modern Medicine Origins

Movement to separate medicine from all other practices

Navaho tradition

Unifying theories Physiological aspects Divine Emulsification gifts of oil & water

Maintaining balance Beauty as health

Medicine as meditation Health as balance Personal care Health care Maintaining balance

TRADITIONAL MEDICINE

PERSONAL CARE

Ancient medicine

A matter of life & death

Preservation

Medicine & meditation Cosmeceuticals

Washing of hands & feet with water Divinely imposed Beauty above all Egyptians & eternal life Ayurveda Mind/body integration

Crossing the Lipid Barrier with the Echo-Derm™ Delivery System ( A Skin-Mimicking, Lamellar Matrix System)

Chapter 6 Pollock Clinical Results, Inc.

Part III CROSSING THE BARRIER

Chapter 7 Majeed & Prakash Sabinsa Corporation

"THP": An All Natural Delivery System Adjuvant

21 Cell renewal serum Lipid replenishing serum P.M Moisture Lock™ Crushed Lava nail buffing cream O.T.C. Pain relief cream

Definition FORMULATIONS

DELIVERY SYSTEM

Skin Lipid components Mimicks natural skin lipid structure Increased permeation Lamellar, bilayer system Higher payload Increases permeation Improved performance Minimizes trans epidermal water loss Restores natural lipid barrier function Oily after-feel decreases Acne Anti-wrinkle Anti-inflammatory Anti-irritants Analgesics Collagen boosters Hair inhibitors Self tanners Sunscreens OTC formulations High end dermal hydro-cream

Topical Delivery Advantages ABOUT SKIN ECHO-DERM™ SYSTEM

Chapter 6 CROSSING THE LIPID BARRIER: ECHO-DERM™ SYSTEM Pollock

Applications

Guidelines Creams No surfactants Preloading Auto-loading

CONSUMER WANTS

First use FORMULATING

Results

PRODUCT SALES

Quick Long lasting Multifunctional All- in- one Truly cosmeceutical Convenience Ease of Use Affordable price

Fragrance Back of Hand rub/feel

Performance Repeat business

Liposomes Topical Nanospheres

Epidermis Dermis Hypodermis Brick & mortar model Barrier function Transepidermal water loss

Packaging

Why worry? Orally Injections Options Topically Rehydration High shear processing

Perfect Product

Cosmetic Marketers Chemists Management Operating Officers Consumers Targeting function Color/aroma Feel Natural Packaging Active Delivery

DELIVERY

FORMULATOR CONTROL

Target function Color/Aroma Feel Natural Packaging Viscosity Claims Active delivery

22

INTRODUCTION

Bioactives Enhancing

Topical delivery

POTENTIAL APPLICATIONS

Bioactives Permeation enhancers Ayurvedic Phytochemistry Neutraceutical ingredients Permeation of actives Spice route

Historical Perspective Folk medicine

BLACK PEPPER

Hair care Skin care

FORMULATION STRATEGIES

Delivery system

Skin

Delivery conduit

Skin

SAFETY PROFILE

Patch testing CONCEPT DEVELOPMENT

Efficacy Chemistry Experimental Evidence Derived from Piperine Mechanism of action Enhanced permeation Pungent principle Anti-inflammatory effect

TETRAHYDROPIPERINE

Ayurvedic Alkaloid Piperaceae

Discovery Tetrahydropiperine

Chapter 7 TETRAHYDROPIPERINE: NATURAL TOPICAL PERMEATION ENHANCER Majeed & Prakash Low irritation

Piperaceae Alkaloid piperine Tetrahydropiperine

Black pepper extract

Bioavailability

Bioactives Neutraceuticals

Keratinocytes Waterproofing Permeability Eleidin Keratin Circadian rhythms Epidermis Sebacious glands Bioavailability enhancer Alkaloid Piperaceae Phytochemistry

Therapeutic molecules Mechanism of action

Nutraceuticals

Microencapsulation: An Overview of the Landscape

Chapter 12

Chapter 8 Lidert

Topical Delivery Systems Based on Polysaccharide Microspheres

Paradigm Chemicals, Inc.

Cattaneo Biovolutions Inc.

Part IV ENCAPSULATION

Chapter 11 Elder & Bell Ciba Specialty Chemicals

Polymeric Encapsulation. Phase Change Materials: A Novel Microencapsulation Technique for Personal Care

Microcapsules as a Delivery System

Chapter 9 Hawkins, et al. Lipo Technologies, Inc. Lipo Chemicals, Inc.

Tagravit™ Microcapsules as Controlled Drug Delivery Devices and Their Formulations

Chapter 10 Kvitnitsky, et al. Tagra Biotechnologies, Ltd.

24

MARKET

Size Trends Pulls

Consumer

Expectation

Formulator Push Materials Used Definitions

Antiperspirants Detergents Enzymes Cleaners Benzoyl peroxide

Acne treatment

Challenges

Calcium peroxide

Toothpaste

Controlled release Harsh environments Survival

Exfoliating Agent Glitter Hand lotion

Lipstick Razors Lubrication

Function

Wine

Aspirin Living Yeast Fungicide

Foot powder Tissues Breathing aid

APPLICATIONS

Chapter 8 MICROENCAPSULATION Lidert

Mechanisms

Menthol

Liquid crystals

Automotive screws

Actives capture Actives release

From Pharmaceutical to Personal Care

Cyclodextrin

Forehead thermometer

Release

Particle Morphology Vectors Processes Materials used

Fragrances

Odor control

Deliver

Protect

Capture

Silicone oil

Taste Masking

Odor control Panty hose

Actives

TECHNOLOGY

Mineral oil

Hand lotion

Soap

Bioadhesion Multiple Sustained bursts release

Non-Chemical

Adhesives

Spray Drying Spray Coating Extrusion Techniques Sponge Technology Liposomes Nano-particles Non-aqueous

Anti-microbials PROCESSES

Nanoemulsions

Molecular encapsulation Gel technology

Encapsulation

Chemical

Coacervation Urea-formaldehyde membrane Amphiphilic Block Copolymers Self assembly

25

LipoCrystal™ capsules

Shower gel

Exfoliant gel

Lipospheres™

Lipospheres™

Lotion with encapsulated fragrance Disinfectant hand gel

FORMULATIONS

INTRODUCTION

Lipstick with pigment

Lipocapsules™

Polyoxymethylene urea process

Encapsulation Sustained release Controlled release Vitamins Food flavorings Personal care

Hand cream

Liposperes™

In-situ polymerization MICROCAPSULES

Water soluble actives Matrix polymers Gelatin substitute

ENCAPSULATION

Agar spheres Typical example

Chapter 9 MICROSCAPSULES: DELIVERY SYSTEM Hawkins, et al.

Improvement Protection Controlled release

Formulation

Product shelf life

FORMULATION ENVIRONMENT

Incompatibility prevention Color cosmetics

Gelatin-based

Encapsulation Microcapsule walls

Water soluble Water insoluble

FEATURES

Effects Wash off formulations

Mechanical rupture RELEASE MECHANISMS

Membrane types Coacervation Gelatin-based

Actives

Encapsulated compound

Improved stability Within formula

COATING SYSTEMS

Aesthetics

System selection Physical forms Custom design Membranes Matrix Physical properties Actives Chemical properties

CONTROLLED RELEASE

Shell material

Solubility Melting Internal rupture Biological degradation

26

Stability testing Moisturizing cream Eye & neck cream After-depilatory lotion Baby cream/paste Wet tissues Make up remover Cream for hair dressing

Guidelines

Model

Preparation CONTEMPORARY METHODS

Recommended COSMETIC FORMULATIONS

Vitamins Retinol Palmitate Alpha Tocopherol Vitamin F Plasticizers

Effects Oil soluble Water soluble Vitamins

Microcapsules Microencapsulation Solvent removal

FORMULATIONS

Determination DELIVERY METHOD

Stability

Unstable Actives Controlled delivery Microcapsules

Effect of Formulation

STABILITY LIPOPHILIC ACTIVES

Actives

Cosmetic formulations

Incorporation Basic Principles Vitamins

Chapter 10 TAGRAVIT™ MICROCAPSULES Kvitnitsky, et al.

APPLICATIONS

Loading

Skin Actives

Stabilization

Unstable Microencapsulation

27

Micro Phase Change Materials Skin cream Shave cream After-sun lotion First aid cream/burns

History Technology

FORMULATIONS

Physical

CIBA ENCAPSULATION

Cooling after-shave

Current

Shaving cream

Potential

Skin creams

Techniques Chemical synthesis

APPLICATIONS

Monomers Polymers Reactive species Polymeric shell or barrier

Encapsulence™

Localized cooling Chapter 11 PHASE CHANGE MATERIALS: MICROENCAPSULATION Elder & Bell

Melting point Preparation Skin surface temperature variation

PHASE CHANGE MATERIALS

ENCAPSULATION TECHNQUES

From textile applications to Personal Care

Sports clothing

Spray drying Spray coating Granulation

Textile applications Outlast™

Distinctions

Selection Controlled release Targeted delivery Component segregation Active ingredient Protection Changing physical form Aiding formulation Differentiating product lines

"EUREKA!" MOMENT

SKIN TEMPERATURE REGULATION CAPSULE PARTICLE SIZE

Definitions Descriptors

28

Vitamin E moisturizing gel

Active ingredient

FORMULATIONS

BACKGROUND

Based on chitosan Eliminates need for surfactants & secondary stabilizers Completely resistant to shear during manufacturing Stable to high temperature Stable to wide range of pH Easily absorbed by skin No residue on skin

Encapsulating ingredient

Good skin tolerance ACCEPTABLE DELIVERY SYSTEM

Overload of systemic absorption

Stability of active No residue left on skin Biodegradability

Retinol delivery

Chapter 12 POLYSACCHARIDE MICROSPHERES Cattaneo NO "GHOSTING"

SLOW ACTIVE RELEASE

Biopolymer matrices Cationic polysaccharide Confers Chitosan bioadhesive properties Interacts with anionic proteins Biodegradable Polymer concentration effects

Inter-couple chitosan chains

STABILITY OF ACTIVE INGREDIENT

CROSSLINKING & COASCERVATION

Disruption of skin lipids Induced by surfactant and strong interaction with stratum corneum components

Reduces toxicity Reduces irritation Provides sustained & controlled release Reduction in vaporization of volatile substances Separation of incompatible ingredients

CHITOSPHERE™ TOPICAL DELIVERY TECHNOLOGY

Eliminate typical undesirable residue following topical application Bioadhesive polymers enable particle to fuse with skin tissue Prolong contact between drug & stratum Enhance corneum "reservoir" effect

Chitosan-based microspheres Provide significantly more retinol active to skin

Toxicity Stability

Excessive penetration of active

SKIN IRRITATION BY SURFACTANTS & SECONDARY EMULSIFIERS

Complex coascervation

Via free amino groups Use of glutaraldehyde Use of negatively charged ions such as polyphosphate Precipitation of polymer encapsulating ingredient by use of oppositely charged polymer Encapsulation of lipophilic materials emulsified in aqueous polymer solution Wall formation of microcapsules

Liposomes in Personal Care Products

Chapter 13 Kulkarni DPT Laboratories, Ltd.

Part V LIPOSOMES

Chapter 14 Yechiel Elsom Research Co., Inc.

Interactive Vehicles in Synergistic Cosmeceuticals: Advances in NanoEncapsulation, Translocation, Transfer and Targeting"

30

Antioxidant delivery Anti-bacterial actives

Oral care

Nail care Gene delivery to hair follicles Hair growth promoters Hair growth retardants Transdermal penetration Topical delivery Protein & enzyme delivery Lipid composition Liposome type Preparation method Liposome charge Surfactant presence

FUTURE TRENDS

Thermal behavior Size Charge Functionality

Wound care

Unilamellar vesicles

EFFICIENCY CLASSIFICATION

Challenges

Multilamellar

Effect of vehicle Gels Creams Lotions Sprays Freeze drying

LIPIDS

Self-assembly Simple lipids Phospholipids Sphingolipids Complex or Miscellaneous lipids Stability Hydrolysis Peroxidation

Stabilization PRODUCTION METHODS

Stability improvement Pitfalls

Prevention

Vesicles

Definition Early discovery Multi-vesicular vesicles Giant unilamellar vesicles

Chapter 13 LIPOSOMES IN PERSONAL CARE PRODUCTS Kulkarni

FORMULATING

One bilayer Conventional Stealth Cationic Targeted

Hydration of dry lipid film

Detergent dialysis

Ethanol injection Detergent dialysis

Premature aging Prevent photoaging Retinol Slimming liposomes Wound care Protein delivery Topical

Intercellular diffusion Transcellular Follicular

Loading of actives

Enzymes Hydrophobic Hydrophilic

APPLICATIONS ENCAPSULATION

Efficiency

SKIN PENETRATION ROUTES

Controlled release Reduced toxicity Increased bioavailability

Size

CHARACTERIZATION ADVANTAGES

Lipid composition Liposome type Preparation method Charge Transmission electron microscopy Light scattering

Lamellarity Capture volume capacity Chemical integrity Nuclear magnetic resonance Differential scanning calorimeter

31

Jojoba Aloe vera Vitamin E

Face cream FORMULATIONS

Rise of cosmeceuticals

Moisturizing wrinkle cream

Green tea Vitamins

Medicinal Cosmetic

NEW DRUG DEVELOPMENT

Formulations

CLAIMS TOPICAL FORMULATIONS

Old drugs...New applications

DRUG DELIVERY TECHNOLOGY

Facilitated transport Differential concentration Proximity Orientation Accessibility Synergistic effects Side effects Interactive vehicles Immune system Deactivation Proximity Orientation Steric hindrance

Definitions What can be claimed? Rejuvinates Delivery Drugs technology old drugs New applications What can be claimed? Defining a category for a formulation

Cosmetics

Performance

CONCEPTS

Chapter 14 INTERACTIVE VEHICLES IN SYNERGISTIC COSMECEUTICALS Yechiel

COSMETICS

Across the barrier

Limitations at site of action CROSSING BARRIERS

Conformational compatability Definition Intradermal Transdermal Topical Injectible Nanoemulsions Nanosomes™ Double emulsions Nanoencapsulation in cyclodextrin

COSMECEUTICALS

VEHICLES ACTIVE INGREDIENTS

Definition Interactions Mobilization Transport

Actives Vehicles for overcoming obstacles Interactions Mobilization Transport Activity loss Active ingredients

Water Oil Amphipathic Mechanical Chemical

Definition

Chapter 19

Practical Application of Fractal Geometry for Generation of Ultra-High Surface Area Personal Care Delivery Systems

Porous Entrapment Spheres as Delivery Vehicles

Chapter 15 Ansaldi Presperse

Lefebvre Steripak

Part VI PARTICLES

Polymeric Porous Delivery Systems: Polytrap™ and Microsponge™

Chapter 16 Saxena & Nacht

Chapter 18 Baschong, et. al. Ciba Specialty Chemicals

Cardinal Health-Topical Technologies

Nanotopes: A Novel, Ultra-Small Unilamellar Carrier System for Cosmetic Actives

Riley-Nacht, LLC

Chronospheres: Controlled Topical Actives Release Technology

Chapter 17 Gruber et. al. Arch

33

Scented hair styling gel Bath & body gel Face scrub Cooling gel Glittering clear gel Deliver actives Deliver colors Deliver fragrances

FORMULATIONS INTRODUCTION

Applications

BEFORE COSMOSPHERES™

Liposomes Microcapsules

Development

Capsule Rupture Mechanisms

Mechanical rupture Dissolution Melting Diffusion through

Capsule wall/shell

Skin care Hair care Bath & body products No shell wall Supplied dry Colored pigments Vitamins Plant extracts Sunscreens

Cosmospheres™

POROUS ENTRAPMENT SYSTEMS

Loaded with:

Scratch & Sniff

Applications

Fragrance

Carbonless carbon paper Complex coascervation

Size is in visible range Emulsifier-free No residue after application Superb aesthetic after-feel Excellent visual effects Microcrystalline cellulose and lactose

Chapter 15 POROUS ENTRAPMENT SYSTEMS Ansaldi

Water insoluble Water soluble

Encapsulate actives

Release characteristics

Overview

Hydrated phospholipids

Advantages

Bipolar fatty acids Antibody directed Methyl/methylene cross-linked Lipoprotein coated Carbohydrate coated Multiple encapsulated Emulsion compatible

Colors

Tactile impact

Conventional Benefits

Stabilization Types

LIPOSOMES

Targeted delivery

Specialty

Controlled delivery Biodegradable Non-toxic Prevent oxidation Controlled hydration

Properties Characteristics

Cooling via heat transfer Cross linking reaction/ formaldehyde

Mechanical properties Heat transport/thermal properties Mass diffusion rate

Visual impact

MICROCAPSULES

Natural lecithin mixtures Identical chain phospholipids Glycolipid-containing

Hardening capsule shell

Preparation

Gum arabic

Form Size Loading Wall strength

Size & hardness Actives Within formulation Shearing action breaks outer membrane

Vary wall thickness

34

Needs in skin care

Oil control moisturizer Gentle exfoliating cleanser with large Polytrap™ particles Tretinoin/Microsponge® 5-Fluorouracil/Microsponge® Hydroquinone/Retinol combination Benzoyl peroxide anti-acne Retinol cream/Microsponge®

Process of incorporating ingredient into polymeric matrix Chemical compositions Particle size

INTRODUCTION FORMULATIONS

Topical products Alpha hydroxy acids Vitamins

Entrapments

Void volume

Porosity

Pore openings Surface area

Cross-linking Resemble spherical sponges Styrene and divinylbenzene Methyl methacrylate Ethylene glycol dimethacrylate Cross-linkers used At time of synthesis One-step process By diffusion

What is it?

Manufacture

Manufacture

Chapter 16 POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® & MICROSPONGE® Saxena & Nacht

Loading Procedures

Mode of action

MICROSPONGE TECHNOLOGY

Benzoyl peroxide Salicylic acid Hydroquinone

POLYTRAP TECHNOLOGY

OTC products

Releases active easily to skin Oil absorption Sebi,

Applications Applications Cosmeceuticals

Wide range

Particle size Strengths & Limitations

Pore diameter Properties Surface area

Scrub applications

Ground apricot Walnut pits Petrolatum Silicone oil

Moisturizers Polyethylene granules

Properties

Wide range

Lipophilic Cyclomethicone Petrolatum Mineral oil

Skin protectant body powders

Porosity/Void volume Wide range

Lauryl methacrylate Ethylene glycol dimethacrylate Peroxide catalyst

Up to 70% Silicone oils Can put into water based or oil-in-water emulsions

Actives delivery

Formulation flexibility Bring two or more incompatible materials together

Wide range

Suspension polymerization

Loading procedures

Retained on Release active skin surface Mode of action to skin over prolonged time Retin-A Micro Tretinoic Rx topical Salicylic products acid Anti-acne Benzoyl peroxide

Alpha hydroxy acids Retinol Vitamin K

What is Polytrap™?

High degree

Free flowing Spherical No particles edges

No greasy after feel Deliver high loads of lipophilic materials Hydrophilic materials hard to load Non-drying Absorbs sebum

35

Lipstick with Chronosphere Hyaluronate Lotion with Chronosphere SAL (Salicylic acid) WetDry face powder Acne Serum Dimethicone Perfluorinated polyethers Methy salicylate Mineral oil Octyl methoxycinnamate Olive oil Panthenol Olive oil unsaponifiables Retinol Ascorbic acid Lactoglobulin sulfonate Collagen Epidermal growth factor Glycerin Glycolic acid Sodium hyaluronate Lactic acid Para-aminobenzoic acid Pyrrolidone carboxylic acid Rosemary extract Salicylic acid Superoxide dismutase Tissue respiratory factor

Powdered delivery system

Diffusion controlled

INTRODUCTION

FORMULATIONS

Empty Filled Porous

Chronospheres

Lipophilic CHEMISTRY

ACTIVES

Chapter 17 CHRONOSPHERES: CONTROLLED TOPICAL ACTIVES RELEASE Gruber, et al.

Acrylates/Carbamates copolymer

PolyMedica Powdered version of ChronoFlex

Hydrophilic

Biocompatible Temperature stable Polymeric matrices Actives Oxygen protected Moisture

HISTORICAL DEVELOPMENT

Brooks Industries Arch Chemical Company

Arch Personal Care

Dispersion of photoinitiator and active MANUFACTURING FUNCTIONAL PROPERTIES

Brittle polyurethanes High glass transition temperature

Knifebox UV exposure Near continuous and batch operation

Into unreacted prepolymer

36

Stability tests Carrier compatibility Squalene oxidation Oil-in-water emulsion Tinoderm™ A Water-in-oil emulsion Gel fluid Oil-in-water emulsion Water-in-oil emulsion Gel fluid

Liposomes Stratum corneum INTRODUCTION

Vesicles

FORMULATIONS

Bilayer

Tinoderm™ E Mono-layered Phospholipid (Lecithin)

NANOTOPE™ SYSTEMS

Far more effective than liposomes at delivering actives Active deposition into skin Superior

SKIN DEPOSITION

Co-surfactant

Stable particle membrane

Formulated nanotopes

In-vivo

Aqueous nanotope solutions

In-vitro

Chapter 18 NANOTOPES: ULTRA-SMALL UNILAMELLAR CARRIERS Baschong, et al. Ultra-small

Protection from environmental stressors

Cosmetic actives

PERFORMANCE NANOTOPE PARTICLES

Oil-in-water formulations

Sodium dodecyl sulfate presence

Particle stability

Turbidity measurements Dynamic light scattering Five times higher stability than liposomes!

20-40 nm Vitamin E Vitamin A esters

Preservative effects Opalescence Smaller than liposomes

Superior carriers than conventional liposomes Penetration into skin Enhanced

STABILITY IN FORMULATION

SURFACTANT STABILITY

Intercalates with lecithin

Much smaller core diameter than liposomes

Unimodal particle size distribution Tinoderm™

Vitamin A palmitate

Stability

Most stable

Empty carriers Phospholipids Membrane structure

Membrane

Light Hydrolysis

Barrier

Very high More compact membrane Less susceptible to surfactant interaction

37

Fractal polymers Antiseptic creams Exfoliant Soap Macadamia oil Fragrance Macadamia oil

Change interface between product and skin Deliver oil fractions in hydrophilic products Deliver water-based fractions in water-based emulsions As a support of the active molecules Performs like nanosponge Low concentration: bacterio-static agent High concentration: topical antiseptic creams

Polymeric structures

FORMULATIONS

Beauty bar soap

IMPORTANCE

Moisturizing cream

Near infinite specific surface area Near zero apparent density Infinitely pleated over themselvs without smooth areas

Molecular brush shape Economic feasibility to "Eureka!" apply fractal geometry to moment polymer chemistry Fractal polymers

Solid forms

Fractal concepts Geometry

APPLICATIONS

Broad-spectrum antiseptic additive

FRACTAL WORLD

Chapter 19 ULTRA-HIGH SURFACE AREA SYSTEMS VIA FRACTAL POLYMERS Lefebvre

Anti-aging preparations delivery system Skin disorders topical creams

Both hydrophilic & lipophilic

Nomenclature

Description Properties Grades Applications FRACTAL POLYMERS

Fractal poly-epsilon caprolactam

Delivery system similar in use to microsponges or ultra-fine powders

Applications

Cantor dust Mandelbrot equation

Statistics Chemistry Sierpinski-Menger sponge

Active substance adsorption Transient immobilization Neo-colloidal state

Single chain statistics Depolymerizing a crystalline polymer

Polypepties Collagen Keratin Change geometry of the interface between product and skin Cleaning At lowest possible agents concentration

Caprolactam

Alveolar structure like Sierpinski-Menger sponge Each microcavity is limited by walls containing nanocavities Self-replicating structure

Application to chemistry

Fractal geometry

APPLICATION TO PERSONAL CARE

Actives penetration rate greatly enhanced

Carry & deliver actives

In water phase In oil phase

Stabilizing agent for emulsions

Carried into skin by fractal polymer Penetration time is halved

Vitamin C Vitamin D Oil-in-water Water-in-oil

Optimizing Skin Delivery of Active Ingredients in Emulsions: From Theory to Practice

Chapter 20 Wiechers Uniqema

Part VII EMULSIONS

Chapter 22 Kanouni & Rosano Ciba Specialty Chemicals

Preparation of Stable, Double Emulsions as Delivery Vehicles for Consumer Care Products

The Delivery System's Delivery System

Chapter 21 Wilmott, et al. The Collaborative Group

39 Importance Theoretical

Relative polarity index

INTRODUCTION

Optimizing solubility

Optimizing driving force Secondary emollient effects

Selection Good solubility

Low molecular weight/volume Low melting point Minimal binding/accumulation in stratum corneum

Emulsifier effects Emollient effects Definition What is Topical delivery? delivery Principles Journey of penetrating molecule

Model penetrants

Chapter 20 EMULSIONS AS ACTIVE'S DELIVERY SYSTEM Wiechers

FORMULATION MAPPING

Through skin

Applications Penetration Determination

Basic principles

Fick's Law Barratt's Equation

"Viable" epidermis

Biochemical activity Predominantly hydrophilic

In-vivo

Volunteers Tracer tests

Measurements Animal skin

Pigskin Rodent skin

Human skin

Skin

Distribution

Penetrant polarity Formulation effects

In-vitro

Franz diffusion cell Bronaugh flow-through cell

SKIN PENETRATION

Test formulations Skin Preparation Diffusion cells Formulations

Determination

Polarity

Emulsifier

Influence

Water Lipid

Penetrating molecule

INGREDIENT SELECTION

Primary emollient selection

Selection

Skin Delivery systems

Emulsions

Penetrants more polar than stratum corneum Penetrants more lipophilic than stratum corneum Use in practice

Non-Destructive

TRANSDERMAL DELIVERY

Formulation effects Dermal & Transdermal DERMAL DELIVERY

Prediction Ingredient selection Theoretical considerations

Inverse correlation

Importance

Needs New

40 Surfactants

SPF 15 Lotion History Mixed chemical & Physical sunscreens

SPF 50 Plus cream

Emulsions Emulsifiers

Contemporary

Chemical sunscreen

Enzymes Growth factors

Self-tanning Lotion with Sunscreen Liposomes

Future

Antioxidants Cytokines

After sun lotion INTRODUCTION

Moisturizing lotion with moisturizing liposome

DNA

Cosmetics

Genetic promoters Aging

Moisturizing cream for Oily skin Moisturizing cream for normal skin

Uneven skin penetration

Moisturizer Skin Disorders

FORMULATIONS

Moisturizing cream for dry skin

Slack skin Cellulite Sensitive skin

Moisturizing lotion Cream

Delivery systems

Suncare

SPF 50 Plus cream

Oily skin Dryness

Anti-Aging

Serum Lotion with salicylic acid in cyclodextrin Serum

Anti-Acne

Sprays Low viscosity serums

Current vehicles

Lightening

Anhydrous

Gel Solid

Antioxidant cream Anti-cellulite lotion

Waxed-based stick Body care

Hand and body lotion Styling cream

Rheological profiles Tactile properties

Hair Care DELIVERY SYSTEMS

Vesicular

Hydrophobic bi-layer Micellar character

Polymeric Clathrate Aqueous phase Formulating with dispersions

Non-aqueous phase

Advantages Adding dispersion of sunscreen to water-thickened with carrageenan biopolymer

Unlimited potential

Mixing various dispersions together

"Eureka!" moment

Topical appications

Chapter 21 THE DELIVERY SYSTEM'S DELIVERY SYSTEM Wilmott, et al.

Interfacial tension Homogeneity Brownian motion

Preservative Introduction of high energy input at low temperatures High shear, high pressure process

Very light; no residual feel Very emollient; noticeable/prolonged residual feel

Issues

Auxillary component migration

Chelating agent Fragrance Buffer

SYSTEM 3

Actives Definining Semi-quantitative Aesthetic scale

Zeta potential Particle size Stability

Crystal formation Water binding activity

Emolliency

Rheological properties

Mixing different dispersions

Temperature effects

Formulating with System3 dispersions Controlled by nature of delivery system; not by properties of vehicle

Manufacturing complexity

Active penetration

EMULSIONS

Scale up issues Damage skin barrier Itching Fissuring Skin Reactions

Surfactant-free Allowing two immiscible substances to mix Liquid crystal phase Liquid crystalline transition temperature Unilamellar Multilamellar phospholipid bilayer

Stinging Roughness

LAMELLAR PHASE DISPERSIONS

Surfactant effects

Contact dermatitis Alter membrane fluidity Disorganize lipid structure Denature proteins and nucleic acids Disrupt barrier function Release inflammatory mediators

41

Interaction between low and high HLB emulsifiers at the o/w2 interface Polyglycerol ester of ricinoleic acid

Surface properties

Determination of minimum amount of primary surfactant in preparation of W1/O emulsion Influence of betaine/sodium lauryl ether sulfate mixture on rheological properties of xanthan gum and resulting emulsion stability Droplet breakup in double emulsion systems Equilibrium adsorption measurements Monolayer experiments Minimum amount

Water-in-oil-water emulsions Drug delivery Uses Cosmetics Foods

INTRODUCTION

Capabilities

INVESTIGATIONS

Primary surfactant

Primary interface

Salt

Thickener

Microscopic and visual Rheological measurements Force-area measurements Surface potential-area measurements Particle size Light determination scattering Pendant drop method

Formulation

Stabilization

Optimum concentration External water phase Pseudoplastic

Active molecule encapsulation Masking tastes & smells Oxidation protection Protection from light Enzymatic degradation protection

Interfacial tension

Monolayer experiments

Chapter 22 MULTIPLE (DOUBLE) EMULSION DELIVERY SYSTEMS Kanouni & Rosano

EVALUATION TECHNIQUES

STABILITY

PREPARATION

Methods Mechanical equipment

Balancing osmotic pressure with Laplace pressure Avoid Ostwald ripening Interactions between low and high HLB emulsifiers at oil/W2 interface Influence of polymeric thickener-hydrophilic emulsifier interaction in outer water phase W2 Decreasing droplet size of internal phase Obtaining optimum ratio of water to oil in W1/O and oil to water in O/W2 Increasing the low shear viscosity of the emulsion

Coascervate Foam Delivery Systems

Chapter 23 Gamez-Garcia Amerchol

Part VIII FOAMS

Chapter 24 Smith & Jagoda-Murphy Regenesis

Hydrophilic Active-Filled Polyurethane Delivery Systems: "Soft Cell Approach to Personal Care"

43

Enhanced

Silicone delivery

Interaction of foams with keratinic substrates during washing Foam stability Film rheology Coascervates partition & adsorb preferentially into the "Crust" of the lamellar "core" Silicone-polymer floc formation Reduce Role of work of surfactants in adhesion Soil washing Solubilize Emulsify Disperse

Common FOAMS

Thin films

PHEONOMENA

Simultaneous action of shear and dilution during washing/rinsing process Lamellar "crust" Lamellar "core" Main Features Granular coascervates in lamellar "core" Foam dilution Polycation molecular weight Surfactant platform Shear rate

Agglomerated air bubbles Aqueous surfactant solutions Air compartments separated by thin liquid films

APPLICATIONS

Chapter 23 COASCERVATE FOAM DELIVERY SYSTEMS Gamez-Garcia

Uncommon

FOAM LAMELLAR STRUCTURE COASCERVATE FOAMS

Two outer layers

Polycation interaction with anionic surfactants

Surface Tension Laplace pressure Double layer repulsion Plateau suction action Marangoni effects Foam-film viscoelasticity Quantification

Degree of coascervate partitioning

Properties

COASCERVATION

Two outer layers Palisade of surfactant molecules forming the crust "Core" containing aqueous surfactant solution

Optical microscopy

"Lochead-Goddard" effect Formation of polycation/surfactant/water effects Typical of shampoos undergoing dilution Cationic Polyquaternium-10 polymers Varying levels of cationic substitution

44 REACTIVE SUBSTRATES

Containing Actives Formulations

Cleansing cushion Make up remover cushion

Skin care

Make up application cushion Nano-foam film cleansing sheets

FORMULATIONS

Formulation PLUS Application

In-situ

Hair cleansing sheets "EUREKA!" MOMENT

Hair care

Temporary hair color sheets

Formulation & delivery system in one! Combine aqueous phase and hydrophilic polyurethane pre-polymer

Hair styling sheets

Molding foam

Elastomers

MANUFACTURING TECHNIQUES

Casting Foam

Rigid

Coating foam film

Films Conventional

Rigid & flexible Hydrophobic

Cast foam

Molded parts

FOAM LAMINATES

Uses

Marketing benefits

Furniture Automotive cushions

Formulation Limitations

Types

Stability

Functional characteristics

Active ingredient released slowly from film coating

Easy to handle liquid pre-polymers

Films are "Nano" foams

Toluene diisocyanate

Aromatic isocyanates

Durability

Diphenylmethane diisocyanate

Stiffness Aliphatic polyisocyanates

Flexibility Combination Hydrophilic Polymers

Rubbery-ness Surface feel

FOAM FILM COATINGS

Encapsulation of solids

Foaming Mechanism

Unstable carbamic acid Amine formation, gas generation Urea chain extension, cross linking formation

Hydrophilic

Selection

Hexamethylene diisocyanate

POLYURETHANES

Retention or release of ingredients from within foam matrix Selection

Isophorone diisocyanate

Foams containing 20 to 65% water

Active Ingredient Substrate carrier

Chapter 24 HYDROPHILIC POLYURETHANES: FOAMS & FILMS Smith & Jagoda Murphy

Performance factors Marketing Benefits

Need preservative Surfactants

High additive loading

Solvents Abrasives Fragrances Colorants Moisturizers

Exothermic reaction at relatively low temperatures Limitations Open celled foam sheet

Cleansing

Can incorporate all types of surfactants into reactive polymer

Conditioning & repair Hair color

Functional characteristics

Styling Convenient wedges leave tightly braided "corn rows" undisturbed

Cleansing

Types Hair Care

Ethnic hair care

SHAPED OR MOLDED FOAMS

Excellent for accepting aqueous surfactants or combinations Moisturizing esters Oils Glycols

Treatments

Functional characteristics

Glycerin derivatives Silicone derivatives

Leave-on hair shampoo ingredients

Emollient waxes Vs. traditional hair care products

Marketing benefits

SHAPED OR MOLDED FOAMS

Anti-aging Skin Care

Types

Facial Make up

Removal Application Aluminum oxide crystals Feldspar

Large or small cells

Dermabrasion

Reticulated or non-reticulated Very flexible or very stiff foam

Ground fruit pits Mini-fibers

Structure

Polyethylene granules

Very wet or dry feeling Dense or airy foam Foam directly into a designed form

Marketing Benefits

Vs. traditional skin care products Recognizably different Hold enourmous amounts of liquids

Chapter 30

Non-Aqueous Delivery Systems With Controlled Rheological Behavior

Sugar Based, Structured Surfactant Systems

Chapter 25 Smadi & Hawkins

Healy

Huntsman

Penreco

Part IX STRUCTURED SYSTEMS

Chapter 29

Cubasomes and Self-Assembled, Bicontinuous, Cubic Liquid Crystalline Phases as Personal Care Delivery Systems

Shear Thinning Lamellar Gel Network Emulsions as Delivery Systems

Chapter 26 Ryklin & Byers

Spicer et al.

Stepan

Procter & Gamble

Chapter 28 Meier & Schreiber Biersdorf

Intelligent Polymers and Self Organizing Liposome Gel Delivery Systems

Pro-Lipid® Skin-Mimetic Lamellar Gel Carrier and Delivery Systems

Chapter 27 Rerek ISP

46

Basic S4 shampoo S4 shampoo S4 body wash Liquid hand soap

Applications

Conventional

Delivery Sucrose Glucose Fructose

Dispersed Lamellar

Carbohydrate

STRUCTURED SURFACTANTS

Structurant

Pushes dissolved surfactant out of solution in form of liquid crystals Inhibits microbiological growth

Spherulitic Lamellar

Drawbacks

Suspending power limited Usually opaque

Freeze thaw stable Shear thinning Personal care

Pourable

Co-structurant

Capable of suspending particles Yield stress

Lyotropic crystal matrix

Can even support Lead Shot Talc Clays Exfoliates Polymer beads Mica Glycerol distearate Glitter Pigments Porous particles/ Microsponges

Expanded Lamellar

Advantages

Role Electrolytes and any water soluble salt that lowers surfactant solubility

Laundry detergent builder Abrasives in hard surface cleaners Pesticides in agrochemical preparations

FORMULATIONS

Chapter 25 SUGAR-BASED STRUCTURED SURFACTANTS Smadi & Hawkins

Suspended additives Pearlizers

Mineral oils Conditioning agents Silicone oils Domains interspersed with electrolyte rich aqueous phase Form when very soluble blends of surfactant are salted out of solution Low viscosity on pouring and high suspending power Most useful type Polarizing microscope

Color immiscible regions Optical

Liquids

Birefringence

PROPERTIES

Lamellar phase

Rheology

Thermal stability

Spherulitic lamellar

Preservative free Characteristic texture Performance Transparent

Non-ionic Cationic Anionic Amphoteric

Optical anisotropy

Speckled effect Colored stripes & swirls Polarized packaging containers

Dispersed lamellar

Expanded lamellar

Key feature

Transparency

SUGARSTRUCTURED SURFACTANTS

Surfactant types

Non-newtonian Pseudoplastic High yield stress

Below zero to above 50 C Osmotic pressure causes dehydration of microbes Salon Foam Potential

47

Emulsions

Therapeutic cream for dry skin with 25% white petrolatum Complete UV ZnO & protective lotion ethyl-p-methoxycinnamate

INTRODUCTION

Water-resistant UVA/UVB sunblock with TiO2 for babies Sensitive skin complete UV protective sunblock with TiO2 and ZnO SPF 32.3

Non-conventional anionic rheology modifier Rheology modifier/emulsion stabilizer Lamellar or crystallline Multiple structuring phase emulsions

Non-whitening effects

"EUREKA!" MOMENT

SPRAYABLE PRODUCTS

SPF enhancement TiO2/organics combination

Sodium stearyl phthalamate Lamellar gel network

Chapter 26 SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS Ryklin & Byers SUNSCREEN FORMULATIONS

ZnO/organics combination Inorganic Sole sunscreen active

Visual assessment Effects Creams Lotions Occlusivity measurements Therapeutic Visual assessment

Crystalline Gel Structuring effects Emulsifier selection

Lamellar phases

FORMULATIONS

Sprayable lotion with silicone

Lotions Shear-thinning behavior

Multi-phase Multiple emulsions Multiple phase, oil-in-water emulsions

Three ingredients PREPARATION

Compatible with natural lamellar structure of stratum corneum lipids

Sodium stearyl phthalamate Low HLB emulsifier Anionic polymeric emulsifier

Pemulen®

Phase transition temperature

MOLECULAR IDENTIFICATION MOISTURIZATION

Chemistry & Function Molecular modeling Interfacial tension Reduction Structural considerations

Conductivity

Skin Toxicology studies

SKIN IRRITATION

CHARACTERIZATION

Phase transition temperature Multiple phase emulsions Non-Newtonian

Rheology Viscoelastic

Shear thinning Thixotropic

48

Moisturizing cream

Clinical study ProLipid® 141

Moisturizing lotion

ProLipid® 151 ProLipid® 141 medium SPF ProLipid® 151, very water resistant sunscreen spray High SPF ProLipid® 141 lotion

Organization

LAMELLAR GELS

Sunscreens

FORMULATIONS

Skin lipids

Organization Stratum corneum lipids Liquid crystalline lipids

"Eureka!" Moment Determining structure Product structure

Lamellar gel

Discovery Restoration of lamellar gel barrier

Chapter 27 PRO-LIPID SKIN-MIMETIC LAMELLAR GEL CARRIER/DELIVERY Rerek

FRAGRANCE RELEASE

Structure

PRO-LIPID

Characterization

Extended

INSECT REPELLANCY

Transmission electron microscopy Crosspolarized optical microscopy Fourier transform infrared spectroscopy Small angle x-ray scattering

Product structuring

Long lasting

Moisturization

Repair & enhancement

Amphipathic molecules

Liquid crystal phase

ProLipid® 151 ascorbic acid stick ProLipid® 151 insect repellant lotion ProLipid® 151 fragrance stick

Extended

Definition Lamellar bilayers Crystalline phase

Stratum corneum

Functional materials LAMELLAR GEL DELIVERY

Substantivity Substantivity

Sun protection Ascorbic acid

ADVANTAGES

Long lasting Pro-lipid® 141 Pro-lipid® 151

Selection Preparation Emulsion Formulation Product structuring Delivery from

49 Fluid liposome dispersions Lamellar gel Liposome gels

Lipids INTRODUCTION FORMULATIONS

Chemical structure Phosphatidylcholine

Lamellar phases

Human skin Formation

New Liposomal gels Polymers for attachment to liposome surface New product delivery vehicles Advantages Crosslinking of two liposomes by a hydrophobically modified, Liposomal water-soluble ABA type polymer gels plus Cross linking several liposomes intelligent with a hydrophobically modified polymers ABA type polymer Polymers for attachment to liposome surface Cross-linking lamellar phase with a hydrophobically modified water-soluble polymer

Current preparation Vesicles

Size Unilamellar Multilamellar

INTELLIGENT POLYMERS

Spontaneous formation

LIPOSOMES

Delivery vehicles

Ease of preparation Formulation flexibility Encapsulation of lipophilic & hydrophilic actives Controlled release of actives Low surfactant content Inexpensive formulations Good skin compatibility No high pressure homogenization

Sonication Extrusion through polycarbonate membranes under high pressure Reverse phase evaporation Non-phospholipid vesicles (Novasomes)

Chapter 28 INTELLIGENT POLYMERS & SELF-ORGANIZING LIPOSOME GELS Meier & Schreiber ADVANTAGES OF LAMELLAR PHASE DILUTION

Stability issues

Lamellar liquid crystals Self-organization Vesicle formation mechanism Controlling vesicle size

Stabilization

Current approaches Polymerize lipids in bilayer membrane Steric stabilization by attachment of large hydrophilic groups

Stealth

Traditional Vesicular phospholipid gels Liposomal gels Cosmetic gels Cross-linking Ternary surfactant systems Intelligent polymers Vesicle Current dispersions Concentrated Enhanced products viscosity Fluid liposome dispersions Gel matrix Vesicles in emulsion-based products Fusion

Phosphatidyl choline is source of linoleic acid and linolenic acid Hydrating and soothing Anti-acne properties Stabilization of foam structures Skin's own active Generally regarded as safe Skin care and hair care ingredient Skin feel additive

Fluid New product delivery vehicles

BENEFITS OF USING PHOSPHOLIPIDS

LIPOSOMAL DISPERSIONS

Lamellar phase

Lamellar phase dilution approach Phospholipids Phosphatidyl choline Benefits High-pressure homogenization Encapsulation of water-soluble actives within the aqueous compartment

Concentrated vesicle dispersions Fluid dispersions in gel matrix

Salicylic acid Retinoic acid Retinyl palmitate

50

Bicontinuous cubic phase liquid crystals Polar lipids Monoolein

FORMULATIONS

Drug delivery vehicles Platforms for adhesives, skin protectants and biomonitoring devices

APPLICATIONS INTRODUCTION

Difficult to handle and apply to human skin Anhydrous lamellar phase of PROPERTIES OF monoolein-water admixture is CUBIC PHASE relatively fluid and easy to apply Highly vapor permeable Hygroscopic on human skin Therapeutic agent Clinical evaluation Controlled release Drug systems delivery

"EUREKA!" MOMENT

Self-assembly of aqueous surfactant systems Thermodynamically stable bicontinous cubic liquid crystalline phases Discrete, sub-micron, nanostructured particles of bicontinuous cubic liquid crystalline phase

Dr. Stig Friberg

Solubilizing high levels of proteins

Drug delivery SKIN CONDITIONING

APPLICATIONS

Personal care

Chapter 29 CUBOSOMES Spicer, et al.

Intercalation with epidermal barrier Loading properties Control of loading and release properties of the active Customizing specific properties of hydrophilic portions Control interactions with actives Small amphiphiles Surfactants

Skin care Hair care Cosmetics Antiperspirants

Spontaneous formation via dilution of monoolein-ethanol-water system FUNCTIONALIZED CUBIC PHASE LIQUID CRYSTALS

PROCESSES

Formulate large amphiphilic polymers or "tethers" into the liquid crystal Optimization of loading, release, partitioning of active ingredients Opportunity for triggered release of actives

Spray drying technology Hydrotrope method Powders of dehydrated surfactant coated with polymer Starch coated cubasome powder Effects on powder quality

Powder precursors that spontaneously form cubosomes upon hydration Property enhancement of cubic phase

Precursors Hydrotrope dilution process POWDERED CUBOSOME PRECURSORS

LIQUID CUBOSOMES

Avoids traditional high-energy dispersion of bulk cubic phase

Particles formed by nucleation and growth

Ternary phase diagrams of hydrotrope Effect of water addition

Addition of ionic surfactants and polymers that strongly associate with solubilized active ingredients

Ethanol, water and monoolein

51 Prototypes Gelled white mineral oil for baby oil gel

FORMULATIONS

Oil-based systems COSMETIC PRODUCTS

Rheologically modify

Non-aqueous phase

Delivery systems

Anhydrous products

Identification Polymer based gels

Skin conditioning agents

"Feel" modifier Isopropyl palmitate Isopropyl myristate C12-15 alkyl benzoate Octyl palmitate Cyclomethicone Hexyl isostearate Jojoba oil

Appropriate Systems Compatible with long chain fatty esters FORMULATING

Identification Unconventional techniques required Heat to required temperature to incorporate gelling agent

RHEOLOGICAL TERMS

Shear stability Shear thickening Shear thinning Viscosity Viscosity index Rheopectic

Proper Procedures

Polymeric Block Copolymers

Most common basic emollient

Personal Care Fully hydrogenated mineral oil

Elastomeric copolymers soluble in mineral oil Styrenic blocks insoluble Heterophase mixture occcurs Blends of di- and triClear, anhydrous, block copolymers thickened systems

RHEOLOGICAL ADDITIVES

Rheological Modifiers

Three dimensional network Degree of cross-linking Mechanism determines gel strength Unusual viscosity increases with increasing shear rate Dilatant Rheological Properties Viscosity increases with time of shearing Rheopectic Water-in-oil emulsions Improves stability Higher "body" More play time Thickener Stabilizes dispersions of fine particles Personal Primary Suspension vehicle Care Function Film former Hydrocarbon oils Silicone oils Alkyl esters

Viscosity index improvers

Oil-soluble emollients Humectants

Chapter 30 NON-AQUEOUS DELIVERY SYSTEMS WITH CONTROLLED RHEOLOGY Healy

THERMOPLASTIC BLOCK COPOLYMERS

THERMOPLASTIC ELASTOMERS

Gelled oils

Ethylene-propylene copolymers Polymethacrylate esters Hydrogenated styrene-diene copolymers Cable fillers Flooding compounds

Styrene-butadiene block copolymers Olefinic copolymers Urethanes Polyester block copolymers Hard and solid at room temperature Two phases Elastomer; low viscosity at room temperture Chemically bonded by block or graft copolymerization Hard Phase

Enhanced emolliency

Unique Characteristics

Provides strength

Phase separated systems Two phase morphology End styrenic blocks are employed as crosslinking agents Physically reversible crosslinks Tie elastomer chains together Prevent entangled elastomer Polystyrene domains chains in network from disentangling Act as reinforcing fillers

Styrene-butadiene-styrene

In between rigid domains are rubbery areas comprised of butadiene

Chapter 34

Linear Silicone Fluid Delivery Systems With Controlled Volatility Features

Cationic Silicone Complexes as Delivery Systems

Chapter 31 O'Lenick & Buffa

Schlosser, et al.

Siltech

Wacker

Biosil

Part X SILICONES

Chapter 33 Postiaux, et al. Dow Corning

Silicone Technology as Delivery Systems for Personal Care Ingredients

"Pro-Fragrant" Silicone Delivery Polymers

Chapter 32 Perry G E Bayer Silicones

53

Clear, softening Two-In-One

Exfoliating

Shampoo Body scrub

Complex delivery Mixed surfactants provide synergistic surface activity Cationic and anionic surfactants form complexes

"EUREKA!" MOMENT

Shampoo

Body wash

Clear Spray on/leave on Chelating, rinse off Spray on, Rinse off Exothermic Spray on Two-in-One Rinse off Creamy Clear, leave In Clear- softening Oily skin

GROUP OPPOSITES

Conditioners

Concept Silicone: a new kind of opposite

Carboxy silicone polymers 3D HLB system Pendant carboxy groups

SILICONE COMPOUNDS FORMULATIONS

Facial cleansers

Quats Incompatible with anionic surfactants Eye irritants Generally hydrophobic: when applied to a substrate, cause reduction in water absorbency

Pomade

Pomade stick

Hair growth products

Spray Self-tanning mousse Water-based

Makeup remover

Leave on; rinse off Facial Oily skin

FATTY QUATERNARY AMMONIUM COMPOUNDS

Chapter 31 CATIONIC SILICONE COMPLEXES O'Lenick & Buffa

Tanning products

Detangler Cleansers Mousse

Self tanning

Anionic compatibility Reduction of eye irritation Improved rewetting Improved compatibility with polyacrylates Improved conditioning Improved combability of hair

Organic quats Silicone quat complexes SILICONE COMPLEX IMPROVEMENTS

CATIONIC SILICONE COMPLEXES

Compatibility Eye Irritation Re-Wet

Shampoo Body wash Cleansing products

Anionic surfactants

Selecting the solubility of the complex increases deposition on hair and skin: i.e., "delivery" Delivery of non-color compounds to hair and skin

Desirable Properties

Anionic Surfactants

Compatibility

Applications

CONDITIONERS

Fatty quat/ carboxy silicone

Wet combability Dry combability

54

Silicate ester and crease-proofing resin Fragrant silicone esters

MOLECULAR RELEASE OF FRAGRANCES

Antiperspirants

Using alkoxy silanes

Silicone- based Grafting chemical moieties onto polymer backbone

Clear deodorant stick with fragrant silicone esters Granular laundry composition with Schiff-base silicone Ointment formulation

FORMULATIONS

Formation of fragrant alkoxy silicones via transesterification

Derivatized lactic acid

Lotion formulation With silicone benzylidenecamphor derivatives

Hydrolytic cleavage

Sunscreens

Perfumed soap

Silicone benzimidazolyl benzothiazole

Antiperspirant/deodorants Polysiloxanes prepared from

SILICONE FRAGRANCE COPOLYMERS

Non-releasing Sunscreens Photostabilizing groups attached to silicon-based substrates

Silicone based

DELIVERY POLYMERS

Aldehydes

Axilla bacteria Enzymes

Ester linkages enzymatically cleaved by underarm flora Si-O bonds

Silicones Personal care

Chapter 32 "PRO-FRAGRANT" SILICONE DELIVERY POLYMERS Perry

Skin smoothing properties

Aldehyde hydrolysis

Anti-acne ACTIVE DELIVERY POLYMERS

Lactic acid Glycolic acid Based on trimethylsily derivatives of:

Retinol Promote new cell and collagen growth without irritation Silicone-based Hydrolysis FRAGRANCE SCHIFF BASES

Hydrolysis Carboxcylic acid derivatives of silanes

SILICIC- ACID ESTERS

Terminal and grafted fragrances easily attached to wide variety of silicone backbones Hydrolysis and release is pH dependent

Active may be released, or remain bound to silicone polymer

Anti-aging

Stearyl alcohol

Alcohols Ketones

Release triggers

Hydrolytic cleavage

Salicylic acid

Slow hydrolysis & sustained release of free fragrant alcohol

Form Schiff base from amino silicone Granular laundry compositions

55 Oil-in-water formulation containing organic sunscreens Oil-in-water & water-in-oil emulsions containing TiO2

Emollients Water barrier Emulsifiers

Suncare

Mild & light shampoo Skin moisturizer with Vitamin E Polyol-in-silicone emulsion containing Vitamin C W/O/W emulsion with alkyl dimethicone copolyol Hand & body lotion with Vitamin C Propylene glycol/oil/water multiple emulsion

Desoaping Conditioning

FORMULATIONS

INTRODUCTION

Silicone Attributes Low toxicity Low surface tension

Emulsifying agents or carriers deliver to skin Low molecular weight volatiles

Polyether Alkyl

Shine

Color cosmetics

Phenyl

High refractive index

Silky, velvet skin feel

Shine Soft feel

APPLICATIONS: BY SILOXANE-BASED MOLECULE

SILICONE DELIVERY SYSTEMS

Gum Resin Elastomer

Chapter 33 SILICONE-BASED DELIVERY SYSTEMS Postiaux, et al.

Improved SPF via formation of homogeneous film Clear shampoos Conditioning shampoos

SILICONE VESICLES POLYOL-IN-SILICONE EMULSIONS

Silicone polyethers and organic quats

SYNERGISTIC EFFECTS

CONTROLLED/ SEQUENTIAL RELEASE

Ingredient coatings Reduce skin irritation Pigment coating for color cosmetics Sunscreen agents

Cross-linked organosilicone fluids Improved skin feel Encapsulation & entrapment SILICONE ELASTOMERS

Enhancement of sun protection factor with alkylmethyl siloxanes

Dimethicone copolyol & organic quaternary compound

Encapsulation with no release

Polar solvent-in-oil emulsions Volatile silicone as continuous phase Exert moisturizing effect via polyol phase No preservatives Pleasant skin feel

Encapsulation with controlled or sequential release of active Sun protection

MULTIPLE-PHASE EMULSIONS

No residue on evaporation

Antiperspirant actives Fragrance delivery Conditioning agent

Volatile carriers

Amino Stronger conditioning Long-lasting Organosilicone lipstick

Silicone copolymers as emulsifiers Polyether modified silicone elastomers Oil soluble vitamins Water soluble vitamins Antimicrobial agents Sunscreeens Entrap Astringents Anti-acne agents Anti-bacterial agents Anti-fungal agents Anti-inflammatory agents

Detackify antiperspirant salts

Formulation aids

Cyclomethicone

Lighter conditioning

Wet & spread

Organofunctional substitution

Linear polydimethyl siloxane

Antiperspirants

Smooth Silky Non-greasy feel

Sensory characteristics

Polar/non-polar oils

Controlled release Lightly cross-linked siloxane chains swollen in diluents such as cyclomethicone or low viscosity dimethicone Absorbs Vitamins A & E and Vitamin A acetate Drug release

Encapsulation Extension to conventional phospholipid-based liposomes Self-organizing Small & large unilamellar vesicles Multilamellar vesicles Separate & protect hydrophilic & lipophilic actives from each other More stable than conventional liposomes Stable at unusually high temperature Water-soluble actives Non-water-soluble actives Reduced skin irritancy Multiple actives isolated and metered out at specific times for long lasting, substantive effect Water-in-oil Alkyl dimethicone copolyols emulsions Polyether modified elastomers Deliver Vitamins A & C

56 Hair shine spray Sunscreen oil Bath oil Body lotion Body lotion spray After shave cream Liquid foundation Long lasting lipstick Face powder Antiperspirant stick

Delivery system for active ingredients like resins & UV filters Reduce tackiness of thickeners Provide silky skin feel Act as emollients during application Improved rub-in characteristics Reduce friction on skin during application Carriers to achieve more uniform distribution of high molecular weight polymers along hair fiber Provide wet combing benefits in conditioners Plasticizers in hair & styling gels for resins and polymers Delivery system in hair gloss sprays for higher molecular weight gloss enhancers Depress foam in shampoos, conditioners & mousses No build up on hair

FORMULATIONS INTRODUCTION

Controlled volatility What is a volatile? Previous volatiles New linear volatile silicones

Skin & Sun Care LINEAR VOLATILE SILICONES

Properties

Hair care

Chapter 34 LINEAR SILICONE FLUID CONTROLLED VOLATILITY DELIVERY SYSTEMS Schlosser, et al.

Clear & colorless Low viscosity between 1 and 3 cS Low heat of evaporation No cooling effect

Non-VOC classification

NEW VOC RULES

Mueller-Rochow process

California "Direct synthesis"

Hydrolysis/condensation

Dimethicones or linear polydimethyl siloxanes Color cosmetics

SILICONE TECHNOLOGY

Functional silicones

Antiperspirants/ deodorants

Delivery system with temperature controlled time-release

California

APPLICATIONS

Vehicle for pigments Drying time reduced

Improve pay-out in sticks Delivery system for actives Good spreadability

Properties How are they different?

Rapid, but controllable evaporation

Lipsticks Foundations Mascara

Good spreading properties lead to consistent pigment distribution Reduce particle agglomeration & enhance free flow Plasticizer for resins Help form thin films; maximize long lasting effects

History of volatile fluids Isodecane Cyclomethicones Hexamethyldisiloxane Small molecules Toxicity studies Greater possibility of skin penetration

Perfumes

Linear volatile silicone fluids with controlled volatility

1990's Chlorosilanes Trimethylchlorosilane Dimethyldichlorosilane

Combination of trimethylchlorosilane with dimethyldichlorosilane

Wacker's Linear technology Complete reaction mechanism of dimethicone production Linear, trimethylend capped polydimethylsiloxanes Hexamethydisiloxane Polyethers Hydroxyl groups Hydrocarbon chains Amino modified hydrocarbons Evaporation rates Molecular weight 164 to 539 Daltons Low toxicity

Starch Based Delivery Systems

Chapter 35 Freers Grain Processing

Part XI STARCH-BASED SYSTEMS

Chapter 36 Wille Bioderm Technologies

Thixogel: Novel Topical Delivery Systems for Hydrophobic Plant Actives

58

Dispersing bath powder Mild body lotion Body wash Washable facial masque Liquid makeup Alpha hydroxy acid cream

Starch granules FORMULATIONS

Body powders Dispersing bath powders Powdered personal wash products Creams Lotions Thickening & Film forming Body wash Shampoos

FORMULATION HISTORY APPLICATIONS

Water-soluble delivery films

Ingredients TRENDS

Properties

Natural & botanical resources Corn Renewable resource

Zea Mays

Decrease starch molecular weight Form film gels

Acid or enzymes

PURE-DENT Aqueous absorption Mineral oil Vitamin oils Oil absorption Petrolatum, 75% and still remains a powder

Technology transfer Water-soluble Film-forming delivery films technology Stable viscosity at high or low pH Rheology modifiers Specifications Requirements

Add body without thickening Facial masks Liquid makeup Encapsulation of Spray active ingredients drying

Bath Underarm Skin Foot

Repeating anhydroglucose units Corn starch Hydrated starch Gelatinized Pre-gelatinized Retrogradation

Moisture absorption Provide soft, powdery feel Dusting powder Washable gels & films

STARCH CHEMISTRY

Amylose Amylopectin Semi-crystalline structure Birefringence

Chapter 35 STARCH-BASED DELIVERY SYSTEMS Freers

Cross-linked starch

Less sensitive to:

Absorbent starch

Formulation enhancement

Products

Derivatized starch

Challenges

Materials absorbed and internalized by starch granule Formulation Hydroxypropyl

Product information Water soluble Personal care

Film-forming delivery

Delivery films Film formation

Film-forming/viscosifier starch

Stabilized starches

Starch granules

Formulation Applications

Functionality

Physically modified starch

Deliver active or non-active ingredients to skin & hair Rheology modifier

Types Film-forming starch

Improved clarity

Cross linked & substituted Clearer gels Maximum stability to acids High shear stable High temperature stable Resists freeze/thaw

STARCH MODIFICATION

Oxidized starch

Hydroxypropyl starch phosphate PURE GEL® Product information

Deliver oil or aqueous active ingredients

STARCH-BASED DELIVERY

Applications

Ingredient encapsulation

Challenges

Functional groups inhibit starch retrogradation Substituted starch Improves water holding capacity Gels and films

starch

Zenia®

PH Agitation Homogenization Elevated temperature Aging

Whiter Gelatinization Swelling in cold water Instant starch In formulations Replace harsh ingredients with less irritating materials

"Short" creamy texture Unmodified corn starch Provide clear, flexible, film-forming properties

Absorbent powder

59 DermSeal

Basic skin barrier gel

EktaSeal

Skin barrier & moisturizing gel

HydraSeal

Moisturizing skin barrier gel

Stable emulsion

VegaSeal

All natural skin moistuizing gel

Basic topical delivery system for hydrophobic plant actives

SanoSeal Gel

Photo-aged skin repair gel Plant active

PhytoSeal C/L FORMULATIONS

Skin barrier & oxygen topical delivery system Skin barrier Witch hazel

TECHNOLOGY

OxyTega Gel

Soothex-Itch-Relief Gel

Protective film-forming properties Softens dry & rough skin Vehicle for hydrophobic drugs & plant actives Oil dispersion in Low concentration aqueous starch matrix of non-iritating surfactants Manufacturing process Oil-in-water emulsions

Hydrocolloid

PhytoSeal R/O

Anti-aging Plant active

PhytoSeal T

Anti-aging Plant active

PhytoSeal L

Hydrophobic types

Gel formation Surfactant-gel interactions Emulsification step

Topical delivery systems

Current Skin hydration Skin protection Reversible hydration Oxygen delivery Anti-microbial Delivery Plant actives system Plant extracts

Emulsifier Humectants Preservatives Plant actives Corn tassel extracts

Greaseless feel

Ease of spreading Rapid drying No undesirable tack

UltraDerm

Antimicrobial hand lotion Plant active

Anti-wrinkling Plant active

Aesthetics

Hyrophobic topical delivery systems

No irritating surfactants

APPLICATIONS BENEFITS

Anti-oxidant

Chapter 36 THIXOGEL: TOPICAL DELIVERY OF HYDROPHOBIC PLANT ACTIVES Wille

Consumers Easy to formulate Cost effective Completely greaseless Leave no oily residue Completely resistant to alcohol Oil-soluble plant extracts can be used

EMULSIFICATION STUDIES

Hydrophobic TOPICAL DELIVERY

Temperature & mixing Starch Concentration Stability

Surfactants

Starch

PROCESSING EFFECTS

Silicone oils Using hydrophobic plant actives Formulating factors

Oil DELIVERY SYSTEM TECHNOLOGY

Binds oil Forms transparent "leave behind" protective film

Combinations

Natural or modified

Starch

ROLE OF KEY INGREDIENTS

Emulsifier Humectants Preservatives Anti-oxidant plant extracts

Anionic, nonionic or cationic Effect on stability

Soluble in the hydrocarbon oil phase layer that develops on the surface of the skin Incorporate permeation enhancers

Oil

Emulsifying agent

Anti-irritant Anti-aging Anti-microbial

Paraffin oil Mineral oil Silicone oil Perfluorocarbons

Emulsifying agent

Saturated hydrocarbons Silicone oils Skin irritation

Plant actives

Plant actives

SURFACE SCIENCE

Interfacial principles Phospholipids as "emulsifiers"

Smart Vectorization: Enzymatically Activated Encapsulation Technologies

Chapter 37

Hart & Perrier Coletica

Part XII ACTIVATED DELIVERY

Chapter 38

Smith & Jagoda Murphy Regenesis

Simultaneous Delivery Systems for Unit Dose, Topical Delivery of Complementary and/or Incompatible Actives: "Thinking Outside the Jars & Bottles"

61

Anti-age day cream Anti-aging serum

FORMULATIONS

ENCAPSULATION

In-vitro

Enzymatic digestion

Penetration improvement Pharmacokinetic In-vivo results Membrane performance Sustained delivery effectiveness Quantifying sustanined delivery profiles Hair follicle penetration

PROPERTIES & PERFORMANCE

Pressure change Temperature change

Chapter 37 SMART VECTORIZATION: ENZYMATICALLY ACTIVATED ENCAPSULATION Hart & Perrier Atelocollagen Interfacial polymerization

Plant proteins

MICRO & MACRO MEMBRANES

Polysaccharides

Extrusion Coascervation Interfacial polymerization Transacylation

Osmotic pressure

Enzymatic digestion TRIGGER RELEASE MECHANISMS

Polylactic acid Polyglycolic acid Nanosponges Release from highly porous surface of synthetic particles Microcapsule in contact with enzyme activity on the skin

Interfacial polymerization

Complex coascervation Complex coascervation Transacylation Newest technology

Thalasphere® Phytosphere® Cylasphere®

Formaldehydebased ENZYMATIC RELEASE

Non-formaldehyde based

Solvent/gel transition

Protease enzymes Formaldehyde or glutaraldehyde based Enzymatic release

Nanoencapsulation

Simple Complex

pH change

Marine collagen

Phytosphere® Design membranes with specific sensitivity to different proteases on skin

Modify bioavailability of beneficial actives Provide consumers with visible innovation Benefits Enzymatically activated release Modulate rate of penetration Purpose Increase stability Obviate reactivity

Microsphere preparation Molecular encapsulation & release

Coascervation

Cyclodextrins

Simple Complex

62

Blemish control Patchless Moisturizing patch composition Manufacture Description Functional benefits Marketing benefits Cleansing followed by a secondary treatment Cleansing and blemish control

Simultaneous delivery

TWO DIFFERENT ACTIVES FORMULATIONS

Same time Multiple effect products Can be unstable together

Keep actives separate "EUREKA!" MOMENT TWIN DERM™ PACK

Until time of use

Two- in- one products desirable Simultaneous delivery on "opening"

Functional characteristics Two step skin care regimins "Eureka!" Two separate products Systems approach to skin care Product A followed by Product B protocol Deep cleansing followed by moisturizing Gentle abrasion followed by anti-wrinkle composition In single back to back wipe

Innumerable

SEQUENTIAL DELIVERY

Tandem™ Pack

PACKAGING DESCRIPTIONS

Skin wipes

Application

Combination products

Anti-aging & moisturizing Blemish control & moisturizing AHA & sunscreens Color foundations & sunscreens Sunscreens & moisturizing Natural & organic Ingredients Alpha hydroxy acid (Side A) & Vitamin C or E

Chapter 38 SIMULTANEOUS DELIVERY FOR COMPLEMENTARY OR INCOMPATIBLE ACTIVES Smith & Jagoda Murphy

Multiple chamber Skin care Applications Wipe on or dab on application Snap Pack™

FORMULATIONS

Aromatherapy Antioxidants & moisturizing Granulated bubble bath powders & natural oils

Double action Wipe Manufacturing Two peelable, heat sealable films for slim pouch Two applicator "plagettes" User peels away & discards top layer Exposes two impregnated plagettes affixed to bottom layer

Fragrance delivery STABILITY

Sustained release

Actives

Deliver film-forming polymer from one compartment Deliver plasticizing formulation from second compartment Combination of two compartments, at time of application results in cosmetically acceptable film patch Virtually invisible

"PATCHLESS" PATCH

Manufacture Simultaneous delivery of combination of assorted liquids, flowable gels & powdered formulations Thermoformed multi-chambered system

Effective solution for incompatibility issues Segregate incompatible actives till use Mixing of ingredients at time of use

In-situ mixing HEIGHTENED EFFECTIVENESS

Eliminates emulsification & stability issues

On skin

Marketing benefits

Increased consumer confidence in "newness" of application method

Water Soluble Adhesive Patch Delivery Systems for Personal Care Actives

Chapter 39 Kantner 3M

Part XIII SUBSTRATE- BASED SYSTEMS

Chapter 40 Smith & Jagoda Murphy Regenesis

Substrate Based, Water- Activated, Anhydrous Delivery Systems: "Dry & Deliver!"

64 Incorporation of active agents into water-soluble films Addition of plasticizer to a water soluble film Preparation of water-soluble film with two actives Preparation of water-dispersible tapes with active in carrier & adhesive Preparation of water-dispersible tapes with active only in the adhesive

FORMULATIONS

DELIVERY VEHICLES

Lotions Creams Ointments Foams Emulsions Powders Deficiencies

Removed too easily from body surface Treatment not complete due to early removal Dissolvable adhesive patch

3M HYDROELEGANCE™

Sunscreen agents Insect repellants Deodorants Antiperspirants Wound dressing First aid bandage Athletic tape wrap Antibiotics Anti-microbial agents Acne Corn, wart or callus removers Wrinkles Psoriasis Dry skin Insect bites or poison ivy exposure Glittering pigments Eye shadow Lip color Rouge Foundation

Place on skin or hair Serve as carriers for actives Care

FEATURES

Chapter 39 DISSOLVABLE ADHESIVE PATCHES Kantner

Decoration

Easy to apply Easy to remove Provide treatment over large area BENEFITS

Applications for: USES & APPLICATIONS

Fluoride

The Carrier

Hair

The Adhesive

Toothache pain Sensitive teeth treatment

Cavity prevention

Pyrophosphate Zinc chloride Baking soda & peroxide Two different layers

Oral Care

MATERIALS OF CONSTRUCTION

Active agents

Tartar

For cold water-soluble applications Plasticizers Water-insoluble film forming polymer for improving strength Lightly crosslinked or uncrosslinked polar polymer and plasticizer Emollients Humectants Conditioners Moisturizers Vitamins Herbal extracts Anti-oxidants Exfoliants

Prolonged teeth whitening

Pigmented, cut to shape coatings Designs & decorations

Dry skin Hair Nails Teeth Mucosal tissue

Protective, abrasion-resistant, solvent-resistant film

Plaque & gingivitis

Triclosan

Coated Disssolved Suspended Emulsified

Actives placed in water-soluble or water dispersible pressure sensitive adhesive Film disintegrates upon water application Actives delivered on film dissolution Thin

Skin

Treatments Two component hair dyes Remove unwanted hair Hair growth stimulating ingredients Depilatories

Strontium chloride or potassium nitrate

Films Fabrics Tapes

Solves problem of too-rapid removal of actives

Fragrances Cover scars, blemishes, disfigurations

Clove oil

Water-soluble or dispersible

Alpha and beta hydroxy acids

Bleaching agents Coloring agents Antifungal/anti-microbial agents Emulsifiers

Nail Care

Support layers

Paper Foils Polymeric films Multilayered laminates

65

Solid lotion coatings Vitamin complexes Antioxidants Lipophilic ingredients Natural ingredients

Incorporate desirable oils & esters Licensing Opportunities U.S. 5,538,732 U.S. 6,001,380

Cleansing Anti-acne Dermabrasion

PATENTS

OVERVIEW

Examples

Lipsticks Facial foundations Antiperspirants

Lotion that does not contain water Skin care

"Melt" is coated onto carrier substrate & cooled

Advantages Limitations Stability Issues

MANUFACTURING

"Hot-melt-like" system Cosmetic waxy base

Concept

Less demanding than aqueous or solvent-based systems

Facial Can include heat sensitive botanical ingredients since no "oven-drying" stage

Loofah Oatmeal Bamboo

Neem oil Jojoba Vitamin extracts Incorporation of solids

Hydroquinone

Cleansing

FUNCTIONAL CHARACTERISTICS

Chapter 40 SUBSTRATE-BASED, WATER-ACTIVATED ANHYDROUS DELIVERY SYSTEMS Smith & Jagoda Murphy

Capable of incorporating & holding skin care ingredients

Molten waxy formulation deposited as uniform film onto a dispensing applicator or carrier substrate Contain no water Solid at room temperature Can incorporate hydrophobic ingredients without the need for Solid anhydrous added emulsifying surfactants formulations Can suspend solid active components easily Incorporate hydrophilic solids to adjust water sensitivity and aqueous dissolution on contact with water

Blemish control SINGLE & MULTIPLE ACTIVE COATINGS

Organic actives & natural ingredients

Skin Care

Make up

Dermabrasion

Skin lightening

Coordinated solubiliztion Integration of two formulas as they are activated Achieve optimum transfer of resulting mixture to skin as wipe is used

APPLICATIONS

Paper

Use coated wipes directly on just cleansed and rinsed skin Controlled agressiveness with gentle particles to "renew" & "brighten" skins surface

PACKAGING

Treatment

Water-activated benzoyl peroxide treatment through process of drying wetted skin

Water-activated

FORMULATIONS

SELECTION OF SUBSTRATE CARRIER

Binderless

Non-woven

Hydro-entangled process Varying lofts, densities and blends Rayon/polyester Nylon/rayon Optimal balance of water absorbency and ability to efficiently dispense anhydrous ingredients on contact with wetted skin

Polyurethane foams

Retistar™ for Cosmetic Formulations: Stabilized Retinol

Chapter 41 Jentzsch & Aikins BASF

Part XIV SPECIFIC INGREDIENT DELIVERY

Chapter 43 Green & Milora NeoStrata

Controlled Delivery of Hydroxy Acids

Controlled Delivery and Enhancement of Topical Activity of Salicylic Acid

Chapter 42 Thau PaCarr

67

Retinol water-in-silicone emulsion with RetiSTAR™ Retinol moisturizing lotion with RetiSTAR™ Retinol daily wear facial lotion with RetiSTAR™ Anti-aging retinol cream with RetiSTAR™

Skin Treatments

Anti-aging

Retinyl palmitate Retinol propionate Retinol acetate Retinal Tretinoin All transretinoic acid Most effective

FORMULATIONS

RETINOL

Chapter 41 RETISTAR™ STABILIZED RETINOL Jentzsch & Aikins

Esters Derivatives of Vitamin A

Carboxcylic acid

RETINOIDS RETISTAR™

Reduce visual appearance of skin aging

Ingredient

Vitamin A Class of Retinoids Highly susceptible to oxidative degradation Light Unstable Heat Oxygen Acids Requires stabilization in personal care formulations

FORMULATING

Aldehydes

Treat fine lines, wrinkles & rough skin surface caused by photodamage Normalizes keratinization of skin Increase epidermal thickness Improved barrier function Helps retain moisture Normalizing effect on skin Helps fight pigmentation age spots

Anti-aging Skin care

Stabilized retinol Retinol & antioxidant vitamin system Advantages Technical Economic Prevents degradation of retinol during storage Eliminates need for inert atmosphere during emulsion preparation & packaging Ratio of Vitamin E (Tocopherol) & Vitamin C (ascorbic acid) important

Synergistic combination

5% retinol in an oil-based dispersion of caprylic/capric triglycerides Easily pourable Readily incorporated into both oil-in-water and water-in-oil emulsions

68

Reducing sebum Glycerophosphate ester or salt Sodium or calcium glycerophosphate

ANTI-IRRITANT SYSTEMS

Alcohol-free Oil-free Won't clog pores Sloughs off dead skin cells Light gel formula leaves no greasy after feel Can be used with moisturizers

Polyurethane type polymers

TOPICAL DELIVERY SYSTEMS

Neutrogena Clear Pore Gel

Polyol prepolymers

ANTI-ACNE TREATMENTS

Polymeric encapsulation

Complex to salicylic acid Molecular inclusion complexes

Cyclodextrins Complex to salicylic acid

Liposome delivery

Un-neutralized salicylic acid localized within the lipidic bi-layers Eliminates need for solubilizers like ethanol Prolonged release profile Reduced irritation

ISP stabileze PVM/MA Decadiene crosspolymer Allyl methacrylates crosspolymer & 2-hydroxy-benzoic acid Salicylic acid inside matrix of porous polymer

Chapter 42 SALICYLIC ACID: CONTROLLED DELIVERY & ENHANCEMENT OF TOPICAL ACTIVITY Thau Treatment of:

Polymeric entrapment

Emulsion delivery Unilever

Powder Controlled time-release delivery Heat & pressure stable 20% salicylic acid

Salicylic acid Benzoyl peroxide Retinol Ascorbic acid Substantivity Improved stability Targeted Novel delivery features Reduced skin irritation Improved ingredient compatibility Enhanced functionality

Acid pH

Gel delivery

Poly-Pore

Chronospheres®

CONTEMPORARY TECHNOLOGY

Derived from: SALICYLIC ACID

Acne Dandruff Psoriasis Willow bark Wintergreen leaves Sweet birch bark

Synthetically produced Keratolytic properties Beta hydroxy acid

Kolbe-Schmidt process

69

Daytime AHA cream with sunscreens AHA + Pro-Vitamin A Cream Face Cream Lactic acid hand cream Night cream Revitalizing peel Glycinamide/glycolic acid complex skin smoothing cream Glycine ethyl ester/glycolic acid complex skin smoothing cream Alcohol-free AHCare Toner AHCare facial toner

Glycolic acid Lactic acid Normalizing effects on skin keratinization Ichthyosis Skin conditions Acne Age spots Warts ALPHA HYDROXY ACIDS

Anti-aging benefits

FORMULATIONS

Skin visual effects

Increased biosynthesis of & collagen fibers Improved quality of elastic fibers Normalized epidermal thickness & differentiation Enhanced cell turnover in stratum corneum

Smoother Firmer Brighter Diminished appearance of fine lines & wrinkles Exfoliation

Absorption

Bioavailability is influenced by formulation pH

Stinging & burning

Upon application Confirms penetration into skin

TOPICAL USE OF AHA

Controlled delivery

Chapter 43 CONTROLLED DELIVERY OF HYDROXY ACIDS Green & Milora 100-600 Daltons optimal molecular weight Molar ratio of AHA to Undissociated, bioavailable AHA complexing agent in 1 to 20 Disassociated anion range of AHA (doesn't

Reduces stinging Temporarily interacting with free acid portion of AHA Slows down usual, immediate penetration of free acid into stratum corneum

Amphoteric AHA complex

Attracting forces

Physical/ chemical evaluation Selection Evidence of existence

penetrate) Complexing agent cation

Ionic/ionic Dipolar/ionic Dipolar/dipolar

Fourier transform infrared

Isolation of amphoteric AHA salts Reduced stinging

Weak binding hydrogen bonds are strong enough to temporarily impede permeation of free AHA into skin Diminishes immediate penetration

MOLECULAR COMPLEXING AGENTS

Application

Clinical Effects

AMPHOTERIC CONTROLLED RELEASE

Reduced irritation Cell turnover benefits

Temporarily bind bioavailable AHA

Provide ability to use higher formulation pH Enable ability to control release into target sites: skin, hair & nails

Lactic acid sting test Nasolabial fold

Commercialization

Amphoteric substances

NeoStrata patents Cognis exclusive rights

Function as acid or base, depending on pH Contain carboxylic acid Amino acids group along with at least optimal one alkalair group such candidates as amino, imino, or guanido Preferred: arginine, lycine, ornithine

Part XV EFFICACY & SAFETY

Evaluating Safety & Efficacy of Delivery Systems and Their Active Ingredients

Chapter 44 Tonucci Interactive Consulting, Inc.

71

Modified Draize protocol Jordan-King Modified Draize protocol

Food & Drug Act

Irritation

Primary

INTRODUCTION

1906

Misuse of technology Clinical safety testing

Testing Sensitization

History

Toxic decomposition products on exposure to sunlight or UV radiation

Phototoxicity

Photoallergenicity/Photosensitization Safety-in-use Mimic real life Systemic exposure Is product leave on? Anticipated frequency of use What part of the body will the product be used on? Are the new ingredients absorbed into the skin? Are any of the ingredients inherently toxic? Are any of the ingredients (or delivery system) a UV absorber?

Efficacy testing SAFETY TESTING PROTOCOLS

Skin barrier function Wound healing Skin moisture content

Impact of products

Intracellular endpoints

Cytokine production MRNA regulation Protein synthesis

Demonstrate that new products will not cause harm Product testing questions Instrumentation CLINICAL TESTING

Nuclear magnetic resonance spectroscopy Ultra violet imaging Doppler imaging Spectrophotometric methods

Cosmetic Regulatory oversight

Post-market surveillance

Chapter 44 SAFETY & EFFICACY EVALUATION OF DELIVERY SYSTEMS Tonucci Based on

Most cosmetics companies have abandoned use of animal testing

Franz cells

Effects of chemicals

Becoming more widely accepted Dermal absorption

Computerized structure-activity relationships Comparison of components with those in an existing product known to be safe in humans

Animals

In-vitro

Comparative analysis

Determine that it will not produce severe or expected toxicity Risk/benefit analysis Dermal Predicting irritation dermal Dermal safety penetration Dermal sensitization

Development

Target population

PRE-CLINICAL SAFETY DATA CLINICAL SAFETY PLAN

Product claims

Definition

Federal Modernization Act IND/NDA approval process

1977

Investigational New Drug/New Drug Application

Route of exposure Product type Proposed ingredients Intended use Due diligence Country United States European Union

Define product specific testing parameters Role of toxicologist Identification Target age group Will product be used preferentially by specific ethnic group? Specific health conditions How many customers will use the product? Geographical considerations impacting safety

How often will consumer use the product Will product be left on or rinsed off after application? Anticipated exposure/use concentration How will body be exposed to product?

Part XVI MARKETING BY DESIGN

Graphisenses: A New Methodology for Identifying Personal Care Opportunities

Chapter 45 Delvaux Dow Corning

73 Oil-in-water skin cream Improved spreading, light feel

Fresh Wave

Oil-in- water skin cream Light feel, silky feel, smooth feel

Tender Delight

Water-in-oil skin cream High consistency, perception of nourishment

Radiant Beauty

Help developers of personal care products examin marketplace Several different perspectives Novel approach Analysis of print Leading skin advertising moisturizers Skin Moisturizers

INTRODUCTION

FORMULATIONS

Water-in-oil skin cream High consistency, rich feel

Velvet Peace

Trendy actives Specialty silicones from Dow Corning Specific fragrances

Philosophy

1. Assemble database of print advertisements

METHOD

Sensory methods Consumer testing

Fresh insight into latest trends Understand market place better Beyond measurement of objective sensory benefits Access to more subtle, subjective parameters Combines objective & subjective views Method good for any delivery/carrier system

Identiify "drivers"

2. Subject drivers of step 1 to objective sensory analysis 3. Develop new formulations that specifically reflect the identified trends& respond to consumer expectations 4. Validation

Four Steps

VALIDATION BY

Chapter 45 GRAPHISENSES: IDENTIFYING PERSONAL CARE OPPORTUNITIES Delvaux Texture & gloss Creaminess at pickup Perception of skin feel when applied Perception of skin feel when absorbed

IDEA GENERATION

Appearance in jar

Sensory evaluation

Start with final consumer communication Comprehensive tool enhances link between raw material suppliers and cosmetic product companies Skin feel mapping

Drivers SECOND STEP

Sensory analysis leads to a kind of "identity card" that qualifies each "driver"

Data base

Procedure

Results Analysis

Leading to "ideal group" of properties

FIRST STEP

Four quadrants of GraphiSenses representation Closely positioned products could be pulled into clusters in order to better define certain "classes" of product

Print advertisements

Collect advertisements & promotional brochures Different countries Magazines Newspapers Specialists describe advertisements

Verbatim responses

Mapping

Graphical Axes Clustering

Analysis of active ingredients & related delilvery system helped map most relevant products into the Sophistication zone

PRODUCT

Marketing manager Market communication specialist Technical service advisor Skin care R&D expert

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Part II Skin Fundamentals

Skin: Physiology and Penetration Pathways

Skin Fundamentals

From Ancient Potions to Modern Lotions: A Technology Overview and Introduction to Topical Delivery Systems

Delivery Systems in Topically Applied Formulations: An Overview

3 Skin: Physiology and Penetration Pathways Bozena B. Michniak-Kohn* University of Medicine and Dentistry of New Jersey Newark, New Jersey Philip W. Wertz Dows Institute, University of Iowa Iowa City, Iowa Mohammad Al-Khalili* College of Pharmacy, University of South Carolina Columbia, South Carolina Victor M. Meidan University of Medicine and Dentistry of New Jersey Newark, New Jersey

3.1

3.2

Biology of the Skin .......................................................................... 78 3.1.1 Overall Structure ................................................................. 78 3.1.2 Cell Replication ................................................................... 79 3.1.3 The Differentiation Process ................................................ 80 3.1.4 The Desquamation Process ............................................... 80 Stratum Corneum ........................................................................... 81 3.2.1 The Permeation Barrier ...................................................... 81 3.2.2 Stratum Corneum Ultrastructure ........................................ 82 3.2.3 Structural Proteins of the Stratum Corneum ...................... 83 3.2.4 Stratum Corneum Lipids..................................................... 84 3.2.5 The Two-Compartment Model ............................................ 85 3.2.6 The Domain Mosaic Model ................................................. 85

∗Current Addresses: Bozena B. Michniak-Kohn, Rutgers University, Piscataway, New Jersey Mohammad Al-Khalili, Iomai Corporation, Gaithersburg, Maryland Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 77–100 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 3.2.7 The Single Gel Phase Model ............................................... 86 3.2.8 The Sandwich Model .......................................................... 86 3.3 Penetration Pathways into the Skin ................................................ 87 3.3.1 The Bulk Stratum Corneum ................................................ 87 3.3.2 The Appendages and Breaches Created in the Stratum Corneum ..................................................... 88 3.3.3 Chemical Enhancement of Permeation .............................. 89 3.3.4 Physical Enhancement of Permeation ............................... 90 3.3.5 Effects of Skin Hydration..................................................... 93 3.3.6 Supersaturation of the Drug Solution .................................. 93 3.4 Delivery System Factors ................................................................ 94 3.4.1 Molecular Weight of the Drug Molecule .............................. 94 3.4.2 Lipophilicity of the Active Molecule ...................................... 95 3.4.3 Effect of the Delivery System on Permeation ..................... 95 3.5 Conclusions .................................................................................... 95 References ............................................................................................ 95

3.1 3.1.1

Biology of the Skin Overall Structure

The epidermis is a thin, stratified squamous epithelium consisting of several ultrastructurally distinct strata as shown in Fig. 3.1.[1][2] The skin structure is discussed moving from the innermost portion out toward the surface. The interface between the epidermis and the dermis (i.e., the basement membrane) is characterized by alternating troughs and ridges sometimes referred to as rete ridges and rete pegs. On the basement membrane, there is a single layer of more-or-less cuboidal basal keratinocytes. Most of the basal keratinocytes have cellular projections extending into the dermis. This results in a highly convoluted epidermal-dermal interface. This interface, in addition to certain specific adhesion molecules, is thought to be of significance in anchoring the epidermis to the dermis. Some of the basal keratinocytes in the deeper parts of the rete ridges have a much flatter interface with the dermis. It has been suggested that these smooth basal cells may be epidermal stem cells, whereas the more “serrated” basal cells may be more important for anchoring the epidermis onto the dermis.[3]

In the immediately suprabasal layers of normal epidermis, the cells are beginning to become wider and flatter as they move outward toward the surface of the skin. They have a spiny appearance in routine histologic preparations, or in transmission electron micrographs, hence this compartment is called the spinous or prickle cell layer. This spiny appearance actually reflects the presence of many desmosomal connections between cells as well as artifactual shrinkage of the cell bodies that occur during the dehydration process used to prepare the specimens for viewing. Above the spinous layer the desmosomes become less prominent, but the cells are characterized by the presence of irregular dense proteinaceous granules known as keratinohyalin granules.[4] In accord with the appearance of the keratohyalin granules under the light microscope, this layer is called the granular layer. Examination by transmission electron microscopy reveals a unique organelle structure that is called a lamellar granule.[5][6] This organelle has also been referred to as an Odland body, a keratinosome, a cementsome or a lamellar body. The organelle is round-to-ovoid in shape, about 200 nm in diameter, and consists of a unit-bounding membrane surrounding internal stacks of membranous disks.

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS

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(b)

(a) Figure 3.1 A cross-sectional diagram of human skin.[232] (a) Full-thickness skin. (b) Expansion of the upper 200µm thickness. (Reprinted with permission.)

Finally, the outermost, fully differentiated compartment of the epidermis, the stratum corneum, contains extremely flattened, cornified cells.[2][7] These cells are the end product of the keratinization process. They serve to prevent desiccation and to protect the underlying tissue against environmental stressors.

3.1.2

Cell Replication

Normal cell replication occurs on the basal layer of the epidermis at a rate sufficient to maintain a constant thickness of epidermis.[2][8] When a basal cell divides, both daughter cells may remain on the basement membrane, but an adjacent keratinocyte is displaced into the suprabasal layer and then enters into differentiation. It has long been postulated that cell replication in the epidermis is subject to some form of feedback regulation. For a number of years, this was attributed to a postulated peptide factor produced by dif-

ferentiating cells and referred to as a chalone.[9] However, attempts to isolate such a factor have produced no convincing results. More recently, it has been demonstrated that there is a gradient of free sphingosine (Fig. 2, base component of ceramides EOS, NS, and AS) across the epidermis with the highest concentration of sphingosine being in the outermost layers. It has been speculated that this sphingosine gradient may be at least one factor involved in the regulation of cell replication.[10][11] In accord with this suggestion, it has been demonstrated that sphingosine inhibits keratinocyte replication in cell culture.[12][13] Ideally, for both personal care and drug delivery, active agents delivered topically would not interfere with the regulation of the replication process. Topical steroids are known to slow the rate of cell proliferation. In cases of epidermal injury, the normally quiescent epidermal stem cells are activated.[8][14] It has been suggested that the basal keratinocytes with the flatter dermal interface, the so-called “non-serrated” basal cells, may in fact be stem cells.[3] The stem

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cells divide, thereby giving rise to “transient amplifying cells.” These cells move into the immediately suprabasal compartment. They undergo several rounds of replication, and the daughter cells then enter into a differentiation process. Eventually, the transient amplifying cells themselves differentiate. This scenario provides a mechanism for rapidly repopulating the epidermis following injury.

3.1.3

The Differentiation Process

As keratinocytes move outward from the basal layer and undergo differentiation, there is an accumulation of three types of species: cytokeratins, other proteins in the keratohyalin granules, and lipids. The lipids are largely packaged into the lamellar granules.[1][6][15] In the late stages of the differentiation process, all of the internal organelles, including the nucleus and the mitochondria, are degraded. As a result, there is an increase of free intracellular calcium.[16] This calcium may be released both from sequestration in the endoplasmic reticulum and from the mitochondria. Lamellar granules are directed to the apical end of the cell, and their lipid contents and hydrolytic enzymes are extruded into the intercellular space. At about this same time, a high molecular weight, highly phosphorylated, histidine-rich protein called profilaggrin undergoes dephosphorylation and proteolysis to produce the smaller molecule, filaggrin. Filaggrin induces aggregation of the cytoskeleton filaments into bundles that lie parallel to the surface of the cell.[17][18] The collapse of the cytokeratin network is associated with the extreme flattening of the corneocytes mentioned previously. Simultaneously, other proteins including involucrin[19] and loricrin[20] are deposited at the cell periphery. These peripheral proteins become highly cross linked through the formation of both disulfide linkages[15] and isopeptide linkages.[21] The latter are formed through the action of a calcium dependent enzyme, transglutaminase 1, on the side chains of glutamine and lysine residues.[21][22] When the bounding membrane of the lamellar granules fuses into the cell plasma membrane, an unusual lamellar granule-associated lipid is introduced to the cell periphery. This unusual acylglucosylceramide molecule contains 30- through 34-car-

bon-long ω-hydroxyacids amide-linked to sphingosine bases. Linoleic acid is ester-linked to the ω-hydroxyl group, and glucose is β-glycosidically attached to the primary hydroxyl group of the long-chain base.[23][24] At about the time of its introduction to the cell periphery, the glucose and linoleate are removed from the acylglucosylceramide to leave an ωhydroxyceramide.[25] The glucose is probably used for energy production via anaerobic glycolysis with production of lactate, while the linoleate may be recycled in the viable epidermis. The ω-hydroxyceramide molecules become ester-linked through the ω-hydroxyl group to the outer surface of the peripheral band of cross linked proteins to complete formation of the cornified envelope.[25]-[27] Attachment of the hydroxyceramide molecules to the envelope apparently is mediated by transglutaminase 1, the same enzyme that generates the isopeptide linkages.[26] The end result of the differentiation process is an array of very flat, keratin-filled cells, bounded by cornified envelopes and embedded in a lipid matrix. This structure is the stratum corneum, the primary permeability barrier of the skin. It is this barrier that an active ingredient must first traverse as it is delivered from a carrier or delivery system, whether it is a personal care active or a drug formulation. The penetration pathway for active ingredients diffusing through the stratum corneum is usually through the intercellular spaces.[28] Under some circumstances, active materials may penetrate through the ducts of sweat glands or through the sebaceous follicles as well.

3.1.4

The Desquamation Process

Cells are constantly being sloughed off from the surface of the stratum corneum and replaced from below. This sloughing process, or desquamation, provides an important protective mechanism for the skin in that it gets rid of microorganisms, physically damaged corneocytes, and potentially harmful agents at the skin surface. This process is essential for maintenance of a healthy skin. It may also prevent penetration of potential active compounds if their rate of penetration is comparable to the rate of desquamation.

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS As cells desquamate from the epithelial surface, new cells are added to the bottom of the stratum corneum. The mechanisms by which cell replication, differentiation, and desquamation are coordinated are poorly understood. However, studies with the epidermis have indicated that desquamation is a programmed part of differentiation, although it may be influenced somewhat by environmental factors including drug or personal care formulations placed on the skin surface. Studies with human skin in vivo as well as a mouse skin organ culture model have implicated cholesterol sulfate in the regulation of desquamation.[29][30] It has been observed that cholesterol sulfate hydrolysis accompanies desquamation, while all other lipids survive the cell shedding process intact.[29][30] In addition, there is the genetic disease called recessive X-linked ichthyosis in which the enzyme that normally hydrolyzes cholesterol sulfate is defective.[31] In this condition cholesterol sulfate is not hydrolyzed, desquamation does not proceed normally, and the skin surface can become extremely rough and scaly. It appears that hydrolysis of cholesterol sulfate is a prerequisite for cell shedding from the skin surface. The most common type of cell-cell junction in the epidermis is the desmosome. In transmission electron micrographs, desmosomes appear as electrondense plaques spanning the intercellular spaces between adjacent cells.[32] Tonofilaments are generally seen in association with the cytoplasmic faces of the desmosome, and the keratin-desmosome network serves to dissipate shearing forces within the epithelium. Shearing forces are produced by anything that rubs or presses obliquely against the skin. In the disorder, epidermolysis bullosa (EB), a defective keratin gene results in a keratin protein that cannot anchor itself to the desmosomal plaque.[33] The result is a very fragile, easily blistered epidermis. Although EB is generally thought of as a blistering skin disease, the most severe and life-threatening symptom of this disorder is the blistering in the oral cavity. This phenomenon makes eating painful and difficult and causes a propensity towards infection. As noted above, desmosomal plaques are most abundant in the spinous layer of normal epidermis. They persist into the epidermal stratum corneum, where they occupy only about 15% of the intercellular space.[32] It appears that degradation of these

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glycolipid-containing cellular junctions is required for normal desquamation. Lundström and Egelrud[34] have developed an in vitro model for studies of desquamation from the skin. This consisted of plantar stratum corneum immersed in buffered saline at 37°C. It was shown that in this system, cells continued to slough off exclusively from the outer surface of the stratum corneum for at least twenty hours. The process could be inhibited by protease inhibitors, and the pattern of inhibition suggested a chymotrypsin-like serine protease.[35][36] Such a protease has been isolated,[37] and it has been demonstrated that this enzyme is also involved in desquamation from nonpalmo-plantar regions of the skin. Several other serine proteases have since also been implicated in degradation of desmosomes as part of the desquamation process. Examples include a trypsin-like protease[38][39] and cathepsin D.[40] It has been suggested that cathepsin D could be used as a marker of keratinization. Cholesterol sulfate has recently been shown to inhibit serine proteases,[41] and this suggests that hydrolysis of this lipid probably precedes proteolysis of the desmosomal proteins.

3.2 3.2.1

Stratum Corneum The Permeation Barrier

The development of a watertight skin was a major, and essential, development in the evolution of life on dry land.[42] It is now known that the stratum corneum generally constitutes the main and rate-limiting step to permeation of applied therapeutic agents and personal care active components through the skin.[43]-[46] Nevertheless, it was not quickly recognized that the stratum corneum provides the primary permeability barrier of the skin. The first experimental evidence to indicate that the permeability barrier of the skin was located in the stratum corneum came from an experiment in which water loss was measured while layers of stratum corneum were removed by abrasion using sand paper.[47] The subjects were anesthetized surgery patients. It was observed that no major increase in water flux occurred until the innermost layers of the stratum corneum were removed! As a result of this

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observation, it was concluded that the permeability barrier is located within the cornified layer. Later, Blank[48] performed a variant of this experiment in which tape stripping was used to progressively remove stratum corneum while monitoring water flux. The results were essentially the same as in the earlier sandpapering experiment. Blank[48] initially concluded from his observations that the innermost portion of the stratum corneum provided the barrier, Scheuplein[49] later proved mathematically that this experiment could not distinguish between a barrier localized to the inner stratum corneum and one uniformly distributed throughout the stratum corneum. Based mainly on anatomical considerations, Kligman[7] promoted a model in which all layers of the stratum corneum contribute more or less equally. This view was subsequently supported by electron microscopic observations on the tissue distributions of electron dense tracers.[46][50] The following sections present the ultrastructure of the stratum corneum based on electron microscopic and X-ray diffraction studies. Following this discussion, the lipid and protein components of the stratum corneum are reviewed. Finally, models used to represent the stratum corneum are summarized.

3.2.2

Stratum Corneum Ultrastructure

Using a light microscope to observe the skin, it is seen that individual cells within the stratum corneum cannot be discerned unless the tissue is first swollen by exposure to alkaline conditions.[51] In rodent epidermis, and to a somewhat lesser extent in some smooth flat regions of human skin, alkali expansion reveals corneocytes aligned and stacked like plates. In most regions of human skin, the cells of the stratum corneum appear to be less well ordered. When stained with silver nitrate and examined from the surface, individual corneocytes can be seen to be hexagonal or pentagonal in shape. There is a minimal zone of overlap at the edges of adjacent cells.[52] Breathnach and associates[53] employed the freeze-fracture electron microscopic technique to demonstrate that the intercellular spaces of the stratum corneum contain multiply stacked membranous structures. Unfortunately, these lamellae could not be visualized by transmission electron microscopy

using standard methodology. It was suggested that the lipids were extracted during the dehydration step in sample preparation, thus creating an artifact.[46] However, in 1987 an improved technique was reported that permitted routine visualization of the intercellular lamellae.[54] This technique involved substitution of ruthenium tetroxide as a post-fixative instead of the more usual osmium tetroxide. Ruthenium tetroxide is a stronger oxidizing agent than osmium tetroxide. The membrane lipids in the stratum corneum have relatively few chemically reactive groups so they react with ruthenium tetroxide but not osmium tetroxide. A major finding in the initial application of ruthenium tetroxide to the study of stratum corneum ultrastructure was that most of the membrane lipids are organized into trilaminar units. These contain a broad-narrow-broad pattern of electron-lucent bands having an overall dimension of 13 nm. Since the initial report, the ruthenium tetroxide method has been widely applied.[55]-[57] The 13-nm trilaminar units appear to be unique to epidermal stratum corneum. The alternating broadnarrow-broad-broad-narrow electron-lucent band pattern is found at all levels within the stratum corneum and persists after desquamation.[25][54] The number of lipid layers within the intercellular spaces varies, but almost always consists of one or more broad-narrow-broad electron-lucent band units. The dimensions of the broad and narrow electron-lucent bands have been estimated at approximately 4 and 2 nm, respectively.[32] The 13-nm width of a broad-narrow-broad unit has further been confirmed by small-angle x-ray diffraction measurements, and two periodicities (13.2 and 6.0 nm) have been demonstrated.[58][59] As described below, possible molecular arrangements have been proposed[58][61] to account for these patterns. In epidermal stratum corneum, the most abundant lamellar arrangements include ones with three, six and nine lucent band patterns.[32][60] The threeband pattern is mainly seen between the ends of adjacent corneocytes. This pattern is thought to represent two lipid envelopes, with the sphingosine tails of the hydroxyceramide molecules extending outward and forming the framework of the central lamella. Free lipids fill the remaining space between the hydroxyceramide aliphatic chains. The six-band pattern, which is found between the broad, flat surfaces of adjacent corneocytes, consists of two broad-

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS narrow-broad electron-lucent banded units. A central pair of broad electron-lucent bands is thought to arise from the edge-to-edge fusion of the flattened lipid vesicles after their extrusion from lamellar granules into the intercellular spaces.[6][32] The outermost broad lamellae consist of covalently bound hydroxyceramide layers. The two lamella between the outermost lamellae and the pair of lamellae in the center of the intercellular space contain sphingosine chains from the covalently bound lipid, as well as linoleate chains from acylceramide molecules of the central pair of bilayers. The nine-band pattern contains three broad-narrow-broad lucent band units. The central lucent band in this pattern contains linoleate chains extending from acylceramide molecules in both adjacent lamellae. In addition to the lipid lamellae, electron-dense desmosomes occupy about 12% of the total length of intercellular space in epidermal stratum corneum.[32] These junctions are thought to be involved in maintaining cell shape and in cell-to-cell adherence. As noted above, desmosomes undergo degradation leading to desquamation. This process can have an impact on penetration of molecules into the skin. Approximately 7% of the length of the epidermal stratum corneum contains amorphous material.[32] Some of this material is electron dense and may represent desmosomal breakdown products. A portion of the amorphous material is less electron dense, and it has been suggested this may represent phase-separated cholesterol esters.

3.2.3

Structural Proteins of the Stratum Corneum

Keratins are the major structural proteins of the stratum corneum. They are a type of intermediate filament.[62]-[64] The filaments formed from these rodshaped proteins have a diameter of about 8 nm. This places them intermediate in size between the contractile microfilaments (~5 nm) and the larger (~24 nm) microtubules observed within the cytoplasm of mammalian cells. The molecular weights of the epidermal keratins range from about 40 kD through 70 kD. In general, lower molecular-weight keratins are found in the inner portion of the epidermis, while higher molecular-weight keratins are expressed as cells move outward toward the surface.[65]

83

There are approximately thirty different keratin genes.[62] Half of these code for type I acidic keratins while the other half code for the type II neutralbasic keratin polypeptides. The type I and type II keratin genes are always expressed in a pair-wise manner. Keratin gene expression varies among different keratinized epithelial regions and as a function of cell differentiation in a given region.[66] Each acidic-basic pair of keratin proteins forms a heteroduplex. These initial heteroduplexes are the building blocks for the keratin filaments, and their structures have been reviewed previously.[67] In epidermal stratum corneum, keratins of 55, 56.5, and 65 kD sizes make up about 85% of the total protein.[65] Near the end of the differentiation program, a series of proteins are expressed and deposited at the cell periphery. These include involucrin, envoplakin, and periplakin.[68] These initially deposited proteins become cross linked to one another as well as to residual membrane proteins and desmosomal components. Eventually, a monolayer of cross linked protein is completed by the process. The attachment of ω-hydroxyceramide to the outer surface of this initially formed shell by transglutaminase 1 is probably a concurrent event. Approximately 80% of the protein in the epidermal cornified envelope is loricrin.[68][69] Loricrin itself is an insoluble protein component of the keratohyalin granules. It is solubilized by cross linking to members of a family of small, proline-rich proteins. Thereafter, it is translocated to the cell periphery and then incorporated into the cornified envelope. As noted previously, the isopeptide cross links are produced through the action of a calcium-dependent transglutaminase.[21] In addition to the envelope-specific proteins, small amounts of keratins and other proteins become incorporated into the envelope. In addition to isopeptide linkages, there are disulfide linkages between envelope proteins. The cross linked protein of the envelope is 10 to 12 nm thick,[15] and the covalently bound lipid is 4 to 5 nm thick.[60] In addition, in the viable epidermis keratin filaments are anchored to the cytoplasmic sides of the desmosomes through specialized adaptor proteins.[70] This network serves to provide physical strength to the epidermis and is important in the dissipation of shearing forces.

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There are three protein families that make up the desmosomes. These include cadherins, plakins, and the armadillo family of junctional proteins.[71] The principal protein components of the desmosomal plaques are the cadherins, or calcium-dependent adhesion molecules. These include two families of transmembranal glycoproteins—the desmogleins and the desmocollins. The detailed composition of desmosomes changes with time as a function of both tissue and differentiation. There are three isoforms of both the desmogleins and desmocollins, and their proportions appear to be critical for cohesion and function of the stratum corneum.[72]

3.2.4

α-hydroxyacid, or ω-hydroxyacid, respectively. The presence of an ester-linked fatty acid is designated with a prefixed E; thus, the least polar of the ceramides shown at the top of Fig. 3.2 becomes CER EOS. This consists of 30- through 34-carbon ωhydroxyacids amide-linked to sphingosine bases with a linoleic acid ester-linked to the ω-hydroxyl group. CER NS consists of long, mostly 24-, 26-, and 28carbon, normal fatty acids amide-linked to sphingosine and dihydrosphingosine bases. CER NP contains the same long-chain normal fatty acids as CER NS, but they are linked to phytosphingosine bases. CER EOP is a relatively minor component and is a phytosphingosine-containing variant acylceramide. CER AS contains both short C16 and long C24–

Stratum Corneum Lipids

In epidermal stratum corneum from most anatomic sites, lipids comprise 10% to 15% of the dry weight of the tissue.[73] The plantar and palmar regions where the concentrations of lipids represent only about 2% of the dry weight are exceptions.[74] Ceramides, cholesterol, and saturated fatty acids are the principal lipids of stratum corneum. These lipids account for about 50%, 25%, and 10%, respectively, of the lipid mass.[75] Cholesterol esters, cholesterol sulfate, and glucosylceramides are present in minor amounts, but phospholipids are absent. The structures of the stratum corneum ceramides were first determined for pig tissue.[76] All of the same species were subsequently demonstrated in human stratum corneum.[25][77] Pig skin is considered an excellent model for human in that the epidermal lipids and barrier function are nearly identical.[1] More recent studies, however, have demonstrated a series of ceramides in humans containing 6-hydroxysphingosine as the base component[78][79] as well as a phytosphingosine-containing acylceramide.[80] This series is absent in the pig. The ceramides are structurally heterogeneous, and representative structures of the different types of ceramides are summarized in Fig. 3.2. The ceramide nomenclature proposed by Motta, et al.,[81] is used in Fig. 3.2. In this system, the base is designated as S, P, or H to indicate sphingosine, phytosphingosine, or 6-hydroxysphingosine, respectively. Likewise, the amide-linked fatty acid is designated as N, A, or O to indicate normal fatty acid,

Figure 3.2 Chemical structures of different types of ceramides. Abbreviations are according to the system of Motta, et al.[81]

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS C28 α-hydroxyacids amide-linked to sphingosines and dihydrosphingosines. The bimodal chain length distribution of the hydroxyacid component of CER AS generally results in a doublet in the carbon density profile of thin-layer chromatograms. CER NH is the ceramide containing normal fatty acids and 6hydroxysphingosine. CER AP contains mainly long α-hydroxyacids coupled to phytosphingosines. CER AH contains α-hydroxyacids linked to 6hydroxysphingosine. Finally, CER EOP is a phytosphingosine-based acylceramide. Cholesterol is the only sterol found in porcine and human stratum corneum.[73] Cholesterol is a widely distributed membrane component, and can either increase or decrease membrane fluidity, depending upon the proportion of cholesterol and the other membrane components. Variation in fluidity can have a major impact on the ability of molecules to diffuse across a membrane. The fatty acids found in the epidermal stratum corneum contain aliphatic chains longer than 18 carbons. These chains are entirely saturated.[1][25] The most abundant, free fatty acids in both porcine and human stratum corneum are the 22- and 24-carbon entities. Aside from the small amount of cholesterol sulfate, fatty acids are the only ionizable lipids in the stratum corneum, and this may be important for the formation of lamellae. These ionized lipids impart a net negative charge to the skin surface. This can result in trapping of cationic substances on the surface and can influence the penetration of any charged species.

3.2.5

The Two-Compartment Model

The stratum corneum barrier has been schematically and mathematically represented as an idealized two-compartment model. This model, represented in Fig. 3.3, is also referred to as the “bricksand-mortar” model.[82][83] It consists of an array of impermeable, keratinfilled cells embedded in a continuous lipid phase. The model has been compared to a brick wall with the corneocytes representing the bricks and the lipid being the mortar. This arrangement provides for a tortuous pathway through the intercellular space of the stratum corneum, and this tortuosity is considered to

85

Figure 3.3 The “brick-and-mortar” model of the stratum corneum. The corneocytes are represented as bricks (shaded). The “bricks” are embedded in lipid “mortar.”

be one component of the skin’s barrier function.[84] The physical properties of the lipid mixture of the stratum corneum provide for greater diffusional resistance than observed with more typical membrane lipids such as phospholipids and cholesterol.[61] The bricks-and-mortar structure is breached with hair follicles and sweat pores, but these openings constitute only 0.1% of the total surface area and, therefore, do not detract significantly from the bricks-andmortar concept.

3.2.6

The Domain Mosaic Model

All of the ceramides and free fatty acids found in the stratum corneum are rod-like, or cylindrical in shape. This makes them well suited for the formation of highly ordered, and thereby relatively impermeable, membrane domains. In fact, a number of physical measurements on stratum corneum lipids have been interpreted as indications of the presence of gel phase domains. It has been suggested that cholesterol serves to fluidize stratum corneum membranes that otherwise would be rigid. The presence of such fluid or liquid crystalline domains could play an important role in determining the pliability of the skin. These ideas have been synthesized by Forslind[85] into the domain mosaic model of the skin barrier. In the domain mosaic model, islands of gel phase domain are imbedded in a continuous liquid crystalline phase as illustrated in Fig. 3.4. Penetrants would diffuse primarily through the liquid crystalline phase, although the rate of penetration would be greatest at the phase boundaries due to chain-packing defects.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 3.2.7

(a)

(b) Figure 3.4 The domain mosaic model of the intercellular lipids. (a) This represents a surface view of one lamella within the intercellular space. Islands of gel phase (black) are embedded within a continuous liquid crystalline domain (white). (b) A cross-sectional view of two lipid lamellae. Gel phase domains are in gray and liquid crystalline domains are white. It is unlikely that liquid crystalline domains will be continuous across multiple lamellae.

The Single Gel Phase Model

Recently, an alternative single gel phase model has been proposed.[86] According to this model, the stratum corneum lamellae behave as a single gel phase on a microscopic level. The lamellae have a low water content and low lipid mobility in this model because of close packing of the lipid chains. The single gel phase model, although elegant and able to account for many observations, appears to be at odds with observations from several physical chemical studies of the stratum corneum.[87] At least some of the discrepancies between the model and existing physical data could be attributed to contaminants such as triglycerides.[88] As such, this model cannot be dismissed. Even if it ultimately proves to be an inaccurate representation, the model has stimulated much useful discussion, thought, and debate.

3.2.8

The Sandwich Model

Another model that has recently been proposed is the sandwich model, illustrated in Fig. 3.5.[59][87] This model is based on molecular geometry and the dominant 13-nm repeat unit observed by x-ray diffraction. Essentially, the same model was proposed independently.[89] In this model, the outer two lamellae of a trilamellar membrane unit are in a gel phase

Figure 3.5 The sandwich model of the intercellular lamellae. The trilaminar units have an overall dimension of 13 nm with wide outer lamellae and a narrow, interdigitated lamella in the center. Notice the linoleate chains from acylceramide molecules in the central lamella. The outer lamellae would be in a gel phase while the central lamella would be more fluid because of the linoleate chains.

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS while the central lamella is in a liquid crystalline state. It is believed that the liquid crystalline state exists primarily because CER EOS is situated with the ωhydroxyceramide portion of the molecule in the outer lamellae and the linoleate in the central lamella. The chains in the central lamella also interdigitate, so the widths of the lamellae alternate in a broad-narrowbroad manner. This interdigitation is consistent with the impression one obtains from looking at transmission electron micrographs.

3.3

Penetration Pathways into the Skin

There is generally a difference between a personal care active and a drug in terms of the desirable penetration depth. Often, personal care actives such as sunscreens and deodorants are designed to stay on the skin surface or remain within the stratum corneum. Since the skin surface is negatively charged, many cleansing lotions incorporate cationic polymers that are designed to adsorb onto the skin surface. By contrast, the frequent aim of drug therapy is for the active agent to penetrate into the deeper layers of the skin or reach the systemic circulation. Some chemicals, such as hair regrowth or anti-acne agents, are designed to reach the hair follicles. In all cases, the penetration of drugs and personal care actives through the skin includes diffusion through the bulk stratum corneum and/or diffusion through the skin appendages such as sweat glands and hair follicles. Each of these pathways is sequentially discussed. While the subject of this book is the delivery of personal care actives, there is much to be gained by an understanding of the well-studied mode of drug actions and their skin penetration in the design and optimization of personal care actives.

3.3.1

The Bulk Stratum Corneum

Since its introduction, the bricks-and-mortar model (Sec. 3.2.5) has formed the basis for understanding the nature of drug and personal care active permeation through the bulk stratum corneum. The model considers permeation to take place either through the intercellular lipid matrices (i.e., intercel-

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lular pathway) or alternatively by permeation through both the keratin-filled corneocytes and the intercellular lipid matrices (i.e., transcellular pathway). However, the importance of the intercellular route was compromised by the early assumption that the intercellular lipid comprises only 1%–5% of the total volume of the stratum corneum. From such erroneous data and other thermodynamic considerations, it was inaccurately deduced that water-soluble molecules permeate in proximity to the water-hydrated surface of the intracellular keratin filaments, while lipidsoluble molecules diffuse through the lipid matrix region between the filaments.[45] Later, Elias, et al., utilized freeze-fracture and electron microscopy to show that intercellular spaces could account for as much as 5%–30% of the total tissue volume.[46] This result, together with other histochemical evidence, led to the hypothesis that the intercellular pathway is, possibly, the major permeation route for most molecules, both hydrophilic and lipophilic. For instance, the permeation of water, or salicylic acid through human skin samples taken from different body regions was, surprisingly, not correlated to stratum corneum thickness. Rather, permeation was correlated to the lipid composition of each sample.[90] Using vapor fixation techniques and electron microscopy, Bodde, et al., shows that for an inorganic ionic species such as Hg2+, the intercellular, rather than transcellular pathway is the major route.[91] Further evidence for the validity of the intercellular route was most clearly indicated by experiments in which tissue was treated with n-butanol prior to exposure to osmium vapor. Surprisingly, the resulting precipitate, a reaction product of the osmium and butanol, was strictly confined to the intercellular spaces.[28] While the existence of separate polar and nonpolar permeation pathways is now widely accepted,[92]-[94] the location of the polar pathway is still in question. Peck, et al.,[95][96] measured the temperature-dependence of passive diffusion for various compounds across both intact, ethanol-treated, human skin, as well as synthetic porous membranes. The results suggested that hydrated corneocytes within the skin formed an aqueous-based porous pathway. However, other workers, employing delipidization techniques, found that the permeation of polar compounds was mediated via intercellular pathways.[97][98] Sznitowska, et al.,[99] used solvent mixtures of different polarity to delipidize the stra-

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tum corneum and then treated it with sodium lauryl sulfate. They concluded that laminar organization discontinuities within the intercellular lipids create aqueous domains, or microchannels, that act as polar pathways. Mathematical modeling of the permeation of tiamenidine, 5-fluorouracil, and estradiol through lamellar lipid membranes indicated that the diffusion coefficients for these compounds were higher than for the corresponding stratum corneum values. However, the data correlated better if the porosity and tortuosity of the intercellular channels were also taken into account. These data indicated that these drugs permeated through the intercellular lipids.[100]-[102] The presence of two routes for permeation does not mean that they are mutually exclusive since a molecule diffusing across the stratum corneum may exploit both pathways simultaneously. However, the proportion by which each pathway contributes to the overall permeation process depends upon the physicochemical properties of both the permeant and the vehicle/carrier. Understanding the pathways followed by molecules transversing the stratum corneum may provide us with a tool for designing better strategies for enhancing permeation, when desired. Such understanding would then lead to the improved design of delivery systems for both personal care actives as well as for drugs.

3.3.2

The Appendages and Breaches Created in the Stratum Corneum

Appendages such as the pilosebaceous units and sweat glands emerge from deep within the dermis. They open up on the skin surface and create breaches in the stratum corneum. These appendages can act as low-resistance, shunt pathways and generate alternative penetration routes for the ingress of personal care actives or drugs. This is especially true for ionic or non-ionic hydrophilic permeants that do not readily transverse the bulk stratum corneum. However, the extent to which these shunts contribute to the overall transport process has been underestimated for many years, and this has been due to several considerations.

The appendages comprise less than 0.1% of the total skin surface area and, therefore, were believed to play only a minor role in transport processes since they represented such a minor part of the total skin area. Second, molecules attempting to permeate inward via these pathways were thought to be washed away outwardly by the upward movement of sebum and sweat. Moreover, a poor correlation was observed between appendageal density and percutaneous absorption when different skin regions were compared.[103] Early mathematical modeling of the diffusion of small non-electrolytes across skin predicted that the shunt route dominates only during the early, non-steady state phase of diffusion. The effect of the shunt route becomes marginal once steady state is attained.[49][104]-[106] Siddiqui, et al.,[175] calculated that shunt pathways contribute to less than 10% of the steady state transport of polar and nonpolar steroids. Experimentally, it is difficult to conclusively determine the significance of the shunt pathways relative to their overall role in the penetration of drug and/or personal actives. Although hairless animal models have been traditionally used to quantify appendageal absorption, these models are not completely devoid of hair follicles. Recent research, especially with visual methods like laser-scanning confocal microscopy, indicates that shunts probably play a more significant role than previously believed by facilitating the permeation of hydrophilic and ionic compounds.[107] Other evidence derived from such disparate techniques as quantitative autoradiography, use of follicle-free scar tissue, and mechanical removal of the follicles, has tended to reinforce this conclusion.[108] The appendages certainly constitute the main transport conduits during iontophoresis of ions, polar compounds, and high molecular-weight peptides.[97][109][110] Interestingly, the follicles have been implicated as the preferential deposition site for various particulate systems, such as synthetic microspheres,[111] as well as liposomes.[112] Such delivery systems are in wide use both for personal care actives and drug delivery. They have the potential for further development with the aim of targeting appropriate personal care or therapeutic agents to the pilosebaceous structures. This approach will be valuable for various dermatological conditions such as acne, alopecia, and several types of skin tumors.

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS 3.3.3

Chemical Enhancement of Permeation

The stratum corneum is remarkably effective in preventing the absorption of most chemicals.[50] Hence, in spite of the many advantages offered by the transdermal route over the more conventional oral and parenteral routes, there are still relatively few drugs available on the market for transdermal applications. Examples of drugs now being delivered transdermally include estradiol, fentanyl, testosterone, scopolamine, clonidine, nitroglycerine, and nicotine. Despite the stratum corneum’s resistance to chemical penetration, a survey of the literature reveals there are hundreds of publications dealing with different approaches for overcoming the low permeability of the skin. These approaches include chemical modification,[113][114] mechanical disruption,[115][116] and electrical disruption[117][118] of barrier function (see Table 3.1). Over the last two decades, an appreciable effort has been expended in order to identify chemicals that can reversibly enhance skin permeability.[114][119] Compounds investigated as potential permeability enhancers include hydrocarbons,[120] sulfoxides[121] (especially dimethylsulfoxide) and their analogues,[122] pyrrolidones,[123] and fatty acids,[124] and their esters,[125] Other potential enhancers investigated include: alcohols,[126] Azone and its derivatives,[127] anionic surfactants,[128] cationic surfactants,[129] and nonionic surfactants.[130] Still other potential enhancers studied include amides (such as urea and its derivatives),[131] polyols,[132] essential oils, terpenes and their derivatives,[120] oxazolidines, polymers,[133] and biodegradable enhancers.[134] These

enhancers have also been extensively reviewed by others in the literature.[114][119] In studying chemical enhancers, many classification approaches have been proposed. Lambert, et al.,[135] classified enhancers into three groups: those that act primarily as solvents and hydrogen bond acceptors (e.g., dimethylsulfoxides, dimethylacetamide, dimethylformamide); simple fatty acids; alcohols, and weak surfactants containing a moderately sized polar group (e.g., Azone). Pfister, et al.,[136] classified chemical enhancers into polar and non-polar based compounds by employing the Hildebrand solubility parameter. Barry[137] and others[138] adopted a classification system based on the lipid-protein-partition theory. This theory suggests the mechanism of accelerant action occurs by at least one of three possibilities: the effect on lipids, the effect on proteins, and a partitioning promotion effect. Knowledge of chemical penetration enhancers and associated mechanisms is highly useful information for personal care formulators as well as drug delivery technologists. What follows is a description of a number of chemical enhancers and how they are envisioned to work. Alcohols and glycols. Short chain alcohols (C2C5) preferably enhance the permeation of polar molecules.[139] Such promoters work by extracting and/or increasing the fluidity of stratum corneum lipids[140][141] as well as by interacting with stratum corneum proteins.[139] As a result of rapid permeation behavior, such compounds are used at relatively high concentration. Polyalcohols such as the propylene glycols are most effective when used in

Table 3.1. Techniques for Enhancing Transdermal Drug Delivery

Chemical Enhancement

Hydration

Physical Enhancement

Alcohols and glycols

Microneedles

Amines and amides

Sonophoresis

Fatty acids and their esters

Iontophoresis

Terpenes Metabolic/biochemical enhancers

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Electroporation

Supersaturation

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

combination with other accelerants such as Azone and oleic acid.[142] Amines and amides. Compounds such as urea and cyclic urea derivatives, amino acids and their esters, amides, as well as Azone and its derivatives, and pyrrolidones belong to the amine and amide category. Azone was specifically designed as a skin penetration enhancer, and it is one of the most intensely studied absorption promoters since it can enhance the permeation of a wide range of drugs.[134][143] This material works primarily by fluidizing the intercellular stratum corneum lipids.[144][145] It is often applied in conjunction with propylene glycol[146] where the combination treatment yields synergistic action. Fatty acids and their esters. A large number of fatty acids have been extensively studied for transdermal permeation enhancement. Unsaturated fatty acids have been found to be more active than their saturated counterparts.[147][148] Potential mechanisms of action for fatty acids include drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption.[149]-[151] Terpenes. Terpenes are constituents of volatile oils. They are commonly employed in cosmetics and in some pharmaceutical products. Such materials are usually well tolerated by the body[152] and are considered as Generally Recognized As Safe (GRAS) compounds. They exhibit good toxicological profiles, high enhancement activities, and low cutaneous irritancy at low concentrations (1%–5%).[152] Terpenes are observed to increase the percutaneous permeation of both hydrophilic and hydrophobic drugs.[153] Polar terpenes have been shown to be more effective in enhancing the permeation of polar drugs, while nonpolar terpenes have been demonstrated to be more effective in enhancing the permeation of lipophilic drugs.[138][154] DSC studies have indicated that terpenes exert their action mainly by disrupting the intercellular lipid layers.[155] Metabolic or biochemical enhancers. These compounds act by interfering with metabolic events, ultimately inducing elevated skin permeability. This increase in permeability can occur either by inhibition of the synthesis of stratum corneum lipids (especially after acute damage)[156] or, alternatively, by promoting the metabolism of existing skin lipids that are responsible for skin barrier function.[157] Patil, et

al.,[157] showed that in vitro topical application of phosphatidylcholine-dependent phospholipase C, triacylglycerol hydrolase, acid phosphatase, and phospholipase A2 enhanced the permeation of benzoic acid, mannitol, and testosterone relative to untreated skin. Tsai, et al.,[156] have shown that fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), cholesterol synthesis inhibitor fluvastatin (FLU), or cholesterol sulfate (CS) have all altered the barrier function of acetone-treated skin. In each case, there was an increase in lidocaine absorption, suggesting permeability enhancement.

3.3.4

Physical Enhancement of Permeation

Recent advances in bioengineering have led to the emergence of several novel physical enhancement techniques that been used to transdermally deliver a diverse range of compounds.[115][158]-[161] The new modalities include microneedle technology, sonophoresis, [162] iontophoresis, [117] and electroporation.[118] Microneedles. Adaptation of microfabrication technology has offered the exciting possibility of manufacturing standardized microdimensional needles that are robust enough to create pores that reach throughout the entire depth of the stratum corneum. Such pores have been observed to facilitate the rapid absorption of drugs including even those with large molecular weights. First generation devices consisted of solid (i.e., non-hollow) indentations that were fabricated directly from silicon by plasma-etch or wet-etch techniques. These microneedles are coated on the outside by the drug or active agent. Use of this technology has been shown to increase the permeation of calciene (623 Da) by 1,000-fold when the microneedles were left embedded in the skin for one second, 10,000-fold when removed from the skin after being embedded for ten seconds, and 25,000-fold when the microneedles were removed from the skin after one hour application. Application of these microneedles permitted an increase in the permeation of both insulin (5,800 Da) and bovine serum albumin (64,000 Da) by more than 10,000-fold above the sensitivity limit. Second generation microneedles are constructed from hollow metal or silicon and are filled with drug

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS solution. Use of this technology can raise the in vitro permeability of calcein, insulin, and bovine serum albumin through human skin by more than 100,000fold above the sensitivity limit.[163] Crucially, with this method, creating microscopic pores in the skin is not observed to produce any pain. Kaushik, et al.,[164] compared the discomfort scored by individuals upon using silicon microneedles, hypodermic needles, and smooth silicon surfaces. The results indicated that while the hypodermic needles were painful, there was no significant difference between the scores obtained with microneedles and those obtained with smooth silicon surfaces. Use of both these latter modalities induced no pain. The applications of microneedle technology in drug delivery were recently reviewed elsewhere.[161] Sonophoresis. Sonophoresis is the use of ultrasound to enhance topical or transdermal drug delivery. The technique has been applied for over 40 years by physiotherapists in order to treat various arthritic and inflammatory conditions. Typically, ultrasound in the 0.5 to 3 MHz frequency range has been employed for this purpose and the treatment conducted on a highly subjective and non-quantitative basis. It has since been demonstrated that this type of application is only modestly effective, if at all, in enhancing the penetration of actives.[162][165] Recent work has shown that only very low frequency ultrasound (i.e., in the 0.02 to 0.1 MHz range) can substantially, and reversibly, increase the permeability of the stratum corneum.[115][166][167] This enhancement process is a result of the development of cavitation, which is the major mechanism of skin permeabilization. The cavitation phenomenon is inversely related to the frequency of the applied ultrasonic beam.[168] Cavitation is the ultrasonically induced formation of gaseous cavities or bubbles in a sonicated medium. The volumetric oscillations and collapse of cavitation bubbles generate sufficient disorder in the lipid bilayers of the stratum corneum to temporarily permeabilize the membrane. The extent of cavitation produced is determined by a host of parameters including the frequency, intensity, and time of application of the applied ultrasonic beam.[168] Low frequency sonophoresis has been reported to facilitate the transdermal delivery of proteins like insulin, erythropoietin, and gamma interferon in vitro.[115] Of vital importance to sonophoresis is that the skin barrier

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function is returned to normal levels only several hours after sonication is completed. Preliminary experiments have shown that low frequency ultrasound seems relatively safe in terms of its application to human skin.[169] However, further work is clearly required to explore the possibilities demonstrated by this method. Iontophoresis. Iontophoresis involves the application of an electrical potential gradient to drive the cutaneous transport of molecules. The technique seems appealing since it offers the possibility of controlling the systemic delivery of drugs, and it is potentially effective for enhancing the penetration rate of any charged molecule. The electrophoretic device basically consists of an anode and a cathode connected to a power supply. Upon application of the electromotive force, charged drug molecules adjacent to the electrode of opposite charge will be repelled into the adjacent tissue.[170] The ions permeate via pathways exhibiting the lowest impedance. Examples of such pathways include sweat glands, sebaceous glands, hair follicles, and skin imperfections.[171][172] At pH values above 4, the skin exhibits a net negative charge.[170] This favors the transport of cations and hinders the transport of anions. Thus, under an applied potential, the skin favors the transport of Na + over Cl − . [173] However, since electroneutrality must be maintained, there is a net increase in NaCl concentrations in the cathodal compartment, and a net decrease in the anodal chamber. Accordingly, this disparity causes an osmotically driven flow of water from anode to cathode. This momentum is then transferred to the neutral drug molecules, thereby enhancing penetration. This phenomenon is known as the electro-osmotic effect. The Nernst-Planck flux equation mathematically describes iontophoresis. The equation indicates that the flux of an ion across a membrane under the influence of an electric field is modulated by three components: a diffusive component, an iontophoretic component, and an electro-osmotic component. The equation is symbolically written as:

Eq. (3.1)

zEFC  dC  J = Cu − D  +D kT  dx 

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where: J = molar flux C = molar concentration u = convective water flow D = diffusivity coefficient dC/dx = molar concentration gradient in the direction of the flow z = ionic valence E = electric field F = Faraday’s constant k = Boltzmann constant T = temperature (Kelvin) According to the Nernst-Planck equation, the efficiency of drug transport depends upon the polarity, valency, and mobility of the charged species, as well as upon the electrical duty cycle and formulation components selected. While current densities less than 0.5 mA/cm2 are generally well tolerated in humans, some workers have suggested that iontophoresis can induce irreversible and undesirable changes in skin morphology.[174] Concerns over the potentially detrimental effects of continuous DC electric current on the skin have led many investigators to use pulsed DC iontophoresis for drug delivery.[175] Buffers are used in iontophoresis to stabilize solution pH in the case of water electrolysis as well as to maintain the drug species in ionic form. These buffers typically are salt solutions of small inorganic ions. Unfortunately, the buffer ions can compete with the drug for carrying the electric current and thus reduce the drug’s flux. It is possible to solve this problem by using large molecular weight zwitterionic molecules such as those present in HEPES buffer.[176] Although electrolytes can impede the transport of charged drugs, they may facilitate the iontophoresis of neutral drugs due to their electroosmotic effect. Physicochemical properties of the permeant such as charge, lipophilicity, and molecular size have a great impact on the iontophoretic flux.[109] Generally speaking, there is an inverse relationship between the molecular weight of the permeating molecule and its iontophoretic flux.[109][177] Phipps, et al.,[178] demonstrated that the delivery rate of a divalent cation was half that of the monovalent species. This was

attributed to the stronger binding of the divalent ion with the fixed negative charges in the skin. Del Terzo[177] showed that for a series of n-alkanols and n-alkanoic acids, the iontophoretic delivery rate decreased as the lipophilicity of the permeant increased. A study conducted on neutral zwitterionic amino acids showed that the same trend existed with those compounds as well.[109] Electroporation. Electroporation involves the application of microsecond or millisecond electrical pulses of approximately 100–1000 V/cm to create transient, deep pores within the bulk stratum corneum. [179][180] When such defects form, both low[181][182] and high molecular-weight[183][184] compounds can be made to rapidly permeate through the skin. Although some studies using FITC-dextrans showed that the molecular cutoff for penetration was around 10 kDa, other workers have shown that electroporation enhanced the flux of neutral and highly charged molecules of 40 kDa by 10–104fold.[185][186] Interestingly, various small and large molecules may improve the efficacy of electroporation by sterically stabilizing the pores created in the skin.[186][187] Anionic lipids have been shown to greatly enhance the permeation of both small and large molecules under electroporation conditions. This effect was both charge- and size-dependent. Transport enhancement for molecules smaller than 1,000 Da occurred irrespective of their net charge, while in the case of large molecules (4,000–10,000 Da), enhancement was observed only for negatively charged ions. Sharma, et al.,[233] studied the influence of the electrical parameters on electroporation in hairless rats using terazosin hydrochloride as a model drug. In descending order of importance, voltage, pulse length, and number of pulses were the three most important parameters observed. Optimal enhancement was obtained by using five or more exponentially decaying pulses of 20 ms duration applying 88 ± 2.5 V over an area of 2.74 cm2. Extending the pulse length to 60 ms while keeping the other parameters fixed resulted in visible changes in the external appearance of the skin. Under similar conditions, but substituting the 2.74 cm2 area electrodes for 0.56 cm2 electrodes, considerably less skin damage developed. The authors described the formation of localized transport regions (LTRs) in the stratum corneum when a potential above 77 V was ap-

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS plied. The number of LTRs increased with voltage and their size increased as additional pulses were given. The pores created by electroporation can also serve as additional transport pathways during iontophoresis. Hence, the two electrical methods can be synergistically combined. Electroporating the skin with a single pulse and thereafter applying iontophoresis increased the flux of luteinizing hormonereleasing hormone by 5–10 times over that achieved by means of iontophoresis alone.[188] Chang, et al.,[189] showed that combined electroporation with iontophoresis resulted in a four-fold increase in the flux of salmon calcitonin over the use of the iontophoresis technique alone. Iontophoretic delivery of parathyroid hormone was increased 17-fold when preceded by electroporation. The skin irritation produced by an electroporation-iontophoresis combination was histologically evaluated in pigs in vivo.[190] While the extent of edema and erythema was observed to increase significantly with increasing iontophoretic current density, application of electroporative pulse did not increase the iontophoretic-induced irritation at any level of current tested. Other hairless mouse studies[191] showed that the erythema produced by electroporation was generally mild and similar to that obtained following iontophoresis.

3.3.5

Effects of Skin Hydration

Although water accounts for 10%–20% of the dry weight of the stratum corneum, upon being soaked in water for less than one hour, this tissue can absorb up to 400%–500% of its dry weight and swell up to 4–5 times its original width.[192] Constituents known collectively as natural moisturizing factor (NMF) are known to mediate the hygroscopic property of the stratum corneum. In most cases, hydration results in decreasing the stratum corneum’s barrier function. Early work showed that permeation of a range of alkanols through fully hydrated stratum corneum was ten times higher than permeation through dry stratum corneum.[45] Other studies with polar acetylsalicylic acid esters showed that skin permeation increased with hydration[193] and similar data has been obtained by others.[194] Although there are no firm theories on the mechanism underlying the enhancement effect, the collective data indicates

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the action is mediated by aqueous solvation of the polar regions of glucosphingolipids and ceramides within the stratum corneum.[195] In vivo, this effect may be associated with disruption of intercellular lamellar bilayers.[196] The occlusive or moisture-retaining nature of transdermal patches as well as certain dressings or hydrophobic ointments is shown to often increase hydration of the underlying skin.[197] This effect can have significant consequences in terms of increased skin permeability, the development of irritation, and sub-patch microbial growth.[198][199] Kligman showed that skin occlusion with an impermeable plastic film did not induce dermatitis after one week, while two week occlusion was moderately harmful to some subjects, and three-week occlusion induced hydration dermatitis in all subjects. The extent of induced dermatitis was independent of race, sex, and age.[200]

3.3.6

Supersaturation of the Drug Solution

Since Fick’s laws of diffusion state that the flux of a molecule is directly proportional to its thermodynamic activity, drug delivery can be optimized by using saturated solutions or suspensions of drugs. Higuchi[201] and later Coldman, et al.,[202] addressed the importance of chemical potential on diffusion and proposed the use of supersaturation to further augment cutaneous transport rates. This concept seems attractive since it does not involve modifying the barrier properties of the stratum corneum by adding potentially irritating chemicals. In order to test this hypothesis, supersaturated systems have been prepared by three techniques: heating and cooling,[203] use of cosolvent mixtures in which the drug has a very low solubility in one component,[204] and solvent evaporation methods employing a range of volatile:nonvolatile solvent mixtures.[205] Unfortunately, supersaturated formulations commonly exhibit instability and both drugs and salts may precipitate out during manufacturing, storage, or application. Stability of such supersaturated systems can be promoted by incorporating polymers that act as antinucleant crystal growth inhibitors such as hydroxpropyl methylcellulose (HPMC) and methyl-

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cellulose (MC).[206] Raghavan, et al., employed supersaturation to maximize the transport of hydrocortisone acetate across a model silicone polymer membrane.[206] By adjusting concentrations of the antinucleant crystal growth inhibitors and supersaturation levels, the workers could modulate the crystallization process. This approach was capable of maintaining high flux rates throughout the duration of the experiment. Polymer concentrations up to 1% yielded the maximum molecular flux, while higher concentrations increased vehicle viscosity, therefore reducing flux. Furthermore, by using inhibitor polymer concentrations greater than 2%, it was possible to maintain supersaturation for one week. Kondo, et al.,[207] adopted a supersaturation approach in order to enhance transdermal nifedipine delivery in rats. Even though the bulk vehicle was stabilized with inhibitor polymers, the formulation formed an appreciable undesirable mass on the skin surface. Overall, the supersaturation approach still has problems associated with stability during manufacture and storage. These problems remain to be resolved.[208]

3.4

Delivery System Factors

Clearly, transdermal absorption of actives into the stratum corneum is a complex process and the design of transdermal formulations remains highly challenging. Such systems must not only maintain the stability of the active drug or personal care active, but also insure that it will be released at a sufficient quantity and rate into the target tissue. Therapeutic moieties have to diffuse through the vehicle on the skin and then partition into the stratum corneum. Thereafter, the molecule must traverse this lipophilic outer skin barrier before partitioning into the more aqueous environment of the viable epidermis. This latter tissue generally offers relatively low resistance to the permeation of most compounds except for very lipophilic compounds. Finally, the drug must partition into the dermis where it then undergoes uptake into the local vascular network and is then delivered into the systemic circulation. Not all drugs are suitable for transdermal delivery. The low permeability of the skin limits the choice of candidates to those of high potency (usually <10 mg/day) and low molecular weight. Other considerations such as skin metabolism and the in-

volvement of the immune system further limit the available drug choices. Thus, there are now relatively few marketable transdermal drugs—even though there are dozens of therapeutic compounds currently being investigated in pre-clinical and clinical trials.[209]-[216] It is important to note that the permeability of a drug or personal care active through the skin depends not only on the properties of the therapeutic moiety itself but upon various formulation factors. Examples of these include compatibility and irritancy, [217] or factors related to skin metabolism,[218][219] as well as inter-site, or inter-subject variability in skin permeability.[220]-[222] The penetration of the active agent also depends upon the type of delivery system, as described in other chapters in this book.

3.4.1

Molecular Weight of the Drug Molecule

In the stratum corneum, the diffusion process is complicated by the presence of rigid corneocytes, as well as intercellular lipids existing in either a gel or liquid-crystalline state. Molecular permeation through this structure can be described by the free volume theory where diffusion occurs by the dynamic exchange of molecules within free volume regions contained within the membrane.[223] The equation describing this behavior can be expressed: Eq. (3.2)

D = D0 exp(−βMV)

In Eq. (3.2), β is a constant and D0 is the diffusivity of a hypothetical molecule exhibiting zero molecular volume.[224] This exponential dependence of solute diffusivity on molecular volume has a great impact in terms of the predictability of mathematical models in describing skin permeation. As a rule of thumb, the maximum cutaneous flux of a permeant decreases by a factor of five for every 100 Da increase in molecular weight.[225] Furthermore, it has been observed that molecules exhibiting a molecular weight greater than 500 Da will generally not absorb through the skin. However, novel approaches to transdermal drug delivery such as the electrically assisted technologies described previously have upwardly shifted the 500 Da limit towards a cutoff in

MICHNIAK-KOHN, WERTZ, MEIDAN, AL-KHALILI: SKIN: PHYSIOLOGY AND PENETRATION PATHWAYS the 5,000 to 10,000 Da range. In personal care systems such as sunscreens, it is important to retain the actives on the surface of the skin. Molecular weight considerations and their effect on penetration is an important consideration for such products.

3.4.2

Lipophilicity of the Active Molecule

The lipoidal nature of the stratum corneum and the aqueous nature of the underlying tissue indicate that the diffusant has to possess an optimal balance between lipophilic and hydrophilic properties. Generally, the skin is most permeable to moderately lipophilic compounds that exhibit an octanol-water partition coefficient of between 10 and 1,000. Molecules that are more lipophilic will tend to become entrapped within the stratum corneum and not partition into the viable epidermis. Hence, quantitative structure permeability equations used to describe passive diffusion-controlled penetration incorporate molecular weight (or molecular volume) and lipophilicity as the main determinants of transdermal absorption.[226][227]

3.4.3

Effect of the Delivery System on Permeation

Delivery systems, which include carriers and vehicles, have received serious attention in the transdermal drug delivery literature since their influence can greatly impact the absorption process. The delivery system contains not only the active drug but also contains other formulation components such as penetration enhancers, stabilizers, and preservatives. All of these functional molecules are necessary for achieving successful drug or personal care active delivery. The physical form of the delivery system/carrier/vehicle is crucial to the absorption process. As discussed in many chapters in this book, forms of these systems range from very small nanosize particles or dispersions to emulsions of both

95

the o/w type and w/o type, as well as lipid lamellar gels and the many other variations. The first step in transdermal absorption is the release and partitioning of the active agent from the delivery system into the stratum corneum—a process governed by the drug or personal active’s partition coefficient. A vehicle should be carefully selected so that it has a high active-holding capacity but, at the same time, it does not suppress transport from the vehicle into the stratum corneum. The thermodynamic activity of the active molecule will continuously change in a volatile vehicle that undergoes evaporation. Moreover, the vehicle may itself absorb into the skin, and there can be variations in the degree of absorption depending upon which part of the body is involved. If the drug or personal care active has a high affinity for the vehicle, it will be carried along as the solvent in the vehicle permeates into the tissue. An absorbed vehicle may also change the partitioning of the drug or active from the formulation into the skin. Additionally, occlusive vehicles can hydrate the skin thus enhancing its permeability to a hydrophilic drug or personal care active. Many studies have documented a synergistic effect exerted by some vehicles on the activity of penetration enhancers. Examples of this type of interaction include Azone-propylene glycol,[146] fatty acids-propylene glycol,[228][229] terpenes-ethanol,[230] and terpenes-propylene glycol.[231]

3.5

Conclusions

This overview of the nature of skin and its behavior relative to penetration by drugs or personal care additives surveys a broad overview of the literature. While much of the work has focused on drug related studies, the same mechanisms are at work during the absorption and adsorption of personal care additives. By understanding these principles, it is possible to alter and design delivery/ carrier systems that are useful for personal care applications.

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4 Delivery System Design in Topically Applied Formulations: An Overview Nava Dayan Lipo Chemicals, Inc. Paterson, New Jersey

4.1 4.2

Introduction ................................................................................... 102 Routes for Skin Penetration .......................................................... 103 4.2.1 Skin Penetration Pathways ............................................... 104 4.2.2 Skin Penetration Enhancers ............................................. 106 4.3 Improvement of the Therapeutic Index ......................................... 106 4.4 Design of Delivery Systems ......................................................... 106 4.5 Examples of Delivery Systems .................................................... 107 4.5.1 Liposomes ........................................................................ 107 4.5.2 Elastic Vesicles ................................................................. 107 4.5.3 Particulate Systems ......................................................... 108 4.5.4 Molecular Systems: Dendrimers ...................................... 109 4.6 Determination of the Site of Action ............................................... 110 4.6.1 Intracellular Delivery .......................................................... 110 4.6.2 Metabolism in the Epidermis ............................................. 110 4.7 Topical Applications: Examples .................................................... 112 4.7.1 Reduction of Melanin Synthesis by Inhibiting Tyrosinase Activity ............................................................ 112 4.7.2 Reducing the Appearance of Wrinkles by Affecting the Collagen-Elastin Network ............................................ 112 4.7.3 Improvement of Acne Condition and Intrafollicular Delivery .. 113 4.7.4 Improving the Appearance of Skin Imperfections and Superficial Delivery .................................................... 114 4.8 Summary and Future Challenges ................................................ 115 References .......................................................................................... 116

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 101–118 © 2005 William Andrew, Inc.

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4.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Introduction

etc.) as well as particulate or molecular carriers (Table 4.1)

The design of a topically applied formulation combines artistic skills with scientific knowledge in physics, chemistry, engineering, and biochemistry. In current times, when consumers are being provided with significant activity claims and information about safety concerns, the design of treatment and personal care formulations becomes more and more challenging. The formulating scientist needs to be aware of a broad range of information. This includes: functionality of the compounds used, ingredient interactions in the formula, global regulatory requirements, and the potential for undesired ingredient interaction with the skin, functional activity, and risk potential. Delivery systems are designed chemical entities that carry a chosen active compound and allow its approach to its site of action. They can be used to overcome many of the limitations of certain raw materials. For example, by encapsulating an active compound that tends to interact with other ingredients, the formulating scientist can create a physical separation between the components. This separation minimizes or eliminates the undesired interaction. The definition of “delivery systems” as we describe them is quite broad and includes the carrier formulations, (i.e., the gel, emulsion, suspension,

The purpose of this chapter is to focus on some of the issues that should be taken into consideration when developing a topically applied formulation intended to contain a delivery system. The potential interaction between the delivery system, the “formula,” and the skin are all of major importance. Potential routes for skin penetration and the active’s fate upon application should all be taken into account throughout formulation development. This chapter has been designed to initiate a process of thinking, searching, and researching that should be at the core of the development of every delivery system-based personal care formulation. The understanding of the possible interaction between a compound in a cosmetic formulation and the skin is crucial for the development of safe and effective products. Topical application pertains to a particular surface area of the skin and affects only that area to which it is applied. Two major outcomes are desired as a result of the application of topical formulations. The first of these outcomes is to support and restore the barrier function of the skin. The second outcome is to improve skin condition, by not only transporting an active compound into the skin, but by maximizing

Table 4.1. Common Rationale Required for the Development of a Delivery System

Rationale for Delivery System

Example

Improve stability

Protection from light/air, prolongation of shelf life, sensitivity to elevated temperature

Modulation of skin penetration properties

Controlled, sustained, or delayed release of active

Protection from component interactions

Prevent contact of incompatible ingredients in the formulation

Change of form

To resolve solubility/incorporation/application limitations. For example, incorporation of oil into a powder to allow the creation of powdered formulation.

Improve skin tolerance

To expand therapeutic index, improve efficacy, and improve safety

Improved esthetics

Consumer appeal

Mask undesirable properties

Change color or eliminate undesired odor

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW its effectiveness as well. When attempting to understand the scope of activity and mechanism of action of an active compound, scientists typically find it difficult to extrapolate data gained on the active’s properties and functionality to the development of a delivery system for that active. Furthermore, it is also quite difficult to extrapolate such behavior to its performance in a finished formulation. To maximize effectiveness, an active compound must demonstrate significant in vitro activity, as well as be delivered to the site of action, at the right concentration and over a sufficient period of time. Delivery systems act by altering the interaction of the “active” with its environment, (i.e., the carrier formula and/or the skin). A careful review of the reasons for needing a delivery system is useful as an initial guideline when designing a development project (Table 4.1). The development of delivery systems in the cosmetic industry has blurred the line between what is considered to be materials that affect the upper layers of the skin and those “active” compounds that affect the skin biochemistry. If the entity that needs to be affected resides within the cell, no effect will be demonstrated unless the active compound actually penetrates through the cell membrane. Obviously, compounds that have been shown to enable penetration into cells in vivo are not legally considered to be cosmetics. If one claims, for example, that a certain compound in a formula is affecting the DNA in fibroblasts, an appropriate set of data should be established in order to support this claim and the FDA needs to approve it. However, even more importantly, one needs to be aware of the risks involved in working with compounds that provide such effects. Over the past few years, with labeling claims becoming stronger and more aggressive, the cosmetic industry has taken further steps to ensure that compounds used are safe. An example of this trend is the growing interest in conducting an AMES test for mutagenicity[1] as well as other tests for measurement of reproduction safety. These are exciting times in the area of topical applications, where the pharmaceutical industry and the cosmetic industry have moved closer together in the ways they develop and analyze designed formulations. The accelerated pace of change, as measured by even more aggressive marketing approaches, increasing competition, and regulatory

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considerations on a global basis, has created an environment and trend that is increasing and cannot be reversed. This trend leads to the development of cosmetic formulations that will not only substantiate claims of altering the appearance of the skin, but protect it as well. Inevitably, this path will lead to the development and use of sophisticated techniques, based on enhanced and advanced scientific knowledge, as well as obtaining excellent clinical testing data for efficacy, but more importantly, for safety.

4.2

Routes for Skin Penetration

During the past two decades, various scientists have explored the ways in which different molecules penetrate the skin and permeate through it. This prior research reveals interesting findings about the structure of the stratum corneum and the whole skin. When a compound permeates through the skin, it is subjected to a sequence of partitioning in the different layers of the skin. These layers include the stratum corneum, epidermis, and dermis. At the deepest level of penetration (i.e., the dermis), the skin’s microcirculation is encountered and this provides an infinite “sink condition.” The term sink condition originates from the fact that the concentration of a molecule on both sides of a biological membrane (such as the skin) may approach equilibrium in a short period of time, where the skin’s dermal circulation acts as a natural sink.[2] In most cases, Fick’s law for simple diffusion has been adopted by workers in this field as the basis for calculating the flux of a compound across the membrane (i.e., through the skin). This flux is a measure of the rate at which a compound passes through the skin to the blood circulation in a given period of time. It is usually expressed as µcg/cm2/hr. The rate of diffusion or transportation across the skin’s membrane is, in most cases, directly proportional to the difference in active concentration on both sides of the membrane.[3] The stratum corneum is known to be a major barrier to the penetration of compounds into the skin. This barrier is thought to be relatively impermeable to most compounds. As the outmost layer of the epidermis, it is a highly organized, two-compartment tissue that forms the main barrier and transport obstacle of the skin. Comprised of 15–30 layers of

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dead keratinized cells, the stratum corneum consists of less than 10% of the skin, as measured from the air/skin interface. However, it contributes over 80% of the skin’s permeability barrier function! This outermost layer is comprised of stacks of flat, partially overlapping corneocytes surrounded by intercellular lipids that are arranged in a multilamellar structure. The cells are covalently linked to each other by protein structures called corneodesmosomes.[4] It is known that the largest molecules that can penetrate from simple systems through intact skin have a molecular weight of about 500. In general, in order to enhance penetration, a molecule must be completely solubilized in the formulation. If this is so, it may then lead to better solubilization of the molecule in the lipid “mortar” of the bricks-and-mortar structure model of the skin. Penetration effectiveness of a molecule will increase if its diffusion capability and partitioning into the skin are enhanced. If the amount of soluble active compound presented to the skin is high enough, the probability for a compound’s passive diffusion (according to Fick’s law) will increase. Since the stratum corneum is lipophilic in nature, two parameters that provide an indication of an active’s penetration effectiveness are a high partition coefficient between oil and water and a low melting point.[5] Although lipophilic compounds may have a tendency to permeate the stratum corneum faster than hydrophilic ones, in many cases such molecules will also tend to form a reservoir in the stratum corneum. In general, polar compounds are more likely to have difficulty in overcoming the ratelimiting barrier to penetration (the stratum corneum). However, when they do, because of the increased water gradiant across the skin, they penetrate more efficiently and to deeper layers, including reaching the level of the blood circulation. The lipophilic nature of the stratum corneum limits permeation of ionized molecules. Since the preferred route for penetration is through the intercellular domains, in general, lipophilic molecules will most likely penetrate easier than hydrophilic molecules. The permeation of a polar solute can be improved if incorporated into a solvent with a lipophilic nature.[6] When incorporated into hydrophilic solvents, the stratum corneum resistance will be elevated for charged molecules and lower for neutral molecules.[7] It has been found that although the flux

of charged molecules through the stratum corneum is lower than that of neutral ones, when such charged molecules do penetrate, the lag time for penetration can be significantly shorter than that observed for neutral molecules. It has been hypothesized that most molecules penetrate either through the pilosebaceous pathway or through specific polar pores.[8] The skin has also shown selectivity to molecular penetration as a function of the type of charge on the active compound. In general, cationic molecules are more likely to penetrate the stratum corneum than anionic ones. One of the reasons for this may be better initial attraction with the negatively charged stratum corneum. When considering penetration of acids or bases, the pH can change the permeation by creating different ratios between ionized and deionized molecular species.[9]

4.2.1

Skin Penetration Pathways

The stratum corneum is composed of dead keratin-filled cells known as corneocytes. These are glued together by a lamellar-structured lipid moiety. There are four major ways for both polar and nonpolar molecules to penetrate this structure, which has been characterized, as mentioned previously, as “bricksand-mortar” model.[10] 1. Intercellular pathway. This pathway occurs between the cells, and through the intercellular lipids. The volume of this area is about 5%–30% of the total volume of the stratum corneum. It provides the permeability barrier for most molecules. Water has been found to penetrate the skin via the intercellular pathway. 2. Transcellular pathway. This pathway occurs through the keratinized corneocytes and is also known as the polar pathway. 3. The pilosebaceic pathway. This pathway occurs via penetration through hair follicles. It is mainly a route for very lipophilic molecules and molecules used in combination with certain surfactants and glycols. Such materials are generally known as skin penetration enhancers and are described in Ch. 3. Although the available area for diffusion in this pathway is approximately 0.1% of the total skin area, this may be, surprisingly, the

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW major route penetration for both charged and large polar molecules. 4. The polar pores pathway. This pathway is comprised of aqueous “islands” that are present between cells and surrounded by polar lipids, which are typically the polar heads of ceramides. The organization of the intercellular lipid domains in the stratum corneum is important for monitoring the integrity of the skin and its barrier function. The stratum corneum lipids are primarily composed of long chain ceramides, free fatty acids, and cholesterol. These compounds form an organized bilayer lamellar structure that demonstrates a multifaceted polymorphism. This means that different bilayer structures will exhibit different transition temperatures for conversion from their gel-organized form to their crystalline liquid form. The intercellular lipids are predominantly present in their gel form, comprising mainly of saturated lipids, but have a subpopulation of less stereo-chemically organized lipids in their liquid crystalline form, which are mostly unsaturated. The stratum corneum corneocytes are surrounded with a 10-nm thick protein envelope that is covered by a 4-nm thick lipid envelope. Proteins have not been found to play a significant role in the behavior of the stratum corneum. The presence of ceramide-1 has been found to be particularly crucial relative to the structure of both the gel and the liquid-crystalline domains. The lipids found between corneocytes can form intercellular passages (virtual pores) with a size of about 30 nm. The number of intercellular lamellae between corneocytes varies within different areas in the stratum corneum. In some regions of the skin, lamellae are absent, and this structure allows for a direct contact between the corneocytes lipid envelopes.[11] It was found that after the application of uniquely designed elastic vesicles to non-occlusive stratum corneum, such vesicles induced changes that led to observable deformation in the stratum corneum structure.[12] These “elastic” vesicles have a higher degree of elasticity and a lower transition temperature than classical liposomes. Microscopic analysis has shown that application of such vesicles results in the creation of pores in the stratum corneum with sizes ranging between 50 and 200 nm. When interacting

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with the extracellular lamellar structures between corneocytes, these elastic vesicles were able to intercalate between lamellar domains and enlarge existing pores in the stratum corneum. This process allowed improved active compound permeation! The enlarged pores are observed to form a fine meshwork of fiber-like channels and are believed to represent imperfections within the intercellular lipid organization in areas with cornified envelopes. These findings have led to the conclusion that, unlike classic phospholipid liposomes, which tend to create an entrapped compound reservoir in the upper layer of the skin, elastic vesicles may be considered as skin permeation enhancers in many cases. Skin permeation enhancers reversibly reduce the barrier resistance of the stratum corneum by altering its lipid or protein domains. Some penetration enhancers, such as oleic acid, act selectively on the extracellular lipids. This interaction causes lipid fluidization, or phase separation, and produces an enlargement in the gaps that exist between corneocytes, thereby, creating pores or additional pathways for actives. It has been shown, for example, that oleic acid reduces the transition temperature of the stratum corneum lipids.[13] This leads to fluidization of the intercellular lipids and ease of penetration. Other works have shown that ethanol-water systems enhance penetration of ionic solutes by affecting polar pathways in the stratum corneum. This enhanced penetration may occur in areas that contact the lipid polar heads and/or protein-containing areas of the stratum corneum. Ethanol has been found to affect the barrier integrity of the stratum corneum by extraction of lipids, that is, leading to their loss and, as a result, separation of the stratum corneum lipid bilayers structure. Macroscopically, this change has been observed to lead to an enhanced transepidermal water loss (TEWL).[14] As stated in Sec. 4.2, most molecules with a molecular weight greater than 500 will not penetrate into intact skin from simple systems. To achieve penetration and significant active concentration levels of such high molecular-weight molecules, the use of skin penetration enhancers has been found to be necessary and effective.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Skin Penetration Enhancers

Skin penetration enhancers can be classified into four major groups: 1. Chemical. These include materials such as azone, urea, fatty acids, ethanol, and glycols. 2. Physical. Effective techniques include iontophoresis (the passage of a small electric current, around 15 mA, through the skin), and sonophoresis (low-frequency ultrasound, 20 kHz). 3. Enzymatic. These penetration enhancers inhibit key enzymes of epidermal lipid synthesis and alter the critical molar ratio of the key stratum corneum lipids. Examples of such enzymes include HMGCoA reductase and acetyl CoA carboxylase. 4. Vesicular carriers. These are artificially made microscopic vesicle spheres into which active molecules can be incorporated. Hydrophilic molecules will be incorporated into the water core of such vesicles, and lipophilic molecules will intercalate within the lipid membrane surrounding the hydrophilic core. Vesicular carriers include liposomes, niosomes (synthetic vesicles), and elastic vesicles. The vesicle walls are usually comprised of phospholipid bilayers for liposomes, or synthetic surfactants for niosomes. When studying the skin permeation properties of a compound, it is important to understand the potential routes of permeation that such an active may take. Changing the active molecular properties, and/ or choosing an appropriate delivery system enhancer or carrier formula, can produce optimal penetration by focusing active passage through a desired penetration pathway. Thus, it can be seen that having an understanding of the various possible routes for skin penetration can provide tools for the design of an appropriate system that will deliver the molecule to the desired site of action.

4.3

Improvement of the Therapeutic Index

The therapeutic index is a parameter that indicates the relative efficacy of a compound to its relative toxicity at various concentrations. It is calcu-

lated by dividing the toxic dose (i.e., the concentration of the active that causes damage by undesired interaction with biological entities that leads to toxic effects) by the therapeutic dose (i.e., the concentration needed to produce the desired results by interacting with the “right” biological entities). This parameter is an important measure of the relative safety of an active being used for a particular treatment. The use of the Therapeutic Index is well known in pharmaceutical practice and is growing for the evaluation of active compounds used in cosmetics, (i.e., “cosmeceuticals”). Examples of such compounds include: alpha hydroxy acids, ceramides, and hyaluronic acid. The release rate of an active compound from a delivery system can affect the skin’s reaction to the compound. It can be generally stated that sustained release is recommended for actives that tend to irritate the skin, are applied at significantly high doses, or demonstrate rapid skin penetration. By extending the exposure time and reducing the amount released per unit of time, not only is effectiveness increased, but the reduced release rate allows the skin “short rest” periods that enable it to adjust and, thereby, improve its ability to tolerate the new conditions.

4.4

Design of Delivery Systems

When designing a delivery system for an active in a topically applied formulation, one should acquire an understanding of the physical properties of the entrapped compound, the delivery system itself, and how the delivery system interacts with the formulation. In this regard, some of the important physical properties of the active compound are its solubility, chemical and physical stability, chemical form (acid, base, salt), physical form when applied (liquid, solid), and lipophilicity. Variations in the choice of delivery system can lead to varying properties that may influence the active’s behavior upon application. It should also be noted the delivery system might alter its properties once introduced into the final formulation. Different vehicles for the delivery system can dramatically change both its properties and the condition of the skin. Important properties that may influence delivery of the active include the percentage of active

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW entrapment, particles/vesicles/molecule size, shape, charge (zeta potential), and elasticity. Moreover, the skin condition itself also plays an important role in delivery efficacy. Even when the skin is healthy and intact, a variety of its conditions can affect delivery. These conditions include the skin’s health, age, thickness (which depends usually on the site of application), temperature, moisture content, and race.

4.5

4.5.1

Examples of Delivery Systems Liposomes

Liposomes are basically lamellar vesicular systems. These can be used to deliver active compounds to and through the skin. The mechanism by which liposomal vesicles deliver actives is not fully understood. It is believed that variations in vesicle properties can influence rate and degree of penetration, and thereby produce a range of delivery profiles. Depending upon their composition and physical properties, vesicles can either serve as a compound’s carriers, skin permeation enhancers, or as a vehicle base which provides a reservoir.[15] Such a reservoir can be created in the stratum corneum, epidermis, or even in the hair follicles and sebaceous glands.[16] Depending upon their physical properties, liposomes can change the nature of their interaction with the skin. Generally speaking, smaller vesicles, with a size of about 120 nm, can penetrate the stratum corneum better than larger liposomes having a size of about one micron and higher. It has been demonstrated that liposomes with a cationic charge show better adherence to the stratum corneum and provide better delivery of an active than adherence obtained with neutral liposomes.[17] Liposomal vesicles are nontoxic, natural, and capable of carrying both hydrophilic and lipophilic compounds. These vesicles typically have a fragile structure. However, they may be stabilized by the inclusion of cholesterol, hydrogenation of phospholipids, and the addition of positively charged molecules.[18] But even with such modifications, liposomes are known to be sensitive to mechanical

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shear, elevated temperature, and destruction by lipids or surfactants contained in the carrier formula. Furthermore, liposomes are generally prone to oxidation and may only provide limited stabilization to sensitive actives entrapped within them.

4.5.2

Elastic Vesicles

Specifically engineered vesicles have been designed by several scientists to facilitate the delivery of active compounds to and through the skin.[19] It has been found that deformable “fluid” vesicles enhance skin permeation and carry the active into deeper layers of the skin. By this means, the lag time for penetration is decreased significantly and the amount of active compound that penetrates is significantly and desirably elevated. The addition of amphiphilic molecules, macromolecules, curved lipids, or other molecules that force a twist on the lamellar structure of the vesicle are all capable of creating defects in the membrane bilayers. This action results in an increase in bilayer curvature and generates an osmotic or electric stress, in or across the membrane. Such defects undesirably prompt membrane merger, trigger vesicle aggregation, and increase their tendency to fuse together into larger structures.[20] Special ultra-flexible vesicles, known as transferosomes, have been shown to penetrate the skin when applied non-occlusively (i.e., uncovered skin, exposed to air). These vesicles have been seen to improve the therapeutic index of topically applied glucocorticosteroids.[21] Elastic vesicles have also been found to perform better than rigid vesicles or traditional micelles in promoting the transdermal delivery of the receptor agonist rotigotine that is being used to treat Parkinson’s disease. In this study, the elastic vesicles were shown to act as the molecule’s carrier and not solely act in the role of penetration enhancers.[22] Flexible vesicles have been found to interact differently with the skin when compared to rigid vesicles (classic liposomes).[23] While no ultrastructural changes were observed in rigid-vesicle–treated skin, skin treated with elastic vesicles showed an accumulation of vesicles in channel-like regions. Rapid partitioning of intact vesicles into deeper

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layers of the stratum corneum was also observed. Transferosomes were found to go through a temporary, reversible, structure deformation when applied to the skin. Being flexible, such vesicles were observed to retain their size before and after pore penetration. They were capable of adapting their shape and volume when passing through the stratum corneum. By contrast, classic rigid liposomes ruptured both during transport through the stratum corneum and when sufficient pressure was applied during use. At applied pressure, below the lower rupture stress, these vesicles tended to clog the pores.[24]

4.5.3

Particulate Systems

Porous microparticles. Porous polymeric particles with high internal surface area are used to entrap active compounds and serve as delivery systems. These materials can be incorporated into gels, creams, liquids, or powders. They can be synthetic in origin, such as polyacrylates, polymethacrylates and polyamides (Fig. 4.1), or naturally occurring as, for example, cellulose. Since these porous particulates are “open” systems, the entrapped active compound is released from the particle by means of simple diffusion. This means that the entrapped compound’s solubility properties and the media into which it is incorporated are crucial factors in affecting its release profile. When designing such a system, physical properties of the particles as well as the final formulation should be carefully reviewed. The effect on an active compound’s release and rate of absorption from such

Figure 4.1 Scanning electron microscopy photo of porous polyamide particles.

particles should be studied in advance. Key physical properties of these particles include:[25] • Particle density (g/cm3), mass per volume • Total specific surface area of pores (m2/g) • Average pore diameter (µm) • Oil absorption capacity (ml/100g) • Particle average size (nm or µm) and size distribution • Zeta potential (mV) It should be noted that zeta potential is an important parameter that is often ignored in evaluating the behavior of particulate delivery systems. When porous particulate compounds come in contact with a liquid, they acquire a charge on their surface. This charge can be quantified by measurement of their zeta potential, which is the electric potential at the shear plane adjacent to the outer carrier liquid. The shear plane is an imaginary surface separating the thin layer of liquid bound to the solid and the bulk phase.[25] Zeta potential can be a significant and useful tool for predicting and controlling the stability of colloidal suspensions or emulsions. When the absolute value of the zeta potential is above 50 mV, the dispersion has better likelihood of being stable due to mutual electrostatic repulsion of the particles. When the zeta potential is close to zero, interparticle coagulation, the formation of large particle assemblies, can be rapid and cause sedimentation (downwards) or creaming (upwards), depending on the relative density of the particles and the external phase. Different external phase conditions can also affect the zeta potential. These include salt concentration, factors determining ion concentration (such as pH), and surfactant concentration. If porous particles are incorporated into a onephase vehicle, such as an ointment, they may lose their absorption capacity. In such cases, the formulation will act only as an occlusive vehicle that protects the skin and retains moisture in the skin by reducing the transepidermal water loss. This means that although porous particles may demonstrate absorption capacity for an active when tested in the absence of a carrier liquid, they may lose their ability to release the active when incorporated into a formulation. If the porous powder particle is incorporated into a two-phase formula (such as a cream),

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW it tends to retain a considerably greater absorption capability than when incorporated into a one-phase vehicle.[26] Depending upon the formulation and the type of application, this phenomenon may be an advantage when one is interested in developing a formulation that will absorb skin secretions such as sebum and sweat. One interesting natural porous delivery system is based on cellulose and patented by Lipo Chemicals, Inc.[27] In this technology, spherical cellulose particles exhibit high chemical stability, high mechanical strength, and are compatible with most compounds used in personal care formulations. These cellulose-based porous particulates provide a smooth feel and spread easily. Since they tend to swell in an anhydrous environment, they act like microsponges and do not scratch the skin. Porous microparticles can be designed as delivery systems for the sustained release of active compounds. One example is a system designed to control the delivery of salicylic acid.[28] This product is marketed by Lipo Chemicals, Inc., under the trade name Liponyl N30SA™. It is a unique delivery system that allows for easy incorporation of salicylic acid into formulations. The product provides better targeting to the site of action (i.e., the epidermis), and produces a significant reduction in the higher irritation level usually seen with salicylic acid alone. Micro- and nanoparticles. As opposed to the open character of porous particles, micro- and nanoparticles are closed systems. There are two major types of such closed particulate systems. The first is a matrix system in which the active component is entrapped by suspending or dissolving it within the particle’s core, and the second one is the core covered by a shell. Matrix systems can possess a fairly homogeneous structure. Both systems can be made in micro- and nanoparticle size and generally are in a size range from below 800 nm (nano) to above 5 µm (micro). Materials employed for this particular type of encapsulation include gelatin, alginate, collagen, cellulose, starch, and a variety of waxes. Synthetic materials used in such systems include polyacrylates, polymethacrylates, polyamides, polyurethanes, polyvinyl alcohol, and derivatives.[29] Both micro- and nanoparticles are capable of controlling the rate of release of the active incorporated in the core and producing sustained release profiles. They are also convenient for effectively separating the

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active from the formulation, and useful for providing enhanced stabilization of the active. Since the trigger for active release in micro- and nanoparticles is either physical pressure or chemical (such as a change in pH or moisture content), the release profile of the active should be carefully studied when designing a formulation. Since the final formulation can affect the release, it is important that experiments be conducted with the final formulation. When the trigger is not consistently applied, or is too weak, the encapsulated compound often tends to remain within the particle and the amount of active compound release can be undesirably insignificant. Marine sponge collagen particles, with a spherical shape and a size ranging from 120–300 nm, have been shown to entrap up to 8% retinol. Their zeta potential was observed to be pH dependent and ranged between zero at a pH value of 2.8 to –60 mV at a pH of 9.0.[30] The particles improved skin permeation of retinol by twofold in comparison to free retinol, but had no effect on retinol stability. Retinol penetration through the stratum corneum was also improved using collagen as a matrix compound for the microcapsules. In this system, retinol was adsorbed onto the surface of microparticles, and these were incorporated into an o/w emulsion-based cream. This technique did not allow for the stabilization of retinol. However, the encapsulation of retinol by this means allowed for a rapid, higher transport rate of retinol into the skin as compared to the non-encapsulated compound. This approach also prevented undesirable retinol crystallization.[31] Poly (lactide-co-glycolide) has been used as a polymer for creation of matrix-type nanoparticles used to entrap the antiviral drugs cidofovir, and acyclovir. When applied to the skin and compared to polyvinyl alcohol solution, the particles significantly increased drug retention in the epidermis and decreased permeation through the skin.[32][33]

4.5.4

Molecular Systems: Dendrimers

Dendrimers, or fractal polymers, are macromolecules with a branched structure. The fundamentals of such polymers are described elsewhere in this book. The salient points are described below.

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As opposed to the usual linear polymeric synthesis, dendrimer synthesis is conducted in steps in which branched monomers in the shape of a tree are linked and an organized core is retained. When large enough, dendrimers form a spherical-shaped macromolecular structure with a well-defined interior and exterior. They can act as a “molecular micelle” to entrap other molecules.[34] Dendrimers typically consist of a core that is usually composed of an amine, or of sugar molecules, and consist of alternating layers of two monomers. One example is the defined structure obtained in poly (amidoamine) dendrimers with a (ethylene diamine) core. These systems are made from two monomers: acrylic acid and a diamine. Different types of dendrimers have been shown to enhance the transdermal delivery of indomethacin, an anti-inflammatory drug.[35] Dendrimer/DNA complexes have been shown to retain an ability to incorporate an exogenous DNA into a cell after drying. This technique, using dendrimer complexes in poly (DL-lactide-co-glycolide), or collagen-based biodegradable membranes, enabled the transfection of DNA in skin cells used to manipulate a variety of cell functions.[36]

4.6

Determination of the Site of Action

Delivery systems for skin applications can be tailored to target the carried compound into different sites of the tissue. Such systems can be designed to produce a variety of desired effects. For example, they can be employed to retain the active on the surface of the skin, allow different partitioning patterns in the epidermis and dermis, or even enhance the permeation of the active through the skin in order to provide transdermal delivery into the circulation. Determining the site of action and understanding the limitations of each of the approaches described are critical to successful product development of a selected active. In today’s demanding environment, just targeting the subtissue for delivery may be insufficient for achieving all of a formulations desired goals. If, for example, the target for the active is an intracellular enzyme, the cell membrane barrier should also be taken into consideration since the active has to cross the barrier.

4.6.1

Intracellular Delivery

Several in vitro experiments demonstrate intercellular penetration and effects on organelles and molecules that are located within the cell. While these results may be impressive, it is almost impossible to find a correlation between in vitro and in vivo activities. A few possible reasons for this include metabolism of the active component, its instability, penetration limitations, and differences in concentration. Further, when a “foreign” compound is applied to the skin and penetrates the stratum corneum, it may be identified as a “nonself.” As a result, the “foreign” compound is most likely to generate an immune system response. This response may alter the skin condition (i.e., create skin inflammation), change the penetration profile, and thereby affect the therapeutic index. When designing a delivery system that is meant to penetrate cell membranes, an understanding should be established of the specific cellular structure, methods of transport (active or passive), cell differentiation and proliferation, body defense mechanisms, pharmacokinetics, and safety. There are different mechanisms for intracellular penetration. The pharmaceutical industry, especially in the field of gene transfection, is seeking to learn and understand these mechanisms, as well as those by which different molecules travel in the cell. It has been shown, for example, that cross-linked gelatin nanoparticles were endocytosed into fibroblasts without being toxic to cells, even at high concentrations.[37] In this system, the physical properties of the delivery system were of high importance. Since cell membranes are negatively charged, cationic lipid vesicles enhanced intracellular penetration in comparison to uncharged vesicles.[38]

4.6.2

Metabolism in the Epidermis

In past times, the skin as a whole and especially its outer layer was considered to be almost inert. This hypothesis existed in spite of the fact that, as the outmost layer of the body, the skin is highly sensitive to interaction with outside stimuli. Examples of such stimuli include physical pressure, contact with chemicals, and temperature change. When developing a delivery system for skin, one must take into

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW account the metabolic changes of both the active as well as the delivery system components. Metabolic changes can be used as an advantage if the active is in a form of a “pro-active” that needs to be metabolized in order to reach its active form. Extensive research of stratum corneum structure and functionality conducted over the past decade has provided a key to understanding the interaction between the skin and compounds that are applied to it. Environmental, as well as intrinsic factors (such as aging or a disease), may alter stratum corneum function and structure, thereby affecting the skin’s reaction. Transport of compounds through the skin is known to bypass “first pass” effect metabolism. The first pass effect is the enzymatic metabolism that a compound goes through when being digested. However, this does not mean that the skin is lacking in enzymatic and metabolic events. Although comprised of dead cells, the stratum corneum should not be considered as an inert or static tissue. In fact, it was shown to respond in a sensitive manner to environmental insults such as injury. As such, it is responsible for many enzymatic and secretion reactions related to such insults. Moreover, sebum and sweat secretions include a variety of enzymes. Study of the stratum corneum structure has produced an improved understanding of the skin’s permeation pathways. Stratum corneum corneocytes are primarily filled with keratin filaments and osmotically active small molecules, such as urocanic acid. These small molecules arise from degradation of filaggrin and occur in response to changes in environmental humidity. The lamellar membranes of the intercellular matrix are composed of ceramides, cholesterol, and long chain fatty acids. Unlike any other biological membrane, the stratum corneum lacks phospholipids.[39] One of the important biological events that take place in the stratum corneum is the creation and mobilization of lamellar bodies that deliver enzymes which hydrolyze lipids to degrade corneodesmosomes. These lamellar granules are also rich in lipids that provide a source for newly generated stratum corneum lipids. These granules consist of ovalshaped bodies with a size of about 100 to 500 nm. The granules are composed of lipids and proteins in a ratio of 2:1, respectively. Mobilization of the lamellar bodies permits shedding of the outer corneocytes while generating lamellar structures. This process is

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a de novo (i.e., pathway by which metabolites are newly synthesized) creation and generates secretions that involve a destructive metabolism. This destructive metabolism releases energy and results in lipid breakdown (catabolism) as well as modification of lipids required for the generation of lamellar extracellular structure. Other events taking place in the stratum corneum are related to the secretion of sebum and sweat as well as the maintenance of a balanced level of bacterial flora. Key enzymatic reactions take place at the stratum corneum-stratum granolosum interface. The disruption of this barrier, for example, results in the rapid secretion of lipid-enriched lamellar bodies at this interface. The process also triggers release of immune signaling compounds, cytokines, and growth factors. The presence of these compounds is responsible for the skin’s inflammatory response.[40] There are multifaceted relationships between epidermal cell production and development, differentiation of keratinocytes to corneocytes, corneocytes maturation, and desquamation. The natural path of living keratinocytes is losing their nucleus, dying, and being filled with keratin during migration from the stratum granulosum to stratum corneum on their way to becoming corneocytes. This process is a dynamic cascade that is controlled by enzymatic reactions acting in different time frames and affected by environmental factors. It is this process that will eventually determine the barrier properties of the skin. This journey of migration takes between 15 to 30 days. Dead cells remain in the stratum corneum for about two weeks before they are shed. The molecules most likely to play a role in cohesion and desquamation are believed to be localized within the intercorneal matrix, and include glycoproteins, lipids, and enzymes. The pH of the skin (normally ranging between 5 and 6) follows a sharp gradient across the stratum corneum. This pH variation plays an important role in controlling the enzymatic activities involved in cellular metabolism and renewal. Skin pH is primarily maintained by sebum secretion, bacterial flora, cellular degradation, and metabolism.[41] A variety of enzymes are present in the intercellular spaces as well as near hair follicles. These enzymes participate in the desquamation process and include esterases, and skin specific proteases; chy-

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motryptic enzymes (chymotrypsin and its activator trypsin). Chymotryptic enzymes are produced by keratinocytes as an inactive precursor that is activated by proteolytic cleavage of short amino-terminal domains. It is thought that desquamation may be regulated by this activation of chymotryptic enzymes.[42] Other enzymes play an important role in the lipid remodeling required to generate the intercellular barrier lamellae. Among these enzymes are desaturases (secreted into the sebum, convert linoleic and linolenic acids into long-chain polyunsaturated fatty acids), as well as other lysosomal enzymes. Enzymes that control keratinocytes differentiation, such as heparanase-1, which is a matrix degradative enzyme, can also be susceptible to genetic modification. Heparanase-1 may be related to the metastatic potential of skin tumor cells.[43] The activity of stratum corneum enzymes is complicated to measure due to the difficulty of isolation and maintaining their biological activity. Such activity is partially regulated by local variations in stratum corneum pH and is modified in abnormal skin conditions such as in atopic dermatitis and psoriasis.[44]

4.7

Topical Applications: Examples

This section describes different topical applications and their claims substantiations. Reviewing the different sites of action and their barrier limitations is essential for providing tools to assist in the design of an appropriate delivery system that ensures both penetration and retention of the active compound at the desired location.

4.7.1

Reduction of Melanin Synthesis by Inhibiting Tyrosinase Activity

One common approach to reducing skin pigmentation is to limit melanin production by inhibiting activity of the enzyme tyrosinase. The first step in the process of melanin generation is the rate-limiting step in the melanogenesis cascade. This step is catalyzed

by the enzyme tyrosinase. Melanin, the coloring agent of the skin, is synthesized in the melanocytes. These cells reside in the epidermal basal layer and they synthesize melanin within specialized organelles called melanosomes. Melanosomes are specialized spherical, or ellipsoidal-shaped organelles that are the site of melanin synthesis and storage. Melanosomes are membrane-bound; they contain melanin as well as approximately fifteen types of proteins (enzymes, structural receptors, etc.). Each melanocyte provides melanin in the form of melanosomes to the surrounding keratinocytes. Epidermal melanosomes are synthesized in the cytoplasm and travel to the end of the melanocyte dendrites. The melanosome-containing dendrite ends are pinched off and endocytosed by keratinocytes.[45] In order to inhibit the tyrosinase enzyme, antityrosinase compounds have to penetrate the stratum corneum, reach the living epidermis, and permeate through the outer cell membranes of both the melanocytes and the melanosomes. The active compound or its delivery system must, therefore, possess cell membrane-permeating properties. Some useful tyrosinase inhibitors such as kojic acid, ferulic acid, and glabridin are also antioxidants.[46] When these are exposed to air or light, they can oxidize. This process may diminish their ability to inhibit the action of the tyrosinase enzyme. It is, therefore, imperative that these molecules be protected when incorporated into the formulation.

4.7.2

Reducing the Appearance of Wrinkles by Affecting the Collagen-Elastin Network

The most significant changes associated with skin aging occur in the dermis. Although the epidermis thins and becomes less hydrated with age, aspects related to keratinization are not altered. Keratin filaments, membrane-coating granules, and keratohyaline granules, involved in both the epidermis keratinization process and epidermis stabilization, are present in normal amounts.[47] In fact, aging changes start at the epidermis-dermis junction. Upon aging, there is a decrease of shared interface between these subtissues, and the degree of linkage between the epidermis and the dermis is reduced with the passage of time.

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW Aging also produces changes in a range of cells and compounds. Fibroblasts, melanocytes, and langerhans cells decrease in density, number, and/ or activity. Changes are observed in the microvasculation, collagen, ground substance (i.e., the intercellular substance of the skin), or proteoglycans, procollagen, and elastin gene expression. By contrast, the activity of collagenase enzyme, responsible for collagen degradation, and other proteolitic enzymes is elevated. This elevation leads to changes in the elastic fibers and collagen network that are largely responsible for fine wrinkling.[48] It is known that collagenase gene transcription and expression in fibroblasts increases with age, and it is hypothesized that aging leads to increased activity and expression of the enzyme protein kinase C alpha. This increased activity results in collagenase overexpression, followed by collagen degradation.[49] To significantly reduce or prevent changes observed with aging, the primary target of action should be the dermis-epidermis junction and the dermis tissues. If the active compound is a collagenase inhibitor, it needs to penetrate the cell membrane. On the other hand, if the intention is to influence collagenase gene expression, the active may need to penetrate the nucleus. The challenge in this approach is to maintain a sufficient concentration of the active at the epidermis-dermis junction. Once this junction has been reached, an active compound can be readily absorbed into the blood circulation from surrounding blood vessels.

4.7.3

Improvement of Acne Condition and Intrafollicular Delivery

When an active compound is selected to improve acne-prone skin, the pilosebaceous pathway is its primary target of action. However, the degree of penetration through this pathway is difficult to determine. One of the major reasons for this is the lack of animal models and methodologies that can distinguish between follicular and other penetration pathways. Another reason for this difficulty is that any topically applied compound can pass through more than one pathway. Nevertheless, a few specific delivery systems, including liposomes and syn-

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thetic microspheres, have been found to localize in follicular and sebaceous areas. This localization serves to provide a reservoir for active compounds. Depending upon the physicochemical properties of the compound delivered, the presence of sebum in the follicles may either limit or enhance the transport of molecules into the follicle. Dissolving the compound in a sebum miscible, lipoidal solvent (such as ethanol) may enhance penetration through the follicle.[50] Liposomes have been shown to enhance follicular delivery of both small polar molecules as well as macromolecules. Androgen hormone penetrated the sebaceous glands more effectively from liposomes than from an alcoholic solution.[51] Polymeric particulate microspheres demonstrated targeted active delivery into pilosebaceous units. In this case, particle size and vehicle composition play important roles. Optimal particle size has been found to be about five microns and the best vehicles were lipophilic in nature and included silicone-type structures such as dimethicone and cyclomethicone derivatives. Fivemicron porous nylon microspheres, for example, deposited within the pilosebaceous unit when topically applied from a lipophilic carrier formulation.[52] Salicylic acid is an active compound used in topically applied formulations for the treatment of acne. It acts as a keratolitic agent as well as having bactericidal and fungicidal properties. This organic acid has some drawbacks that limit its use. One of these limitations is its relative ease of absorption into the skin. This may lead, in some cases, to systemic toxicity, and, at the same time, result in reduced activity within its target of action (i.e., the sebaceous gland within the living epidermis).[53] Salicylic acid permeation properties and bioavailability have been shown to vary substantially among different formulations and delivery systems.[54] As a result of solubility limitations, ethanol is often used in topical applications that include salicylic acid. The use of ethanol further accelerates skin permeation. When salicylic acid is formulated to slow its release and penetration to the skin, these changes often result in a reduction in skin irritation. It has been shown that incorporation of salicylic acid into porous hydrophobic polymer particles of polyurethane (polyolprepolymer-15) produce a slow, controlled delivery of salicylic acid.[55] A delivery system developed using polymeric, porous nylon particles containing an anhydrous so-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS role in the prevention of penetration and reduction of irritation as measured by changes in the therapeutic index.

lution of salicylic acid has been shown to create a reservoir of salicylic acid within the epidermis. This reservoir significantly reduces percutaneous absorption (see Fig. 4.2).[28]

The presence or absence of appropriate protective ingredients, such as dimethicone and cyclomethicone in emulsions, may prevent irritation from sunscreens contained within the formulation.[56]

Figure 4.2 describes the flux of salicylic acid through the skin upon application of two different formulations containing the same percentage of salicylic acid in vitro. During the first eight hours of the experiment, the free salicylic acid flux through the skin was significantly higher than the flux obtained with the delivery system containing adsorbed salicylic acid. Extraction of the skin at the end of the experiment showed a higher reservoir of salicylic acid in the epidermis occurred when using the adsorbed salicylic acid.

4.7.4

Microporous beads with a size between 10 and 25 microns have been used as a delivery system for sunscreens. Data has shown this approach to be capable of reducing such irritation. In fact, any encapsulation system, whether core-shell or matrix type, that will be transparent to UV light and will not release the entrapped component, will most likely reduce irritation.[57] An example of a delivery system developed to protect the active component and prevent its interaction with the skin is a novel technology that combines fluorescence and light scattering. The product, called LipoLight™, exhibits an approach for the creation of a synergistic effect that results in a reduction of the perception of skin imperfections.[58] This system is composed of a fluorescent molecule fixed to porous nylon particles and encapsulated in a translucent shell of cross-linked polyvinyl alcohol. When formulated properly into creams, lotions, or gels, these particles allow for a dramatic reduction in the appearance of skin imperfections (Figs. 3a and 3b).

Improving the Appearance of Skin Imperfections and Superficial Delivery

Some important ingredients used in topically applied formulations are intended to protect the skin or alter its appearance by only affecting its optical properties. Such compounds need to be formulated and incorporated into delivery systems so their penetration into the skin will be minimal. Examples of such products include sunscreens and optically activated compounds. Here as well, the design of the formulation and the delivery system plays a major

Flux (mcg/cm2/hr)

1.2 1 0.8 0.6 0.4 Free SA

Adsorbed SA

0.2 0 0

1

2

3

4

5

6

7

8

Time (hr.)

Figure 4.2 Flux through the skin of free salicylic acid (SA) vs SA adsorbed in porous nylon particles (Liponyl™ N30SA).

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW

(a)

115

(b)

Figure 4.3 (a) Before and (b) after the application of optically activated particles.

4.8

Summary and Future Challenges

The challenge of developing a topically applied formulation that appeals to consumers both in terms of efficacy and safety is of great importance. However, in today’s world of greatly expanded competition, there is a need for stronger, more impactful marketing claims. Further, consumers are developing a higher level of awareness related to safety issues of certain products. Today’s formulator is constantly challenged by the need to develop products that will not only look and feel elegant, but have powerful and meaningful claims based on good clinical data, and be highly effective and safe as well. Delivery systems can be used to overcome some of the challenges cited in this chapter. A careful review of the formula’s application, site of action, limitation of raw ingredients, and other parameters described in this chapter is necessary to begin the design of an optimal delivery system. When studying the permeation properties of an active compound, it is important to understand all of the possible permeation pathways into the skin. Changing the molecular properties, and/or choosing the delivery system or carrier formula, can significantly alter the preferred path of active penetration. Understanding the

possible routes for penetration can provide insight for the design of an appropriate system that will deliver the molecule to the desired target of action. The extensive research of stratum corneum structure and functionality conducted over the past decade has provided an in-depth understanding of the interaction between the skin and compounds applied to it. Environmental, as well as intrinsic factors (such as aging or disease), may alter the stratum corneum function and structure, and thereby affect its reaction to application of different active compounds. Further research is required to better understand the structure and function of the stratum corneum and to provide an enhanced understanding of the whole skin in order to develop more sophisticated products that will produce results desired by consumers as well as being safe. Penetration beyond the stratum corneum requires careful and extensive safety studies. The industry is faced with challenges in developing delivery systems for hydrophilic ingredients, as well as release triggering approaches that are selective for different conditions. Improved bioavailability and obtaining the desired concentration at the desired site of action are also a major challenges yet to be addressed.

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References 1. Ames, B. N., McCann, J., and Yamaski, E., Methods for Detecting Carcinogens and Mutagens with Salmonella/Mammalian Microsome Mutagenicity Test, Mutat. Res., 31:347–364 (1975) 2. Abdou, H. M., Hanna, S., and Muhammad, N., Dissolution, Remington, The Science and Practice of Pharmacy, 20 th Ed. (A. F. Gennaro, ed.), Lippincott Williams & Wilkins (2000) 3. Kanga, V., Skin Care Delivery Systems, Happi Magazine, pp. 47–54, (January 2004) 4. Madison, K. C., Barrier Function of the Skin: “la raison d’etre” of the Epidermis, J. Invest. Dermatol., 121:231–241 (2003) 5. Finnin, B. C., Transdermal Drug Delivery— What to Expect in the Near Future, Drug Delivery, Business Brief, pp. 192–193, (2003) 6. Roberts, M. S., Targeted Drug Delivery to the Skin and Deeper Tissues: Role of Physiology, Solute Structure and Disease, Clin. Exp. Pharmacol. Physiol., 24:874–879 (1997) 7. Dayan, N., Ph.D. Thesis, Enhancement of Skin Permeation of Trihexyphenidyl HCl, The Hebrew University of Jerusalem (2000) 8. Ghanem, A., Mahmoud, H., Higuchi, W. I., Liu, P., and Good, W. R. The Effect of Ethanol on the Transport of Lipophilic and Polar Permeants Across Hairless Mouse Skin: Methods/Validation of a Novel Approach, Intl. J. Pharm., 78:137–156 (1992) 9. Nair, M. K., Chetty, D. J., Ho, H., and Chein, Y. W., Biomembrane Permeation of Nicotine: Mechanistic Studies with Porcine Mucosae and Skin, J. Pharm. Sci., 86:257–262 (1997) 10. Hsu, T. M. R, Jacobson, E., Hickey, A., Luo, E., and Gricenko, N., Transdermal Delivery of Hydrophilic Drugs: The Current Status and Potential for Future Drug Delivery, Drug Del. Tech., 4:58–60 (2004) 11. Bouwstra, J. A., Honeywell-Nguyen, P. L., Gooris, G. S., and Ponec, M., Structure of the Skin and its Modulation by Vesicular Formulations, Prog. Lipid Res., 42:1–36 (2003)

12. Honeywell-Nguyen, P. L., Wouter Groenink, H. W., de Graaff, A. M., and Bouwstra, J. A., The In Vivo Transport of Elastic Vesicles into Human Skin: Effects of Occlusion, Volume and Duration of Application, J. Contr. El., 90:243– 255 (2003) 13. Francoeur, M. L., Golden, G. M., and Potts, R. O., Oleic Acid: Its Effects on Stratum Corneum in Relation to (Trans) Dermal Drug Delivery, Pharm. Res., 7:621–627 (1990) 14. Levang, A. K., Zhao, K., and Singh, J., Effect of Ethanol/Propylene Glycol on the In Vitro Percutaneous Absorption of Aspirin, Biophysical Changes and Macroscopic Barrier Properties of the Skin, Intl. J. Pharm., 181:255– 263 (1999) 15. Verma, D. D., Verma, S., Blume, G., and Fahr, A., Liposomes Increase Skin Penetration of Entrapped and Non-entrapped Hydrophilic Substances into Human Skin: A Skin Penetration and Confocal Laser Scanning Microscopy Study, Eur. J. Pharm. Biopharm., 55:271–277 (2003) 16. Ciotti, S. N, and Weiner, N., Follicular Liposomal Delivery Systems, J. Liposome Res., 12:143–148 (2002) 17. Verma, D. D., Verma, S., Blume, G., and Fahr, A., Particle Size of Liposomes Influences Dermal Delivery of Substances into Skin, Intl. J. Pharm., 258:141–151 (2003) 18. Manosori, A., Kongkaneramit, L., and Manosori, J., Stability and Transdermal Absorption of Topical Amphotericin B Liposome Formulation, Intl. J. Pharm., 270:279–286, (2004) 19. Trotta, M., Peira, E., Carlotti, M. E., and Gallarate, M., Deformable Liposomes for Dermal Administration of Methotrexate, Intl. J. Pharm., 270:119–125 (2004) 20. Cevc, G., and Richardson, H., Lipid Vesicles and Membrane Fusion, Adv. Drug Deliv. Rev., 38:207–232 (1999) 21. Fesq, H., et al., Improved Risk-benefit Ration for Topical Triamcinolone Acetonide in Transferosome in Comparison with Equivalent Cream and Ointment: A Randomized Controlled Trial, Br. J. Dermatol., 149:611–619 (2003)

DAYAN: DELIVERY SYSTEM DESIGN IN TOPICALLY APPLIED FORMULATIONS: AN OVERVIEW 22. Honeywell-Nguyen, P. L., Skin Penetration and Mechanism of Action in the Delivery of the D-2 Agonist Rotigotine from Surfactant Based Elastic Vesicles Formulations, Pharm. Res., 20:1619–1625 (2003) 23. Honeywell-Nguyen, P. L., de Graaff, A. M., Groenink, H. W., and Bouwstra, J. A., The In Vivo and In Vitro Interactions of Elastic and Rigid Vesicles with Human Skin, Biochim. Biophys. Acta, 1573:130–140 (2002) 24. Cevc, G., Schatzlein, A., and Richardson, H., Ultradeformable Lipid Vesicles Can Penetrate the Skin and Other Semipermeable Barriers Unfragmented—Evidence for Double Label CLSM Experiments and Direct Size Measurements, Biochim. Biphys. Acta, 1564:21–30 (2002) 25. Schott, H., Colloidal Dispersions, Remington: The Science and Practice of Pharmacy, 20th Ed. (A. R. Gennaro, ed.), pp. 294–304 (2000) 26. Juch, R. D., Rufli, T., and Surber, C., Pastes: What Do They Contain? How Do They Work?, Dermatol.,189:373–377 (1994) 27. Sojka, M., Sustained Release Compositions and Controlled Delivery Method, US Patent Application 30530/38803 (Jul 2003) 28. Dayan, N., and Basak, K., A Delivery System for Salicylic Acid to Overcome the Drawbacks of its Use in Topically Applied Formulas, C&T Manufacture World Wide Magazine, pp. 114–118 (2003) 29. Bross, C., Soulif, J. C., and Bross, J. C., Preparation of Microcapsules for Skin Allergy Testing by Solvent Evaporation Process, J. Microencapsul., 17:111–116 (2000) 30. Swatschek, D., Schatton, W., Muller, W., and Kreuter, J., Microparticles Derived from Marine Sponge Collagen (SCMP’s); Preparation, Characterization and Suitability for Dermal Delivery of All-trans Retinol, Eur. J. Pharm. Biopharm., 54:125–133 (2002) 31. Rossler, B., Kreuter, J., and Ross, G., Effect of Collagen Microparticles on the Stability of Retinal and its Absorption into Hairless Mouse Skin In Vitro, Pharmazie, 49:175–179 (1994) 32. Santoyo. S., de Jalon, E. G., Ygaruta, P., Renedo, M. J., and Blanco-Prieto, M. J., Op-

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timization of Topical Cidofovir Penetration Using Microparticles, Intl. J. Pharm., 242:107–113 (2002) 33. de Jalon, E. G., Blanco-Prieto, M. J., Ygaruta, P., and Santoyo, S., Topical Application of Acyclovir-loaded Micro Particles Quantification of the Drug in Porcine Skin Layers, J. Control Rel., 75:191–197 (2002) 34. Kanga, V., What’s New in Cosmetic R&D, Happi Magazine, 41:1–7 (2004) 35. Chauhan, A. S., Sridevi, S., Chalasani, K. B., Jain, A. K., Jain, N. K., and Diwan, P. V., Dendrimer-mediated Transdermal Delivery: Enhance Bioavilability of Indomethacin, J. Contr. Rel., 90:335–343 (2003) 36. Bielinska, A. V., Yen, A., Wv, H. L., Zahos, K. M., Sun, R., Weiner, N. D., Baker, J. R. Jr., and Roessler, B. J., Application of Membrane-based Dendrimer/DNA Complexes for Solid Phase Transfection In Vitro and In Vivo, Biomaterials, 21:877–887 (2000) 37. Gupta, A. K., Gupta, M., Yarwood, S. J., and Curtis, A. S., Effect of Cellular Uptake of Gelatin Nanoparticles on Adhesion, Morphology and Cytoskeleton Organization of Human Fibroblasts, J. Control Rel., 95:197–207 (2004) 38. Dayan, N., and Touitou, E., Carriers for Skin Delivery of Triethexyphenidyl HCl: Ethosomes vs. Liposomes, Biomaterials, 21(18):1879– 1885 (2000) 39. Feingold, K. R., and Elias, P. M., The Biochemical Basis and Regulation of Cutaneous Permeability Barrier Homeostasis, Skin: Interface of a Living System (H. Tagami, J. A. Parrish, and T. Ozawa, eds.), pp. 39–51, Elsevier, Amsterdam (1998) 40. Pierard, G. E., Goffin, V., and Hermanns-Le, T., and Pierard-Franchimont, C., Corneocyte Desquamation, Intl. J. Mol. Med., 6:217–221 (2000) 41. Brysk, M. M., and Rajaraman, S., Cohesion and Desquamation of Epidermal Stratum Corneum, Prog Histochem. Cytochem., 25:1–53 (1992) 42. Simon, M., Expression Analysis of Stratum Corneum Chymotryptic Enzymes (SCCE) and its Precursor at the Surface of Human Epi-

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43. Dempsey, L. A., Brunn, G. J., and Platt, J. L., Heparanase, A Potential Regulator of Cellmatrix Interactions, Trends Biochem. Sci., 25:349–351 (2000) 44. Beisson, F., Aoubala, M., Marull, S., Moustacas-Gardies, A .M., Voultoury, R., Verger, R., and Arondel, V., Use of the Tape Stripping Technique for Directly Quantifying Esterase Activities in Human Stratum Corneum. Anal Biochim, 290:179–185 (2001) 45. Nordlund, J. J., and Boissy, R. E., The Biology of Melanocytes, The Biology of the Skin (R. K. Freinkel and D. T. Woodley, eds.), pp.113–131, The Parthenon Publishing Group, New York (2000) 46. Toda, S., Kumura, M., and Ohnishi, M., Effects of Phenolcarboxylic Acids on Superoxide Anion and Lipid Peroxidation Induced by Superoxide Anion, Planta Medica, 57:8–10 (1991) 47. Maltolsy, A. G., Desmosomes, Filaments, and Keratohyaline Granules: Their Role in the Stabilization and Keratinization of the Epidermis, J. Invest. Dermatol., 65:127–142 (1975) 48. Peterson, M. J., Aging of the Skin, The Biology of the Skin, (R. K. Freinkel and D. T. Woodley, eds.), pp. 209–217, The Parthenon Publishing Group, New York (2000) 49. Ricciarelli, R., Maroni, P., Ozer, N., Zingg, J. M., and Azzi, A., Age-dependent Increase of Collagenase Expression Can Be Reduced by Alpha-tocopherol via Protein Kinase C Activity, Free Radic. Biol. Med., 27:729–737 (1999) 50. Lauer, A. C., Percutaneous Drug Delivery to the Hair Follicle, Percutaneous Absorption, (R. L. Bronaugh and H. I. Maibach, eds.), pp. 427–449, Marcel Dekker, Inc. (1999)

51. Bernard, E., Dubois, J. L., and Wepeirre, J., Importance of Sebaceous Glands in Cutaneous Penetration of an Antiandrogen: Target Effect of Liposomes, J. Pharm. Sci., 86:573– 578 (1997) 52. Mordon, S., Sumian, C., and Devoisselle, J. M., Site-specific Methylene Blue Delivery to Pilosebaceous Structures Using Highly Porous Nylon Microspheres: An Experimental Evaluation, Lasers Surg. Med., 33:119–125 (2003) 53. Parfitt, K. (ed.), Salicylic Acid, Martindale, The Complete Drug Reference, 32nd Ed., pp. 1090–1091, The Pharmaceutical Press, US (1999) 54. Tsai, J., Chuang, S., Hsu, M., and Sheu, H., Distribution of Salicylic Acid in Human Stratum Corneum Following Topical Application In Vivo: A Composition of Six Different Formulations, Intl. J. Pharm,. 188:145–153 (1999) 55. Rhein, L., Chaudhuri, B., Jivani, N., and Fares, H., Targeted Delivery of Salicylic Acid from Acne Treated Products Into and Through the Skin: Role of Solution and Ingredient Properties and Relationships to Irritation, J. Cosmet. Sci., 55:65–80 (2004) 56. Nichols, K., Desai, N., and Lebwohl, M. G., Effective Sunscreen Ingredients and Cutaneous Irritation in Patients with Rosacea, Cutis, 61:344–346 (1998) 57. Embil, K., and Nacht, S., The Microsponge Delivery System (MDS): A Topical Delivery System with Reduced Irritancy Incorporating Multiple Triggering Mechanisms for the Release of Actives, J. Microencapsul., 13:575– 588 (1996) 58. Sojka, F. M., Dayan, N., Riemer, J., Ortega, L., Cummins, P., and Hawkins, S., Optically Activated Particles for the Reduction of the Appearance of Skin Imperfections, Intl. Symp. Control Rel. Bioact. Mater., 072, Controlled Release Soc, Proc., Scotland (2003)

5 From Ancient Potions to Modern Lotions A Technology Overview and Introduction to Topical Delivery Systems Elishalom Yechiel Elsom Research Co., Inc. San Antonio, Texas Rosemarie L. Coste Elsom Research Co., Inc. San Antonio, Texas 5.1 5.2

5.3

5.4 5.5

Introduction ................................................................................... 120 Origins of Delivery Systems ......................................................... 120 5.2.1 Defining Delivery Systems ................................................ 120 5.2.2 Delivery Systems in Nature .............................................. 121 5.2.3 Nature-Inspired Delivery Systems Technology ................. 122 Origins of Personal Care: When Medicine and Cosmetics Were One ..................................................................................... 124 5.3.1 Ancient Medicine: Unifying Theories and Philosophical Aspects ...................................................... 124 5.3.2 Traditional Medicine: Maintaining Balance ......................... 126 5.3.3 Modern Medicine: Separation and Reunion of Medicine and Cosmetics ................................................................. 127 Foundations of Personal Care Technology ................................... 128 5.4.1 Technology in Ancient Formulae ....................................... 128 New Technology for Personal Care: An Introduction to Delivery Vehicles ........................................................................................ 130 5.5.1 Nanosomes™ ................................................................... 130 5.5.2 Nanoemulsions and Dispersicles™ ................................. 130 5.5.3 Nanoencapsulation ........................................................... 130

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 119–134 © 2005 William Andrew, Inc.

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Conclusions .................................................................................. 130 Formulations ................................................................................. 131 5.7.1 Acne Treatment (Traditional Chinese), Enhanced with Nanoencapsulation .................................................... 131 5.7.2 Oil of Anointing (Ancient Hebrew), Enhanced with Nanoemulsion ................................................................... 131 5.7.3 Pain Relief Gel (Ayurvedic), Enhanced with Nanosomes™ ................................................................... 132 References .......................................................................................... 132

5.1

Introduction

Delivery systems for drugs and active ingredients, and size-reduction technologies such as microtechnology and nanotechnology, are at the frontier of advances in modern biotechnology. In particular, developments in transdermal delivery systems carry new hope for replacing current high-risk intravenous applications and drastically reducing undesirable side effects of drugs and active ingredients. Quite surprisingly, these seemingly new advances in the state of the art have natural counterparts and many are inspired by nature. More surprisingly, delivery systems and miniaturization technologies have been practiced since ancient times. This chapter is an overview of some of the ideas and practices that have created and complicated the current status of the field of personal care delivery systems. It provides starting points for further reading; a lengthy but far from comprehensive list of references is provided, from what, at first glance, may be a surprising assortment of fields. These include: linguistics, library science, history, botany, zoology, anthropology, religion, and, of course, chemistry. The wide range of fields is representative of the significant opportunity to draw on principles of technology transfer to generate new delivery systems technology. Our goal is to develop a broad understanding of three key concepts and how they relate to each other: topicals, miniaturization, and delivery systems. Examining what a delivery system is, at the level of its most basic components, will make it possible to appreciate current refinements in context. There are varied interpretations of what is and what is not “personal care” and what is and what is not “medicine.” We will show that personal care is on a continuum with other fields, including medicine, and all of these

rely upon delivery systems to make their formulations effective. The idea of connecting “effectiveness” to personal care products is problematic, since there are regulatory requirements restricting claims of effectiveness to the realm of medicine rather than cosmetics. Some of the origins of and recent responses to this problem are also discussed.

5.2

Origins of Delivery Systems

Recent technological progress[1] has drawn attention to the usefulness of delivery systems in both medical and cosmetic formulations. However, delivery systems are not a new idea. Examples of delivery systems abound in nature and in the record of early human technology.

5.2.1

Defining Delivery Systems

The Oxford English Dictionary[2] records an archaic use of “deliver” as an adjective: a person, place, or thing may be described as deliver if it is free of encumbrance; agile, nimble, active. The word deliver derives from the same Latin root as liberty and persists in Modern English as a verb. In general usage, this verb relates to transportation, as in the delivery of packages by the postal service. The definitions and synonyms offered in the Oxford English Dictionary, however, are clear reminders that the word is not so much about movement as about freedom. “To deliver” is to save, rescue, set free, release, rid, divest, unload, assist, disburden, speak,

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS surrender, yield, abandon, recite, report, and communicate, as well as to transfer. What are delivery Systems? Delivery cannot be accomplished by a single item in stasis; some change of condition or location is required to enable a person to be delivered from slavery to freedom, or a parcel to be delivered from one mailbox to another, or a drug to be delivered to its target organ. Change is essential, and change can be accomplished in only a few ways. Physical or chemical energy must be applied, and that energy must have a source. The combination of the material to be changed, and the material or method creating the change, comprises a simple system. More complex combinations may define larger systems and produce more complex changes. This is especially true when new techniques of micro- and nanotechnology are employed. What problems are delivery systems intended to solve? In the context of personal care, delivery systems are most often implemented to overcome barriers[3] such as the outer layers of the skin; we will name such delivery systems “intradermal vehicles.” In topical medicinals, we can define “transdermal vehicles,” in which a drug must penetrate through the skin, and even the membrane surrounding a cell, or be transferred to the blood stream and internal organs. A material may exist on one side of a barrier, but be useful only on the other side of the barrier and that material, due to its size or other features of its chemical structure, is unable to cross the barrier. For example, vitamin A, which is an oil-soluble molecule, cannot penetrate the skin. Another material may be able to penetrate the barrier but is unable to accomplish anything useful once it does. For example, liposomes, and particularly small liposomes that are amphipathic, are able to penetrate into skin. (For more information on liposomes’ structure and function, see Ch. 14 in this book). Properly combining two materials such as by encapsulating vitamin A (the useful material) into liposomes (the barrier-crossing vehicle) creates a system capable of delivering beneficial material to the previously inaccessible location protected by the barrier. As in the examples mentioned above, vitamin A can be transported by a liposome into the skin. New methods of creating such combinations, and new information about the properties of materials when combined, are at the root of new developments in personal care and in drug delivery systems.

5.2.2

121 Delivery Systems in Nature

The need to move material from one location to another, perhaps changing its form as well as its location to make it useful, is solved in varied ways in nature. The digestive process takes in bulk raw material and reduces it to usable nutrients by breaking down complex materials into small particles or into singular molecules. This process is called miniaturization or micronizing. It combines the molecules with bile salts. This combination of oil-soluble molecules with bile salts is emulsification; emulsions are effective delivery vehicles. The emulsified materials are then transported to the body, via the intestinal wall, to be used as nutrients. There are counterpart topical delivery systems that are based on downsizing, loading onto vehicles, and transporting through the skin. The reproductive process combines simple materials into the beginnings of a complex new organism and is largely dependent on mediation and translocation of materials to an effective proximity (see more about “proximity” in Ch. 14 of this book). In the process of infection, tiny organisms are carried in or on the bodies of larger organisms, to destinations in or on larger organisms, and are mechanically transported by puncturing the skin, just as injections are performed with syringes. Not surprisingly, some of the delivery systems technology developed by humans are very similar in structure and function to the delivery systems developed by natural organisms. Reproduction. All forms of sexual reproduction depend upon delivery systems. For aquatic invertebrates and some fish, that delivery system is the water in which they live. For these creatures, reproductive material is released into the water, and the water carries it into the proximity of other reproductive material with which it can combine. There is not much targeting (for more information about targeting, see Ch. 14 of this book) and the method of fertilization is based on excess material. This may initially appear to be waste but is necessary for reproductive success. Wind-pollinated grasses use the air the same way and rely upon air currents to circulate reproductive material among immobile individuals. Such systems are only successful because vastly more reproductive material is produced and released into the air or water than ever reaches

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another fertile individual of the same species. Most of the material is wasted, lost in transit, but excess production improves the odds of some of the material reaching its target. This is similar to treating a headache by a medicine that spreads all over the body, including areas that are not in pain. Other plants, such as dandelions, use the air to carry ripe seeds to distant locations. Following such transport, these seeds can sprout without competing with the parent plant. Coconuts use the tide and burrs use the fur of passing animals in the same way, to carry their seeds from one location to another. Pollination mediated by an animal, such as a bee, bird, or bat, is an example of a much more complex and targeted natural delivery system. Understanding this process provides a useful model for understanding the technological delivery systems that are explained in Sec. 5.2.3. With the animal acting as the delivery vehicle, the delivery process can only succeed if the flower’s pollen-bearing anther is the right shape to deposit pollen on the animal. The pollen-receiving stigma must also be the right shape to collect that pollen from the animal, and the animal must be the right size to reach them both. If the flower’s parts are too large or small, or otherwise inaccessible or unattractive, delivery will fail.[4] Similarly, technological delivery systems, no matter how advanced their construction, are only successful when the delivery vehicle, the material to be delivered, and the source and target of the material, are carefully matched. Problems with size, shape, and orientation at the proximity of the site of action can prevent a liposome, as surely as they can prevent a honeybee, from acting as an effective delivery vehicle.[3] Infection. A delivery system moves material to a location where it can be used. In the case of insect-vectored infection, the highly mobile insect carries a pathogenic organism to a suitable plant or animal host. The pathogen is most often a virus but possibly a bacterium, fungus, or nematode. Since “most pathogens are relatively immobile in their own right, part of the vector’s role in disease transmission is to deliver the pathogen to the appropriate part of the host’s tissue from where the pathogen can continue its life cycle.”[5] The best known insect vectors of human disease pathogens, such as mosquitoes carrying malaria or fleas carrying bubonic plague, accomplish the delivery by means of injec-

tion. They use their mouth parts to puncture the epidermis and deliver the pathogen into the circulatory system. The circulatory system then delivers the pathogen to the appropriate internal organ. However, topical delivery of disease pathogens is also possible. Cockroaches, for instance, spread pathogens simply by walking, regurgitating, or excreting. If those pathogens end up infecting a host’s digestive system, it is because that host completed the delivery process by ingesting the roach-delivered pathogens from the contaminated surface.[5] Digestion. Digestion “transforms food into energy, nutrients, and waste products, all of which are sent to appropriate parts of the body for dispersal and disposal.”[6] These transformation and transportation processes rely on the downsizing of large material into usable particles. Transformation, especially downsizing, is accomplished by mechanical methods such as chewing, and by chemical interactions between the food material, hydrochloric acid, and enzymes in the digestive system. Emulsification with bile salts and fatty acid salts enhances absorption of the downsized particles, making it possible for the body to put them to use. Transportation of food materials also requires mechanical operations such as swallowing and peristalsis before they are in the right place and of the right size to move from the digestive system to the circulatory system. After successfully making this passage, they are able to provide fuel for the rest of the body. The process of releasing the energy stored in raw material so that it can provide energy to a living organism is one of the most complex examples of a natural delivery system.

5.2.3

Nature-Inspired Delivery Systems Technology

Topical delivery. Many mammals find ways to cool, soothe, and protect their skin by using natural substances. For example, large mammals with relatively thin coats of hair, such as elephants, hippopotami, and pigs, cover themselves in mud in order to protect themselves from heat and insects and, perhaps, to heal injuries and diseases. Humans also exhibit similar behavior. Some spend large sums of money to purchase clay facial treatments or have themselves covered in mineral-rich mud in spas or

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS at resorts such as those on the Dead Sea in order to obtain beneficial effects on their health and wellbeing. Substantial success has been recorded in treating skin diseases such as psoriasis and vitiligo, as well as rheumatism symptoms, with Dead Sea water and mud.[7][8] The effectiveness of such treatments may be because the minerals in mud increase hydration and remove impurities from the skin. In these cases, the mud is operating as a simple delivery system, moving water, minerals, and sometimes organic material into the skin and taking waste products away. The mudpack is an example of a slow release system. A slow release system is a form of encapsulation of beneficial ingredients, slowly diffusing from the center of a capsule, such as the mudpack, into the skin. Injectible delivery. Sharply pointed insect stingers and mouth parts are perfect natural models of the process of injection. By this means, material is moved into, and sometimes out of, a target. Their operation obviously resembles that of modern syringes used to insert drugs into or remove blood from the circulatory system.[5] Oral delivery. Encapsulation in an oral delivery system is demonstrated by edible berries. The outer coating, colorful and tasty, is attractive to the vehicle, a bird, which consumes the entire berry. In this process the bird removes the coating by digesting it as food, carries it some distance away from its parent plant, and deposits the indigestible seed, stripped of its coating, along with some fertilizer, so that it is ready to sprout.[4] In medicine, encapsulation is required to protect a drug from harm and/or to protect the organism from the drug until it reaches its target organ, where it must be decapsulated in order to become active. Tablets are often coated in such a way as to protect the contents from digestion until they reach the appropriate part of the digestive system. The capsule coating can be acid-resistant, so it is protected in the stomach; base-resistant, so it is protected in the duodenum; or it can be resistant to both acid and base and only degradable by microorganisms in the intestines. On a much smaller scale, material in liquid form can be microencapsulated and nanoencapsulated to protect it until it reaches its target. Targeted delivery. Many home gardening enthusiasts are able to make general observations relating a flower’s form to the characteristics of the

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flower’s major pollinator. Such knowledge helps a gardener select flowers based on which pollinating animals are desired in the landscape. Hummingbirdpollinated flowers tend to be thin and tubular, hanging at an angle comfortably visited by hovering birds, which collect sticky pollen on their beaks. Butterflypollinated flowers are often open and platelike, allowing butterflies to rest and walk on their surfaces while they eat, collecting pollen on their feet and mouths. Bat-pollinated flowers open in the evening and are large, open, and hairy, dusting visitors’ fur with pollen. Bee-pollinated flowers tend to be round and deep; bees are often required to walk some distance into a tunnel to collect nectar and pollen. Botanists have confirmed these general observations and added detailed understanding to the mutualistic relationship between plant and pollinator. For example, study of the hummingbird-dependent bromeliad Aechmea pectinata in Brazil confirms that, although many varieties of hummingbirds, with many lengths, shapes, and angles of beaks, are available in its habitat, the size, shape, and angle of its blossoms conforms to the straight, sharp beak of its primary pollinator Thalurania glaucopis.[9] Because Thalurania is highly territorial, and Aechmea grows in dense groups of related individuals, each carrying numerous clusters of flowers designed to deposit pollen on a beak shaped exactly like Thalurania’s, the hummingbird is likely to feed within its territory and thereby transport pollen only among Aechmea flowers. This is an example of a highly specific and highly targeted delivery system existing in nature, demonstrating the necessity of proper shape, affinity, and targeting for effective delivery. Shape-matching is a mechanical form of targeting which determines whether it is even possible for the interaction between the vehicle (bird) and the active (pollen) to take place. When the size and structure of the vehicle perfectly matches the size and shape of the target, other vehicles may not be able to interact with the active at that target. Just as a bird and flower may interact most effectively with each other, so a vehicle will lock into only the active with which it has a “key and lock” relationship. Just as an animal prefers a specific flower to others, while other animals may be uninterested or may dislike the aroma or the taste of the flower, so is affinity between vehicle and active. When there is high chemical affinity, the vehicle and the active

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will lock on each other preferentially over interactions with other molecules. This is a very efficient delivery system in nature and in medicine since the rate of success of pollination, just as the rate of interaction between vehicle and active, is very high. In such a situation, very low quantities of vehicle and active can be effective. In drug or active delivery systems, such efficient delivery is the greatest challenge. For example, a liposome containing a drug for a specific cell type in a specific organ is embedded with antibodies to antigens that are expressed only in that cell type from only that organ, and only by those cells that are afflicted with the disease to be cured. When within proximity of the site of action, there are “key and lock”-type targeting problems to be solved in order for a vehicle, such as a liposome, to release the active directly into the site of action with minimal waste. The active must reach every cell and be released in a way that it will be in contact with only those cells, and all those cells. For more information on proximity-related targeting, see Ch. 14.

5.3

Origins of Personal Care: When Medicine and Cosmetics Were One

Delivery systems exist in nature and in human technology that mimics nature. It should not be surprising, therefore, to find such systems in “natural remedies” from many sources. The belief that personal care (cosmetics) is an undertaking separate from health care (medicine) has not been widely held in human cultures. In some ancient traditions, welldocumented but no longer practiced, perfumery and medicine were both seen as divinely given and were both regulated as sacred activities. In some currently practiced traditions with ancient roots, health practices depend on maintaining beauty and harmony among many internal and external elements. In these traditions, not only body and mind must be kept in balance, but relations between the person and the environment must also be harmonized. In more recently established Western, and especially American, practices, treatment of disease is seen as necessarily separate from the creation of personal or

environmental beauty; however, current trends toward educating new physicians in the basics of “alternative medicine,” as well as the growing interest among personal care practitioners and consumers in “functional cosmetics,” suggest that this sense of separation is weakening.

5.3.1

Ancient Medicine: Unifying Theories and Philosophical Aspects

Divinely attributed formulae for medicine and perfume are provided in some of the oldest texts available from the region now called the Middle East. These include the Sumerian tale of Emmeduranki, the Hebrew Exodus story, and the Egyptian Book of the Dead. What these traditions from neighboring peoples have in common is a deep concern with respect for proper formulation and an insistence on regulating uses that would now be called medical or cosmetic. Health and beauty were affairs of the highest importance in these cultures, and related activities were described in their time as elements of religion. Perhaps the modern necessity to scrupulously abide by FDA regulations, lest disaster befalls, comes close to the ancient determination to follow divine instructions about the creation and use of these materials. Medicine: A Divine Gift. A Sumerian tale of one human’s encounter with friendly gods[10] recounts two gifts the gods gave their new friend. First, “they showed him how to observe oil on water—a secret of Anu, Enlil, and Ea.” The combination of oil and water is an emulsion. Emulsification is central to the formulation of both medicines and cosmetics, with the emulsion serving as a basic delivery system.[1] The second divine gift, perhaps the necessary companion to the first, was that “they taught him how to make calculations with numbers.” Knowledge of mathematics, along with knowledge of emulsification, makes possible the complex formulations necessary for the “first pharmacoepia” recorded on a clay tablet in Sumer more than four thousand years ago.[11] Personal Care: A Matter of Life and Death. “Cleanliness is next to godliness” is an old, overused expression. Perhaps its origin is found in this section of the Book of Exodus, which describes procedures

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS for making and operating the Tabernacle that would travel with the People of Israel: “When they come into the Tent of Appointment they are to wash with water so that they do not die, or when they approach the slaughter-site, to be-in-attendance, to send up fire-offerings in smoke […], they are to wash their hands and their feet, so that they do not die. It is to be for them a law for the ages, for him and for his sons, throughout their generations.” Exodus 30:20-21[12] The simplest personal care procedure, that of washing hands and feet with water, thus becomes an urgent and permanent command, divinely imposed. The Exodus narrative proceeds from instructions on personal washing to instructions about the making and use of perfumed oil. After a list of ingredients (included among the formulations below), the commandment is issued to “make (from) it anointing oil of holiness, perfume from the perfume-mixture, of perfumer’s making; anointing oil of holiness it is to be” (Exodus 30:23-25[12]) and to strictly limit its use. This oil is to be used on the Tabernacle and its contents, including the priests, but “On any (other) human body it is not to be poured out; in its (exact) proportion, you are not to make any like it—holiness is it, holiness it shall remain for you. Any man who mixes-perfumes like it or who puts any of it on an outsider is to be cut off from his kinspeople!” Exodus 30:32-33.[12] Ingredients for “smoking-incense, perfume, of perfumer’s making” follow: “fragrant-spices, dropgum, onycha, and galbanum, (these) fragrances and clear incense; part equaling part;” like the oil, it is forbidden to create this incense for ordinary purposes: “…you are not to make any for yourselves in its (exact) proportion; holiness shall it be for you, […]. Any man that make any like it to savor it is to be cut off from his kinspeople!” Exodus 30:34-38.[12] It is clear from these prohibitions that there was a preexisting practice of perfumery, making oils and incense for personal use and enjoyment. So long as such products did not follow the exact formulae of the holy oil and incense, they were permitted.

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Very strong wine,[13] which had a high alcohol content, was used with the preparation of fragrances, and the grinding process was aimed at grinding the spice particles as finely as possible.[14] The chief of the formulators was required to chant “downsize them finer, grind downsize them finer” because, as it was said, the sound waves are good for the process. According to Maimonides,[15] each spice was ground separately while immersed in very strong wine. The special sound waves of the notes chanted were considered to allow better extraction than the much stronger sound of the pestle hitting the mortar, even if that pestle had a bell added to soften its sound. Sonic-mediated extraction is today a state-of-theart technology, allowing improved penetration of the extracting solvents into the powdered substance. Choice of suitable sound waves to maximize the extraction is, amazingly, an issue elaborated upon and argued in depth about an extraction process practiced in the Temple in Jerusalem more than 2,000 years ago. Preservation: beauty above all. In ancient Egypt there were active practitioners of both cosmetics and medicine. Practitioners of both of these arts were considered to be high-status professionals. One physician, Imhotep, was honored with deification as the god of medicine, the only commoner to have achieved such an honor.[16] Although medical practitioners were admired, their skill was seen as transitory since it was of no use after death. Medicine could keep the body alive, but could not give access to the afterlife. Cosmetics, rather than medicine, were of lasting importance since only the outward appearance was believed to survive. By sustaining the body’s appearance of life, cosmetics made the afterlife possible. Ancient Egyptians believed that “eternal life” after death was possible only so long as the body remained intact. Their efforts to prevent the natural process of decomposition led to development of a complex burial process, including mummification and the construction of pyramids and other elaborate tombs.[16] Preserving the body meant maintaining its normal appearance by preserving the visible portions of the body. Skin, muscle, and bone contribute to appearance and so were preserved. The brain and internal organs, considered rapidly decaying waste matter, were removed. Their places were filled with resins, sawdust, and linen to preserve appear-

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ance by restoring the empty body cavity to its normal shape. After the mummy was wrapped, final steps were taken to help the spirit recognize its body. A cosmetician painted the lips, eyes, cheeks, nails, palms, and soles, and the body was fitted with a wig, all in the interest of accurately representing the deceased person’s living appearance. The body was provided with the necessary supplies for the afterlife, including cosmetics, lotions, oils, wigs, razors, and mirrors. It was believed that, should any supplies be depleted, the soul would be sustained by the images of those items painted on the walls of the tomb.

5.3.2

Traditional Medicine: Maintaining Balance

In Native American, Hindu, Chinese, and possibly many other living traditions, treatment of physical ailments is inseparable from treatment of spiritual, mental, and environmental imbalances. The current excitement over the new concept of the “cosmeceutical,” describing cosmetic materials with activity beyond that of simply improving appearance,[17] would be amazing in any of these traditions, since they contain no expectation of a separation between “personal care” and “health care.” The Western definition of medicine has narrowed over time. It has separated itself from fields of study and treatment dealing with aspects of the body that are too external (appearance being “merely cosmetic,” as if there were no likely connection between being healthy and looking healthy) or too internal (happiness being “just a state of mind,” as if the mind and body did not influence each other). Habitual linguistic markers such as the above “just” and “mere” serve to minimize the terms they commonly accompany and provide a strong sign of the social status of those terms. Drugs are not referred to as “merely medical,” even when they have some effect on disease but no effect on appearance. This insistence on medicine as separate from, and superior to, all other fields has not been the majority opinion throughout human history. Perhaps the current interest in “complementary” or “alternative” or “traditional” health practices signals a growing recognition of the difficulty of sustaining such a position.

Beauty as health. In the Navajo tradition, for example, good health is one aspect of hozho, a life of beauty and harmony. When beauty and, therefore, health is lost, healing practices are undertaken to “again achieve harmony, order, to again establish beauty, and remove ugliness.”[18] It is essential that the healing practice itself be beautiful if it is to be effective in restoring beauty. Carefully created sand paintings, sounds, and aromas are all necessary to establish an environment in which health can be supported. Clearly, a distinction between the cosmetic, dealing with beauty, and the medical, dealing with health, is not useful in this tradition. Medicine and meditation. English is an IndoEuropean language.[19] It shares the roots of its vocabulary and structure with Sanskrit. The Vedas are Hindu sacred texts written in Sanskrit that detail, among other things, healing practices and medicinal formulations. As Fields points out in Religious Therapeutics,[20] the family of words derived from the Indo-European root med, “to take appropriate measures,” demonstrates that the English words “medicine” (by way of the Latin mederi, “to take care of”) and “meditation” (from Latin meditari, “to think about”) originally described complementary rather than competing projects in the roots of English-speaking Western tradition. The complementarity between action and thought remains central to Ayurvedic medicine. Ayurveda originated in ancient India and assumes that mind and body are integrated. It focuses on supporting the body’s ability to maintain its own balance through the five elements of earth, water, fire, air, and ether. These elements are seen as combining and interacting into the three doshas. An individual’s levels of each dosha determines that person’s predilections for health problems caused by imbalance.[21] Health problems associated with each dosha are both physical and emotional. For example, people who are of the Pitta dosha are likely to experience problems with allergies and indigestion, and to become jealous and obsessive/compulsive when unbalanced. Treatment for these conditions usually begins with detoxification, followed by formulations of herbs and minerals to restore balance. This traditional way of addressing health issues is surprisingly similar to the modern possibilities created by using liposomes as carriers to correct imbalances in cell membrane structures by delivering beneficial materials and removing harmful ones.[3]

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS Health as balance. Chinese and Ayurvedic medicine are said to be related originally.[20] The philosophical center and practical goal of traditional Chinese medicine is to create and maintain balance among the many forces in the body: yin and yang, the chi, and the five elements (wood, fire, earth, metal, and water), must all be kept in equilibrium if the body is to be healthy. Poor health is seen as the result, not the cause, of imbalance.[22] Practitioners of traditional Chinese medicine generally provide simultaneous internal and external treatments to their patients. The sample acne treatment formulations included below, selected and adapted from the options in Liang’s A Handbook of Traditional Chinese Dermatology,[23] demonstrate an effort to correct internal and external imbalances simultaneously, by correcting the cause of acne, said to be an excess of heat in the lung, spleen, and stomach.

5.3.3

Modern Medicine: Separation and Reunion of Medicine and Cosmetics

It is difficult to put a label on “the way most people here do most things now” without committing at least the crime of “presentism,”[24] suggesting that every idea from a different time or place is in some way inadequate. As the preceding sections demonstrate, that is not at all the project of this chapter. Labels such as “modern,” “Western,” “orthodox,” “allopathic,” “biomedical,” and “scientific” are all used in the literature to describe current, mainstream practices, as opposed to the labeling of other practices as “ancient,” “Eastern,” “alternative,” “naturopathic,” “traditional,” “complementary,” and “folk.” Whatever labels are used to name the differences between these systems, it is important to identify and account for those differences. We assert that the central difference may be one of regulation. While both “modern” and “traditional” systems rely on age-old collections of lore about appropriate treatment and formulation techniques, “modern” practitioners are regulated by governmental bodies, rather than by the expectations of religious leaders, professional peers, or consumers. This means such individuals must operate under externally provided definitions of what is and what is not acceptable as

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an ingredient, a practice, or claim. In the United States, the primary sources of Federal authority over cosmetic claims are the Federal Food, Drug, and Cosmetic Act [enforced by the Food and Drug Administration (FDA) in the Department of Health], the Fair Packaging and Labeling Act, and the Federal Trade Commission Act [both enforced by the Federal Trade Commission (FTC)]. A Memorandum of Understanding, issued in 1954, regulates interaction between the FTC and the FDA.[25] Separate information. In modern times, the movement to separate medicine from all other practices can be tracked, to a great extent, by observing changes in the publication of medical information. The United States Pharmacopoeia (USP) was first published in 1820. It offered standardized names, descriptions, and standards of purity for medicinal substances. The USP omitted much information about medicinal plants and other commonly used materials. These deficiencies were addressed in the Dispensatory of the United States (USD), first published in 1833. The USD was used, and strongly favored, over the USP by pharmacists for its focus on practicality, until USD publication ceased in 1973 as “compounding moved away from the physician, out of the community pharmacy, and into a mass production and industrial manufacturing setting.”[26] As the practice of custom-formulating materials became rare, so did information about how and why to engage in that practice. Currently, the USP and the National Formulary are published annually in a combined form as the USP-NF. It provides physicians with a single, centrally controlled source of information about what materials may be used and how they may be combined or, more realistically, how they have already been combined at a drug factory. In Grieve’s 1931 A Modern Herbal,[27] the editor notes that “botany and medicine came down the ages hand-in-hand until the seventeenth century; then both arts became scientific, their ways parted, and no new herbals were compiled. The botanical books ignored the medicinal properties of plants and the medical books contained no plant lore.”[28] Other fields separated from medicine in Western tradition even earlier. Philosophy, religion, chemistry, and cosmetics, like botany and pharmacy, are now studied, practiced, and regulated separately from medicine. One result of this separation is that basic information in one field is effectively hidden from

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practitioners of another. Perhaps this secrecy began long ago as a way of ensuring job security. It controlled and protected the secrets of healing as a means of earning a livelihood, so that no one outside the family or guild could become a competitor.[29] There is no shortage of speculation as to more sinister reasons for compartmentalizing and centrally controlling access to knowledge and therefore power.[24] Separate regulation. The 1938 Food and Drug Cosmetic Act created separate legal definitions for cosmetics and drugs. It remains at the basis of the expectation, especially in the United States, that a material may be either a cosmetic or a medicine but not both.[30] The Act describes a cosmetic as: “(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and

traditions such as those discussed above. The strict definition of medicine becomes blurred under such circumstances. Recent studies of practitioners and students show increasing interaction between practitioners of Western and complementary or alternative medicine, growing consumer expectation that nurses and pharmacists can make recommendations reconciling multiple traditions, and frequent consumer attempts to combine, appropriately or not,[33][34] therapies from traditional and biomedical sources. The list of references at the end of this chapter identifies some very recent studies on relationships between biomedical and alternative practices and practitioners;[35]–[45] many more such studies are available in the literature, including Ernst’s Plural Medicine, Tradition and Modernity, 1800-2000.[30] Proposals for an “integrative medicine” approach, training medical students to identify and use the best available therapy from a variety of traditions, are strong signs that the separation of medicine from all other practices will not long continue.[46]

(2) articles intended for use as a component of any such articles; except that such term shall not include soap.”[25] The problem has become the word “for,” as in “for cleansing…;” that “for” has been interpreted as “only for.” Material that is useful for the listed cosmetic purposes and for additional purposes, such as healing, cannot be considered a cosmetic and therefore must be considered a drug. Thus, its use must be controlled by health care practitioners, such as physicians, rather than personal care practitioners, such as massage therapists. Materials that are perceived as exclusively of interest as drugs or cosmetics, but not both, are not problematic under this legally based dichotomy. The growing interest in “active cosmetics”[31][32] creates a lengthening list of substances claimed by practitioners on both sides of the divide. Currently, if a material may be used as a cosmetic or a drug then it must be considered a drug. Insistence that personal care products can be effective as health care products has the legal effect of limiting, rather than expanding, their use. Cosmeceuticals: a trend toward reunion. Although practitioners of Western allopathic medicine must operate in an environment in which “personal care” and “health care” are legally separated, they must also treat a growing population of consumers who are knowledgeable participants in more holistic

5.4

5.4.1

Foundations of Personal Care Technology Technology in Ancient Formulae

The basic technology used to create modern personal care products is very old. Ancient texts and archeological finds demonstrate that, in fundamental ways, not much has changed. Many of the ingredients, procedures, and final products remain highly recognizable, as shown in this brief examination of ancient emulsification, extraction, and downsizing practices that strongly resemble current delivery systems technologies. Emulsification. A Sumerian clay tablet containing more than a dozen remedies includes instructions on formulating botanical, zoological, and mineralogical materials into salves and filtrates to be applied externally and liquids to be taken internally. It gives some detailed insight into early techniques for combining oil and water.[11] Compounding of a salve usually required three steps: pulverizing one or more samples of plant, animal, or mineral material; infusing the powder with wine; spreading cedar oil

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS and other tree oil over the mixture. Downsizing particles by grinding can reduce particle size into the micron and even the submicron range. Tree oils such as cedar and pine are powerful solvents. Mixing pulverized particles with oil and wine will amount to organic extraction of the finely ground ingredients mediated with alcohol to enhance penetration into the particles and thereby enhance the extraction. Another Sumerian formula used powdered river clay, kneaded it in water and honey as a means of water extraction, and covered it with “sea oil.” Cooking oils with alkaline soda ash provided a detergent that helped emulsify the oil- and water-soluble ingredients and provide the first known potent vehicle for transdermal transportation of materials via topical application. Additional instructions in the Sumerian text show familiarity with processes of filtration, decoction, and purification. Extraction. All delivery systems, natural and technological, exist to solve one basic problem: the movement of materials to a location and condition in which they can be useful. Whole plants, for example, often contain substances that can be used by the human body, but not in their original form. Those substances can be used only if they can be extracted from the plants and moved into the body. The very simple technology of adding herbs to heated water facilitates the movement of beneficial materials into the body. In an herbal bath, warm water opens pores so that chemicals found in plants can be absorbed through the skin. Steam makes it possible for volatile oils to be inhaled through the nose and mouth and into the lungs. Once inhaled, these materials are absorbed into the bloodstream for further transport and, via the nerve receptors in the nose, perhaps as a message to the brain.[47] Lavender, native to mountainous areas around the Mediterranean (its name derived from the Latin lavare, “to wash”) has been used in this way since classical times. Dried lavender flowers contain up to three percent volatile oil. The chief constituents of lavender oil are linalool and its acetic ester, linalyl acetate, as well as cineol, pinene, limonene, geraniol, borneol, and tannins. A second ester, linalyl butyrate, is also present, [27] as are coumarins, flavenoids, and triterpenoids.[47] External application of essential oil distilled from lavender has traditionally been employed as an antiseptic and a remedy for a variety of ailments, including nervousness, insomnia, fatigue,

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toothache, migraines, sprains, and rheumatism. Such benefits accrue from material delivered from the plant to the human body by inhalation or topically. Downsizing. Reducing the size of a material to make it usable is a most ancient and basic technological process. Even such a simple procedure as cutting wood to fuel a cooking fire demonstrates the necessity of downsizing. Small strips of kindling catch fire much more easily, and are much more practical to carry home, than a giant tree trunk. Similarly, slicing meat and vegetables into small pieces enables them to cook more rapidly, and absorb seasonings more thoroughly, than would be possible if an entire organism were cooked at once. The smaller the particle the larger its surface-per-volume is, achieving faster and more efficient interaction with the environment at the site of action. Archeological discoveries of early human handtools for cutting, chopping and grinding show that human beings have been creating and improving downsizing technology for almost our entire existence. Technological progress of early humans is tracked to a large degree by observing continued refinements of axes, knives, and other downsizing tools. Similarly, current technological breakthroughs have centered on progress in miniaturization in many fields, including personal care formulation. Physical studies of Egyptian cosmetics from as long ago as 2060 BCE show that the grinding technology used to produce colored eye cosmetics from mineral ores produced results very similar to those produced by grinding the same minerals in the modern laboratory. It is as yet unclear what roles moisture and heat played in the Egyptian formulating process and whether room-temperature storage for millennia may have caused any changes.[48] These ancient cosmetic powders are based on black galena (PbS), as eye cosmetics homemade in the region continue to be. White lead compounds are added to change the color (PbCO3, cerrusite) and to prevent infection (PbOHCl, laurionite, and PB2Cl2CO3, phosgenite). The nanotechnology discussed in the next section continues the downsizing project by making nanometer-range particles, the smallest yet, possible. By enabling new uses and combinations, nanotechnology does more than simply continue the effort to produce smaller and smaller particles.

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5.5

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

New Technology for Personal Care: An Introduction to Delivery Vehicles

In their 1999 Novel Cosmetic Delivery Systems, Magdassi and Touitou mention liposomes and microemulsions as having been “only recently introduced in the development of cosmetic products.”[1] Today, liposomes and microemulsions are gaining popularity in topical formulations, though they are still far from being completely exploited. The newest breakthrough developments are found at a smaller nanometer scale, as demonstrated by Nanosomes™, nanoemulsions, and nanoencapsulation.

5.5.1

Nanosomes™

Nanosome(s)™ (nanoliposomes) is our trademark name for very small liposomes in the low nanometer size range. Nanosomes can act as both encapsulation and delivery systems. The Elsom Research website includes some illustrated information about anti-aging effects of Nanosomes, at http:/ /www.elsomresearch.com/learning/technology/ nanosomes.pdf. For more information on Nanosomes, see Ch. 14.

5.5.2

Nanoemulsions and Dispersicles™

Dispersicle(s)™ is our trademark name for emulsion and emulsion-like particles in the low nanometer size range. Nanoemulsion creates a large surface-to-volume ratio for emulsion particles that contact skin, so more active ingredients contact the skin at the surface-to-surface interaction between the emulsion and the skin. Small emulsion particulates will not clog the pores and will allow air and water to flow between them. Curvature definitions of small emulsion surface components can affect emulsion potency and interaction characteristics with skin. Information about the usefulness of combining nanoemulsion and liposome technology (double emulsion technology) is available at the Elsom Research website, at http://www.elsomresearch.com/learning/

technology/DAD-DET.pdf. For more information on nanoemulsion and Dispersicles™, see Ch. 14.

5.5.3

Nanoencapsulation

Nanoencapsulation is encapsulating ingredients into capsules in the low nanometer size range, including encapsulation in Nanosomes. Nanoencapsulation can operate on as small a scale as encapsulating an individual molecule within another individual molecule. Nanoencapsulation of actives can improve their function, increase the range of their activity, reduce the concentration required for effectiveness, increase shelf life, reduce color and odor of actives, protect the active from rapid degradation, and protect the skin from prolonged exposure to actives. For more information on nanoencapsulation, see Ch. 14.

5.6

Conclusions

Encapsulation and delivery vehicles exist abundance in nature and have been used, separately and together, since the beginnings of human culture. Advancements in encapsulation and vehicle development have the recognition of “encapsulation” and “vehicle” as separate concepts. They could then be regarded and developed as distinct and emerging technologies and improvements and advancements in each were carried out by tailoring them to a multitude of tasks. Tailoring technologies to specific tasks is a process of refinement and targeting multitudes of different applications. This identifies the collective technologies as a field with highly specialized solutions for different problems. Such specialized solutions are characteristic of modern technological processes. In the last several decades, advancements have occurred in the miniaturization of vehicles and capsules. Miniaturization technology has also enhanced specificity and characteristics of encapsulation and release processes, mobilization, penetration, and targeting of drugs and active ingredients. Very recently, nanotechnologies have been implemented in capsule and vehicle design. These newest technologies are targeted at single-molecule encapsulation and mobilization vehicles, where capsules, vehicles, and the

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tools for their construction are sometimes simultaneously developed.

Radix Glehniae Littoralis (Sha Shen: “glehnia root”)

Nanometer-range technologies are reaching the molecular realm. They present unique problems in design, engineering, and mechanical handling since the demand for seemingly simple operations may require the construction of special tooling. It is simple enough to insert a nail or a screw in a piece of wood using a screwdriver or a hammer. How does one insert one molecule into another? This is the opportunity and challenge of nanoencapsulation. Nanotechnology is the art and the science of simultaneous construction of complex nanostructures and the nanotools that are utilized in the process. A nanometer is not merely one thousand times smaller than a micron. Events at the nanometer scale occur in a different realm than the micron scale, just as a subparticle in an atom of iron does not reflect a mere miniaturization of an iron bar or a nail. At the present time, nanotechnology is as much at the apparent human limit as it is the new human frontier.

2. Mix with mashed Semen Juglandis Regiae (Hu Tao Ren: “English walnut”).

5.7

Formulations

In this section, updated versions of age-old formulae are discussed along with suggestions for enhancement by our state-of-the-art nanotechnologies; these formulae include acne treatment, anointing oil, and a pain relief gel.

5.7.1

Acne Treatment (Traditional Chinese), Enhanced with Nanoencapsulation

This is an adaptation of formulae found in Liang’s Handbook of Traditional Chinese Dermatology.[21] Common names of plants have been added and the steps have been numbered. FORMULAE: internal and external acne treatment, to be administered simultaneously.

3. Make into pills the size of Chinese parasol tree seeds. 4. Take 10 g with water every night. Topical formula: 1. Equal parts Radix Et Rhizoma Rhei (Da Huang: “rhubarb root”), Cortex Phellodendri (Huang Bai: “philodendron bark”), Radix Scutellariae Baicalensis (Huang Qin: “baikal skullcap”), and Radix Sophorae Flavescentis (Ku Shen: “sophora root”). 2. Grind into a fine powder. 3. Mix 10 ml of this medicinal powder with 100 ml distilled water and 1 ml carbolic acid. For external application only. Clears heat and facilitates astringency, stops itching and disperses inflammation in the treatment of dermatitis due to chemical (allergy), eczema, folliculitis, etc. In order to enhance the above topical formulation with state-of-the-art nanotechnology, the following is recommended: 1. Add an oil phase to the above formulation, which has only a water phase originally. The oil phase should be comprised of precious oils, such as rose hip seed oil and evening primrose oil, and essential oils, such as geranium and lavender, and oil-soluble vitamins, such as vitamin A and vitamin E. Formulate the oil phase into nanoemulsion Dispercicles, obtainable from Elsom Research. 2. Add nanoencapsulated actives, obtainable from Elsom Research. The updated formulation is a fine topical with light texture which is non-greasy and readily absorbed.

Internal formula: 1. Powder equal portions of Radix Salviae Miltiorrhizae (Dan Shen: “red-rooted sage”), Radix Codonopsis Pilosulae (Dang Shen: “bastard ginseng”), Radix Sophorae Flavescentis (Ku Shen: “sophora root”), and

5.7.2

Oil of Anointing (Ancient Hebrew), Enhanced with Nanoemulsion

This is an approximation of the ingredients listed in Exodus 30:22-25 for formulation of “anointing oil

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of holiness, perfume from the perfume-mixture, of perfumer’s making” in Fox’s 1995 translation.[12] Note that the instructions for making and using this oil are followed in Exodus by instructions that it must never be made “in its (exact) proportion” for any purpose other than anointment of the Tabernacle and the priests; since neither exists today, it follows that actually producing this perfumed oil would always be inappropriate, even if all the materials and measures could be identified and obtained. 500 shekel-weight of fragrant-spices, essence, streaming-myrrh (sap of Commiphora myrrha) 500 shekel-weight of cinnamon-spice (bark of Cinnamomum zeylanicum) 250 shekel-weight of fragrant-cane (“sweet calamus,”[49] root of Acorus calumus; or perhaps lemongrass, Cymbopogon citratus) 250 shekel-weight of cassia (bark of Cinnamomum cassia)

Sunthi (Zingiber officinale, “ginger”) 7.5 milligram Shallaki (Boswellia serrata, “frankincense”) 7.5 milligram Pudina (Mentha arvensis, “mint”) 60 milligram Tvak (Cinnamomum zeylanicum, “cinnamon”) 30 milligram Sarala (Pinus roxburghii, “chir pine”) 55 milligram Gandhapura taila (Gaultheria fragrantissima, “Indian wintergreen”) 55 milligram Formulation of the above into 1000 mg of nanoemulsion Dispersicles can be provided by Elsom Research. The result is a highly fragrant fine cream with light texture and excellent penetration. For deep penetration, formulation by Elsom Research can be provided with both Dispersicles and Nanosomes, a double emulsion technology with unmatched performance.

1 hin (perhaps about 5 liters) of olive oil (fruit of Olea) This formula does not contain a water phase. Though presumptuous to improve on a divinely specified formula, its alteration using Elsom Research nanoemulsion Dispercicles will provide a unique aromatherapy-type topical cream. Formulation of fragrant oils into nanoemulsion can be provided by Elsom Research. This will result in a fine oil-in-water type aromatherapy nanoemulsion which is nongreasy and easily absorbed.

5.7.3

Pain Relief Gel (Ayurvedic), Enhanced with Nanosomes™

This is our variation of Rumalaya gel, a topical analgesic based on ginger, mint, cinnamon, cedar, pine, and other fragrant botanical extracts. For each plant material, Ayurvedic names, botanical names, and common English names are provided.

References 1. Magdassi, S., and Touitou, E., Eds., Novel Cosmetic Delivery Systems, Cosmetic Science and Technology Series, Vol. 19. Marcel Dekker, Inc., New York (1999) 2. Brown, L., Ed., The New Shorter Oxford English Dictionary on Historical Principles, Clarendon Press, Oxford (1993) 3. Yechiel, E., More Than the Sum of Ingredients: Interactive Vehicles in Advanced Cosmeceuticals, Personal Care Ingredients/ Technical Expo. Sheraton Hotel, New York (Apr. 15, 2004) 4. Capon, B., Botany for Gardeners: An Introduction and Guide, Timber Press, Portland, OR (1990)

Nirgundi (Vitex negundo, “chaste tree”) 7.5 milligram

5. Speight, M. R., Hunter, M. D., and Watt, A. D., Ecology of Insects: Concepts and Applications, Blackwell Science, Malden, MA (1999)

Devadaru (Cedrus deodara, “deodar cedar”) 7.5 milligram

6. Puotinen, C. J., Herbs for Improved Digestion: Herbal Remedies for Stomach Pain,

Ingredients:

YECHIEL AND COSTE: FROM ANCIENT POTIONS TO MODERN LOTIONS Constipation, Ulcers, Colitis, and Other Gastrointestinal Problems, NTC Contemporary, New Canaan, CT (1996) 7. Abels, D. J., and Vitaly, K., Bioclimatology and Balneology in Dermatology: A Dead Sea Perspective, Clinics in Dermatology, 16(6):695– 698 (Nov. 12, 1998) 8. Hodak, E., Gottlieb, A. B., Segal, T., Politi, Y., Maron, L., Sulkes, J., and David, M., Climatotherapy at the Dead Sea is A Remittive Therapy for Psoriasis: Combined Effects on Epidermal and Immunologic Activation, J. American Academy of Dermatology, 49(3):451–457 (2003) 9. Canela, M. B. F., and Sazima, M., Aechmea Pectinata: A Hummingbird-dependent Bromeliad with Inconspicuous Flowers from The Rainforest in Southeastern Brazil, Annals of Botany, 92(5):731–737 (Nov. 2003) 10. Sitchin, Z., Divine Encounters: A Guide to Visions, Angels, and Other Emissaries, Avon Books, New York (1995) 11. Kramer, S. N., History Begins At Sumer: Thirty-nine Firsts in Man’s Recorded History, Philadelphia U. of Penn. Press (1989) 12. Fox, E., The Five Books of Moses, trans. Schocken Books, New York (1995) 13. Masehet, Y., Jerusalem Talmud, trans. by E. Yechiel, 4:41, Col. D. 14. Masehet K., Babylonian Talmud, trans. by E. Yechiel, p. 6, side B. 15. Maimonides, Laws of the Utensils of the Temple, trans. by E. Yechiel, Ch. 2, law 5. 16. Ruiz, A., The Spirit of Ancient Egypt, Algora Publishing, New York (2001) 17. Kligman, A. M., Cosmeceuticals: Do We Need a New Category?, Cosmeceuticals: Drugs vs. Cosmetics, (H. I. Maibach, ed.) Cosmetic Science and Technology Series; Vol. 23, Marcel Dekker, Inc., New York (2000) 18. Faris, J. C., The Nightway: A History and A History of Documentation of A Navajo Ceremonial, Univ. New Mexico Press, Albuquerque, NM (1990) 19. Baugh, A. C., and Cable, T., A History of the English Language, 4th Ed., Prentice Hall, Englewood Cliffs, NJ (1993)

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20. Fields, G. P., Religious Therapeutics: Body and Health in Yoga, Ayurveda, and Tantra. SUNY Series in Religious Studies, State Univ. New York Press, Albany, NY (2001) 21. Dupler, D., Ayurvedic Medicine, The Gale Encyclopedia of Medicine, 2nd Ed., (J. L. Longe, Ed.) 5 Vols., Gale Group, Farmington Hills, MI (2001) 22. Bruno, L. C., Traditional Chinese Medicine, The Gale Encyclopedia of Medicine, 2 nd Ed., (J. L. Longe, Ed.) 5 Vols., Gale Group, Farmington Hills, MI (2001) 23. Liang, C., Ting-liang, Z., and Flaws, B., A Handbook of Traditional Chinese Dermatology: Originally Entitled Chang Jian Pi Fu Bing Zhong Yi Zhi Liao Jian Bian; or, A Brief Compendium of the TCM Treatment of Common Skin Diseases, Blue Poppy Press, Boulder, CO (1988) 24. Bradley, J., Medicine on The Margins? Hydropathy and Orthodoxy in Britain, 1840–1860, Plural Medicine, Tradition and Modernity, 1800–2000, Routledge Studies in the Social History of Medicine, Vol. 13, (W. Ernst, ed.) Taylor & Francis, New York (2002) 25. Aust, L. B., Cosmetic Claims Substantiation, Cosmetic Science and Technology Series; Vol. 18, Marcel Dekker, Inc., New York (1998) 26. Flannery, M. A., Building a Retrospective Collection in Pharmacy: A Brief History of the Literature With Some Considerations for U.S. Health Sciences Library Professionals, Bulletin of the Medical Library Association, 89(2):212–221 (Apr. 2001) 27. Grieve, M. A Modern Herbal: The Medicinal, Culinary, Cosmetic, and Economic Properties, Cultivation, and Folklore of Herbs, Grasses, Fungi, Shrubs and Trees with All Their Modern Scientific Uses, 1931, revised 1973, (H. Leyel, ed.) Dorset Press, London (1994) 28. Leyel, H., ed., Editor’s Introduction, A Modern Herbal: The Medicinal, Culinary, Cosmetic, and Economic Properties, Cultivation, and Folklore of Herbs, Grasses, Fungi, Shrubs and Trees with All Their Modern Scientific Uses, 1931, revised 1973, Dorset Press, London (1994)

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29. Timbrook, J., Virtuous Herbs: Plants in Chumash Medicine, Ethnobotany: A Reader. (P. E. Minnis, ed.) Univ. Oklahoma Press, Norman (2000)

39. Coulter, I. D., The Rise and Rise of Complementary and Alternative Medicine: A Sociological Perspective, Med. J. Australia, 180(11):587–589 (Jun. 7, 2004)

30. Ernst, W., ed. Plural Medicine, Tradition and Modernity, 1800-2000, Routledge Studies in the Social History of Medicine, Vol. 13. Taylor & Francis, New York (2002)

40. Zick, S. M., Bridging CAM Practice and Research: Teaching CAM Practitioners About Research Methodology, Altern. Ther. Health Med., 10(3):50-56 (May-Jun. 2004)

31. Eskinazi, D., Botanical Medicine: Efficacy, Quality Assurance, and Regulation, Mary Ann Liebert, Inc., Larchmont, NY (1999)

41. Sibinga, E. M., Parent-Pediatrician Communication about Complementary and Alternative Medicine Use for Children, Clin. Pediatr., 43(4):367–373 (May 2004)

32. Elsner, P., and Maibach, H. I., eds. Cosmeceuticals: Drugs vs. Cosmetics, Cosmetic Science and Technology Series; Vol. 23 Marcel Dekker, Inc., New York (2000) 33. McCune, J. S., Potential of Chemotherapyherb Interactions in Adult Cancer Patients, Support Care Cancer, 12(6):454–462 (Jun. 2004) 34. Furrer, M. “Hazards of An Alternative Medicine Device in A Patient With A Pacemaker, N. Engl. J. Med., 350(16):1688–1690 (Apr. 15, 2004) 35. Dutta, A. P., Bwayo, S., Xue, Z., Akiyode, O., Ayuk-Egbe, P., Bernard, D., Daftary, M. N., and Clarke-Tasker, V., Complementary and Alternative Medicine Instruction in Nursing Curricula, J. Natl. Black Nurses Assoc., 14(2):30–33 (Dec. 2003) 36. Dutta, A. P., Daftary, M. N., Egba, P. A., and Kang, H., State of CAM Education in U.S. Schools of Pharmacy: Results of a National Survey, J. Am. Pharm. Assoc., 43(1):81–83 (Jan.-Feb. 2003) 37. Lie, D., and Boker, J., Development and Validation of the CAM Health Belief Questionnaire (CHBQ) and CAM Use and Attitudes Amongst Medical Students, BMC Med. Educ., 4(1):(Jan. 12, 2004) 38. Mills, E. J., Hollyer, T., Guyatt, G., Ross, C. P., Saranchuk, R., and Wilson, K., Teaching Evidence-based Complementary and Alternative Medicine: 1. A Learning Structure for Clinical Decision Changes, J. Alt. and Compl. Medicine: Research on Paradigm, Practice, and Policy, 8(2):207–214 (Apr. 2002)

42. Kolstad, A., Use of Complementary and Alternative Therapies: A National Multicentre Study of Oncology Health Professionals in Norway, Support Care Cancer, 12(5):312– 318 (May 2004) 43. Simon, G. E., Mental Health Visits to Complementary and Alternative Medicine Providers, Gen. Hosp. Psych., 26(3):171–177 (May-Jun. 2004) 44. McPherson, F., Use of Complementary and Alternative Therapies Among Active Duty Soldiers, Military Retirees, and Family Members at A Military Hospital, Military Medicine, 169(5):354–357 (May 2004) 45. Shuval, J. T., Changing Boundaries: Modes of Coexistence of Alternative and Biomedicine, Qual. Health Res., 14(5):675–690 (May 2004) 46. Kligler, B. “Core competencies in integrative medicine for medical school curricula: a proposal.” Academic Medicine: J. Assoc. Amer. Med. Colleges, 79(6):521–531 (Jun. 2004) 47. McIntyre, A., The Medicinal Garden: How to Grow and Use Your Own Medicinal Herbs, Henry Holt & Co., New York (1997) 48. Deeb, C., Walter, P., Castaing, J., Penhoud, P., Veyssiere, P., Transmission Electron Microscopy (TEM) Investigations of Ancient Egyptian Cosmetic Powders, Applied Physics A: Materials Science and Processing, 79(4):393–396 (Jul. 2004) 49. Fisch, H., trans. The Jerusalem Bible, Koren Publishers, Jerusalem (1992)

Part III Crossing the Barrier Crossing the Lipid Barrier with the Echo-Derm™ Delivery System ( A Skin Mimicking, Lamellar Matrix System)

Crossing the Barrier

"THP": An All Natural Delivery System Adjuvant

6 Crossing the Lipid Barrier with the Echo-Derm™ Delivery System (A Skin-Mimicking, Lamellar Matrix System) David Pollock Clinical Results, Inc. St. Petersburg, Florida

6.1 6.2 6.3

What is a Delivery System? ......................................................... 137 Anatomy of a “Perfect Product” .................................................... 138 Skin’s Functions ........................................................................... 139 6.3.1 Background: Skin Structure .............................................. 139 6.3.2 Bricks-and-Mortar Model ................................................... 139 6.4 Why Worry About Delivery ........................................................... 140 6.5 Delivery Options ........................................................................... 140 6.5.1 What is a Liposome? ........................................................ 141 6.5.2 What are Nanospheres? ................................................... 142 6.5.3 Changing the Cosmeceutical Landscape ......................... 142 6.5.4 The Echo-Derm™ Delivery System ................................. 142 6.6 Formulating Guidelines ................................................................. 145 6.6.1 Preloading ......................................................................... 145 6.6.2 Auto-Loading ..................................................................... 145 6.6.3 High End Dermal Hydro-Cream ........................................ 146 6.7 Sample Formulations ................................................................... 147 References .......................................................................................... 156

6.1

What is a Delivery System?

Everyone’s perception of a delivery system is different. If you say to someone outside the personal care industry that you are trying to determine what delivery system to use, they may suggest you use FedEx or UPS.

To those in the cosmetic industry, the response may also vary greatly. If you are speaking to some, the delivery system would refer to the product’s packaging, such as a bottle with lotion pump, a tube, aerosol, etc., and how it delivers the product. To others, the delivery system means whether the formulation is a cream or gel.

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 137–156 © 2005 William Andrew, Inc.

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To the cosmetic formulators, a delivery system is the method of delivering active payloads onto the skin, then having them pass through the lipid barrier and, finally, reaching the targeted lower layers beneath. The key to successful delivery of the active and creation of the “perfect product” is to determine what type delivery system is required, if any, for that active.

or become extinct. Formulators must face the challenge of creating products that address the needs of today’s consumer. These needs continue to become more advanced, more therapeutic, and more demanding as consumers become evermore educated in the internet environment. Today’s consumer is looking for products that provide these characteristics: • Quick results; the faster the better • Long-lasting results • Multifunctional, all-in-one type products

6.2

Anatomy of a “Perfect Product”

What is the “perfect product?” Much like delivery systems, perceptions of what is, or is not, the perfect product varies greatly. Cosmetic marketers want products with stronger claims, shorter time frames for producing visible results, and clinical studies to substantiate the claims. They also want something so unique that it has never been seen by another individual on the face of the earth. Oh yeah, and they need it next week for their upcoming presentation or tradeshow. Chemists spend hundreds of hours developing and testing the most unique “emulsion,” with the newest raw materials presented by their suppliers…but since the product doesn’t have the right fragrance, or was not sampled to the marketing department in a fancy jar, the projects are constantly getting shot down. Management has the difficulties of presenting the Research & Development concepts to the marketing people, who do not understand the technology, and dealing with the Research & Development Department that does not know, or care about, the bottom line and selling the product. Operating officers try to balance the cost of packaging, raw materials, inventory forecasting, etc. Then, they begin to wonder why the formulation has to even use a unique ingredient since it causes inventory and production issues. It may even be asked “do we really even need another product on the shelf?” But the real answer to what the “perfect product” is lies with consumers, and what they perceive is “perfect.” The world of cosmetics is changing …and fast. Personal care companies need to adapt,

• Truly cosmeceutical products…that quickly deliver results as promised and can be seen by the consumer • Convenience, ease of use • An affordable price In the face of these realities, and standing on the foundation of a baby-boomer generation that wants no wrinkles when it looks in the mirror, our industry has accelerated its drive to satisfy these needs; the inevitable result is new products and profits. A “perfect” product is more than a stable emulsion with the right active material. There are three points where a product sale is made: • The first is the packaging. In a store, the consumer faces a virtual sea of products. In a matter of seconds, she or he must scan the store shelves and decide which product to select. This scan is done while keeping an eye on the children, answering the cell phone, and evaluating what it is that they are truly looking for. A combination of packaging and the claims a product makes are key factors in the consumer’s decision. • The second point a sale is made is when the consumer first uses the product. Every person, no matter who they are, opens the product for the first time and evaluates it by first smelling it in its container. If the fragrance meets with their approval, they will then rub a dab on to the back of their hand to test the overall feel. It’s as if the consumer has some magical power to evaluate, in just a matter of seconds, if the product will deliver the claimed promise to reduce wrinkles in thirty days or whatever is promised on the container. Let’s face it, it is human nature that the consumers’ initial perception of the prod-

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM uct will determine if she or he is going to use it each day, or return it to the place of purchase. • The third point a sale is made is based on the performance of the product. If the product actually delivers on its promises, the performance is what earns the sale that really counts—the repeat sale. This is the key to the success of a product for any brand, and must be the key focus for any cosmetic scientist, formulator, and marketer. With these critical sales points in mind, a formulator must consider the following parameters and be in control of them: • Function. Targeting the function of the product, and what key ingredients or actives will provide those functions, etc. • Color/aroma. Producing a product that provides the expected perception, has a pleasant or non-chemical odor, etc. • Feel. Creating a balance of nice feel with the expected, ideal absorption rate as it is rubbed into the skin. • Natural. Do the ingredients conjure up some nasty long-worded list of ingredients or some natural and familiar ingredients. • Packaging. Including the viscosity of the formulation. And most importantly: • Delivery. Delivering the actives where and when you want them so they provide the desired results claimed on the package.

6.3

Skin’s Functions

139

well as other external threats. Kind of ironic, when as a formulator you are working to nourish and improve the skin, yet the lipid barrier is working to defend or block your efforts to deliver the beneficial ingredients.

6.3.1

Background: Skin Structure

While cosmetic scientists understand chemicals, some do not take into consideration the structure of the skin and the impact of this structure on the delivery of the active. This organ, the largest in the body, is comprised of several different and distinct layers, each with its own specialized function: • Epidermis. This outermost layer provides resistance and protection. The epidermis is comprised of several distinct layers starting with the stratum corneum or horny cell layer through to the basal cell layer. The epidermis is continually being sloughed off and regenerated. • Dermis. The dermis provides flexible support structure and contains collagen types I and III, and glycosaminoglycans (hyaluronic acid, chondroitin sulfate, dermatan sulfate). It is where collagen and elastin are synthesized, and it contains the blood vessels, nerves, sweat glands, hair follicles, and sebaceous glands. The dermis is the targeted area in some of the recent breakthroughs in skin care. • Hypodermis. This layer contains the adipose tissue (subcutaneous fat) and provides a thermal barrier and mechanical cushion, plus attaches the dermis to the underlying tissues

Our skin has three basic functions: 1. Keep our bodies and organs intact, otherwise there would simply be a pool of organs sitting here reading this chapter. 2. Provide a barrier function that keeps moisture in, and minimizing transepidermal water loss (TEWL). 3. Protect the body’s organs and tissues from impurities, chemicals, pollutants, let alone 80% of ultraviolet B irradiation, as

6.3.2

Bricks-and-Mortar Model

Using the traditional bricks-and-mortar model (see Fig. 6.1), we can take a closer look at the outermost layer of the skin, the stratum corneum. The “bricks” portion of the model represents the approximately 15–20 layers of metabolically inactive, protein-rich cells embedded in the “mortar” or intercellular lipid domains.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS in the area of drugs, and many of these concepts are being applied to personal care delivery, this chapter is focused on the skin care and cosmetic applications and benefits.

Figure 6.1 Bricks-and-mortar model of the skin.

Upon closer examination of the lipid domain, we find the hydrophobic lipid molecules form lamellar sheets which are in the form of a bilayer matrix. (see Fig. 6.1). The lamellar membranes of the intercellular matrix are naturally enhanced with a balance of essential and nonessential fatty acids, ceramides, and cholesterol. When the lipids are synthesized by the cells, they are “packaged” into tiny organelles called lamellar bodies. The lamellar bodies release lipid content that converts polar lipid precursors and replenishes the stratum corneum with moisture-binding lipids. The skin’s impermeability to water and other hydrophilic ingredients is a result of the presence of the lipid molecules and the arrangement of the cells within the context of the lipid matrix. From a delivery point of view, it is useful to entrap the active and “trick” the skin into allowing selected hydrophilic actives to permeate the stratum corneum barrier.

6.4

Why Worry About Delivery

The search for new solutions to formulate more effective or therapeutic products is not just about finding new ingredients. It is also about finding better methods of administering these actives, and maintaining their bioavailability prior to and following delivery to the specified target. While there are endless possibilities and needs for new delivery systems

Different product formulations for personal care applications require targeting different layers of the skin or working with the skin in different formats, and depends on the type of product being formulated. The stratum corneum is composed of dead, protein-rich cells and intercellular lipids so, if creating a facial peel, exfoliator, depilatory, body wash, self tanner, etc., products would be formulated to intentionally affect these surface layers and not permeate deeper into the skin. However, if creating an anti-aging cream, targeting dark circles around the eyes, hoping to improve collagen synthesis, generate relief from pain, etc., the formulation would enhance the delivery actives beneath the epidermis to the dermis layer. In this way, the ingredients can interact with the appropriate part of the skin and have a better chance of achieving the targeted results.

6.5

Delivery Options

When targeting the delivery of actives to the body, there are three basic pathways for personal care applications: • Orally. Examples include a pill, or liquids, oral delivery combined with the application of topical cosmetics; this is a significant emerging trend since useful synergisms are known with this dual approach. • Injections. Puncturing the skin, and injecting a nerve-deadening agent known as Botox has become one of the most popular treatments for eliminating wrinkles. It is remarkable the lengths some will go to eliminate wrinkles! • Topically. This approach relies on getting the skin to work synergistically with topically applied formulations and active delivery to the key layers. Topical delivery options. Cosmetic scientists continually focus on new ways of “crossing the lipid barrier” and delivering active payloads to the targeted areas. An effective delivery system can help

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM enhance the performance of a product, as well as reduce the required amount of an active necessary to achieve the desired results. The latter is especially important for many sophisticated, high-cost actives. In today’s aging baby-boomer world, these actives really need to be present in concentrates high enough to make a difference, rather than being there in too low a concentration and providing advertising benefits only. There are a variety of options based on both the type of product and the type of active selected by the formulator/marketer team. Therapeutic, or active, ingredients can be included in traditional topical preparations and formulations. These systems may be oil-in-water, waterin-oil, or multiple emulsion systems, and utilize emulsifiers and stabilizers to disperse and stabilize the active product. The incorporation or use of topical delivery systems, such as those discussed in this book, are highly useful methods to increase permeation of the active payload. Further, the delivery system can do much more: • Protect and diminish the degradation of the active payload from emulsifiers or other aggressive materials incorporated into the product formulation. • Improve compatibility of active payloads with formulations. • Improve performance of an active payload, minimizing the concentration required to achieve desired results. • Extend the formulation shelf-life. • Allow addition of the active payload at low temperatures since certain active payloads are sensitive to temperature and will degrade if the payload is too hot. • Minimize reaction or irritation to the skin.

6.5.1

What is a Liposome?

Liposome technology was the first generation of delivery systems that provided significant benefits in topical formulating. These benefits included enhanced delivery, improved active stability, and increased efficacy of active ingredients. Liposomes are microscopic spherical “containers” or vesicles

141

that are comprised of phospholipids. These entrap the active payload. The two most common methods for preparing liposomes are rehydration and high shear processing. • Rehydration. This method includes depositing vesicle-forming lipids as a thin film layer and allowing them to dry. The dried films are then slowly rehydrated with a lipophilic or hydrophilic aqueous buffer which contains the active material. The end result of this process is the formation of multilamellar vesicles (MLVs) (or liposomes). Multilamellar simply means multiple layers or several vesicles forming, one inside the other. The structure is similar to the layers of an onion where the diameter of each vesicle gets progressively smaller and ranges from about 10 microns all the way down to about 0.05 microns. While optimal sizes would be in the range of 0.2–0.4 microns, the rehydration-processed MLVs should be further reduced in size by means of homogenization, sonication, or membrane extrusion. The drawback of this type of delivery system is the intricate processing required, the size of the MLVs, the poor encapsulation efficiencies of hydrophilic materials (e.g., typically only 5%–15% of the desired active payload), and the lack of long-term stability as characterized by leakage over extended periods of time. • High-shear processing. Another type of liposome is the single phospholipid bilayer sphere. This type inherently likes to encapsulates hydrophilic material. With ultra highshear processing, unilamellar liposomes are formed which commonly have diameters less than about 200 nanometers and uniform in size. With the high-shear process, another type of multilamellar liposomes can be formed. This type of mulitlamellar vesicle (MLV) will have a number of concentric lipid bilayers, each of which is separated by a hydrophilic phase. Unilamellar liposomes have a higher encapsulation efficiency capability when compared to multilamellar liposomes. However, they still face the formulation challenges of extended stability, limitations towards hydrophilic materials and

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

their natural tendency for leakage of the active payload. They also are limited by the tendency for easily influenced fusion of the various vesicles due to poor encapsulation efficiencies, the need for specialized equipment processing, and permeation.

6.5.2

What are Nanospheres?

Nanospheres are aqueous suspensions of acrylic copolymer nanoparticles. Typically, these are positively charged with a specific quarternary ammonium type function. Nanospheres are very small matricial particles, typically 100 nanometers in size, constituted with a porous polymer or polystyrene that acts as a mini-reservoir and enables the nanosphere to absorb and deliver the active payload. The challenges of using the nanospheres phase are the low encapsulation efficiencies, requirement of having the loaded nanospheres supplied by an outside source, and overall cost.

6.5.3

Changing the Cosmeceutical Landscape

While there are several types of topical delivery systems as described previously, we believed there must be a better way to address the needs of such systems. Several years were spent investigating various ingredients that must be capable of interacting with the lipid barrier. The criteria employed was to develop a system that improved upon the various deficiencies cited above. These were included: • Higher encapsulation efficiencies • Improved active delivery and product performance • Improved potential for decreasing the level of active ingredients • Decreased overall product cost • Minimization of skin irritation and transepidermal water loss • Ease of incorporation into formulations by requiring only minimal agitation and low temperature processing Beyond all of these, let’s also allow loading with the active payload in-house or during manufacture

of the finished product, as opposed to purchasing from a contractor. If this was possible, it would provide cost savings, lower inventory requirements, and minimize timelines for completion of product development. Clinical Results, Inc., R & D efforts to produce the ideal delivery system eventually addressed and successfully found a solution for the many needs described above. This solution is known as the EchoDerm™ delivery system. It was developed to address the challenges faced when using existing types of delivery, or entrapment systems, by echoing or mimicking the skin’s natural lipid bilayer structure.

6.5.4

The Echo-Derm™ Delivery System

Although the skin is very thin, the stratum corneum layer provides protection and resistance to undesired penetration of environmental insults, chemical irritants, and other foreign substances. As described previously, the horny cell layer is comprised of two phases: the corneocytes (bricks) and the lipid matrix (mortar) between the corneocytes. The lipid barrier is comprised mainly of phospholipids, ceramides, and cholesterol, while the surface skin lipids are comprised of triglycerols and squalene. The membrane structure of the lipid matrix is of primary importance to the skin’s barrier function. More specifically, the lipids located between the corneocytes within the stratum corneum are responsible for the barrier function of the skin. While lipids are nonpolar (hydrophilic), the lipid membranes have a polar hydrophilic head with lipophilic tails. These membranes are comprised of parallel lamellar lipid structures with an amphiphilic arrangement. These natural bilayers found in the stratum corneum contain primarily free fatty acids, ceramides, sphingolipids, cholesterol, triglycerides, but only trace levels of phospholipids. The Echo-Derm delivery system is comprised principally of components of skin lipids. These include very specific phospholipids, ceramides, sphingolipids, cholesterol, and triglycerides. Instead of spherical liposomal vesicles, Echo-Derm is based on a bilayer sheet structure. This structure is a multicomponent system comprised of a parallel, lamellar matrix structure containing micelles. The micelles

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM contain active material entrapped in higher concentrations than is possible if the actives are simply dissolved in water and/or lipids alone. The Echo-Derm structure is arranged with the lipophilic tails on the inside of the lamellar structure, facing each other, and “protected” on the outside with the hydrophilic heads (see Fig. 6.2). This bilayer structure provides the most stable configuration for amphipathic lipids. The nature of this structure provides greater protection for the skin’s barrier function than if the same lipids were not arranged in a lamellar form. While traditional liposomes rely on simple phospholipids, or lecithin to encapsulate and deliver the active ingredients across the membrane they form, they lack the essential ingredients that are naturally found in the stratum corneum. The Echo-Derm delivery system optimizes active delivery performance (see Fig. 6.3) by echoing or mimicking the natural lipid structure of the skin. It utilizes free fatty acids, ceramides, sphingolipids, cholesterol, triglycerides, and highly refined phospholipids. The phospholipid composition of the lecithin in the Echo-Derm system is critical to its performance. It is a common misconception that lecithin is lecithin, and there is no difference, as long as the raw material has the same INCI name. This is absolutely incorrect! There is a tremendous performance difference between food grade lecithin, refined lecithin, and all the other variations in between. One of the key components of the lecithin is the phosphatidylcholine (PC). Unsaturated phosphatidylcholine contains choline, omega-6 unsaturated fatty acid (more specifically, linoleic acid), plus omega-3 fatty acids (more specifically, gamma-linolenic acid). These are all essential for human life; the body is unable to synthesize them. The goal for achieving optimal delivery performance is to use a pure, highly refined form of lecithin that is high in phosphatidylcholine with a low level, or absence, of residual glycerides. Varying grades of lecithin affect emulsion

Figure 6.2 The bilayer lamellar structure of EchoDerm™.

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stability, the feel of the overall product, consumer perception and, most importantly, the nature of the interaction with the skin’s lipid barrier which directly affects the overall product performance. Sphingolipids play a role in cell signaling and in the regulation of cell growth. The sphingolipid has a long hydrocarbon tail and a polar domain that includes an amino group. This amino group can form an amide bond with a fatty acid carboxyl to yield a ceramide. More specifically, the loss of sphingolipids comprise the majority of ceramides and are present in far greater concentration than the glycosphingolipids. Permeability of actives seeking to penetrate one stratum corneum barrier is proportional to the ratio of neutral lipids to sphingolipids. The skin’s natural lipid bilayer structure is normally very fluid. However, at low temperatures, phospholipid membranes can undergo a transition to a crystalline state. Cholesterol is primarily lipophilic, but it has one polar group thereby making it an amphipathic molecule. By inserting cholesterol into the Echo-Derm bilayer structure, with the cholesterol’s lipophilic ring adjacent to the fatty acid chain, the hydroxyl group of the cholesterol forms a hydrogen bond with the polar head group. The bilayer structure formed as a result then has a fluidity that is the intermediate in nature between that of a liquid crystal and a fully crystalline solid. In other words, the cholesterol blocks transition to the crystalline state, thereby playing a key role in maintaining fluidity of the lipid bilayer structure.

Figure 6.3 Increased permeation using Echo-Derm™ delivery system.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

As we age, the number of lamellar bodies produced in the skin’s barrier layer decreases. The amount of lipid material contained within the lamellar bodies also decreases as does the lipid content capable of being released into the extracellular matrix. As a result, the stratum corneum’s ability to naturally repair itself is diminished with age and its integrity more easily compromised. With less moisture-binding lipids, the stratum corneum suffers a loss of moisture resulting in drier skin and an increase in fine lines and wrinkles. The Echo-Derm delivery system has been carefully designed to incorporate an anchoring ingredient that traps the active payload between the lipid bilayers. This results in an increase in hydration of the stratum corneum, an increase in its thickness, and enhancement of the prolonged release of the payload. As such, the Echo-Derm delivery system allows for unique formulating properties. For example, it is possible to include up to a 40% lipophilic phase without an oily after feel! The resulting structure lowers the interfacial surface tension between x and y, while trapping and suspending oil droplets within the bilayer matrix. Depending upon the type of active material being loaded (i.e., hydrophilic or lypophilic) the active will be anchored either between the tails or between the heads (see Fig. 6.4). Echo-Derm provides several advantages in the topical delivery of therapeutic ingredients. These include a more effective, and efficient means of stabilizing readily oxidizable lipophilic and/or hydrophilic materials, as well as improving entrapment and delivery efficiencies. This allows for a higher payload level, minimization of any type of undesirable greasy after feel, restoration of the natural lipid layer in the damaged skin and reduction of transepidermal water loss. The powerful technology has been patented in over 100 countries and has introduced a whole new landscape in cosmeceutical formulation.

• Provides restoration of the natural lipid barrier function • Enhances the overall product feel by decreasing oily after-feel • Decreases product costs through use of efficient delivery system, decreases required usage level and overall costs The Echo-Derm system is formulator friendly: • Easy to incorporate into current formulations • Able to load an active payload at the point of manufacture • Both compatible with hydrophilic and lipophylic ingredients • Protects and diminishes the degradation of the active payload from emulsifiers, or other aggressive materials incorporated into the formulation • Improves compatibility of active payloads with formulations • Extends the formulation shelf-life, • Allows addition of the active payload at lower temperature levels • Stabilizes active ingredients • Improves topical delivery of actives The Echo-Derm delivery system was designed to improve the performance of a wide range of personal care products which include, but are not limited to:

In summary, the Echo-Derm™ lamellar, bilayer system mimics the skin’s natural structure and provides a number of benefits: • Increases permeation of the active payload • Improves product performance • Interacts with the lipid barrier, thereby minimizing irritation and minimizing transepidermal water loss (TEWL)

Figure 6.4 In Echo-Derm™ delivery system, actives will be anchored either between the tails or between the heads.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM • acne treatments • anti-wrinkle agents • anti-inflammatories • anti-irritants • analgesics, pain relief products • collagen boosters/synthesizers • hair inhibitors (to slow the growth of hair, often used in body lotions to help retard or slow the regrowth of hair on women’s legs or upper lip) • self-tanners and tan enhancers • sunscreens (SPF: Sun Protection Factor) • a variety of OTC formulations • and much, much more Active payloads for the Echo-Derm system may include: antioxidants, hydrating agents/humectants, melanin regulators, lipo-regulators, anti-acne and antiaging/anti-wrinkle agents. They also may include: ultraviolet (UV) protectors, emollients, exfoliators, anti-inflammatories, cooling agents, and pain relief analgesics. Still other useful payloads include: antibacterials, insect repellents, antidandruff treatments, hair inhibitors, and anti–hair-loss/hair-growth promoters. The considerable list continues with colorants, botanicals, vitamins, minerals, nutrients, etc.

145

may be added directly to the Echo-Derm system with only conventional medium shear technology at ambient temperatures. Incorporating the Echo-Derm system into a formulation is simple and the autoloading process does not require any heat. There are three methods: preloading, autoloading, and dermal hydro-cream.

6.6.1

Preloading

With appropriate agitation, achieved through standard types of production mixers such as double planetary agitators, the Echo-Derm system entraps the active payload into its microvesicles and then disperses the vesicles between the parallel, lamellar bilayers. This is all accomplished without the need for rehydration and/or high-shear agitation. The desired amount of the Echo-Derm delivery system is generally about 5% to 20% of final formulation. With medium degrees of agitation, slowly mix in the active payload until it is homogenous. Thereafter, simply introduce the preloaded Echo-Derm into an oilwater emulsion during the final phases of the manufacturing process and mix well once the batch is below 55ºC. Key considerations include: • The active payload should be easy to disperse or pre-dispersed.

6.6

Formulating Guidelines

The Echo-Derm delivery system was developed to obtain a neutral, skin-mimicking method of “merging” with the lipid barrier. This merging phenomenon provides optimal delivery of key ingredients, without irritation, and minimization of transepidermal water loss when used in the range of about 5%–20% levels. The Echo-Derm based products are typically creams and can be made without the use of surfactants. As such, the Echo-Derm system can be used to produce delivery systems that allow for unique formulating properties such as inclusion of up to 40% of a lipophilic phase without having an oily afterfeel. This structure lowers the interfacial surface tension while trapping and suspending oil droplets within the bilayer matrix. Almost any lipophilic or hydrophilic therapeutic ingredient or active payload

• The pH range of payload should be between 3.5 and 7.5. • Homogenization is recommended, but not required.

6.6.2

Auto-Loading

Weigh the desired amount of the Echo-Derm delivery system (5%–20% of final formulation). With medium degree of agitation, slowly introduce into the delivery system an emulsion once the batch temperature has been cooled to below 55°C. While mixing, slowly add the active payload to batch. Mix well; thereafter the bilayer structure will immediately start aligning and entrapping. Make sure to allow sufficient time for the bilayer structures to capture the key ingredients.

146 6.6.3

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS High End Dermal Hydro-Cream

By their very nature, surfactants and stabilizers can be extremely disruptive to the skin’s own natural lipid barrier since they actually emulsify and remove the lipids. As a result, the potential for increased irritation, transepidermal water loss, and premature signs of aging may occur. The EchoDerm™ system can be used as a stand-alone, highperformance dermal cream. It can actually be used by itself as the emulsifying and stabilizing system for high-end dermal formulations when used at levels of 50% or more. Formulating such a hydro-cream product involves three steps: Step 1: Disperse a thickening agent, such as Carbomer Ultrez or a variety of others. Step 2: Weigh out the Echo-Derm™ delivery system. With a medium degree of agitation,

slowly mix A into B. Continue agitation and mix in the easy-to-disperse, or pre-dispersed active payload. Mix in any other desired ingredients. Step 3: Neutralize the batch, and add preservative. Useful ingredient ranges: • The Echo-Derm™ delivery system, when creating a Dermal Hydro-Cream, should comprise 50% to 80% of the final product. • The lipophilic phase may comprise about 10% to 30% of the formulation. • The hydrophilic phase may be about 10% to 50% of the formulation. • Echo-Derm™ may be used as a co-stabilizer, such as a Pemulen, Sepigel, etc.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM

6.7

Sample Formulations

While loading and formulating with EchoDerm™ is rather easy to do, the resulting benefits are considerable. Cosmetic scientists may want to experiment with different active payloads, or “tweaking” one of the following formulations for specific

147

needs or market positioning. To provide a starting point, sample formulations have been provided (see Formulations 6.1–6.5) for the following: Cell Renewal Serum, Lipid Replenishing Serum, P.M. Moisture Lock™, Crushed Lava Nail Buffing Cream, and O.T.C. Pain Relief Cream.

Formulation 6.1: Cell Renewal Serum

This light texture, highly effective serum helps maintain moisture balance, while promoting skin renewal and delivering essential intercellular lipids. It helps to maintain smooth, supple, more radiant-looking skin.

• Visibly creates more even skin tones. • Utilizes Echo-Derm™, patent pending technology that echoes, or mimics the skin’s own lipid system thereby enhancing the delivery of key ingredients, and replenishing the lipid barrier.

Demonstrated benefits: • Increase in cell turnover rate by 25%.

Usage:

• Reduction of the appearance of fine lines and wrinkles.

Massage a small amount over face and neck area, before using moisturizer or applying make-up.

• A dramatic increase in oxygen consumption of the cells.

Phase

Ingredients

Function

Vendor

1. Deionized water A

B

C

Weight % QS to 100

2. Glycerin

Humectant

6.00

3. Xanthan gum

Thickener

0.40

4. Tego Care 450

Emulsifer

Goldschmidt

2.00

5. Squalane

Skin conditioner

Tri-K/Centerchem

1.00

6. Jojoba oil

Skin conditioner

Desert Whale

1.50

7. Caprylic/capric triglyceride

Skin conditioner

2.00

8. Cetearyl octanoate

Ester/feel

5.75

9. Seamollient

Nourishing

Collaborative

5.00

10. Germaben II

Preservative

ISP/Sutton

1.00

11. Sepigel 305

Emulsifier

Seppic

0.60

12. Echo-Derm™

Delivery system

AdvantaChem

5.00

13. OxyPeptide™

Cell renewal

AdvantaChem

3.00

14. Fragrance

Fragrance

Belmay

0.20 (Cont’d.)

D

E F

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 6.1: (Cont’d.)

Preparation: Prepare Phase A by heating water to 75°C–80°C. Separately, mix Ingredients #2 and 3 into a paste form. With moderate shear, slowly add to batch. Mix until fully wetted. Separately, combine and heat Phase B to 75°C–80°C. When A and B are at a temperature of 75°C–80°C, slowly add A into B using medium agitation. Mix 15 minutes then begin cooling. After switching to low agitation, side sweep. When batch is below 65°C, mix it in with C using low agitation. When the batch is below 45°C, use medium agitation and slowly add in each ingredient of Phase D, mixing well between each ingredient addition. Separately, mix Phase E. With low agitation, mix Phase E into batch. Mix until uniform. Then, mix in Phase F. Mix well. NOTE: The pH may be adjusted with sodium hydroxide (25% solution). Do NOT use TEA (triethanolamine). Specifications Appearance

Opaque med. beige serum

pH range

6.0 to 6.8

Odor

Fresh/buttermilk musk

Color

Med. beige

Viscosity range

7,000 to 13,000 cp, using Brooksfield Viscometer Model RVDV-I+ spindle #6 @ 10 rpm

Specific gravity

0.8743 ± 0.02

Formulation 1 Cell Renewal Serum has passed the following tests: Accelerated shelf life Extreme heat testing Freeze/thaw testing (3 cycles) Aroma stability Color stability The information provided herein this Formulation is based on our research and believed to be accurate, but no guarantees, representations or warranties of any kind are made as to its accuracy, suitability for particular applications or results to be obtained. The formulations are provided for informational purposes and to suggest a starting point for creating your own product formulations. You are urged to perform the necessary testing to determine the acceptable quality and suitability for a particular purpose before full scale production or marketing of these formulations. Nothing contained herein is to construe or to imply the nonexistence of any relevant patents or to be considered as permission, inducement or recommendation to practice any invention covered by any patent, without permission of the patent owner.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM

149

Formulation 6.2: Lipid Replenishing Cream

This formulation is an advanced moisturizing and renewal system that delivers milk protein. The protein is comprised of approximately 22 amino acids, including a number of essential amino acids that the body does not produce naturally. Protein provides the building blocks for connective tissue. Formulation 2 is an elegant-feeling moisturizer that visibly reduces deep wrinkles and skin roughness for overall improved skin. It leaves skin feeling silky, with a dewy feel all day long. Features and benefits: • Visibly reduces fine lines and deep wrinkles.

• Reduces overall skin roughness. • Light weight, fast absorbing. • Employs Echo-Derm™ (patent pending) technology that mimics the skin’s own lipid system, thereby enhancing the delivery of key ingredients and replenishing the lipid barrier. Usage: Each morning, massage a small amount over the face and neck area until it is absorbed. The product can be used under make-up.

• Increases moisturization of the skin.

Phase

Ingredient

Function

Vendor

1. Deionized water A

B

C

QS to 100

2. Carbomer Ultrez 10

Thickener

3. Glycerin 99%

Humectant

10.00

4. Stearic acid, TP

Emulsifier

1.20

5. Cetearyl alcohol 70/30

Neovone

Rita Corp.

2.00

6. Crodamol OHS

Emollient

Croda

5.35

7. Cyclomethicone (DC345)

Emollient

Dow Corning

2.50

8. Polysorbate 80

Solvent

0.75

F

2.58

10. Sodium hydroxide (25% solution)

pH modifier

11. InstaFirm – MP

Firming

AdvantaChem

0.50

Skin conditioner

Tri-K/Maybrook

0.50

13. Dermonectin

Skin conditioner

Vevy

0.25

14. Echo-Derm™

Delivery system

AdvantaChem

5.00

15. Fragrance

Fragrance

Belmay

0.01

16. Germaben II

Preservative

ISP/Sutton

1.00

17. TEA

pH modifier

12.Wheat amino acids E

0.51

Emulsifier

9. Deionized water D

Weight %

0.17

QS pH (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 6.2: (Cont’d.)

Mixing Procedure Weigh out Ingredient #1. Using shear agitation, slowly sprinkle in Ingredient #2. Then, switch to low agitation and mix in Ingredient #3. Heat to 75°C–80°C. Separately, combine Phase B and heat to 75°C– 80°C, mixing with low agitation. When Phases A and B reach 75°C–80°C, mix A into B using medium agitation. Maintain heat. Continue agitation and mix in Phase C. Mix 15 minutes. Switch to low agitation and begin to cool. Separately, mix Phase D. When batch is below 45°C, mix in Phase D with low agitation and side sweep. Separately, combine Phase E, then, add it to the batch with low agitation. Continue agitation and add remaining ingredients. Mix until uniform. Adjust pH to match specification. Specifications Appearance

Light beige, opaque cream

pH range

5.7 to 6.20

Odor

Pleasant, floral

Color

Light beige

Viscosity range

36,000 to 43,000 cp, using Brooksfield Viscometer Model RVDV-I + spindle #6 @ 10 rpm

Specific gravity

1.004

Formulation 2 Lipid Replenishing Cream has passed the following tests: Accelerated shelf life Extreme heat testing Freeze/thaw testing (3 cycles) Aroma stability Color stability The information provided herein this Formulation is based on our research and believed to be accurate, but no guarantees, representations or warranties of any kind are made as to its accuracy, suitability for particular applications or results to be obtained. The formulations are provided for informational purposes and to suggest a starting point for creating your own product formulations. You are urged to perform the necessary testing to determine the acceptable quality and suitability for a particular purpose before full scale production or marketing of these formulations. Nothing contained herein is to construe or to imply the nonexistence of any relevant patents or to be considered as permission, inducement or recommendation to practice any invention covered by any patent, without permission of the patent owner.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM

151

Formulation 6.3: PM Moisture Lock™

An exceptionally rich, high-performance nourishing crème formulated for dry, mature skin, Advanced Moisture Lock™ technology actually helps draw moisture from the air and lock it in. The skinmimicking system conditions the skin and enhances delivery of the key ingredients. It helps develop and maintain noticeably softer, more radiant, youngerlooking skin.

• Filled with skin-beneficial nutrients. • Utilizes Echo-Derm™ (patent pending) technology that mimics the skin’s own lipid system, enhancing the delivery of key ingredients and replenishing the lipid barrier. Usage: Each night, after cleansing face, massage a small concentrated amount over the face and neck area until absorbed.

Benefits: • Moisture Lock™ technology holds 800 times its weight in water, helping to deliver desperately needed hydration.

Phase

Ingredient

Function

Vendor

1. Deionized water

Weight % QS to 100

2. Carbomer Ultrez 10

Thickener

Neovone

0.10

3. Butylene glycol

Solvent

3.00

4. Glycerin 99%

Humectant

3.00

5. Hydrolite 5

Moisturizer

Symrise

1.00

6. Moisture Lock™

Moisturizer

AdvantaChem

0.01

7. Ajidew N50

Humectant

Ajinomoto

0.01

8. EDTA Na2

Chelating agent

9. Liponate NPCG-2

Skin conditioner

A

B

0.10 Lipo

2.00

10. Finsolv TN

Emollient

6.00

11. Cetearyl octanoate

Emollient

2.00

12. Crodamol OHS

Emollient

13. Ceraphyl 847

Skin conditioner

1.50

14. Cetyl alcohol

Thickener

0.30

15. Shea butter

Conditioner/lipids

Tri-K

2.00

16. Rita Pro 300

Emulsifier

Rita Corp

1.30

17. Stearic acid, TP

Emulsifier

1.25

18. GMS 165

Emulsifier

2.50

19. Lipovol MOS-130

Emollient

Croda

Lipo

3.00

4.50 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 6.3: (Cont’d.)

Phase C

D

E

Ingredient

Function

Vendor

Weight %

20. Cyclomethicone (200–300)

Emollient

1.50

21. Sepigel 305

Emulsifier

Seppic

2.00

22. BotaniCell™ Calming

Skin conditioner

AdvantaChem

0.50

23. Sodium hyaluronate1%

Humectant

Tri-K

0.10

24. Tocopherol acetate

Skin conditioner

1.00

25. Retinyl palmitate

Skin conditioner

0.10

26. Echo-Derm™

Delivery system

27. TEA

pH modifier

28. Fragrance

Fragrance

29. FDC Blue #1 (1% Solution)

Colorant

AdvantaChem

5.00 0.20

Belmay

0.08 0.14

Mixing Procedure Weigh out Ingredient #1. Using shear agitation, slowly sprinkle in Ingredient #2. Then, switch to low agitation, heat to 75°C–80°C. While heating, continue low agitation and add in remaining ingredients in Phase A. Separately, combine Phase B and heat to 75°C– 80°C, mixing with low agitation. When Phases A and B reach 75°C–80°C, mix A into B using medium agitation. Mix 5–10 minutes. Switch to low agitation and begin to cool. When batch is 50°C–60°C, use medium agitation and slowly add in Phase C. Mix well. Separately, mix Phase D. When batch is below 45°C, use low agitation and add Phase D to batch. Mix well. Continue agitation and add remaining ingredients. Mix until uniform. Adjust pH to match specifications. Specifications Appearance

Light blue, opaque cream

pH range

6.1 to 6.7

Odor

Pleasant, floral

Color

Light blue

Viscosity range

65,000 to 85,000 cp, using Brooksfield Viscometer Model RVDV-I+ Spindle #6 @ 10 rpm

Specific gravity

0.9379

Formulation 6.3 Moisture Lock™ cream has passed the following tests: Accelerated shelf life Extreme heat testing Freeze/thaw testing (3 cycles) Aroma stability Color stability The information provided herein this Formulation is based on our research and believed to be accurate, but no guarantees, representations or warranties of any kind are made as to its accuracy, suitability for particular applications or results to be obtained. The formulations are provided for informational purposes and to suggest a starting point for creating your own product formulations. You are urged to perform the necessary testing to determine the acceptable quality and suitability for a particular purpose before full scale production or marketing of these formulations. Nothing contained herein is to construe or to imply the nonexistence of any relevant patents or to be considered as permission, inducement or recommendation to practice any invention covered by any patent, without permission of the patent owner.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM

153

Formulation 6.4: Crushed Lava Nail Buffing Cream

Creates smoother, shinier, healthier looking nails easily. Crushed lava smoothes ridges, while supplying natural lipids to create healthier, shinier, stronger looking nails. No more filing. Simple to use. Restores natural firm feeling to nails. Incredible results. Features and benefits:

• Echo-Derm™ (patent pending) technology that mimics the skin’s own lipid system, replenishing lipids. Usage: Massage a concentrated amount over nails, applying light pressure. Wipe with soft cloth.

• Crushed lava for smoothing of ridges. • Creates shinier, healthier-looking nails.

Phase

A

B

C

D

Ingredients

Function

Vendor

Weight %

1. Shea butter

Conditioner/lipids

Tri-K

2. Beeswax

Thickener

Frank B Ross

3. Paraffin wax

Thickener

Dussek/Campbell

4. Olive oil

Emollient

2.00

5. Evening primrose oil

Emollient

0.10

6. Macadamia nut oil

Emollient

0.10

7. Borage oil

Emollient

0.25

8. Squalane (olive)

Emollient

9. Sweet almond oil

Emollient

9.80

10. Pumice

Exfoliator

12.75

11. Propylene glycol

Solvent

0.85

12. Propylparaben

Preservative

0.15

13. Calcium gluconate

Conditioner

0.10

14. Echo-Derm™

Delivery system

15. Tocopherol acetate

Conditioner

16. Fragrance

Fragrance

Tri-K/Centerchem

AdvantaChem

QS to 100 1.25 14.50

0.01

2.00 1.00

Belmay

0.02 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 6.4: (Cont’d.)

Mixing Procedure Combine ingredients in Phase A and heat to 65°C (do NOT overheat). Use low agitation and mix well. Continue agitation and slowly add in Phase B. Continue low agitation while cooling to 45°C. Separately, mix Ingredients #11and #12 until clear, then dissolve Ingredient #13. Mix into batch. Mix in remaining ingredients one at a time. Continue mixing until hardening point. Specifications Appearance

Pale grey, thick paste

pH range

N/A

Odor

Clean, fresh

Color

Light grey

Viscosity range

N/A

Formulation 4 Crushed Lava Nail Buffing Cream has passed the following tests: Freeze/thaw testing (3 cycles) Aroma stability Color stability The information provided herein this Formulation is based on our research and believed to be accurate, but no guarantees, representations or warranties of any kind are made as to its accuracy, suitability for particular applications or results to be obtained. The formulations are provided for informational purposes and to suggest a starting point for creating your own product formulations. You are urged to perform the necessary testing to determine the acceptable quality and suitability for a particular purpose before full scale production or marketing of these formulations. Nothing contained herein is to construe or to imply the nonexistence of any relevant patents or to be considered as permission, inducement or recommendation to practice any invention covered by any patent, without permission of the patent owner.

POLLOCK: CROSSING THE LIPID BARRIER WITH THE ECHO-DERM™ DELIVERY SYSTEM

155

Formulation 6.5: Pain Relief Cream (OTC)

Temporarily relieves minor aches and pains of muscles and joints due to arthritis, simple backaches, sprains, etc. Stability testing and assays have been performed and are available upon request. To utilize the OTC testing performed requires this formulation EXACTLY and in the pretested packaging of a Delta Plastics two-ounce jar.

• simple backaches • sprains Usage: Adults should apply directly to affected area. Do NOT use more than 3 or 4 times per day. Ask a doctor before using on children of any age. Active ingredients:

Benefits: Temporarily relieves minor aches and pains of muscles and joints due to:

Menthol 5%

Topical Analgesic

Capsiacin 0.025%

Topical Analgesic

• arthritis

Phase

Ingredient

Function

Vendor

1. Deionized water

A

B

C

D

E

Weight % 54.86

2. EDTA Na2

Chelating agent

Akzo Nobel

0.10

3. Methylparaben

Preservative

4. Carbomer 934

Stabilizer

Noveon

0.60

5. Aloe Vera 200x

Conditioner

BioChemical

0.10

6. Menthol

Analgesic

Amend

5.00

7. Brij 721

Emulsifier

Uniqema

1.20

8. Brij 72

Emuslifier

Uniqema

4.00

9. Emu Oil

Conditioner

BioChemical

1.00

0.20

10. Propylparaben

Preservative

0.10

11. Echo-Derm™

Delivery system

AdvantaChem

20.00

12. Capsicum extract

Analgesic

Bio-Botanica

5.00

13. MSM

Conditioner

Cardinal

1.50

14. Neolone 950

Preservative

Symrise

0.10

15. Sodium Hydroxide (10% solution)

pH Modifer

0.60

16. Deionized water

5.00

17. Chondroitin sulfate

Conditioner

Freeman Ind

0.01

18. Glucosamine sulfate

Conditioner

0.01

19. D-Glucosamine

Conditioner

0.001

F

(Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 6.5: (Cont’d.)

Phase

G

Ingredient

Function

Vendor

Weight %

20. Blue cypress oil

Essential oil

Australian Ess Oil

0.01

21. Squalane (olive)

Emollient

Tri-K/Centerchem

0.01

22. AminoCell™

Peptide/conditioner

AdvantaChem

0.10

23. Fragrance 138513-0896N

Fragrance

Belmay

0.50

Mixing Procedure Weigh out water in suitable vessel equipped with proper agitation. Slowly disperse Ingredient #2. Heat Phase A to 45°C. Continuing strong agitation, slowly mix in remaining ingredients in Phase A. Separately, weigh out and combine ingredients in Phase B. Heat to 45°C. (Do NOT overheat). Wth medium agitation, slowly add Phase A to Phase B. Mix well, while cooling. Avoid aeration. Using homogenizer, mix in Phase C. Mix until uniform. With medium agitation, slowly add ingredients from Phase D one at a time. Mix well. Slowly mix in Phase E to neutralize carbomer. Mix well. Separately, combine ingredients in Phase F, then mix into batch. Continue by adding each ingredient from Phase G to batch. Mix well. Specifications Appearance

Soft white cream

pH range

6.1 to 6.75

Odor

Fruity, pina colada

Color

White to off white

Viscosity range

15,500 to 20,500 cps using Brooksfield Viscometer Model RVDV-I+ Spindle #6 @ 20 rpm

Specific gravity

0.9293

Required assays

Menthol 5% (range 5.00%–5.5%), capsiacin 0.025% (range 0.0250– 0.0275%)

References 1. Appa, Y., et al., Clinical Evaluations of Hand and Body Moisturizers that Heal Skin Dryness, 1992 American Academy of Dermatology, poster presentation, San Francisco (Dec. 6–7, 1992)

4. Lipid Complex data, Nippon Fine Chemical, Inc., Cosmetic Ingredients Division. 5. Happi Magazine, (Mar. 1997)

2. Gazzaini, Giovanni, U. S. Patent 5,980,925.

6. Lautenschläger, Hans, Dr., Handbook of Cosmetic Science and Technology, pp. 201– 209.

3. Product information brochures, Exsymol.

7. Product information, American Lecithin, Inc.

7 Tetrahydropiperine A Natural Topical Permeation Enhancer Muhammed Majeed and Lakshmi Prakash Sabinsa Corporation Piscataway, New Jersey

7.1 7.2

Introduction ................................................................................... 158 Historical Perspective ................................................................... 158 7.2.1 The Spice Route and Black Pepper[29]............................ 158 7.2.2 Use of Black Pepper in Folk Medicine .............................. 159 7.2.3 Discovery as a Delivery System ....................................... 159 7.3 Concept Development .................................................................. 160 7.3.1 Skin as a Delivery Conduit for Bioactives ......................... 160 7.3.2 Black Pepper Extract as Bioavailability Enhancer for Nutraceuticals .............................................................. 162 7.3.3 Tetrahydropiperine (THP): Unique Black Pepper Constituent Derived from Piperine .................................... 165 7.3.4 Mechanism of Action ........................................................ 165 7.4 Scientific Basis for Efficacy .......................................................... 166 7.4.1 Chemistry of Tetrahydropiperine (THP) ............................ 166 7.4.2 Experimental Evidence for Topical Formation Enhancement Efficacy of THP ......................................... 168 7.5 Safety Profile ................................................................................ 172 7.5.1 THP: Low Skin Irritation Potential ...................................... 172 7.6 Enhancing Topical Delivery of Bioactives with THP ..................... 173 7.6.1 Potential Skin and Hair Care Applications......................... 173 7.7 Formulation Strategies ................................................................. 173 7.7.1 Skin Care .......................................................................... 173 7.7.2 Hair Care........................................................................... 173 7.8 Summary ...................................................................................... 173 7.9 Formulations ................................................................................. 174 References .......................................................................................... 176 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 157–178 © 2005 William Andrew, Inc.

158

7.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Introduction

trointestinal tract, increased emulsifying content of the gut, and enhanced active-nutrient transport.

The quest for novel topical delivery systems for bioactives, with emphasis on “natural” and “safe,” is an area of dynamic research in the pharmaceutical, cosmetics, and nutritional fields. Tetrahydropiperine is a natural topical permeation enhancer for active compounds. Derived from black pepper fruit, the product is effective in very small quantities (0.01%–0.1% by weight in formulations containing actives). It has no irritant or sensitization side effects.

The skin shares many of the characteristics of the gastrointestinal epithelium. It is fitting, therefore, that a natural compound derived from black pepper fruit be used to enhance the topical permeation of actives into the skin. Tetrahydropiperine (THP) thus offers a natural solution to formulators challenged with poorly absorbed topical actives.

Prepared using a proprietary process, this branded ingredient is gaining popularity in a wide range of topical formulations. Its efficacy in enhancing the topical permeation and uptake of various classes of active compounds has been scientifically validated. The ingredient is compatible with commonly used formulation bases and does not adversely affect the sensory profile of cosmetic compositions.

7.2

A salient feature of tetrahydropiperine is that it is derived from black pepper fruit, a familiar culinary spice. Members of the botanical family Piperaceae, to which black pepper (Piper nigrum) and long pepper (Piper longum) belong, are believed to be among the first plants cultivated by humans for medicinal and food use. Black pepper and long pepper have a history of medicinal use in the Ayurvedic tradition. Ayurveda literally means the “science of life” and is comprised of a system of lifestyle recommendations, along with the use of specific herbs and minerals, in the management of disease conditions. Ayurvedic texts, dating back to three thousand years ago, recommend “Trikatu” or three acrids, a mixture of black pepper, long pepper, and ginger in a wide range of formulations for optimal health and wellness. In recent years, extensive research data on the phytochemistry and unique pharmacological actions of these plants have also become available. This has led to their popularity as nutraceutical ingredients. One branded black pepper extract is a clinically proven bioavailability enhancer. It improves the gastrointestinal uptake and utilization of orally administered nutrients by functioning as a thermonutrient. Several mechanisms of action have been proposed. These include augmented blood supply to the gas-

7.2.1

Historical Perspective The Spice Route and Black Pepper[29]

Black pepper (Piper nigrum) and long pepper (Piper longum) are the best-known species of the plant family Piperaceae. They are probably among the most recognized culinary spices in the world. Black pepper alone is reported to account for approximately 35% of the world’s spice trade. By some chronicles, family Piperaceae was among the first plants cultivated by the early human. It is believed that the earliest European travelers who visited India found cultivated pepper vines on the Malabar Coast in southwestern India, over two thousand years ago. As a matter of fact, the demand for Indian black pepper was so great that historical accounts of its trade often portray dramatic events. Some of these events altered the course of world history. Black pepper was among the Indian spices on which the Romans levied duty at Alexandria about 176 C.E. In the fifth century C.E., Roman writers reported that Attila the Hun demanded, among other things, three thousand pounds of pepper in ransom for the city of Rome. Several centuries later, the high cost of pepper led the Portuguese to seek their own sea route to India, and this came to be called the “spice route.” Successful in their mission, trade in this spice became a monopoly of the Crown of Portugal until the eighteenth century. In January 1793, an agreement was made between the Rajah of Travancore and the English. The Rajah was to supply large quanti-

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER ties of pepper to the Bombay government in return for arms, ammunition, and European goods. Historically, this agreement became known as the “Pepper Contract.” From the sixteenth to the eighteenth centuries, the struggle for control of spice-producing regions in the Far East led to a series of wars between Portugal, Holland, and England over this source of immense wealth. The United States entered the world spice trade towards the end of the eighteenth century, and began exchanging its salmon, flour, and soup for tea, coffee, and spices. One reason that spices in general, and pepper in particular, became so important in international trade was their popular culinary role. In those times, tough, heavily salted, long-stored meat was standard fare, and spice additives made these meats more palatable, while simultaneously masking off-flavors. All of the commercial and political attention that black pepper has received throughout the centuries has been due to its pungency. The pungency of pepper evokes a familiar sensation of warmth in the mouth which, after a relatively short time, spreads throughout the body. This characteristic is primarily due to the presence of the alkaloid piperine, which was isolated at the beginning of the nineteenth century by the German scientist Derstad. A small quantity of tetrahydropiperine was recently isolated from long pepper (Piper longum),[30] and is also reported to be present in black pepper oleoresin.[31]

7.2.2

Use of Black Pepper in Folk Medicine[29][32][33][35]–[38]

Piper species have been used in traditional medicine for reducing intermittent fevers and to promote the secretion of bile. They are also recommended for neurological, bronchopulmonary, and gastrointestinal disorders. These include dyspepsia, flatulence, constipation, and hemorrhoids. Some traditional applications employ black pepper in gargles for sore throat and in poultices for the topical management of inflammation and pain. In Ayurveda, black pepper, long pepper, and ginger are often used together in equal proportions in a preparation known as “trikatu,”[16] a Sanskrit word

159

meaning “three acrids.” Out of 370 compound formulations listed in the Handbook of Domestic Medicines and Common Ayurvedic Remedies, 210 contain either trikatu or its individual ingredients.[8] According to Ayurveda, the three acrids collectively act as “kapha-vata-pitta-haratwam” which means “correctors of the three biological humors (doshas) of the human organism.” The sharp-tasting ingredients in trikatu are used to increase the protective gastrointestinal mucous secretion, a long-standing Ayurvedic treatment that has proven successful for both acute and chronic gastrointestinal conditions. The advantage of utilizing black pepper (as opposed to the standard quinine) in the treatment of refractory intermittent fevers, (symptomatic of malarial infections), was first reported by Dr. C. S. Taylor in The British Medical Journal, September, 1886. Long pepper was also used for patients who had chronic malaria with splenomegaly (enlarged spleen). In traditional Chinese medicine, black pepper has been used for the treatment of epilepsy.[34] Based on this traditional application, a new anti-epileptic drug called Antiepilepserine has recently been synthesized by Chinese researchers. Antiepilepserine is a chemical relative of piperine, the main alkaloid phytochemical found in plants of the family Piperaceae. In traditional Middle Eastern medicine, black pepper has been used as a nerve tonic.

7.2.3

Discovery as a Delivery System

Our research on tetrahydropiperine as a potential skin permeation enhancer for topical actives was based on the known bioavailability enhancement of nutrients and drugs by the parent compound piperine. Studies on piperine with rifampicin,[23] Piperine with isoniazid, pyrazinamide, and rifampicin,[21][22] piperine with propranolol and theophylline,[25] and piperine with phenytoin[24] are reported in the literature. Beta-carotene absorption has been shown to be variable among humans, with some individuals consistently absorbing it well, while others do not. Recently, an original bioavailability study showed that a standardized extract of black pepper (Bioperine®) increases gastrointestinal absorption of beta carotene in humans.[39] Bioperine is about 98% pure piperine obtained from pepper through a proprietary

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

extraction process. A small amount of Bioperine (5 mg) combined with a formula containing 15 mg of beta carotene, given as a food supplement once a day, increased almost twofold the blood levels of beta carotene in human volunteers. These results suggest that Bioperine possesses the potential to increase the bioavailability of nutrients as well. Incidentally, the dose of piperine that increased the bioavailability of beta carotene was several times lower than the estimated amount of piperine consumed daily in the diet by an average individual in the USA.[29] Coenzyme Q10,[27] L(+)-selenomethionine, vitamin B6, vitamin C (with propranolol hydrochloride), and herbal extracts such as curcumin showed enhanced bioavailability when co-administered with Bioperine.[29] When 5 mg of Bioperine was added to a mixture of vitamin C with propranolol hydrochloride, the bioavailability of the nutrient was enhanced while the bioavailability of the drug remained unchanged. Based on these properties, we tested a derivative of piperine (viz., tetrahydropiperine) to determine if it had better bioavailability enhancement properties. Excellent results were obtained. This data provided a basis for a novel bioavailability-enhancing natural compound for topical use in personal care applications. We developed a novel process to convert natural piperine in black pepper oleoresin to tetrahydropiperine and then tested its biological activity. Three interesting observations came to light in preliminary studies. Tetrahydropiperine, at very low levels in formulations, enhances the bioavailability of bioactive molecules (with potential applications in the topical delivery of drugs and nutrients), increases topical permeation of bioactive molecules (with potential cosmeceutical, cosmetic applications) and increases the dermal penetration of insecticides (with potential applications in pesticides, anthelmintics, and insecticides). The discovery that tetrahydropiperine can be used to enhance active-molecule penetration through the skin in topical applications, as well as for the penetration of pesticides, fungicides, herbicides, and foliar fertilizers applied to pests or plants, formed the subject of our patent application.[28] Derivatives of tetrahydropiperine were also included in the patent application.

7.3 7.3.1

Concept Development Skin as a Delivery Conduit for Bioactives

The skin is the largest organ in the body. It has far-reaching functions such as being a barrier to the environment and an interface with the outside world, and the capability to accentuate aesthetic appeal and beauty. The skin also participates in nourishing and healing the body. It contains actively metabolizing cells that constantly imbibe nutrients and facilitate their transport to the underlying tissues and organs in the body. Simultaneously, with the “intake” processes, metabolic wastes are excreted through perspiration. Conventional nourishment is conveyed through the skin from environmental sources such as light, moisture, and sensory stimuli. These inputs affect neurohormones. Noxious substances in the environment trigger the immune response. Deliberately applied substances and stimuli that can potentially heal, renew, and revitalize the body can be similarly conveyed through the skin. It is not surprising, therefore, that pharmacologists and cosmetologists alike look to the skin as a potential conduit for nutrients and drugs. By analogy, the skin functions quite like the gastrointestinal tract. Although easily accessible, the skin presents unique opportunities and challenges when it comes to the delivery of pharmaceuticals, nutritional compounds, nutraceuticals, and cosmeceuticals. The skin and its appendages (i.e., sweat glands, sebaceous glands, hair, hair follicles, and nails) constitute a dynamic metabolic system with intricate functions. An active compound applied to the skin needs to be absorbed through the protective five-layered epidermis, transported into the dermis and, thereafter, enter the metabolic cycle by absorption into the blood microcirculation. The outermost layer of the epidermis, the stratum corneum, is made of cornified or keratinized cells. It is in a state of dynamic shedding and renewal. This layer is a consequence of maturation of keratinocytes. These are cells that originate four layers down from the outermost stratum corneum layer in the bottom (basal) layer of the epidermis (stratum basale). Looking outward from this layer, a layer

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER just above the basal layer, the stratum spinosum, produces “waterproofing” material (a mixture of lipids and glycoproteins) that regulates skin permeability. This is topped by the stratum granulosum, which manufactures keratohyalin, an amino acid complex believed to be metabolized into eleidin in the layer above it (the stratum lucidum). Eleidin is converted to keratin, the tough protective protein of the skin, hair, and nails, in the stratum corneum. The epidermis is also home to several specialized cells. These include, for example, Merkel cells, which play a role in an early warning system against noxious stimuli to the skin. Langerhans cells, which function as immune cells, and melanocytes, which provide protection against excess UV light with potential influence on the circadian rhythms, are also part of the epidermis. Underlying the epidermis is the dermis. It is comprised of a cushion-like network of elastic fibers (collagen), capillary blood vessels and lymphatic vessels, fine-touch receptors (Meissener’s corpuscles), pressure receptors (Pacinian corpuscles), temperature sensors and pressure receptors (Krause’s end bulbs). It also contains bundles of smooth muscles attached to hair follicles (when activated giving an appearance of “goose bumps”), eccrin sweat glands (the “sex” glands), wax glands and sebaceous glands. By analogy with the gastrointestinal tract, this complex array of specialized cells and structures permits the skin to communicate with the outside world by selectively permitting nutritious stimuli into the body, while at the same time preventing the entry of noxious stimuli. It also provides for the evacuation of metabolic waste material (by way of the sweat, sebaceous, and wax glands). A variety of therapeutic molecules such as corticosteroids, steroid hormones, and nonsteroidal antiinflammatory agents (NSAIDs) have been typically delivered topically. Their efficacy and availability has been assessed by monitoring the biological effects or levels of actives in the plasma. However, attempts to optimize/maximize the delivery of such bioactive compounds is an area of dynamic research. By contrast, other nutrients and drugs, whether protein or peptide in nature, present unique delivery problems of their own, since factors such as molecular size and the charge present in the compound can have a major impact on their ability to be delivered.

161

A number of different pathways exist for the penetration of actives through skin. These include: intercellular penetration between stratum corneum (mainly hydrophobic, lipid soluble materials), transcellular (through the stratum corneum and consisting primarily of small water-soluble molecules), and via hair shafts and follicles as well as via sebaceous glands.[1] It is generally assumed that hydrophobic molecules of molecular weight less than five hundred can easily penetrate the stratum corneum, although the penetration through the deeper layers of the epidermis and dermis is questionable.[1][54] However, for proteins with molecular weight higher than five hundred, as well as charged molecules, even penetration through the stratum corneum is doubtful. For these materials, and for delivery of actives into the blood stream, several strategies have been attempted. A variety of “chemical penetration enhancers” have been used in the past to increase penetration of drugs into and through the skin. These include: solvents such as DMSO, ethanol, and other alcohols and glycols such as propylene glycol, etc. Fatty acids such as oleic acid and others have been used, as well as trans fatty acids that disrupt the lipid bilayer structure of the stratum corneum. Still other examples include detergents such as sodium lauryl sulfate, polyoxyethylene lauryl ethers, chaotropic agents such as thioglycolate, urea, mercaptoethanol, and many others.[1] Most of these agents increase penetration of certain drugs; they also have the potential to cause damage to the stratum corneum and to increase the probability of irritation. Most of these agents work by perturbation of the intercellular lipid bilayers present in the stratum corneum.[2] Several other strategies have also been used to deliver drugs through the skin. Designing prodrugs that can be cleaved enzymatically within the skin has been one such strategy. The prodrug is designed to improve skin penetration by initially increasing the hydrophobicity, or by neutralizing the charge on the molecule, until it is cleaved enzymatically. This strategy can utilize parameters such as lipid solubility, partition coefficient, and molecular volume.[3] A third strategy for increasing penetration is entrapment of the drug, nutraceutical, or cosmeceutical inside liposomes, or other skin penetrable vesicles.[4] Liposomes have been extensively stud-

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ied and suggested as a vehicle for topical delivery systems. It has also been suggested that liposome size makes a difference in the rate of penetration of the drug through the skin.[5] Penetration efficacy has been found to be inversely proportional to the size of the liposomes. Liposomes modified with hyaluronic acid have been suggested as better carriers of topical drug delivery, especially for delivering drugs for wound healing.[6] In addition, liposomes also accelerate delivery of materials via both pilosebaceous units[7] and a follicular route.[11] Various formulation strategies have been applied to induce delivery of actives into the skin. Skin penetration of alpha tocopherols can be greatly enhanced by formulating them in hydroalcoholic gels. [8] Microemulsions are suitable carriers to stabilize and deliver ascorbic acid derivatives and estradiol into skin.[9][10] The nutraceutical industry has begun to use this strategy to deliver nutraceuticals via the skin as an alternative to oral supplements. Skin permeation enhancement technologies also include the use of phospholipid vesicles and cyclodextrins as delivery vehicles, as well as the use of essential oils, fatty acids, squalene, alcohols, and other compounds. Two natural ingredients derived from black pepper extract have been demonstrated to enhance the gastrointestinal and topical absorption of nutrients. Both these ingredients are patented by Sabinsa Corporation.[12]-[15][28]

7.3.2

Black Pepper Extract as Bioavailability Enhancer for Nutraceuticals[12]-[15]

Do all nutritional supplements consumed, or all topically applied products, provide optimal health benefits? Typically, the answer to this question depends upon how well they are absorbed along their delivery route. Bioavailability encompasses availability, absorption, retention, and utilization of nutrients. Absorption in the body is a key factor for the nutrient to be biologically effective. Black pepper extract, or to be more precise, its active alkaloid component piperine, has been shown to enhance bioavailability when co-administered with nutrients.

The spicy or “hot” taste of pepper when sprinkled on food is well known. The perception of heat is stronger when fresh pepper is used. This heat is, in fact, a manifestation of the biological activity of some of the active compounds found in pepper, the most notable of these being piperine. Black and long peppers stimulate the skin as well as the tongue. They have, therefore, also found wide use in topical applications. These peppers have been found to have broad antimicrobial, antiparasitic, and insecticidal properties. Peppers have been traditionally used as local anesthetics, but the mechanism of this analgesic (pain-relieving) action has only recently been described.[17] It is believed that piperine, the active constituent in black pepper and long pepper, acts in a similar (but not identical) way to capsaicin, another well-known pungent phytochemical, found in cayenne peppers (Capsicum annuum). Black and various red peppers, including cayenne, chili, and paprika, are all spicy but are not related botanically. According to one hypothesis, piperine may cause depletion of the neurotransmitter called “Substance P,”[29] from the sensory nerves. Substance P’s appearance and concentration is correlated with the experience of pain. This action may cause local desensitization to pain stimuli. It has been proposed that Bioperine acts through thermoreceptors, both locally in the skin nerve endings, and systemically, throughout the nervous system. This action, in turn, interferes with pain stimulus transmission and causes desensitization of pain receptors.[29] The proposed mechanism for pain reduction through thermoreceptors (sensors of heat energy) in the body may provide clues to the mechanism of thermogenic (heat-generating) action of pepper and piperine. The thermogenic effect of piperine and other components of spices such as capsaicin, gingerol, and shogaol is now broadly discussed as a new application of spices traditionally known for their ability to regulate body temperature. Thermogenesis is scientifically linked to the metabolic processes in the body and the metabolic rate. The higher the metabolic rate, the greater is the heat energy produced by the body. Could it be that thermoregulation by piperine is a mechanism through which metabolism can be regulated, including the absorption and utilization of nutrients and drugs? In light of the profound effects of piperine on nutrient absorption when given orally in a dose as small as a few milligrams,

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER the compound deserves to be called a “supernutrient.” In view of its possible thermogenic effect in the body, it could also be dubbed a thermonutrient.[18] The concept of thermogenesis is not documented in Ayurveda, the ancient Indian system of medicine. However, its texts describe the empirical use of certain combinations of herbs and minerals specifically targeted to improve the digestibility of food. Recent experimental evidence shows that piperine has antiinflammatory and antioxidant properties.[19] Piperine may thus facilitate nutrient absorption by reducing inflammation at the site of active molecule absorption. The mechanisms underlying the beneficial action of piperine, as one of the principal ingredients of numerous formulas for digestive health and respiratory support employed by Ayurveda, certainly requires further investigation. Particular attention needs to be paid to the traditional understanding that restoring optimal gastrointestinal function is an effective means of preventing disease and improving overall nutrition through improved nutrient absorption. Black pepper and long pepper are thus potentially useful herbs in the management of a variety of gastrointestinal and related problems. Future research on pepper and its constituents may further explore the origin, evolution, and effects of its pungency, a property that has attracted attention since ancient times. Pliny commented some two thousand years ago: “It is quite surprising that the use of pepper has come so much in fashion, its only desirable quality being a certain pungency; and yet it is for this that we import it all the way from India!”[20] The pungency of pepper is now understood to be an offshoot of the biological properties of piperine. This compound can, in fact, regulate neurohormones, and thereby increase thermogenesis, or the production of heat by the body. Scientific research has now revealed that the “hot” pepper taste is due to the production of heat energy. The thermogenic effect is also attributed to the ability of piperine to stimulate the thyroid gland and increase the action of thyroid hormones The biological mechanism of piperine is thus clearly linked to its hot taste, further validating its representation as a nutraceutical or “functional food.”

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The biological properties of piperine have been extensively studied only in recent years. [21][22] The proposed mechanism for the increased bioavailability of drugs co-administered with piperine is attributed to the interaction of piperine with enzymes that participate in drug metabolism. Examples of these are mixed function oxidases found in the liver and intestinal cells. Interaction with the synthesis of drug chelating molecules in the body such as glucuronic acid has also been proposed. Piperine may also interact with the process of oxidative phosphorylation, or the process of activation/deactivation of certain metabolic pathways, thereby slowing down the metabolism and biodegradation of drugs. This action of piperine results in higher plasma levels of drugs, thereby rendering them more available for pharmacological action. One of the first scientific experiments to confirm that pepper could enhance the bioavailability of drugs was performed in the late 1970s by Atal and coworkers at the Regional Research Laboratory, Jammu-Tawi in India.[21] These experiments revealed that Piper longum orally co-administered to rats with the drugs vasicine and sparteine increased the blood levels of vasicine by 232% and sparteine by more than 100% as compared to control animals who did not receive P. longum. In subsequent experiments, piperine has been proven to enhance the bioavailability of a number of drugs including rifampicin, phenytoin, propranolol, and theophylline.[22][23][25] The successful use of piperine to increase bioavailability of certain drugs has created interest in its use for nutrient and food absorption. Nutritional deficiencies due to poor gastrointestinal absorption are an increasing problem in developing countries as well as in Western nations; therefore, the use of piperine represents an opportunity to alleviate these deficiencies. While overall gross malnutrition may be the culprit for this problem in developing countries, incidence of poor gastrointestinal absorption is increasing in Western nations due to a larger percentage of aging baby boomers in the population. Nutritional deficiencies in Western nations are further exacerbated by “junk food diets,” allergies, gastric ulcers, and chronic yeast infections (Candidiasis). Bioperine® is a standardized extract manufactured by Sabinsa Corporation from the fruits of Piper nigrum L. (black pepper) or Piper longum L. (long

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pepper). It contains a minimum piperine content of 95% compared to the 3%–9% and 3%–5% found in raw forms of Piper nigrum and Piper longum, respectively. Bioperine may be co-administered with various nutrients to produce improvements in both human and animal health.[12]-[15] When optimal oral delivery of nutrients is required, Bioperine may be co-administered in low amounts (5 mg) with the nutrients to increase absorption and bioavailability. The efficacy of Bioperine in this regard is supported by clinical data as shown in Figs. 7.1–7.4.

Nutritional materials which may be co-administered with Bioperine, include the following groups: • Herbal extracts • Water-soluble vitamins • Fat-soluble vitamins • Antioxidants • Amino acids • Minerals Bioperine was effective in increasing nutrient absorption with a dose several times lower than that

Figure 7.1 Effect of Bioperine® on the mean serum beta carotene levels during a fourteen-day supplementation trial.

Figure 7.3 Efficacy of Bioperine® on the bioavailibility of vitamin B6 absorption in human volunteers.

Figure 7.2 Effect of Bioperine® on the mean serum selenium levels during a six-week supplementation trial.

Figure 7.4 Effect of Bioperine® on the mean serum CoQ10 levels during a twenty-one day supplementation trial.

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER commonly used to bioenhance blood levels of a drug. Incidentally, the dose of piperine, which increased the bioavailability of beta carotene,[26] was several times lower than the estimated amount of piperine consumed daily in the diet by an average individual in the USA.[29] Similar bioavailability enhancement was observed on co-administration of other nutrients including coenzyme Q10,[27] L(+)-selenomethionine, vitamin B6, vitamin C (with propranolol hydrochloride) and herbal extracts such as curcumin with Bioperine.[29] These experimental results provide strength to the concept that nutrient delivery through the skin could similarly be enhanced by piperine and related compounds.

In view of these properties, tetrahydropiperine is a potential transdermal bioavailability enhancer when co-administered topically with nutrients or other active compounds. Improved absorption of topically beneficial nutraceuticals is expected for carotenoids, ascorbic acid, vitamin A, mineral nutrients, 7-keto DHEA, herbal extracts, amino acids, and other topically beneficial nutraceuticals and cosmeceuticals. With regard to safety, tetrahydropiperine does not irritate the skin when used in cosmetic formulations, as revealed by occlusive patch testing performed on human volunteers.[55]

7.3.4 7.3.3

Tetrahydropiperine (THP): Unique Black Pepper Constituent Derived from Piperine

Tetrahydropiperine, a compound present in small amounts in black pepper and long pepper extracts, can be commercially prepared from piperine by using a proprietary process. This process produces a concentrate containing pure tetrahydropiperine in the form of a light tan powder. The material is suitable for use in cosmetic formulations and topical delivery systems for drugs, nutrients, and other bioactives. When added in low amounts (0.01–0.1%) to such formulations, this product enhances the skin uptake and bioavailability of actives in the formulations. Laboratory studies with betamethasone dipropionate (BMDP), a steroidal anti-inflammatory agent that is commonly used in topical anti-inflammatory formulations, revealed faster absorption of the drug when combined with tetrahydropiperine. Similar enhanced permeation was observed in studies with other active materials including Coleus forskohlii extract (forskolin, green tea extract [polyphenols]) and tetrahydrocurcuminoids (derived from tumeric root extract). For example, the permeation of forskolin was enhanced when the concentration of tetrahydropiperine was 5% of forskolin concentration. Similarly, about 30% improvement in bioavailability of the other botanical extracts was observed when they were co-administered with tetrahydropiperine.

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Mechanism of Action

Based on clinical experimentation with its parent compound piperine, tetrahydropiperine is a potentially versatile adjuvant for nutrient and cosmeceutical delivery into the skin. As discussed previously, piperine in oral dosage forms is reported to enhance the gastrointestinal absorption of drugs and nutrients in animals and humans. Compounds successfully studied include drugs such as vasicine, pyrazinamide, rifampicin, isoniazid, propranolol, theophylline, and phenytoin. Similar action has been seen for nutrients such as fat-soluble beta carotene, water-soluble vitamin B6, vitamin C, coenzyme Q10 and the mineral selenium in the form of L-selenomethionine.[29] In vitro studies with tetrahydropiperine, using systems that simulate dermal absorption showed promising results. An application analogous to gastrointestinal bioavailability enhancement by piperine is therefore likely. This result presents exciting alternative inroads for new directions in nutrient delivery. Effective topical delivery of essential nutrients could provide an accessible and affordable means of disease prevention and sustaining good health. This above stated rationale is based upon the physicochemical factors that influence skin permeation of topically applied substances, and the mode of action of known permeation and bioavailability enhancers. Selective nutrient absorption is an important physiological property of the skin. The process begins at outermost epidermal layer, the stratum corneum, the barrier against the external environment.[44] This barrier function is effected by the

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unique composition of the lipid moieties in the epidermis.[45]-[48] Lipids produced by actively metabolizing keratinocytes are released into the intercellular spaces, where they undergo enzymatic processing to produce a lipid mixture consisting of ceramides, cholesterol, and fatty acids. These intercellular lipids are organized to form a selectively permeable barrier. These intercellular lipids mediate transdermal delivery of both lipophilic and hydrophilic molecules.[49] Fatty acids in epidermal lipids play a pivotal role in regulating nutrient bioavailability because they are important components of cell membranes and form the hydro-lipid skin surface film.[50] It is known that topical application of certain fatty acids can lead to changes in permeation of co-administered topical bioactives. Fatty acids may restore a damaged stratum corneum barrier, or enhance nutrient and drug transport through the skin, by increasing cell membrane fluidity. Increased cell membrane fluidity results in a better fit for the bioactive molecule and translates to increased uptake. Research shows that regulating the composition of intracellular lipids in the skin can increase or decrease the bioavailability of topically applied actives. It is known that a diet deficient in essential fatty acids, repeated exposure to organic solvents, or prolonged topical application of agents that interfere with lipid synthesis can reduce the barrier function of the skin, rendering it more porous.[47] Examples of these agents include lovastatin, fluvastatin, and cholesterol sulfate. This decrease in barrier function would trigger increased synthesis of lipids, DNA, and relevant types of epidermal cells to compensate for the deficiency in the protective barrier. These natural defense mechanisms serve to restore the integrity of the skin barrier and its functions. It should also be noted that providing an artificial barrier, for example, by applying a topical sealant, blocks the natural defense mechanisms that serve to repair the skin structure.[47] This observation indicates that the epidermal lipid composition might be able to be modified sufficiently in order to permit the entry of beneficial molecules. In studies with drug molecules, it has been observed that supersaturation of the active ingredient could effect enhanced permeability. Alternatively, when the skin is viewed as a delivery conduit, it can

contain ingredients that may decrease the diffusional (electrostatic) resistance of the lipid bilayer to the active molecule. Topical liposome preparations are a good example of such materials. They function as effective penetration enhancers for the delivery of certain co-applied drugs and biological compounds, (e.g., interferon). The mechanism of action is believed to be due to their role in increasing cell membrane fluidity.[52][53] It is also known that an increase in blood supply to the skin can enhance the absorption of topically delivered nutrients. [51] In the case of tetrahydropiperine, the increase in skin permeation/bioavailability effected could be due to a synergistic combination of all the modes discussed above.[43] While more experimental data are needed to further elucidate the bioenhancing mechanism of tetrahydropiperine, data from experiments done both in vitro and in vivo with the parent compound piperine indicate that the compound may be influencing either of two events favorably: 1. Membrane fluidity 2. Affinity of nutrient/drug to the cell membrane Another aspect to be considered is that tetrahydropiperine, which is a lipophilic compound, may increase solubilization of the intracellular lipid moiety in the skin. This, in turn, would help to enhance the permeation of topically applied active compounds.

7.4 7.4.1

Scientific Basis for Efficacy Chemistry of Tetrahydropiperine (THP)

Tetrahydropiperine is an arylpentanamide found naturally in small amounts in Piper nigrum and Piper longum. It can be synthesized from piperine by controlled hydrogenation in methanol using palladium carbon catalyst. This indicates that enzymes responsible for the biochemical transformation (hydrogenation) of piperine do occur in nature in low amounts. Table 7.1 describes the chemistry of THP.

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Table 7.1. Chemistry of Tetrahydropiperine (THP)

Tetrahydropiperine

Piperine

Chemical Name

1-[5-(1, 3–Benzodioxol–5 yl)-1-oxo – pentanoyl]-Piperidine

Molecular formula

C17H23NO3

Molecular weight

289.36

Percentage composition

C: 70.56%, H: 8.01%, N: 4.84%, O: 16.59%

Specifications of Tetrahydropiperine Description

Off-white, low melting solid with characteristic odor.

Solubility

Soluble in alcohols (ethanol, methanol, sparingly soluble in propylene glycol), insoluble in water.

Melting point

41°C–42°C

Assay by HPLC

Minimum 99.5%

Chromatographic impurities

Not more than 0.5%

Spectral characteristics

(See Fig. 7.5.)

Figure 7.6 shows the HPLC chromatogram of pure tetrahydropiperine. The procedure is summarized here. Mobile Phase: Mix acetonitrile and water in the ratio of 50:50, filter and degas. Standard Preparation: Weigh 50 mg of the standard and transfer into a 50 ml volumetric flask. Add 25 ml of methanol to dissolve and dilute the volume, mix. Sample Preparation: Weigh 50 mg of the sample and transfer into a 50 ml volumetric flask. Add 25 ml of methanol to dissolve the sample and dilute to volume, mix.

Chromatographic System: The liquid chromatograph is equipped with 230 and 241 nm UV detector and a 250 × 4.6 mm column that contains the packing C18 or ODS (Sigma Aldrich column is used). The flow rate is 1.0 ml per min. The relative standard deviation for replicate injections of standard preparation should not be more than 1.0%. Procedure: Separately inject equal volumes (20 µl) of the standard preparation and sample preparation into the chromatograph, record the peak responses obtained for the major peaks, and calculate the percentage as follows: Area of Sample × Standard Concentration × Standard Strength Area of Standard × Sample Concentration

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 7.4.2 Experimental Evidence for Topical Formation Enhancement Efficacy of THP Three sample botanical extracts used as cosmeceutical ingredients were tested for bioavailability enhancement by tetrahydropiperine: green tea extract (polyphenols rich, a well known antioxidant), Coleus forskohlii extract (providing forskolin, a skin conditioning agent) and tetrahydrocurcumin (derived from curcuminoids extracted from tumeric root, a potent antioxidant).[56] The permeation of green tea extract and forskolin in the presence and absence of tetrahydropiperine was studied in a Franz diffusion cell system, and carried out across a hydrated skin substitute. The bioenhancing potential of tetrahydropiperine was similarly evaluated in experiments with the steroidal anti-inflammatory drug betamethasone dipropionate (BMDP), and an anthelmintic, fenvalerate. The antioxidant effect of tetrahydrocurcumin in the presence and absence of tetrahydropiperine, was also evaluated.

Figure 7.5 Spectral characteristics of tetrahydropiperine.

In the experiment involving BMDP, the skin preparation was mounted in a Franz diffusion cell in two compartments: “donor” and “receptor.” The drug (100 mcg/ml) was applied with 0.1% (active sample) or without (control sample) of tetrahydropiperine in the donor compartment. Subsequently, the absorbances of the fluid in the receptor compartment for the presence of BMDP and THP were measured in time intervals of 5, 10, 15, 20, 30, 45, and 60 minutes. The active sample resulted in 100% diffusion of the BMDP within the first 10 minutes. The control sample resulted in 29% diffusion of BMDP after 45 minutes and only 54% diffusion after 60 minutes.[40] Example 1: Increased efficacy of an antiinflammatory agent (BMDP).

Figure 7.6 HPLC chromatogram of tetrahydropiperine.

Materials. A Franz diffusion cell was utilized in the experiment. The test drug, BMDP, with or without tetrahydropiperine (control), was applied on one side of the skin (donor compartment). The drug’s transport to the receptor side of the skin was estimated using a UV spectrophotometer at predetermined time intervals.

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER Instruments. Franz diffusion cell (fabricated); capacity of receptor compartment: 36 ml; area of skin mounted: 10.18 sq.cm.; UV/VIS spectrophotometer (JascoV-530); FTIR spectrophotometer (Jasco 5300). Chemicals. Betamethasone dipropionate (Nucron Pharmaceuticals, Ltd.); sodium chloride; Tween 20; propylene glycol. All chemicals were of analytical grade. Standard BMDP solution (100 µg/ml). In a volumetric flask of 100 ml, 10 mg of BMDP was taken and dissolved in 50 ml saline with Tween 20 solution and volume was made up with the same. Tetrahydropiperine solution (1% w/v). In a volumetric flask of 25 ml, 0.25 g of tetrahydropiperine was made up with propylene glycol. Methods. Hydrated skin was mounted on the Franz diffusion cell with the shaved surface facing the donor compartment. The receptor fluid (saline with Tween 20 solution) was maintained at 37 ± 0.5°C and stirred continuously at 200 rpm. The experiments conducted are described below.

• The absorbance of tetrahydropiperine was minimum at 256 nm while it was good for BMDP. The difference in the absorption value at λ256 is the maximum. • The calibration curve was prepared using receptor fluid to simulate the conditions for BMDP, present in test solution (Table 7.2.) Considering that absorbance is an additive property, the concentration of BMDP in the permeation study was determined by exploiting the curve subtraction facility of software V500 provided by Jasco. The absorbance at 256 nm was obtained by subtracting the curve of the spectrum of tetrahydropiperine from the spectrum of BMDP with tetrahydropiperine. The percentage of drug diffused in control and test are given in Table 7.3.

Table 7.2. Calibration Curve for Betamethasone Dipropionate in Saline with Tween 20 (0.05%); λ 256 nm

UV absorption spectra of BMDP solutions show absorption at 238 nm when prepared in saline with Tween 20 solution. We selected 256 nm as the wavelength of analysis for the following reasons: • Tetrahydropiperine showed absorbance at 228 nm and 275 nm.

Absorbance

Conc. (µg/ml)

Control. Propylene glycol, 0.5 ml, was applied to the mounted skin and kept for one hour. The receptor fluid was removed and replaced with fresh receptor fluid. BMDP solution, 0.5 ml (50 µg), was applied and sampling was carried out for a period of three hours. The sample volume was 2 ml each time, which was replaced by fresh receptor fluid. Absorbance of each sample was measured by UV spectrophotometer at the wavelength of 256 nm. Test. Tetrahydropiperine solution, 0.5 ml, was applied to the mounted skin and kept for one hour. The receptor fluid was removed and replaced with fresh receptor fluid. BMDP solution, 0.5 ml (50 µg), was applied and sampling was carried out for a period of three hours. The sample volume was 2 ml each time, which was replaced by fresh receptor fluid. Absorbance of each sample was measured by UV spectrophotometer at the wavelength of 256 nm.

169

5

0.090

10

0.12

15

0.147

20

0.197

25

0.248

30

0.310

Table 7.3. Effect of Tetrahydropiperine on Transdermal Diffusion of BMDP

Time (min)

Percent Diffuse Control

Test

5

--

95.06

10

--

102.55

15

--

--

20

--

--

30

--

--

45

29.05

--

60

53.847

--

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Table 7.3 shows that, in the first thirty minutes, the amount of drug diffused in the control is undetectable. However, in the presence of tetrahydropiperine, all the drug has diffused within ten minutes. This demonstrates the increased permeation of BMDP in the presence of tetrahydropiperine (Fig. 7.7). Example 2: Bioavailability enhancement of antioxidant botanical extracts. Two sample botanical extracts used as “cosmeceutical” ingredients were tested for bioavailability enhancement by tetrahydropiperine: green tea extract (polyphenols rich)[41][56] and tetrahydrocurcumin (derived from curcuminoids extracted from tumeric root).[40] Materials. Franz diffusion cell (Permegear #4G01-00-09-05), Permegear station stirrer (Permegear #V6), egg shell membrane, buffer (50 mM phosphate buffer, pH 6.8), green tea extract (containing 70% polyphenols), DMSO, tetrahydropiperine. Method.[42] Green tea extract, dissolved in the buffer in 3 mg/ml concentration, was used as the stock solution. A blank solution (B) was prepared from the green tea stock solution containing 0.2 % DMSO, and a test solution (T) was prepared from the green tea stock solution containing 1% THP in 0.2% DMSO. Fresh membrane was removed from the egg shell, washed five to six times with the buffer, and kept in the buffer for twenty minutes for stabilization. The receiving chamber had 5 ml of the buffer.

Membrane of uniform thickness was cut and placed between the receiving chamber and the donor chamber. One milliliter each of the solutions B and T were added to the respective receiving chambers of the Franz diffusion cells at constant temperature with stirring. Samples were collected from the receiving chambers after 5, 10, 20, and 40 minutes from both the B (without THP) and T tests (series with THP). The samples were analyzed for the total polyphenol contents based on the reaction of polyphenols with phosphomolybdotungstic acid, forming a bluecolored complex, and the absorbance was measured at 760 nm. Tetrahydropiperine enhanced the permeation of green tea polyphenols across the egg membrane by about 30% on average (Fig. 7.8). In another similar experiment, the bioenhancing potential of tetrahydropiperine on the free-radical scavenging properties of topically applied tetrahydrocurcuminoids (THC) was evaluated. In this in vitro DPPH radical scavenging method, the ability of an antioxidant to bind and inactivate the 1,1 diphenyl-2-picrylhydrazyl radical, or DPPH, was measured. DPPH is considered an example of a very stable free radical. The control sample contained 0.01% of THC while active samples contained 0.01% of THC with tetrahydropiperine concentrations ranging from 0.1%–0.0001%. Additionally, controls containing various concentrations of tetrahydropiperine alone were also tested for DPPH binding. While tetrahydropiperine by itself did not show any significant antioxidant properties, together with THC it was shown to enhance the antioxidant properties of THC by up to 30% compared with THC used alone (Fig. 7.9). Even in its highest dilution of 0.0001 mg/mL, tetrahydropiperine still displayed some beneficial bioenhancing activity with THC.[40]

Figure 7.7 Transdermal absoprtion study with betamethasone dipropinate (BMDP).

Example 3: Enhanced permeation of forskolin, a skin-conditioning agent.[41] In vitro permeation studies of forskolin, a diterpenoid compound which has various therapeutic effects (bronchodilation, prevents platelet aggregation, antihypertensive, anti-glaucoma, anti-inflammatory, weight management, and cellulite care support) were performed. Fabricated Franz diffusion cells of capacity 67 and 69 ml were used for the study. Hydrated skin was used as the membrane for permeation studies.

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Figure 7.8 Effect of THP on penetration of green tea polyphenols across egg membrane.

The study was conducted by replacing the medium in the receptor compartment with methanol instead of phosphate buffer. In both the receptor and donor compartments, methanol was used as the medium in the permeation studies. Test. In the donor compartment, 2 ml of methanol containing 50 mg of forskolin and tetrahydropiperine (5% forskolin conc.) was taken. The receptor compartment consisted of 69 ml of methanol maintained at 35°C. The permeation study was carried out for a period of one hour. Samples were withdrawn at 15-, 30-, and 60-minute intervals and the amount of forskolin present was analyzed by HPLC. Figure 7.9 Bioavailability enhancement of tetrahydrocurcumin by tetrahydropiperine.

Apparatus. Fabricated Franz diffusion cells with receptor compartments of 67 and 69 ml capacities. Materials. Solutions used in the study: • 2.5% forskolin in methanol. • 0.05% tetrahydropiperine in 2.5% forskolin in methanol. • 0.1% tetrahydropiperine in 2.5% forskolin in methanol. Methods. Procedure. Hydrated skin was mounted on the Franz diffusion cell with the outer layer of the skin facing the donor compartment. The receptor fluid was maintained at 35°C using a thermostatic magnetic stirrer.

Control. In the donor compartment, 2 ml of methanol containing 50 mg of forskolin was taken. The receptor compartment consisted of 65 ml of methanol maintained at 35°C. The permeation study was carried out for a period of one hour. Samples were withdrawn at 15-, 30-, and 60-minute intervals and the amount of forskolin present was analyzed by HPLC. Results. Fig. 7.10 shows the transdermal permeation of forskolin in the presence and absence of tetrahydropiperine (5% forskolin conc.) Table 7.4 gives a comparative release data of forskolin in the presence and absence of tetrahydropiperine. The permeation of forskolin was enhanced when the concentration of tetrahydropiperine was at a level of 5% forskolin concentration. The phenomenon appears to be concentration-dependant since at a lower tetrahydropiperine of 2% (forskolin concentration), enhanced permeation was not observed.

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Figure 7.10 Effect of THP on the dermal penetration of Forskolin. Table 7.4. Transdermal Release/Permeation of Forskolin

7.5

Time (minutes)

Forskolin Release Control

15

1.28

1.64

28.12

30

4.05

5.64

39.25

60

8.45

8.88

5.09

Safety Profile

Safety is of prime concern in selecting a suitable topical delivery system. Although tetrahydropiperine is based on a pungent principle, it is non-irritant and interacts with the skin in a manner different from other pungent principles such as capsaicin from cayenne pepper. Capsaicin is recognized by the US FDA as an OTC counterirritant and topical pain reliever in a dose of 0.025%. However, besides the pain relieving action this dose provides, it often causes skin reddening due to vascular engorgement as well as a slight skin tingling sensation. This reaction to capsaicin can occur within minutes or a few hours after topical application. The reaction usually lasts from half an hour to several hours from the moment it occurs. It tends to subside with regular, sustained use of topical capsaicin in a pain-relieving dose. Tetrahydropiperine, derived from the pungent compound piperine, does not irritate the skin when used at therapeutically significant levels.

Forskolin Release with THP

7.5.1

Increase in release (% of Forskolin)

THP: Low Skin Irritation Potential

Determination of skin irritation potential— patch test in human volunteers.[55] A study was conducted to determine whether tetrahydropiperine at levels of 0.01% and 0.1% (an effective dose range for the compound) would produce symptoms of topical irritation.[57] A skin patch test using tetrahydropiperine in a petrolatum vehicle was conducted on fifty healthy volunteers for 48 hours and the results were read after 48 hours and 72 hours. Neither dose caused skin irritation at the time of clinical evaluation of the study subjects. The supervising physician, a practicing dermatologist, reported the irritation score as 0. This study was conducted by the US FDA accredited BioScreen Testing, Inc., laboratory. These results indicate that tetrahydropiperine does not act as a skin irritant in a dose range considered effective for topical nutrient delivery. Details of this study are presented below. The 48-hour Repeat Insult Patch Test was used to evaluate skin irritation potential of the test compound.

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Fifty male or female subjects between ages 18 and 87 years participated in the study. Five male and 41 female subjects completed the study. The subjects were in good health and were not using any medications for thirty days prior to the commencement of the study.

ing anti-aging skin care market is one area where the versatile tetrahydropiperine finds many applications. When co-administered with antioxidant herbal extracts, amino acids, and other nutrients, tetrahydropiperine is expected to effectively enhance their permeation and bioavailability.

Materials and methods. The test material was applied occlusively, 0.1% w/w diluted in petrolatum. Two-tenths gram or 0.2 cc of the test material was dispensed into the skin of the upper back. Paper tape such as 3M Micropore® or Kendall Tenderskin® was used for fixation after preparation of the surrounding skin with an adhesion enhancer such as Mastitol®. The subject was instructed to avoid exposure to water or to direct sunlight during the 48-hour observation period. The tape was removed at the test facility at the end of the exposure period and evaluated by trained personnel under the supervision of the principal investigator.

Skin care formulations that would benefit from use of tetrahydropiperine are expected to be lotions, creams, gels, massage oils, sun protection formulations containing natural herbal extracts, minerals, growth factors, enzymes, and other nutrients. Hair care formulations that will benefit include hair oils, creams, treatment products, conditioners, styling gels, and other compositions that contain nutrients to support healthy hair.

Reactions were scored based on the appearance of erythema or edema immediately following removal of the patch and again at twenty-four hours following removal. Subjects were instructed to report any delayed reactions occurring after the final reading. Results. No erythema or edema reactions were observed in any of the subjects after forty-eight hours’ exposure of the skin to the test material. Conclusion. The test material when tested as described under 48-hour occlusive patch testing on fifty subjects appears not to produce primary (contact) irritation. Therefore, tetrahydropiperine has low skin irritation potential.

7.6

Enhancing Topical Delivery of Bioactives with THP

7.7 7.7.1

Potential Skin and Hair Care Applications

In recent years, the role of topically delivered nutrients has been of great interest to personal care formulations. This is especially true with the emerging significance of “cosmeceuticals” in cosmetics and dermatological formulations. The rapidly evolv-

Skin Care

Suggested levels of usage in formulations range from 0.01%–0.1% in skin creams and lotions. A typical skin cream formulation is shown in Formulation 1 (see end of chapter). This formulation includes “bioprotectant” tetrahydrocurcuminoids, a colorless product derived from the yellow curcuminoids extracted from tumeric root. This material functions as a versatile antioxidant, with potential applications in anti-aging, UV protection, and skin tone lightening compositions. In addition, the formulation contains another active ingredient, a freeze-dried coconut water composition to support skin texture and effect moisturization. This extract is rich in amino acids, enzymes, and growth factors that nourish and soothe tired skin.

7.7.2 7.6.1

Formulation Strategies

Hair Care

A base formula for a nourishing hair treatment is shown in Formulation 7.2 (see end of chapter). Herbal extracts may be included as desired. The formulation contains a freeze-dried coconut water composition to support healthy hair growth and effect moisturization. This extract is rich in amino acids, enzymes and growth factors that nourish and soothe.

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7.8

Summary

The quest for novel topical delivery systems for bioactives, with emphasis on “natural” and “safe” is an area of dynamic research in the pharmaceutical, cosmetics, and nutritional fields. Tetrahydropiperine is a natural topical permeation enhancer for active

7.9

compounds. Derived from black pepper fruit, the product is effective in very small quantities (0.01%– 0.1% by weight in formulations containing actives), with no irritant or sensitization side effects. The evolution of this ingredient, from concept development to its applications in formulations, is described in this chapter.

Formulations

Formulation 7.1: A Typical Skin Cream

Phase

A

B

C

D

Ingredients

Function

% w/w

Paraffinum liquidum

Emollient/Solvent

10.0

Petrolatum

Emollient

1.5

Acetylated lanolin

Emollient

2.2

Lanolin alcohol

Emollient

1.4

Laneth-10

Viscosity control

0.5

Glyceryl monostearate SE

Emulsifying agent

3.0

Carbomer (Carbopol 940, BF Goodich)

Viscosity modifier

0.1

Sodium methylparaben

Preservative

0.2

Sodium propylparaben

Preservative

0.02

Sodium hydroxide (10%)

Buffering agent

2.5

Water (aqua)

Solvent

Tetrahydrocurcuminoids

Active

Tetrahydropiperine (Cosmoperine®, Sabinsa Corporation)

Active

Coconut (Cocos nucifera) fruit juice (Cococin, Sabinsa Corporation)

Active

qs 100.0 0.5% 0.1% 2.0 (25% colloidal suspension in 1,4-butylene glycol)

Blend Phase A ingredients maintaining temperature at 80°C. Separately blend Phase B ingredients at 80°C. Add Phase C ingredients to blended Phase A, maintaining the temperature at 80°C, with agitation, and mix the blended Phases A + C with Phase B in a homogenizer until thoroughly emulsified. Adjust the pH to neutral with citric acid solution. Cool to 50°C. Add Phase D slowly with homogenization. Cool to desired fill temperature.

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER

175

Formulation 7.2: A Base Formula for a Nourishing Hair Treatment

Phase A

B

C

Ingredient

Function

Weight Percent

Deionized water

Solvent

82.10

Xanthan gum

Stabilizer

0.60

Caprylic/capric triglyceride

Emollient/Solvent

3.00

Myristyl myristate

Emollient

3.00

Cetyl alcohol

Emollient/solvent

1.50

Emulsifying wax NF

Emulsifying agent

2.50

Sodium methylparaben

Preservative

0.2

Sodium propylparaben

Preservative

0.1

Tetahydropiperine (Cosmoperine® Sabinsa Corp)

Active

0.1

Coconut (Cocos nucifera) fruit juice (Cococin, Sabinsa Corp)

Active

Cyclomethicone

Antistatic agent

5.00 25% colloidal suspension in 1,4 butylene glycol

3.00

Heat water from Phase A to 50°C and sprinkle in xanthan gum, mixing well, and then heat mixture to 75°C. Combine ingredients of Phase B with mixing and heat to 75°C. Add Phase B to Phase A using agitation, mix for 20 minutes and maintain temperature at 70°C–75°C. Cool to 40°C, add Phase C with mixing and cool to desired fill temperature.

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References 1. Goldsmith, L. A., ed., Cutaneous pharmacology, pathophysiology and dermal biology, in: Physiology, Biochemistry and Molecular Biology of the Skin, Vol. II, Oxford University Press, New York (1991) 2. Potts, R. O., Mak, V. H., et al., Strategies to enhance permeability via stratum corenum lipid pathways, in: Advances in Lipid Research, Vol. 24 (Elias, P. M., ed.), Academic Press (1991) 3. Sloan, K. B., Wasdo, S., Designing for topical delivery: pro-drugs can make the difference., Med. Res. Rev., 23:763–793 (2003) 4. Verma, D. D., Verma, S., Blume, G., Fahr, A., Liposomes increase skin penetration of entrapped and non-entrapped hydrophilic substances into human skin: a skin penetration and confocal laser scanning microscopy study, Eur. J. Pharm. Biopharm., 55:271–277 (2003) 5. Verma, D. D., Verma, S., Blume, G., Fahr, A., Particle size of liposomes influences dermal delivery of substances into skin, Int. J. Pharm., 258:141–151 (2003) 6. Yerushalmi, N., Arau, A., Margalit, R., Molecular and cellular studies of hyaluronic acidmodified liopsomes as bioadhesive carriers for topical drug delivery in wound healing, Arch Biochem. Biophys., 313:267–273 (1994) 7. Bieb, L. M., Ramachandran, C., Egbaria, K., Weiner, N., Topical delivery enhancement with multilamellar liposomes into pilosebaceous units, J. Investig. Dermatol., 99:108–113 (1992) 8. Rangarajan, M., Zatz, J. L., Effect of formulation on the topical delivery of alpha tocopherol, J. Cosmet. Sci.,54:161–174 (2003) 9. Spiclin, P., Homar, M., Zupancic, A., Gasperlin, M., Sodium ascorbyl phosphate in topical microemulsions, Int. J. Pharm., 256:65–73 (2003) 10. Peltola, S., Saarinen-Savolainen, P., et al., Microemulsions for topical delivery of estradiol, Int. J. Pharm., 254:99–107 (2003) 11. Ciotti, S. N., Weiner, N., Follicular liposomal delivery systems, J. Liposome Res.,12:143– 148 (2002)

12. Majeed, et al., Use of piperine to increase the bioavailability of nutritional compounds, United States Patent No. 5,536,506 (1996) 13. Majeed et al., Use of piperine as a bioavailability enhancer, United States Patent No. 5,744,161 (1998) 14. Majeed, et al., Use of piperine as a bioavailability enhancer, United States Patent No. 5,972,382 (1999) 15. Majeed, et al., Process for making high purity piperine for nutritional use, United States Patent No. 6,054,585 (2000) 16. Johri, R. K., Zutshi, U., An Ayurvedic formulation ‘Trikatu’ and its constituents, J. Ethnopharm., 37:85–91 (I992) 17. Szallasi, A., Vanilloid (capsaicin) receptors in health and disease, Am. J. Clin. Pathol., 118(1):110–121 (Jul, 2002) 18. Walker, M., Piperine in black pepper: one of a newly recognized class of thermonutrients, Health Foods Business (April, 1997 ) 19. Lee, E. B., et al., Pharmacological study on piperine, Arch. Pharmac. Res., 7:127–132 (1984) 20. Dymock, W., Warden, C. J. H., Hooper, D., Piper nigrum: pharmacographia Indica, published by The Institute of Health & Tibbi Research under auspices of Hamdard National Foundation, Pakistan, Vol. III, 372–374 (l 972) 21. Atal, C. K., Zutshi, U., Rao, P. G., Scientific evidence of the role of Ayurvedic herbals on bioavailability of drugs, J. Ethnopharm., 4:229–233 (1981) 22. Atal, C. K., et al., Biochemical basis of enhanced drug availability by piperine: evidence that piperine is a potent inhibitor of drug metabolism, J. Pharmacol. Exptal. Therap., 232:258–262 (1985) 23. Zutshi, U., et al., Influence of piperine on rifampicin blood levels in patients with pulmonary tuberculosis, J. Assoc. Physicians India, 33:223–224 (1984) 24. Bano, G., et al., The effect of piperine on the pharmacokinetics of phenytoin in healthy volunteers, Planta Medica., 53:568-570 (1987)

MAJEED, PRAKASH: TETRAHYDROPIPERINE: A NATURAL TOPICAL PERMEATION ENHANCER 25. Bano, G., et al., The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers, European J. Clin. Pharm., 41:615–618 (1991) 26. Badmaev, V., et al., Piperine, an alkaloid derived from black pepper, increases serum response of beta-carotene during 14 days of oral beta-carotene supplementation, Nutrition Research, 19(3):381–388 (1999) 27. Badmaev, V., et al., Piperine derived from black pepper increases the plasma levels of coenzyme q10 following oral supplementation, J. Nutritional Biochemistry, 11(2):109–113 (2000) 28. Majeed, et al., Method of increased bioavailability of nutrients and pharmaceutical preparations with tetrahydropiperine and its analogues and derivatives, United States Patent No. 6,849,645 (2005). 29. Majeed, M., et al., Bioperine®: Nature’s own thermonutrient and natural bioavilability enhancer, Nutriscience Publishers Inc. Piscataway, NJ (1999) 30. Madhusudan, P., Vandana, K. L., Tetrahydropiperine the first natural aryl pentanamide from Piper longum, Biochemical Systematics and Ecology, 29:537–538 (2001) 31. Loder, J. W., Moorhouse, A., and Russel, G. B., Tumor Inhibitory plants, Australian J. Chem., 22:1531–1538 (1969) 32. Satyavati, G. V., Gupta, A. K., and Tandon, N., eds., Medicinal plants of India, Indian Council of Medical Research, New Delhi, India, 426–456 (1987) 33. Nadkarni, A. K., Indian Materia Medica, Popular Book Depot, Bombay, India (1954) 34. Pei, Y. Q., A review of pharmacology and clinical use of piperine and its derivatives and uses, Epilepsia, 24:177–181 (1983) 35. Perry, L. M., Medicinal Plants of East and Southeast Asia: Attributed Properties and Uses, MIT Press, Cambridge (1980) 36. Charaka, et al., Charaka Samhita, 3rd ed., Nirnaya Sagar Press Bombay, India [in Sanskrit] (1941)

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37. Vagbhat, Ashtang Hridaya, Chowkhamba Sanskrit Series, Varanasi, India [in Sanskrit] (1962) 38. Kaviraj, K.B., Sushruta Samhita, Vol. 3, 2nd ed., Chowkhamba Sanskrit Series, Varanasi, India [in Sanskrit] (1963) 39. Research Report, Sabinsa Corporation (April 2000) 40. “Studies on Transdermal Penetration Enhancement Activity of RD/TP/09” Research Report, Sami Labs Ltd. (April, 2000) 41. Research Report, Sami Labs Ltd. (May, 2000) 42. Barry, B. W., Dermatological Formulations: Percutaneous Absorption, Drugs and the Pharmaceutical Sciences, Vol. 18, Marcel Dekker, New York (1983) 43. Badmaev, V., and Majeed, M., Skin as a delivery system for nutrients, nutraceuticals and drugs; THP, a natural compound with the potential to enhance the bioavailability of nutrients and drugs through the skin, Agro-Industry Hi-Tech., 6-10 (Jan/Feb, 2001) 44. Marjukka, S. T., Bouwstra, J.A., Urtti, A., Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations, J. Controlled Release, 59(2):149–161 (May 20, 1999) 45. Prokosch, F., Prokosch, E., Regulation of the epidermal permeability barrier by lipids and hyperproliferation, Hautarzt, 43(6):331–338 (June, 1992) 46. Wertz, P. W., Lipids and barrier function of the skin, Acta Derm. Venereol. Suppl., (Stockh) 208:7–11 (2000) 47. Proksch, E., Holleran, W. M., Menon, G. K., Elias, P. M., Feingold, K. R., Barrier function regulates epidermal lipid and DNA synthesis, Br. J. Dermatol., 128(5):473–482 (May, 1993) 48. Prokosch, E., The epidermis as metabolically active tissue: regulation of lipid synthesis by the barrier function, Z. Hautkr., 65(3):296– 300 (Mar, 1990) 49. Tsai, J. C., Guy, R. H., Thornfeldt, C. R. , Gao, W. N., Feingold, K. R., Elias, P. M., Metabolic approaches to enhance transdermal drug delivery; 1. Effect of lipid synthesis inhibitors, J. Pharm. Sci., 85(6):643–648 (Jun. 1996)

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50. Schneider, I. M., Wohlrab, W., Neubert, R., Fatty acids and the epidermis, Hautarzt 48(5):303–310 (May, 1997) 51. Hadgraft, J., Passive enhancement strategies in topical and transdermal drug delivery, Int. J. Pharm., 184(1):1–6 (Jul. 5, 1999) 52. Golden, G. M., McKie, J. E., Potts, R. O., Role of stratum corneum lipid fluidity in transdermal drug flux, J. Pharm. Sci., 76(1):25-28 (Jan. 1987) 53. Short, S. M., Rubas, W., Paasch, B. D., Mrsny, R. J., Transport of biologically active interferon-gamma across human skin in vitro, Pharm. Res., 12(8):1140–1145 (Aug. 1995)

54. Bos, J. D., Meinardi, M. M., The 500 Dalton rule for the skin penetration of chemical compounds and drugs, Exp. Dermatol., 9(3):165– 169 (Jun. 2000) 55. Research Report, Sabinsa Corporation (2001) 56. “Studies on Transdermal Penetration Enhancement Activity of RD/TP/09” Research Reports, Sami Labs Ltd. (2000–2003)

Part IV Encapsulation

Topical Delivery Systems Based on Polysaccharide Microspheres

Microencapsulation: An Overview of the Landscape

ENCAPSULATION

Microcapsules as a Delivery System

Polymeric Encapsulation. Phase Change Materials: A Novel Microencapsulation Technique for Personal Care

Tagravit™ Microcapsules as Controlled Drug Delivery Devices and Their Formulations

8 Microencapsulation: An Overview of the Technology Landscape Zev Lidert Paragon Chemicals Inc. Dresher, Pennsylvania

8.1

Background .................................................................................. 181 8.1.1 Definitions ......................................................................... 182 8.2 Microencapsulation Technology Vectors ....................................... 182 8.2.1 Scope and Market Size ..................................................... 182 8.2.2 What Is Being Encapsulated Today? ................................ 183 8.2.3 Why Encapsulate? ........................................................... 184 8.2.4 Effects Desired ................................................................. 185 8.3 Bringing It All Together:The Encapsulation Technology Landscape .. 185 8.3.1 Non-Chemical, Mechanical ............................................... 186 8.3.2 Non-Chemical, Aqueous ................................................... 186 8.3.3 Chemical, Aqueous .......................................................... 188 8.4 Microencapsulation Technology Challenges and Market Trends .. 188 8.4.1 Technology Challenges ..................................................... 189 8.4.2 Market Trends ................................................................... 189 8.5 Conclusions .................................................................................. 189 References .......................................................................................... 190

8.1

Background

With the growing use of delivery systems in a variety of areas, including consumer care, it is essential that a newly appointed R&D manager in a personal care company, or an academic researcher planning to start an encapsulation project with his students, be aware of the current state of the art.

While some readers will already be familiar with many aspects of the microencapsulation market and the technologies at play, others will be learning of it for the first time. Forming a clear picture of the current microencapsulation technologies and their utility, as well as their strengths and weaknesses, is not a trivial pur-

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 181–190 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

suit. The subject involves a great variety of methodologies and raw materials, and offers a considerable number of problems requiring solutions. Having such clarity is, however, critical to making good investment decisions. The intention of this chapter is to guide a newcomer in the thinking process required to generate a working knowledge of the microencapsulation field. Real world commercial applications are described and, where the field has room to grow and generate new opportunities, directions are noted. This overview provides insights for developers of new delivery technology. It describes a real-life experience of a major chemical producer looking for areas where its core technologies could be merged with existing or embryonic delivery system technologies, in order to form new commercial ventures.

8.1.1

Definitions

The standard reference sources tend to use the terms encapsulation and delivery systems interchangeably. Although many experts profess a distinction, in this chapter we will follow the less precise, but perhaps more common, practice of using the two terms interchangeably. A survey of authoritative sources points to a number of definitions of encapsulation. For example: • Eric Perrier, Director of Research at Coletica, the largest encapsulator of actives in the personal care industry says that “…to encapsulate, is to surround an active ingredient with a molecule, a membrane, or a network made of a polymer, or of a specific organization of simple molecules.”[1] • Frost & Sullivan, a major market research firm says “…microencapsulation is one of a number of techniques which are being used by cosmetic formulation chemists in order to protect and deliver active cosmetic ingredients in today’s increasingly complex products.”[2] • Kline and Company, another major market research firm explains that “Delivery systems for personal care products were initially developed to enhance active stabiliza-

tion; however, increased penetration of the active into the skin has become a very important aspect of their use. Delivery systems can be broadly classified into two segments: (1) particles incorporated into cosmetic and toiletry formulations that are then applied to the skin; and (2) patches that are placed directly on the skin. Particles can be further classified into three segments on the basis of their size/diameter and level of skin penetration: (1) nanoparticles, (2) microcapsules, and (3) millicapsules.”[3]

8.2

Microencapsulation Technology Vectors

Building upon the above-mentioned definitions requires organization of the considerable, but apparently chaotic body of knowledge about delivery systems. Such categorization provides meaningful “folders,” enabling trends and opportunities to stand out. The approach taken to create such folders was to study the field of microencapsulation along the following vectors: 1. The scope to which encapsulation is used by key players in consumer care markets; the size of the opportunity and an estimation of a compounded growth rate. 2. The classes of “benefit molecules” projected today. 3. The reasons for encapsulation. 4. The technology involved: • Processes used to encapsulate • Materials used in the processes • The resulting particle morphology • Mechanisms for actives capture and release

8.2.1

Scope and Market Size

The determination of future opportunities for the encapsulation market inevitably depends on knowing who the major players are now and what kinds of products employ this type of technology.

LIDERT: MICROENCAPSULATION: AN OVERVIEW OF THE TECHNOLOGY LANDSCAPE A multitude of companies are engaged in encapsulation of a variety of benefit molecules. These are used for a wide range of finished goods: 3M • Adhesive coated screws in automotive applications Arden •

Cellulite® hand lotion, (“glitter” capsules for visual effect)

Avon

183

• Gillette razor (lubrication, dimethicone capsules) Hallcrest • Forehead Thermometer (encapsulated cholesteric liquid crystals) Kimberly Clark • Kleenex® tissues (encapsulated menthol) P&G • Vicks Breathe Right® (pressure-released menthol)

• Skin-so-Soft® hand lotion (mineral oil capsule)

• Bounce® antistatic dryer product (encapsulated fragrance)

• Avon lipstick (dimethicone capsules for sustained release)

• FeBreeze® (cyclodextrin spray for odor control)

Bayer • Aspirin (taste masking, release in the alkaline intestine environment) Biopredict • Encapsulated living yeast (for increased alcohol content in wine) Clorox • Spic and Span® (encapsulated enzyme) Colgate-Palmolive • Soft Soap® body wash (fragrance) Dial • Dial Soap® (fragrance) Dr. Scholls® • Foot powder (sponge technology for delivery of a fungicide) Euracli • Cosmetiq® pantyhose (encapsulated phase transfer materials for temperature control as well as odor control antimicrobial actives and fragrances)

Personal Care Products • Buff puff® (exfoliating agent) Triplex • Triplex® toothpaste (encapsulated calcium peroxide) Unilever • Gain® detergent (encapsulated enzyme) While not intended to be all-inclusive, this list shows that microencapsulation technology is a significant contributor to product quality and provides an opportunity for product differentiation. According to market studies by Kline and Company Consultants, Frost & Sullivan, and statements from selected fragrance companies, the combined market for microencapsulation in the US and the EU, in 2002, was about $260 MM. Of this total, $200 MM was in fragrance applications and $60 MM in cosmetic actives. It is expected that this market is likely to grow at a respectable compounded growth rate of about 10% over the next five years and, therefore, represents a good opportunity for investment.

Exact • Exact® acne treatment (sponge technology for benzoyl peroxide)

8.2.2

What Is Being Encapsulated Today?

Gillette • Degree® underarm product (heat-activated, antiperspirant release)

At least eight industry segments routinely utilize microencapsulation to deliver improved performance of a variety of actives and benefit molecules. Table 8.1 provides some examples:

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 8.1. Eight Market Areas for Microencapsulated Products

Personal Care

Household Care

Food Industry

Pharmaceuticals

Fragrances

Fragrance

Probiotics

Drugs

Therapeutic Cosmetic Actives

Ironing Aids

Antioxidants

Enzymes

Anti-wrinkle Agents

Vitamins

Peptides

Bleaches and Bleach Activators

Fish Oil

DNA

Antiperspirants Cooling Agents Sunscreen Actives Whitening Agents Pigments and Colorants Decorative Liquid Crystals

Enzymes for Fabric Care Optical Brighteners Odor Control Agents

Industrial Sector Catalysts

Paper Industry Ink

Textile Industry

Agrochemicals

Phase Transfer Agents

Insecticides

Reagents

Antimicrobial Agents

Fungicides

Adhesives

Fragrance

Herbicides

Flame Retardants

8.2.3

Why Encapsulate?

The entry of encapsulation technology into consumer care markets is a consequence of a classic push/pull mechanism. On one hand, there is the desire of consumers and formulators to have better products on the market. On the other hand, there is a powerful technology push from supplier companies, such as those contributing many chapters of this book. Consumer Pull: • Consumers connect microencapsulation with science-based excellence and improved performance. Visible capsules “mean” the presence of useful actives. • Consumers expect improved performance and formulators often respond by providing evermore sophisticated delivery systems for popular actives.

Formulator Pull: • Formulators are driven by cost-reduction targets achieved by protecting fragrances and expensive actives. They want to use less active, but achieve the same effect. • They like the improved performance opportunities created by controlled-release technology. • They desire a competitive advantage, and microencapsulation helps to strengthen health and performance claims. • They want new product concepts, and encapsulation offers such new concepts as well as reinforcing the image of innovation. Technology Push: • New solutions are moving from the pharmaceutical technology base to consumer care markets. Nanotechnologies and ad-

LIDERT: MICROENCAPSULATION: AN OVERVIEW OF THE TECHNOLOGY LANDSCAPE

8.3

vanced material science offer unprecedented opportunities for innovation in the personal care, household, and cosmetic fields.

8.2.4

Effects Desired

Expectations of consumers and formulators for the improved performance obtainable by microencapsulation may be grouped into three classes: functionality, formulation, and appearance (Table 8.2).

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Bringing It All Together:The Encapsulation Technology Landscape

By focusing on (1) encapsulation processes, (2) polymeric materials used to encapsulate, and (3) capture/release mechanisms, three technology “folders” containing several “files” may be identified.

Table 8.2. Microencapsulation Grouped by Classes

Improve Functionality Make actives bio-available; control where to release, e.g., skin vs sweat gland, pH 5 vs pH 7 environment Penetrate barriers: transdermal delivery Improve adhesion, substantivity, and deposition: deposit onto fabric, skin or hair, and make the active stick onto the substrate Deliver a therapeutic dose, rather than all at once: minimize skin irritation, avoid side-effects Provide an even distribution on skin, hair, or fabric Control the release kinetics, eliminate release when undesired Reduce health hazards: reduce skin contact and the risk of inhalation when it is hazardous, (e.g., sunscreens, preservatives, worker exposure to enzymes in detergents) Build in release triggers such as: temperature, pH, ionic strength, diffusion, moisture, and enzymatic degradation

Improve Formulation Separate incompatible components such as: catalysts, pigments, antioxidants, bleach, and bleach activators Stabilize formulations by designing a barrier around ingredients sensitive to surfactants, UV light, heat, acidity or alkalinity, enzymes, radicals, and oxidizing agents Mask odor and taste Concentrate payload

Improve Appearance Enhance visual appearance and give consumer a visible cue of the presence of beneficial actives by suspending in cosmetic formulations millicapsules and droplets of liquid crystals containing actives, and delivering eye-pleasing opalescent and iridescent effects

186 8.3.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Non-Chemical, Mechanical

Folder 1 contains “non-chemical” processes based on the combination of a “payload of active and encapsulating polymer,” brought together mechanically, in a neat form. Spray drying. The most common “file” in this “folder” is spray drying of the active payload when blended with natural gums. These gums may include: gelatin, acacia, maltodextrin, agar, chitosan, and foodapproved synthetic polymers. Such active/polymer blends are typically sprayed in atomization towers to remove required solvents and, thereby, produce actives dispersed in a polymer matrix. In the pharmaceutical sector, supercritical carbon dioxide finds increasing use as a solvent of choice. This preference results from its ability to offer extremely mild encapsulation conditions suitable for dealing with fragile bioactive molecules such as enzymes and peptides. Spray drying provides the most rudimentary level of functionality often used for the purpose of providing easier handling of liquid actives or fragrances. Payload capacity in this type of process is limited and seldom approaches a 1:1 ratio of payload to encapsulating polymer. In the Consumer Care sector, this technology finds its main use in fragrance encapsulation (a nearly $200 MM market), as well as the sizable laundry enzyme segment. Spray coating. Spray-coating technology operates on a principle similar to spray drying. However, the payload is insoluble, hence, the gum forms a coating on the surface of the encapsulated payload particle. This method is often employed to encapsulate pigments in order to prevent their agglomeration in a formulation. Extrusion techniques. Apart from spray drying and spray coating, a number of extrusion-based technologies are also employed to encapsulate actives. The most common of these are the hot-melt and prilling processes. Many variations on these themes exist. The key principle of this approach always remains the same: the payload of actives and the encapsulating polymers are extruded through a system of concentric tubes and the payload occupies the central tube. Consequently, extrusion techniques result in a capsule architecture in which the polymer membrane surrounds a payload of the active.

As for the polymers used in extrusion technologies, these are typically natural or semisynthetic materials such as starch, cellulose, and alginates. However, simple polyacrylates and polyacrylamide are also useful in this regard. On the whole, payloads employed in this type of process cannot be too fragile. Further, they should be soluble in organic solvents and also be able to withstand oxidative processing conditions. Actives encapsulated in membranes obtained by extrusion technologies, referred to as spheres, have a higher level of functionality than those obtained by the spray-drying process. Such spheres exhibit a higher degree of stability in many cosmetic formulations, hence providing some of the formulation stability benefits listed previously.

8.3.2

Non-Chemical, Aqueous

Folder 2 contains “non-chemical” processes based on “payload of active and encapsulating polymer brought together in an aqueous environment.” The sponge technology. The sponge technology is based on sequestration of a dispersed, or solubilized, payload of actives. This sequestration usually employs a polymeric, super-absorbing “sponge” that is often made of cross-linked polymethacrylate. Such synthetic, super-absorbing sponges are able to “soak up” a surprisingly large payload of actives in the ratio of 1:10 or more. Uptake is dependent upon polarity of the payload and its chemical similarity to the polymer employed. Typically, the capacity of sponges for hydrophobic payloads is higher than their capacity for hydrophilic ones. A key property of the sponge technology is its ability to provide a controlled-release mechanism. This mechanism results from a combination of diffusion and shearing conditions being applied during product application. If diffusion of the active out of the matrix is too rapid, active transport may be reduced to more useful rates. Such lower rates can be achieved by means of a surface coating covering the sponge particle. An example of such a coating is a phospholipid bilayer. Such a coating may not only curtail the rate of diffusion, but also can increase substantivity to the skin. The phenomenon is similar to that achieved with phospholipid bilayers surrounding liposomes and is described for such systems else-

LIDERT: MICROENCAPSULATION: AN OVERVIEW OF THE TECHNOLOGY LANDSCAPE where in this book. Control of the diffusion rate is especially important on the hydrophobic environment presented by the skin’s surface. Liposomes. The widely used liposome technology is based on the principle of sequestration of actives from aqueous dispersions and their incorporation into multilamellar, vesicle-type structures. These vesicles are formed in situ, or pre-formed from amphiphilic molecules such as fatty acids and phospholipids. Often, high-shear techniques are used to re-form the spontaneously formed lamellar structures into nanosize vesicles having one or more outer barrier layers. A key property of liposomes is that they are capable of penetrating through the stratum corneum and, therefore, find use in creams and lotions. The phenomenon is associated with the lipophilic character of the liposomal bilayer and its similarity to skin lipids. The capacity of liposomes for payload is low and seldom reaches a 1:1 ratio. The stability of liposomes in formulations is frequently less than desired because the liposome lipid barrier membrane is easily disrupted by attack from surfactants intent on re-equilibrating themselves within the membrane. Such surfactants are found in many personal care formulations and are necessary, for example, as emulsifying agents. Unlike phospholipids-based vesicles, those based on silicone polyether copolymers have much higher stability. Further, these materials appear to have costperformance superior to the phospholipids-based liposomes. They are worthy of a closer look, especially when the phospholipid-based liposome systems present deficiencies in certain surfactant-containing formulations. Nanoparticle technologies. Most often, these technologies are based on solid lipid nanoparticles (SLN). Depending upon the method of preparation (by means of supercooled liquid or dispersion), such nanoparticles form a more-or-less coherent film on skin after adsorption, drying, and coalescence. The release profile from SLN depends upon the distribution of payload within the particle. Distribution can be controlled and manipulated by proper selection of the surfactant system involved in the preparation. A gradient of actives within the nanoparticle provides zero order kinetics and a steady release that can be as long as six weeks. By contrast, a uniform

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distribution of actives throughout the nanoparticle provides a “burst” of actives’ release. Initial problems associated with the need to apply high pressure to the manufacture of SLN have now been resolved. In addition to one process based on high pressure, a new “3-phase emulsification technology” has allowed the incorporation of SLN into commercial o/w emulsions. This technology relies upon a “shock-cooling” process by which a conventional emulsion concentrate at 65°C is diluted with cold water. Under some conditions, the shock-cooling technology may result in the formation of a multilamellar lipid layer surrounding the SLN. The presence of this outer layer is likely to provide the SLN system an additional level of functionality. This approach is available for commercial exploitation in the future. One additional feature of nanoparticle technology is quite exciting: the formation of nanoparticles may be combined with bioadhesive, polymeric surface coatings to achieve the holy grail of increased substantivity to the target surface. Examples of such polymers include those containing polyquat moieties. This need is especially critical in rinse-off products such as shampoos, conditioners, and laundry detergents. Nonaqueous nanoemulsions. These systems (glycerine, propylene glycol, PEG-400, etc.) are emulsified in a volatile cyclomethicone fluid. nanoemulsions based upon this approach appear to be particularly suitable for delivering a broad range of hydrophilic actives ranging from enzymes to ascorbic acid. Furthermore, such materials have intriguing antimicrobial activity based on their ability to fuse with bacterial cell membranes.[4] nanoemulsions may be incorporated into both water-in-oil and oil-in-water emulsions, thereby generating multiple emulsions. Such systems offer high storage stability and low viscosity. The materials are suitable for the manufacture of sprayable products, foams, and emulsioncoated skin-care pads. Molecular encapsulation (cyclodextrin). Cyclodextrins are cyclic oligosaccharides consisting of six or seven anhydroglucose units with a hydrophobic inner molecular-sized cavity. They are produced from starch by a specific enzyme and used to entrap fragrances and cosmetic actives, on the basis of a 1:1 molecular ratio, from aqueous solutions or dispersions. This type of molecular encapsulation involves inclusion complexes of cavitands

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like clathrates with cyclodextrin. A prime example of this type of encapsulation is the use of retinol— the system has been termed the “smallest beauty case in the world.” Monomolecular encapsulation offers a much-desired delayed release of fragrances and cosmetic actives. Gel technologies. Some classes of super-absorbing polymers produce gels when swollen with an organic payload. These gels find uses in skin treatment and as delivery vehicles. A new embodiment of gel technology affords sol-gel conversion at body temperature.[5] This property may be of interest for applications including oral care, invisible skin patches, and shaving creams.

8.3.3

Chemical, Aqueous

Folder 3 contains “chemical” processes in which “the encapsulating polymer is formed in-situ on the surface of payload droplet in an aqueous environment.” This type of process leads to the formation of a membrane around the active payload. A number of examples are described below. Coacervation. The coacervation process is initiated by dispersing or emulsifying the payload of active in a gelatin solution (2%–10% gelatin) containing a polyanion such as gum arabic. When the pH is adjusted to about 4, and the solution is cooled to about 10°C, the positively charged gelatin and the negatively charged polyanion react to form a “complex coacervate” membrane on the surface of the payload. This membrane is further strengthened by cross linking it with an aldehyde. Such complex coacervates based on cationically modified hydroxy ethyl cellulose have been used to entrap silicone oil in foams as described elsewhere in this book. Variations on the polymers described above have been employed. For example, gum arabic may be replaced by a number of synthetic and natural polyanions. It is more difficult to find a material that would replace gelatin without some loss of product quality. However, with a varied degree of success, experimenters have used chitosan and other natural gums. Overall, gelatin remains the best material for the majority of coacervation processes. Membranes obtained by coacervation are known to break under the applied shear of the application process (i.e., rubbing on the skin), and it is this break-

down that releases the payload. This process is a valuable release mechanism, although it is limited in its scope since it does not offer the possibility of providing sustained release characteristics. The key benefit of the coacervation technique is that it provides good protection from surfactants. This benefit is especially useful when the formulation requires the presence of sensitive payloads. In addition, the coacervation technique leads to large, visible capsules that are attractive to consumers. Such capsules must have sufficient strength to resist breakdown during their incorporation into a formulated product prior to their use. Care must be, therefore, taken during processing of the finished goods using such materials. Alternatively, the strength of the outer wall can be adjusted to increase its resistance to breakdown by applied shear during processing. Urea-formaldehyde membrane formed by in-situ polymerization on the surface of an oil droplet. Although this approach is the dominant encapsulation technology in many industrial market segments, its success to date in personal care applications has been limited. Amphiphilic block copolymer self-assembly. This process is based upon the principle that amphiphilic block polymers, in water, form micellar nanostructures whose core is hydrophobic. Once formed, these micelles may be swollen with a hydrophobic payload and the hydrophilic exterior may then be cross linked to form a “shell.” Although still in the development stage, this technology appears very promising, especially for applications requiring release triggers such as pH triggers, ionic strength triggers, or change of polarity triggers.

8.4

Microencapsulation Technology Challenges and Market Trends

From the distillation of research conducted among customers and suppliers, a number of key technology challenges and market trends have become apparent. A clear understanding of these challenges and trends is expected to provide guidance for prospective developers of new microencapsulation technology.

LIDERT: MICROENCAPSULATION: AN OVERVIEW OF THE TECHNOLOGY LANDSCAPE 8.4.1

Technology Challenges

Design/develop multicomponent delivery systems allowing for multiple release mechanisms. • Combine multiple bursts of actives with sustained release capability. • Control the release of several vitamins, of different polarities, in a coordinated fashion. Identify new block polymers to manipulate bioadhesion properties. • The need for bioadhesion in rinse-off products (such as body washes) continues to be an unresolved scientific challenge due to the presence of surfactants for cleaning purposes. This need offers a significant opportunity for new product concepts. Replace liposomes with more efficient transdermal penetration systems to achieve the following:

8.4.2

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Market Trends

Having reviewed the technology landscape, we pose the following question: “Which of the microencapsulation technologies described are poised to address the unmet needs and challenges faced by the personal care industry?” A successful answer to this key question is expected to result in new products that will win a significant share of the personal care market. In the absence of a crystal ball, some educated guesses have been made based on an analysis of current market pull and technology push. This scenario is presented in Table 8.3 and is based on extensive interviews with suppliers, as well as data available in the public domain, on the size and growth of the encapsulation markets.

8.5

Conclusions

• Lower cost. • Stability in the presence of surfactants. • Better skin feel. Replace gelatin with a non-animal-derived, water soluble, amphoteric polymer. • Provide access to European skin care markets for coacervation products. These markets are now inaccessible because gelatin, a protein of animal origin, is perceived as a threat in the aftermath of the Bovine Spongiform Encephalopathy (BSE) scare. • Reduce the cost of coacervation in order to permit broader use in price-sensitive market segments. Achieve cost-performance feasibility in mass markets such as laundry and household products without compromising effectiveness. • Develop a new generation of capsules that not only can survive the harsh environments of heavy-duty liquid/fabric-softener/detergent systems, but are also capable of encapsulating and releasing fragrance in a controlled fashion.

Up to this point, we have focused our attention on developing and presenting a deeper understanding of the encapsulation technology landscape. We have pointed to the value of encapsulation for suppliers, formulators and consumers alike, and have identified future market trends. For a chemical company contemplating how to enter and grow a delivery systems business, gaining such an understanding is but the first, critical step in the game. Inevitably, this step is followed by projecting the acquiring company’s areas of expertise onto the technology landscape and identifying the best match. As a result of this superposition, a business strategy will evolve that makes optimal use of the core competencies of both the chemical company and the acquisition partner. By the nature of things, identifying such a winning strategy is a job that each of the chemical company players has to do individually. There is no infallible recipe for doing it “right.” The intention of this chapter has been to provide the reader with a starting point for “doing it right.” It describes one line of thinking that creates an acquisition strategy for the microencapsulation technology. This approach represents a path with high probability of success.

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Table 8.3. Push/Pull Analysis

% Market Share 2002

Value $ MM

Technology

% Market Share 2007

Value $ MM

70

182

Spray-drying, spray-coating extrusion technologies

50

210

11

29

Liposomes

8

34

6

16

Cyclodextrin

5

18

5

13

Coacervation

10

40

3

8

Microemulsion technologies

5

18

3

8

Interfacial polymerization

2

8

<1

2.5

Nanoparticle technologies

10

40

<1

0

Sponges

10

40

2

5

Other such as gels and silicates and emerging technologies such as amphiphilic block copolymers

?

?

Trend

?

References 1. Eric Perrier, Controlled Release Systems in Cosmetic and Personal Care Workshop, Lyon, France (May 23–24, 2002)

3. Kline and Company, In-Cosmetics, London (April, 2002)

2. Frost & Sullivan, Market Engineering Consulting Report, Executive Summary, p. 4, (2001)

5. Eyal Ron, US Patent 6,316,011

4. www.nanobio.com

9 Microcapsules as a Delivery System Scott Hawkins and Mike Wolf Lipo Technologies Inc. Vandalia, Ohio Geraldine Guyard,* Stephen Greenberg and Nava Dayan Lipo Chemicals Inc. Paterson, New Jersey

9.1 9.2

Introduction ................................................................................... 192 Microcapsules .............................................................................. 192 9.2.1 Selecting an Appropriate Microencapsulation System ..... 193 9.2.2 Coating Systems for Water-Insoluble Actives .................. 193 9.2.3 Coating Systems for Water-Soluble Actives ..................... 194 9.2.4 Effect of Formulation Environment ................................... 194 9.2.5 Physical Forms of Microcapsules .................................... 194 9.3 Microcapsule Release Mechanisms............................................. 195 9.3.1 Mechanical Rupture .......................................................... 195 9.3.2 Controlled Release ........................................................... 195 9.4 Encapsulation by In Situ Polymerization ....................................... 198 9.5 Formulations: Features and Benefits ........................................... 203 9.6 Conclusions .................................................................................. 204 9.7 Formulations ................................................................................. 205 References .......................................................................................... 213

* Present Address: Geraldine Guyard, L’Oreal USA, 30 Teminal Avenue, Clark, NJ 07066 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 191–214 © 2005 William Andrew, Inc.

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9.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Introduction

The need for protection of a variety of new, active compounds has greatly increased due to the sensitivity, reactivity, and short shelf life of products used in many areas of industry. This need for protection is a result of a variety of factors such as harshness of the surrounding environment, interaction with other components, and the volatility and toxicity of the active ingredients. The technology pull issues described have led to the development of a variety of membrane- and matrix-type microencapsulation systems that effectively address these important issues. The concept of encapsulation has been considered and practiced by a wide range of industries over many years. The pharmaceutical industry, in particular, has pioneered this field. The development of large gelatin capsules has provided a distinct dosage form and, to some degree, a method for tastemasking solid drug particles. The concept of sustained, or controlled, release has been developed through the use of enteric coating of pills and drug granules. Once coated, these drugs are then incorporated into gelatin capsules, thereby providing yet another dosage form. Many vitamins and vitamin preparations are readily oxidized or hydrolyzed and, as a result, have a very limited shelf life. Emulsification techniques utilizing a variety of natural colloid materials have evolved which provide some limited protection against air oxidation and the effects of moisture. However, while emulsification technology is useful, microencapsulation technology has provided more effective solutions to such problems. Research and development efforts are continually evolving in order to improve these techniques and provide novel delivery systems to resolve the myriad of problems that arise in such formulations. In the food industry, for example, prepared foods have become a mainstay of the culture of many peoples around the world, and the need for efficient encapsulated components has flourished. Protected components currently used in this industry are termed “locked in” or “trapped” flavors. These are essentially flavor components adsorbed, or entrapped on or in, an edible matrix. One of the basic requirements of this area is the effective isolation of reactive components in order to extend the finished

product’s shelf life. Food flavoring materials are usually comprised of a complex solution of reactive, organic compounds. In their unprotected form, they will rapidly deteriorate due to high volatility, interaction with other components, and auto-oxidation processes. By contrast, the encapsulated flavors are less susceptible to these shortcomings and, as a result, a prepared food product containing encapsulated flavors will have a longer shelf life. The effective separation of reactive components in a formulation is encountered in fields as diverse as the adhesive, chemical, and agricultural areas. In each of these areas, microencapsulation affords useful solutions. The cosmetic, personal care, and fragrance industries have also benefited from the use of encapsulated components. These benefits range from simple aesthetics, wherein colored microcapsules are suspended in clear gels, to complex delivery systems. In the latter type of system, reactive components are protected from each other while in formulations, yet are released on demand when applied to the skin. Fragrance advertising has seen a significant surge in the demand for inks containing encapsulated fragrances used in printing applications. Indeed, there are few magazines in print today that do not contain at least one fragrance advertisement printed using a microencapsulated fragrance.

9.2

Microcapsules

Microcapsules are composed of a polymeric skin, wall, or matrix enclosing a liquid, solid, or gaseous core. The capsule wall is inert to the substance it contains. It generally possesses sufficient strength to allow for normal handling without rupture and the shell is sufficiently thin to permit a high core volume-to-wall ratio. The contents of the capsule are typically kept within the wall until released by some means that serves to break, crush, melt, dissolve, rupture, or remove the capsule shell. Another route to releasing the contained actives is an activated diffusion process wherein the active passes out of the core and through the capsule wall.[1] Microencapsulation technology encompasses many processes in which a solid, liquid, or gas can be surrounded by a membrane or matrix. These processes are var-

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ied and are based on scientific principles that deal with polymerization, surface energy, and reaction kinetics. Although microencapsulation relies on both physical and chemical processes, the application and manufacture of microcapsules continues to remain more an art form than a science.

should be prepared with answers to the following areas:

It is important to understand and know how each microcapsule system will respond in a given formulation environment, so that the desired mechanism of release can be tailored to create an effective finished product. To achieve this goal, it is essential to deal with experts in microencapsulation because they have extensive experience in the variety of technologies available.

2. In what environment will the microcapsules be used? For example, what is the nature of the base formulation? Will it be a wash-off or leave-on product?

9.2.1

Selecting an Appropriate Microencapsulation System

The decision as to which microencapsulation system is best for a particular formulation is dependent upon a variety of factors. Typically, each system is custom designed for the active to be used and the formulation environment expected. Thus, it is difficult to put together a simple fact sheet as to the type of capsule system that will work best for the myriad of personal care formulations that are available. The best course for the prospective formulator is to work closely with an experienced manufacturer of microcapsules. During this process, it will be necessary to explain the properties of the active to be delivered, its target of action, and the desired base formulation into which the microcapsules will be incorporated. This kind of information sharing is paramount to the overall success of the project. From a research and development perspective, the potential systems that can be employed to produce a suitable delivery system are extensive. They range from simple adsorption/absorption procedures where active materials are “soaked” on top of a substrate to complex membrane and matrix coating systems. The appropriate system of choice can generally be determined by taking into account seven basic attributes. These seven characteristics of the final system are the essential basis for preparation of customized encapsulation systems. Before approaching a suitable producer of the required microcapsules, a personal care formulator

1. What are the physical/chemical characteristics of the material to be encapsulated and what are its sensitivities and incompatibilities?

3. Are there any restrictions on the origin of materials to be used in the product, i.e., are they animal or non-animal derived? 4. In what form must the capsules be supplied? For example, will the required form be dry or slurried and in what type of liquid? 5. Rupture mechanism—what are the requirements for the microcapsule’s behavior relative to its rupture mechanism? Should the capsules be soft or hard and is sustained release required? 6. What is the desired capsule size? Should they be large and visible or small and invisible? 7. What color is desired, if any?

9.2.2

Coating Systems for WaterInsoluble Actives

The active compound to be encapsulated and its nature should be the first consideration for detailed review when designing a successful encapsulation system. The majority of membrane encapsulation systems are typically designed to coat water-insoluble materials. Some examples of these internal phase materials include: natural oils, essential oils, fragrances, and water-insoluble solids. Such materials are typically the most successful forms of microencapsulation. Generally, they require protection from the formulation environment. In such cases, complete deposition of the membrane material onto the internal core phase is critically dependent upon the interfocal tension between the liquid coating phase and the liquid core phase. In the case of a solid core phase, the wetting and spreading charac-

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teristics of the liquid coating material on the solid core material is of critical importance.

9.2.3

Coating Systems for WaterSoluble Actives

Coating systems designed to encapsulate water-soluble materials are generally more difficult to develop, because the equipment required to perform the encapsulation process is more complex and generally requires ancillary equipment to handle solventbased coating processes. Technology has been developed to deal with this issue without the use of undesirable solvents and this is discussed elsewhere in this book. These types of coating processes are more prevalent in the pharmaceutical industry since the majority of active drug components are watersoluble. It is imperative, therefore, that the physical and chemical characteristics of the active material are well-known when discussing applicable microencapsulation systems.

9.2.4

Effect of Formulation Environment

After full consideration of the active’s hydrophilic or lipophilic properties, the next most important consideration is the formulation environment. This environment will have a significant effect on the stability of the microcapsules. It is important to understand the nature of individual raw materials used to formulate the finished base. While most of the raw materials used in personal care vehicles generally present minimal difficulties regarding compatibility with the standard shell materials, the possibility does exist that some of these may have the ability to penetrate the shell, or dissolve the wall material. If this process were to occur, it could lead to premature release of the internal active phase. The type of base/vehicle into which the microcapsule will be incorporated is a good indicator as to the type of capsule that should be used. For example, wash-off formulations can typically employ capsules comprised of shell materials that are cross-linked chemically in order to make them water insoluble. Examples of such polymers include gelatin and polyoxymethylene urea. Because the polymer shell

is cross-linked, it will remain on the skin once the capsule is ruptured by a pressure-induced mechanism (i.e., rubbing on the skin). The shell fragments are washed away following rupture, and the internal phase is left behind on the skin as the product is washed off by the consumer. By contrast, leave-on products employ different types of capsule systems. These will normally involve non-cross–linked polymeric materials such as agar or alginate. Such capsules are also ruptured by pressure to deliver the internal phase, but the shell material is designed to dissolve and “rub out” upon application. As a result of the present day concerns about the use of animal-derived raw materials (i.e., gelatin) and the nature of most of today’s personal care formulations, there is a need for the use of non-animal–derived membranes. Recent regulations by the European Community have resulted from the Bovine Spongiform Encephalopathy (BSE) epidemic. This potential contamination of gelatin-based materials has changed the outlook for these types of capsules, since cross-linked gelatin has been one of the major types of shell materials and has been successfully used for many years resulting in the need for non-animal–derived replacements. To date, there have been only a few choices for membrane-type capsules that do not employ such animal-derived materials. To address this significant dilemma, gelatin membrane-type capsules are often being replaced with a matrix-type capsule. In these systems, the microcapsule wall is composed of a vegetable-based material such as agar or alginate.

9.2.5

Physical Forms of Microcapsules

Microcapsules can be supplied in three different physical forms: a slurry, wet cake, and dry powder. The slurry form is a suspension of microcapsules in water containing preservatives. The percentage of capsule solids range from about 5 wt% to 40 wt%. The wet cake form is a slurry that has been filtered to approximately 50% to 70% capsule solids, with the remaining weight being water containing preservatives. The wet cake (i.e., slurry) forms generally apply to all microcapsule sizes and are independent of the type of microcapsule produced. By contrast, the dry powder form of micro-

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM capsules contains less than 5 wt% moisture. This form is typically provided only for capsules that are about 500 microns or less in size and is also dependent upon the type of capsule that has been employed. All dry capsules require membrane-type coatings, since most of the matrix types of capsules used to prepare the coatings do require a certain amount of water in order to remain stable.

9.3

Microcapsule Release Mechanisms

The structure and components of the capsule wall determine the release mechanism of the encapsulated active compound. Generally, the mechanisms of release can be classified in the following manner: 1. Mechanical rupture 2. Controlled release

9.3.1

Mechanical Rupture

Mechanical rupture of capsules can be accomplished by either applying direct pressure or abrasion during the application of the formulation to the skin. Such capsules can be dried as individual entities, or by means of coating upon a substrate, such as fragrance capsules coated to a magazine insert. When this type of coating is used, capsule rupture is readily accomplished. Rupture strength is inversely proportional to the size of the capsule. If, however, the capsules are suspended in a slurry, and are relatively small in size (10 microns or less), mechanical rupture becomes more difficult because of the elastic state of the capsule. In these cases, the degree of direct pressure required to release the internal phase from the capsule would be high. Rupture strength is a parameter that can be controlled and modified during the formulation phase of capsule preparation. Key parameters include a degree of cross-linking and the ratio of weight of wall material to amount of internal phase. Solubility of shell material. The solubility of the shell material is of particular concern in both food and pharmaceutical applications where the capsules

195

need to be digested. In these cases, the capsule wall is provided in an unhardened form. In this form, it will readily dissolve when suspended in a warm aqueous medium (approximately 45°C). Changes in the pH of the capsule environment can also lead to transition from insoluble to soluble forms of the shell material and consequent release. Such release can be further enhanced by the addition of plasticizers to the shell material during the coacervation process. Examples of such plasticizers include sorbitol or triethyl citrate. Melting of the shell material. Melting of the shell material is a viable release mechanism depending upon the melting point of the coating material. The requirement in this case is that the capsules be suspended in a carrier or matrix that can be heated to a temperature that is high enough to melt the wall material. Melting points of the shell material can be adjusted through certain hardening techniques in order to facilitate active release at specific predetermined temperature ranges. Internal rupture of the shell material. Internal rupture involves volatilization of the internal phase from within the capsules. The capsules are essentially exploded due to the incorporation of a heatsensitive material that decomposes at a certain temperature, or a highly volatile liquid that can produce a large volume of gas. Biological degradation of the shell material. Biological degradation involves the consumption of the capsule wall by microbial action. Another type of such degradation involves food and pharmaceutical applications where humans or animals ingest the capsules and the wall is stripped by digestive action.

9.3.2

Controlled Release

Controlling the release rate of the internal active phase of its microcapsules and sustaining that rate is primarily employed in the pharmaceutical industry. In these applications, the internal phase is allowed to migrate through the capsule shell at a diffusion rate determined by several factors. Those factors include solubility of the internal phase in the environment, type of polymer shell employed, molecular weight of the polymer coating, and particle size of the capsule. Other factors include the weight

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ratio of wall material to internal phase and temperature of the environment. All of these parameters may contribute to the development of a sustained-release profile for a specific encapsulation system.

Typically, gelatin’s isoelectric point can range between 7.8 and 8.5. As evidenced from the isoelectric point, the gelatin composition consists primarily of the amino acids lysine and arginine (Fig. 9.1).[4]

Membrane types. The most common form of microcapsule is the membrane type. A good analogy for a typical microcapsule is that of an egg. An egg is nature’s example of a microcapsule in which the embryo is surrounded by a thin shell, which protects the “internal phase” from the outside environment. The standard industry commercial processes employed to form these types of microcapsules are gelatin coacervation, polymer condensation/precipitation, and phase separation from organic solvents.

Gelatin is the primary (positively charged) component in this type of microencapsulation system, and the complex coacervation process is carried out in a dilute solution containing the gelatin as well as a negatively charged colloid such as gum arabic or carboxymethylcellulose. The coacervation process is first initiated by dilution and adjustment of the pH of the mixture. Both colloids used in the solutions must be ionic in nature and able to exist in stable form in mixtures with opposite charges. This stability may be achieved by proper selection of the colloid materials or, in the event both colloids are amphoteric, by adjusting the pH of the solution in which the hydrophobic internal phase (the material to be encapsulated) is dispersed.[1]

Encapsulation by gelatin-based coacervation. Gelatin coacervation was commercially developed in the 1950s by Barrett Green and Lowell Schleicher of the NCR Corporation.[2] This process was developed primarily for the encapsulation of water-insoluble materials such as lipophilic oils and water-insoluble solids. This process has also been referred to as complex coacervation. The method involves complexation of a positively charged colloid which is complexed in an aqueous environment with a negatively charged colloid in order to create a polymer-rich phase. A colloid is a dispersion of a very finely divided material suspended in a liquid. The dispersion is tiny enough so Brownian motion keeps it suspended. This phase can then be induced to deposit upon a substrate based on its borderline solubility in the liquid being employed. Following adsorption onto the substrate, the coacervate gel is then cross-linked to form the finished microcapsule, which has a hard outer core. The first commercial application of this type of microcapsule was for carbonless paper and this technology is still in use today.[3] Gelatin-based microcapsule walls. Gelatin is classified as an amino acid consisting of both amino and carboxy units that form a polypeptide backbone. The gelatin commonly used, type A bone gelatin (300 bloom = gravimetric value relating to gel strength), is considered as the positive colloid. The isoelectric point of gelatin can have minor variations because it is a naturally derived material. It is critical to the success of the coacervation process because it allows a positive or negative charge to be placed on the gelatin with respect to the pH of the continuous phase. This is required to allow for the complexation with the negative colloid during processing.

Typically, the pH of the system is kept above the isoelectric point of the gelatin during the dispersion of the internal phase. This prevents coacervation and allows a more uniform dispersion of the internal phase. Within this dynamic system, there are three key factors that affect the deposition of the polymer to the substrate. These are the solution temperature, dilution ratio of active to solvent, and the pH of the system. Once selection of the negative colloid is made, it is best to standardize the dilution factor based on a phase diagram created by these key parameters. Thereafter, the formulator will only have to monitor two of the conditions required to induce coacervation. The primary factor is pH; it is the key to inducing polymer deposition. If the pH is out of the calculated range, based upon the desired size of microcapsule, homogenous deposition of the gelatin polymer will occur and the batch will contain unacceptable levels of free polymer. An example of a phase diagram using a gelatin and gum arabic encapsulation system is shown in the ternary diagram in Fig. 9.2. [1] The shaded area numbered 30, at the top of Fig. 9.2, shows the region in which various concentrations of gum arabic and gelatin will form coacervates when the pH of the gelatin solution is held at its isoelectric point of pH 8. Such a diagram may be made for any two colloids that form a complex coac-

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM

197

Figure 9.1 Common amino acids from proteins. (Reprinted with permission from DynaGel Incorporated.)

ervate to be used as a microcapsule coating. This will give the formulator a pictorial representation of the range of conditions required to coacervate the colloids. Under these conditions, a stable homogenous sol is formed wherein the oppositely charged materials will not interact (i.e., are compatible) with each other and will not precipitate. If the concentration of colloid material is too high, as in the region under curve 31, the sols will then be incompatible and form two phases. Diagrams such as those shown in Fig. 9.2 are made by testing mixtures of the sols without an internal phase, since inclusion of the internal phase will make the mixture opaque. Under these circumstances, observation of the cloud point, the prime method for indicating incompatibility or coacervation behavior, cannot be seen.[1]

If the mixture of both colloids cannot be made to form a complex coacervate, both the pH and the temperature can be adjusted up or down to a point where experiments show that coacervation will take place upon dilution.[1] Once coacervation has been induced, the system is slowly allowed to cool at a specific rate. During this slow cooling process, the coacervate deposits at the solid/liquid interface to form a membrane around small droplets of the core material. Once deposition of the coacervate is complete, the gelatin is then cross-linked by addition of an appropriate cross-linking agent, such as glutaraldehyde. Thereafter, the finished capsules can be stored or used in slurry form. They can also be separated by filtration and, depending on their size, they may be dried and used in their free-flowing form.

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Figure 9.2 Ternary diagram showing complex coacervation region for mixtures of gum arabic and gelatin aqueous solutions at pH 4.5.

9.4

Encapsulation by In Situ Polymerization

A second type of membrane encapsulation is in situ polymerization. This process is ideal for protecting hydrophobic materials and involves the deposition of a polymeric material at the solid/liquid interface. The most common process of this type used in industry today employs aminoplast (amino-functional) polymers. Generally, these are urea-formaldehyde– type polymers. The urea-formaldehyde (polyoxymethylene urea or PMU) encapsulation system was commercially developed by G. W. Matsen of the 3M Company in the 1960s.[5] This system was developed as an alternate method for the encapsulation of waterinsoluble liquids and solids. In situ polymerization is a process in which the capsule shell is formed by the polymerization of monomers added to the encapsulation reactor. In this process, polymerization occurs exclusively in the continuous phase and at the interface formed by the dispersed core material and the continuous phase. Polymerization of reactants located in the continuous phase produce a low

molecular weight pre-polymer. As this pre-polymer grows in size, it deposits onto the surface of the dispersed core material. Continued polymerization, with cross-linking, continues to generate a solid capsule shell.[5] The PMU encapsulation process. The general process for preparation of PMU-type capsules depends upon four distinct parameters: concentration, shear rate, temperature, and pH. This system is very sensitive to reaction kinetics, and each of these factors contributes to the rate at which polymerization and deposition proceeds. As in the case of the gelatin-based capsules, if any of these parameters are allowed to deviate from acceptable ranges, the resultant product will generally be of poor quality. The first step in the PMU process involves the preparation of an aqueous solution of a water-soluble, low molecular weight pre-condensate. This pre-condensate is comprised predominately of low molecular weight reaction products of urea and formaldehyde. An example of such a pre-condensate is dimethylol urea (Fig. 9.3).[5]

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM The solution shown in Fig. 9.3 has a solids content of about 3% to 30% by weight of the total aqueous pre-condensate. Preparation of the pre-polymer is generally carried out under alkaline conditions, at a temperature ranging between 60°C and 80°C. The internal (actives) phase is then added into the pre-condensate, at a suitable ratio of core material to wall material. The internal phase must be dispersed in the solution as microscopically sized, discrete droplets or particles, in the absence of wetting agents. The dispersion of the internal phase must be maintained throughout the precipitation process in order to prevent irreversible agglomeration of the dispersed droplets or particles. The dispersion method employed generally involves high shear rates that tend to increase the temperature of the system as mixing of the dispersion continues. The temperature of the reaction must also be monitored since it has a direct effect on the rate at which the polymer precipitates onto the dispersed active phase. For optimum results, the temperature should be maintained in the range of 10°C to 50°C

199

Once a suitable particle size range has been reached, acid is then added to the system. This acid should be of sufficient concentration to bring the pH range of the dispersion into a range of 1 to 5, thereby promoting acid catalysis of the pre-condensate. Polymerization of the pre-condensate is allowed to continue for several hours, while maintaining the core material as finely dispersed particles. Upon completion of the deposition phase, the resulting membrane is allowed to cure (de-water) at a temperature of 60ºC, in order to cross-link the polymer (Fig. 9.4) and create a stable microcapsule slurry.[5] The resulting slurry of microcapsules is then neutralized. Thereafter, it may be stored for use as a slurry, or the capsules can be separated by filtration and dried for powder applications. Encapsulation of water-soluble actives. As a final example of membrane-type encapsulation systems, the process in which water-soluble solids can be encapsulated is being described. This process is based on phase separation due to polymer/polymer incompatibility with an organic solvent. This method

Figure 9.3 An example of a dimethylol urea pre-condensate.

Figure 9.4 Chemical reaction showing curing of the resulting membrane.

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is most often used in the pharmaceutical industry to supply either taste-masked, or sustained-release dosage forms of water-soluble drugs. This system is also employed in non-pharmaceutical industries when there are requirements for the sustained release of a water-soluble solid. A novel aspect of this process is the presence of clear liquid phases. Each of these phases contains, almost exclusively, only one species of polymer. This technique makes the system well suited for the encapsulation of solid particles. When a solid, in the form of small particles, is dispersed into a solution of a polymer, and a second polymer is then added, the least-soluble polymer of the two separates out and deposits around the suspended solid particles. As the addition of the second polymer is continued, the separated polymer phase continues to be desolvated. During this process, it becomes more viscous, forming a clear continuous liquid layer around the core material, thereby creating membrane-type microcapsules. Capsules formed by this phase-separation process can then be hardened, or solidified, to facilitate their removal from the external phase. The liquid encapsulating phase is desolubilized by the addition of a nonsolvent, or cross-linked by a chemical reagent. This results in the formation of discrete polymer-coated particles. In such systems, the polymer wall can be plasticized which produces a more elastic capsule with improved permeability characteristics. The capsules are then washed in a nonsolvent to complete the desolvation process. The resulting capsule cake is then dried in drying equipment suitable for use with solvents.[1] Before a separated liquid phase can be effectively utilized for encapsulation, it must possess specific properties relating to concentration, viscosity, phase ratios, and purity. These parameters must be effectively controlled in order to deposit the liquid layer of polymer around the core material, thereby providing sufficient protection of the internal phase. Since this type of encapsulation system is designed to form a coating on the internal phase of water-soluble solids, the polymer wall must provide some degree of protection against water or water vapor. Thus, permeability of the polymer capsules is dependent on the rate at which the aqueous medium can extract the internal phase through the capsule wall. This rate of extraction is dependent on many

factors. Examples include the polymer material, the solubility of the internal phase in water, and the solubility of the internal phase in the solvent system. Other important parameters include the particle size of the internal phase, the viscosity of the polymer solution, the ratio of core material to wall material, and the type of hardening system employed. A variety of polymeric materials can be utilized with this type of capsule formation. Examples include ethylcellulose or nitrocellulose. A typical example. A typical example of this type of system uses cyclohexane as the continuous phase, ethylcellulose as the shell material (1% to 4%), and polyethylene as the phase inducer (1% to 4%). The reactants are all added to the reaction vessel under an inert environment. They are then agitated in order to suspend the particles. The internal phase (water-soluble solid) is then charged to the system. The resulting dispersion is then heated to 80ºC in order to solubilize the reactants. The ethylcellulose dissolves first, and once the temperature exceeds 70°C, the polyethylene begins to dissolve. As the polyethylene dissolves, the ethylcellulose undergoes phase separation due to polymer/polymer incompatibility with the polyethylene; hence the polyethylene is referred to as a phase inducer. As the ethylcellulose becomes desolvated, it forms a clear, continuous layer around the internal phase particles. The system is then allowed to cool slowly in order to harden the shell. Once the system reaches ambient temperature, the capsule slurry is washed with fresh solvent, and the capsules are separated by filtration. These types of capsules are generally supplied only as a dry powder, since there may be residual organic solvent present. Encapsulation with matrix polymers as a substitute for gelatin. Concerns regarding the safety of animal-derived polymers have resulted in the development of matrix-type capsules. These replace the animal-derived gelatin with vegetable-derived materials and/or synthetic polymers. Such materials are usually designed as microspheres. Examples of useful polymers include gums extracted from seeds and seaweed, exudate gums, microbial gums, starch, and cellulose. Synthetic polymers used to form sphere matrices include polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene oxide. In most cases, a number of these materials are blended together to form the matrix material. Microspheres

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM have also been produced using wax as the base material. The uses and benefits of these spheres are based on matrix walls, in most cases, similar to those for the microcapsules. However, there are significant differences between the properties and the methods of manufacturing the two types of products. Differences in the final properties include integrity of the shell, maximum and minimum loading attainable, rubout characteristics (feel), maximum size, and the nature of materials that can be used in the core. In general, these differences can be controlled by the properties of the individual gums/polymers and the methods of manufacturing. Materials used to make spheres with matrix polymer coatings cannot be used to form complex coacervates since different methods of processing are required. The production of matrix encapsulated microspheres depends more upon the physical properties of the actives and matrix materials such as solubility, surface tension, thermal properties, and gelforming abilities. There are a number of methods for manufacturing matrix-coated microspheres, i.e., forming the gums/polymers into spheres. The exact process is dependent upon the polymer(s) used, but there are some common elements that affect the final properties. First, the spheres are generally made from oilin-water emulsions. During manufacture, the polymers are first solubilized in water. Next, the active materials to be encapsulated are emulsified in the aqueous polymeric solution. The resulting emulsion is then transformed into spheres. As a result of the characteristic properties of these oil-in-water emulsions, the maximum loading of oils into microspheres is approximately 25%. Higher loadings carry the risk of inversion to water-in-oil emulsions and, thus, are not practical. Since this is a double emulsion technique, inversion will occur during the processing phase. Agar spheres. An example of this process is the manufacture of agar spheres. First, a solution of agar is prepared. Oil(s) are then emulsified into the solution. At this point in the process, the system must be kept at a temperature that is above the gelation point of agar. The resulting emulsion is then dispersed into a continuous phase medium like an oil, using mechanical agitation, where the spheres are formed.

201

The temperature is then reduced below the set point of the agar gelation point by passing all of the material through a heat exchanger. This process solidifies the agar. The spheres are then separated from the continuous phase and collected. Agar is particularly well suited for the manufacture of spheres (see Fig. 9.5) in view of the high hysteresis characteristics of these gels. In other words, the gelation temperature of these gels is much lower than their melting temperature. This unique feature of agar allows the spheres to be manufactured, and then to withstand the elevated temperatures required to further process them into final formulations. When making alginate-based spheres, a different method is employed than the one used for agartype spheres. The process begins similarly and the sodium alginate is put into solution. The oil and/or actives are then emulsified into the alginate solution. The resulting emulsion is then dipped or sprayed into an aqueous solution of calcium chloride. Through the process of ion exchange, the calcium from the dissociated calcium chloride in the aqueous solution exchanges with the sodium ions in the alginate polymer. The net result is water-insoluble, calcium alginate spheres. These spheres are then collected by filtration. Care must be taken in the preparation of alginate spheres because the sodium/calcium ion exchange process employed is reversible. If precautions are not taken, and the spheres are placed into an environment containing free monovalent metallic ions such as potassium or sodium, the calcium ions

Figure 9.5 Agar spheres, 1,000 microns. (Reprinted with permission from Lipo Technologies, Inc.)

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in the spheres are free to exchange with the monovalent metallic ions. This will have the undesirable result of making the spheres water-soluble. Another variation of the method of producing alginate spheres would be to include a sequesterant, such as sodium polyphosphate into the alginate formulation. Inclusion of the phosphate ion will aid in controlling the ion exchange. It may also affect the gel’s properties, especially its strength. As can be seen in Fig. 9.6, there are a variety of methods to manufacture spheres. Due to the variety of available matrix materials, each type of sphere has unique properties and may require modifications to a particular manufacturing process—or even the development of an entirely new process. Unlike membrane-type capsules, microspheres can be made without an internal phase (oils or active ingredients). This represents a decided cost ad-

vantage when the end use is for visual effect only. The spheres can be produced in a wide range of sizes, rubout characteristics, and, with the addition of select pigments, colors can be added to give the desired visual and tactile appeal. Another key difference between membrane capsules and spheres is the fact that it is possible to incorporate water-soluble materials into sphere formulations. The critical factor, in this case, is not whether the active material can be added to the spheres, but whether it can be retained within the spheres. A case in point would be the addition of citric acid to agar spheres. Since the agar and the citric acid are both water soluble, it is not difficult to solubilize them both in the same solution. If the proper method to form the spheres is chosen, the citric acid will be included in the spheres. If these spheres are then incorporated into an anhydrous base, or dried, the citric acid will be retained. By contrast, how-

Figure 9.6. Sequestration of calcium ions by sodium polyphosphates.[9] (Courtesy of J. R. Van Wazer.)

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM ever, if the spheres are formulated in an aqueous base, a portion of the citric acid will diffuse through the sphere matrix and, undesirably, end up in the aqueous formulation. The extent of such a migration depends upon a number of factors. These include type of gum, gum concentration, amount of water, and other ingredients present in the gel. A major benefit of using spheres in place of capsules is the feel or rubout properties of the spheres. Since many sphere formulations do not require crosslinking to insure stability, the sphere matrix is generally softer than the cross-linked polymeric wall of a capsule. Therefore, unlike the capsules, the spheres can be completely rubbed out on the skin, thereby leaving no shell or residue. This is an advantage for any personal care leave-on application. At the other end of the spectrum, it is possible to manufacture spheres that are very difficult to rupture. This can be accomplished by cross-linking the sphere matrix. The ability to tailor this property is a major advantage. Factors that affect the feel properties of such spheres include selection of gum or polymer, polymer concentration, blending of matrix materials, addition of materials such as glycerin, adjusting the loading, and varying the moisture content. There are many additional considerations when choosing spheres for personal care delivery systems, and most of these relate to the intended end use of the spheres in a finished product. Bacterial contamination of spheres made with natural gums is a concern. Most of these materials are wonderful sources of food for bacteria. Agar has been used extensively as a culture media for many years. It is recommended that sampling procedures and manufacturing processes for these products should be conducted in the same manner as for food-grade products. Additional concerns in the use of these products are pH of the final product, processing temperatures, mixing and filling conditions, and manufacturing equipment. Many of these natural gum materials form thermally reversible gels. Operating a process at a temperature that is too high will result in undesirable sphere melting. Since the spheres are generally soft, processing equipment that introduces high shear must be avoided.

9.5

203

Formulations: Features and Benefits

Formulations 9.1 through 9.6 provide examples of the features and benefits of encapsulation. Improve aesthetics. Microcapsules can be used simply to improve the aesthetics of a formulation and are a useful marketing tool to catch consumer’s attention. An example of this approach is the use of colored microcapsules in clear gels (see Formulation 9.1). Protect the encapsulated compound. Encapsulating a compound can protect it from the environment and the surrounding atmosphere, and avoid incompatibilities arising within formula ingredients. Encapsulation can also prevent the evaporation of the active compound and reduce its toxicity upon application by slowing the rate of delivery. Improve stability and increase finished product shelf life. Oils, with unsaturated fatty acids have a tendency to turn rancid. Encapsulation can protect oils containing unsaturated fatty acids from oxygen and humidity, thereby reducing rancidity and prolonging shelf life. Vitamins may also turn rancid. Tocopherol (vitamin E) is an easily oxidized compound. It can neutralize free radicals that initiate chain reactions resulting in the form of compounds capable of causing irreversible harm to the skin. Formulation 9.2 is an example of a product that improves stability and shelf life. Prevent incompatibilities within the formulation. The encapsulation of water-insoluble materials (oils or water-insoluble solids) allows the incorporation of oils into aqueous systems and keeps the two phases separate. This is accomplished without the inclusion of surfactants, which may provide irritation to the skin. Formulation 9.3 allows incorporation of oils into a gel. The oil will only be released from the spheres during application and rubout on the skin. Control the release of the encapsulated compound. Encapsulation can lead to a controlled release of the encapsulated compound, depending on the release mechanism designed into the system.

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Usually, in cosmetic applications, the mechanism of release will be a mechanical rupture (i.e., applying external pressure to the cream or lotion on the skin). Thanks to this process, the encapsulated compound is delivered on the spot where its action is required (Formulations 9.4 and 9.5). Formulating color cosmetics. In color cosmetics, PMU LipoCapsules™ can be used to encapsulate pigments and achieve long wear characteristics. As a result of their small size, PMU LipoCapsules help intensify product color and provide shine upon rubout during application. Formulation 9.6 is an example.

9.6

Conclusions

Microencapsulation as a delivery system has proved itself useful in a variety of commercial applications in many areas of industry. The techniques used to produce these capsules range from simple blend operations to complex polymeric coating systems. The systems discussed in this chapter provide only a brief introduction to the world of microencapsulation and its potential applications. It would be extremely difficult to list all the potential applications for encapsulation systems as the list would be vast, but it can be summarized by the following statement. “The applications of microencapsulation are only limited to the creativity of the individual formulator, and the experience of the encapsulation scientist.”

It is only through a joint effort between the formulating company and the microencapsulation experts that an effective solution can be created to solve specific problems within any given formulation. The field of cosmetic science holds a bright future for the use of microencapsulation as a delivery system for useful personal care actives. The personal care industry has seen a recent surge in the use of active compounds used to treat skin deficiencies rather than simply masking the problem. As the need for more active compounds increase, the formulation problems increase in proportion to this need. It is a scientific fact that the more active the compound, the more reactive it becomes with the environment in which the compound is placed. This is especially true with respect to typical cosmetic formulations that can be considered harsh environments for active compounds. It is in this arena that the microencapsulation techniques can solve resulting stability issues and deliver the material in an active state to treat the problem areas. Features and benefits of using microencapsulation to enhance personal care formulations include improving aesthetics, protecting the encapsulated compound, improving stability and increasing the shelf life of the finished product, preventing incompatibilities within the formula, controlling the release of the encapsulated compound, and assisting in formulating color cosmetics.

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM

9.7

205

Formulations

Formulation 9.1: Shower Gel with LipoCrystal™ Capsules

This low viscosity gel will moisturize the skin as it cleans. LipoCrystal™ Capsules provide an iridescent visual effect. In order to maintain an iridescent effect, liquid crystals need to be kept chemically separated from an anhydrous system. LipoCrystal Capsules are en-

Phase

Ingredient

Function

capsulated cholesteryl esters. Encapsulation allows their incorporation into systems that include oils, surfactants and fragrances. These custom encapsulates are available utilizing gelatin or agar. They range in size from about 100 to 2,000 microns.

Trade Name

Manufacturer

Weight %

Deionized water

Diluent

Water

Methylparaben

Preservative

Methylparaben

B

Carrageenan

Gellant, suspending agent

Viscarin SD 389

FMC Corp.

0.50

C

Glycereth-26

Humectant

Liponic™ EG-1

Lipo Chemicals, Inc.

2.00

Sodium laureth sulfate

Detergent

Standapol ES-2

Cognis Corp.

12.00

Cocamidopropyl betaine

Detergent, foam booster

Velvetex BA-35

Cognis Corp.

4.00

Imidazolidinyl urea

Preservative

Liposerve™ IU

Lipo Chemicals, Inc.

0.25

A

D

E

Deionized water Thickener

0.25

Deionized water

1.00

Sodium chloride (25% solution)

0.90

F

Sodium chloride

G

Water, gelatin, cellulose gum, cholestrol Capsules for a nonanoate, cholesteryl visual effect chloride, cholesteryl Isostearylcarbonate

LipoCrystal™ Capsules Green

H

Violet 2

FD&C Violet #2

Colorant

78.10

Lipo Technologies, Inc.

Manufacturing Procedure: 1. Combine Phase A and heat to 78°C. 2. Slowly sprinkle in Phase B into Phase A with propeller mixer at medium speed with batch temperature at 78°C, and mix until completely in solution. 3. Switch to slow sweep mixing and cool to 45°C. 4. Add Phase C to the batch at 45°C with slow sweep on overhead mixer. 5. Add Phase D in order of addition and continue cooling to 35°C. 6. Add premixed Phase E at 35°C and continue cooling to 25°C. 7. Add Phase F to the batch. 8. With low agitation, add Phases G and H at 25°C.

1.00

TMS

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Formulation 9.2: Hand Cream with LipoSpheres™

This emollient cream contains a wide variety of products including an emulsifying wax blend, an emollient ester, a humectant, a skin conditioner, and a preservative system. The agar LipoSpheres™ con-

Phase

A

B

C

Ingredient

tain sunflower oil and vitamins (A and E). On rubout, the contained actives are delivered completely onto the skin.

Function

Trade Name Manufacturer

Weight %

Deionized water

Diluent

Deionized water

Trisodium EDTA

Chelating agent

Hampene Na3EDTA

Aloe barbadensis leaf juice

Moisturizer, skin protectant

Aloe vera gel

Glycereth-26

Humectant

Liponic™ EG-1

Lipo Chemicals, Inc.

1.50

PEG-75 Shea butter glycerides

Emulsifier, emollient

Lipex 102 E-75

Jarchem Ind.

1.50

Phenoxyethanol, methylparaben, butylparaben, isobutylparaben, ethylPreservatives paraben, and propylparaben

Liposerve™ PP

Lipo Chemicals, Inc.

0.60

Acrylates/C10–C30 alkyl Thickener and acrylate crosspolymer suspending agent

Carbopol 2020 (2% aqueous disp.)

Noveon, Inc.

Neopentyl glycol dicaprylate/dicaprate

Emollient (ester)

Liponate™ NPGC-2

Lipo Chemicals, Inc.

5.00

Capric/caprylic trigylceride

Emollient (ester)

Liponate™ GC

Lipo Chemicals, Inc.

5.00

Cetearyl alcohol, polysorbate 60 stearate, Oleth-10, PEG-75 lanolin, PEG-150 stearate, and Steareth-20

Emulsifiers

Lipowax™ R2

57.75 Hampshire

0.05 0.50

Lipo Chemicals, Inc.

Cetyl alcohol

Co-emulsifier

Lipocol™ C

Lipo Chemicals, Inc.

Ricinoleam-idopropyl ethyl-dimonium ethosulfate

Conditioner

Lipoquat™ R

Lipo Chemicals, Inc.

20.00

3.00

0.50

0.25 (Cont’d.)

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM

207

Formulation 9.2: (Cont’d.)

Phase

Ingredient

Function

Trade Name

Weight %

Deionized water

Diluent

Deionized water

1.00

Triethanolamine, 99%

Neutralizing agent

Triethanolamine, 99%

0.60

Deionized water

Diluent

Deionized water

1.00

Imidazolidinyl urea

Preservative

Liposerve™ IU

Lipo Chemicals, Inc.

0.25

Fragrance

Fragrance

Fragrance - 01AP486

Western Flavors and Fragrances

1.00

Water, agar, sunflower oil, tocopheryl acetate, retinyl palmitate, and ultramarine

Spheres to protect oils and vitamins from oxidation

LipoSpheres™ Blue with sunflower oil, vitamin E acetate and vitamin A

Lipo Technologies, Inc.

0.50

Red 4

Colorant

FD&C Red #4

D

E

F

Manufacturer

TMS

Manufacturing Procedure: 1. Heat Phase A to 80°C while mixing on overhead mixer with propeller blade at medium speed. 2. Heat Phase B to 78°C and add to Phase A. 3. Pre-mix Phase C after heating to 78°C until clear. Add to batch at medium/high speed. Cool to 75°C. 4. Add pre-mixed Phase D slowly and mix until uniform. Cool batch to 40°C. 5. Add pre-mixed Phase E at medium speed and cool to 35°C. 6. Switch to sweep blade and add Phase F at low shear.

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Formulation 9.3: Exfoliant Gel with LipoSpheres™

This low-viscosity, quick drying, clear gel suspends agar LipoSpheres™ which contain oils. Agar LipoSphere, derived from a renewable marine source, offers a wide range of encapsulation possibilities. LipoSphere products consist of many small droplets of material entrapped in a polymer matrix. They can be made in a size range of about

Phase

A

B

Ingredient

400–4,000 microns. They are currently available in red, green, blue, and white. These spheres provide the visual effects previously only available with gelatin capsules, while offering the same ease of formulation. Agar LipoSpheres leave little or no residue upon rubout.

Function

Deionized water

Diluent

Water

Disodium EDTA

Chelating agent

Na2EDTA

E

Manufacturer Weight % 82.10 0.05

Phenoxyethanol, methylparaben, butylparaben, Preservatives isobutylparaben, ethylparaben, propylparaben

Liposerve™ PP

Lipo Chemicals, Inc.

0.30

Glycereth-26

Humectant

Liponic™ EG-1

Lipo Chemicals, Inc.

1.00

Acrylates/C10–C30 alkyl acrylates crosspolymer

Thickener and suspending agent

Carbopol ETD 2020 (2% aqueous disp.)

Noveon, Inc.

Deionized water

Diluent

Deionized water

1.00

Triethanolamine, 99%

Neutralizing agent

Triethanolamine, 99%

0.30

Butylene glycol

Solubilizer, solvent

Butylene glycol

2.00

Salicylic acid

Exfoliant

Salicylic acid

0.25

Water, agar, chromium hydroxide Green, titanium dioxide, mica, spearmint oil, and eucalyptus oil

Agar LipoSpheres™ containing oils in an aqueous system to protect from incompatibles

LipoSpheres™ Lipo Green, with spearmint oil Technologies, and eucalyptus Inc. oil

0.50

C

D

Trade Name

12.50

Manufacturing Procedure: 1. Heat Phase A to 80°C while mixing on overhead mixer with propeller blade at medium speed. 2. Add Phase B at medium speed. 3. Pre-mix Phase C and add slowly to batch. Mix until uniform. 4. Add pre-mixed Phase D and cool batch to 40°C. 5. Switch to sweep blade and add Phase E at low shear.

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM

209

Formulation 9.4: Lotion with Encapsulated Fragrance

This formulation is a light lotion containing an encapsulated fragrance. The product will transfer the scent of the lotion when rubbed into the skin. The incorporation of fragrances into the gelatin LipoCapsules™ creates an isolation of the compounds in order to extend the shelf life of the finished product. An unprotected form rapidly deteriorates due to its high volatility, concentration, and auto-oxidation.

Phase

Ingredient Deionized water

A

B

C

LipoCapsule™ gelatin products are distinguished by a clear, nonpigmented shell surrounding a single droplet, or particle of a hydrophobic core material (the internal phase or “IP”), with or without a color. These capsules can vary in size from about 5–3,000 microns. They usually contain emollient oils and vitamins. Such materials enhance both the tactile and visual appearance of cosmetic and personal care products.

Function Diluent

Deionized water

69.35

Phenoxyethanol, methylparaben, butylparaben, Preservatives isobutylparaben, ethylparaben, propylparaben

Liposerve™ PP

Lipo Chemicals, Inc.

0.40

Trisodium EDTA

Chelating agent

Hampene Na3T

Hampshire

0.05

Carbomer

Thickener and suspending agent

Carbopol 2984 Noveon (2% solution)

Neopentyl glycol dicaprylate/dicaprate

Emollient ester

Liponate™ NPGC-2

Lipo Chemicals, Inc.

3.50

Hydrogenated polyisobutene

Polymeric emollient, lubricant, moisturizer

Panalane® L-14E

BP

1.50

Glyceryl stearate, PEG100 stearate

Emulsifier and viscosity builder

Lipomulse® 165

Lipo Chemicals, Inc.

1.50

Cetyl alcohol

Co-emulsifier

Lipocol™ C

Lipo Chemicals, Inc

0.60

PEG-150 distearate

Emulsifier

Lipopeg™ 6000 DS

Lipo Chemicals, Inc.

0.50

Deionized water

Diluent

Deionized water

1.00

Triethanolamine, 99%

Neutralizing agent

Triethanolamine, 99%

0.35

Deionized water

Diluent

Deionized water

1.00

D

E

Trade Name Manufacturer Weight %

17.50

(Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 9.4: (Cont’d.)

Phase E

F

Ingredient

Function

Trade Name

Manufacturer Weight %

Imidazolidinyl Urea

Preservative

Liposerve™ IU

Lipo Chemicals, Inc.

0.25

Fragrance

Fragrance

Lotion Fragrance #5073-10542M

Belmay, Inc.

0.50

Fragrance, gelatin, water, and propylene glycol

LipoCapsules™ for a controlled release of the fragrance (upon rub-out)

LipoCapsules™ with Encapsulated Fragrance #50791054M

Lipo Technologies, Inc.

2.00

Manufacturing Procedure: 1. Premix Phase A and heat to 78°C. 2. Heat Phase B to 50°C and add to Phase A on overhead mixer at medium/high speed. Bring batch temperature back to 78°C. 3. Heat Phase C to 80°C and add to batch at medium/high speed. 4. Add pre-mixed Phase D to batch and cool to 35°C. 5. Switch to sweep blade and add pre-mixed Phase E to batch at low/medium speed. Cool to 25°C. 6. At 25°C, add Phase F in order.

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Formulation 9.5: Disinfectant Hand Gel with LipoSpheres™

This easily prepared gel contains alcohol to disinfect and Liponic™ EG-1 and LipoSpheres™ with glycerin encapsulated to moisturize the skin.

Phase

Ingredient

Function

Trade Name

Manufacturer

Weight %

Deionized water

Diluent

Deionized water

Glycereth-26

Humectant

Liponic™ EG-1

Lipo Chemicals, Inc.

B

Carbomer

Thickener, suspending agent

Carbopol ETD 2001 (2% aqueous disp.)

Noveon, Inc.

C

SD Alcohol 40B

Solvent, antiseptic

SD Alcohol 40B

30.00

Triethanolamine, 99%

Neutralizing agent

Triethanolamine, 99%

0.60

Deionized water

Diluent

Deionized water

1.00

Water, agar, glycerin, titanium dioxide, mica, carmine, and Red #30

LipoSpheres™ for controlled release

LipoSpheres™ Lipo Pink with Technologies, glycerin Inc.

0.50

A

D

E

47.90

Manufacturing Procedure: 1. In a suitable beaker, weigh Phase A ingredients and mix with an overhead mixer and propeller blade. 2. Add Phase B to Phase A. Mix well at a medium speed. 3. Add Phase C to the batch and mix well. 4. Add pre-mixed Phase D slowly; mix until gel is homogenous. 5. Switch to slow sweep mixing and add Phase E.

5.00

15.00

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 9.6: Lipstick with Pigment LipoCapsules™

A long-lasting, elegant lipstick containing a microencapsulated pigment, which imparts renewed color.

Phase

A

B

Ingredient

PMU LipoCapsule™ products employ a precipitation of a synthetic polymer around a hydrophobic core material. These capsules can range from about 5–100 microns in size.

Function

Trade Name

Manufacturer

Euphorbia Cerifera (Candelilla) Wax

Film former, wax

Candelilla Wax

Hansotech, Inc.

5.00

Copernica Cerifera (Carnauba) Wax

Wax, shape builder

Carnauba Wax

Hansotech, Inc.

5.00

Synthetic beeswax

Binder, emulsifier

Lipobee® 102

Lipo Chemicals, Inc.

8.00

Ricinus communis (castor) seed oil

Dispersant, emollient

Lipovol™ CO

Lipo Chemicals, Inc.

25.20

PEG-4 diheptanoate

Emollient

Liponate™ 2-DH

Lipo Chemicals, Inc.

6.00

Isopropyl palmitate

Emollient, lubricant

Liponate™ IPP

Lipo Chemicals, Inc.

12.00

Tridecyl trimellitate

Emollient

Liponate™ TDTM

Lipo Chemicals, Inc.

10.00

Neopentylglycol dicaprylate/dicaprate

Emollient

Liponate™ NPGC-2

Lipo Chemicals, Inc.

10.00

Propylparaben

Preservative

Propylparaben

0.20

BHA

Antioxidant

BHA

0.10

Titanium dioxide (and) castor oil

Colorant pigment

50% TiO2 paste in castor oil grind (roller mill)

0.50

Red 6 and castor oil

Colorant

50% FD&C Red #6 in castor oil grind (roller mill)

5.00

Iron oxides

Pigment

Iron Oxide Maroon #335138

Sun Chemical Corp.

10.00

Iron Oxides

Pigment

Iron oxide Red #33128

Sun Chemical Corp.

1.00

Neopentylglycol dicaprylate/dicaprate, tridecyl trimellitate, Red 30, and polyoxymethylene urea

Capsules to impart LipoCapsule™ renewed color PMU and long wear

Lipo Technologies, Inc.

2.00

Manufacturing Procedure: 1. Into main kettle, combine Phase A under Lightnin' mixing and heat to 80°C–85°C. 2. Add Phase B and continue mixing for a 30 minutes with Lightnin' mixing. 3. Cool the batch to 70°C–75°C and pour batch in a suitable container for molding.

Weight %

HAWKINS, GUYARD, GREENBERG, DAYAN, WOLF: MICROCAPSULES AS A DELIVERY SYSTEM

References 1. Gutcho, M. H., Microcapsules and Microencapsulation Techniques, pp. 1, 8–9, 133–135, Noyes Data Corporation (1976) 2. Green, B. K., US Patent 2,374,862 (1945) 3. Green, B. K., US Patent 2,712,507 (1955); National Cash Register Co., (NCR), British Patent, 751,600 (1956) 4. Ward, A. G., and Courts, A., The Science and Technology of Gelatin, p. 78, Academic Press (1977) 5. Matsen, G. W., Minnesota Mining and Manufacturing Company, US Patent 3,516,846 (Jun. 23, 1970) and US Patent 3,516,941 (Jun. 23, 1970)

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6. Goodwin, J. T., and Somerville, G. R., Physical Methods for Preparing Microcapsules, Am. Chem. Soc., Div. Org. Coat. Plast. Chem., pp. 611–617 (Aug. 1973) 7. Whistler, R., and Bemiller, J., Industrial Gums, Polysaccharides and Their Derivatives, pp. 88–147, Academic Press (1993) 8. Golding, B., Polymers and Resins, pp. 264– 283, D. Van Nostrand Company (1959) 9. Van Wazer, J. R., Phosphates in Food Processing, (J. M. DeMan, ed.), pp. 1–23, AVI Publishing Co., Westport CT (1971)

10 Tagravit™ Microcapsules as Controlled Drug Delivery Devices and Their Formulations Emma Kvitnitsky, Natalia Lerner, and Yury E. Shapiro Tagra Biotechnologies, Ltd. Netanya, Israel 10.1 10.2 10.3 10.4 10.5

Microencapsulation: A Delivery Method for Unstable Actives ....... 216 Contemporary Microencapsulation Techniques ........................... 217 Preparation of Microcapsules for Skin Applications ..................... 220 Microencapsulation of Unstable Lipophilic Actives ....................... 221 Stability Determination of Microencapsulated Vitamins in Various Formulations ................................................................................. 223 10.6 Model Formulations Developed for Stability Testing of Tagravit™ Microencapsulated Products ........................................................ 224 10.6.1 Stability Variables .............................................................. 224 10.6.2 Effects of Stability Variables.............................................. 224 10.7 Effect of Formulation on Stability of Microencapsulated Vitamins ..... 226 10.7.1 Increased Stability of Microencapsulated Retinol Palmitate .. 226 10.7.2 Increased Stability of Microencapsulated α-Tocopherol ... 226 10.7.3 Increased Stability of Microencapsulated Vitamin F ......... 228 10.7.4 Effect of Plasticizers in the Microcapsular Wall on Stability of Active ............................................................... 228 10.7.5 Effect of Loaded Amount of Encapsulated Retinol Palmitate on its Stability in Formulation ............................ 230 10.8 Incorporation of Tagravit/Tagrol™ Microcapsules into Cosmetic Formulations ................................................................................. 231 10.8.1 Basic Principles ................................................................ 231 10.8.2 Application of Tagravit™/Tagrol™ Microcapsules ............. 233 10.9 Conclusions .................................................................................. 233 10.10 Model and Recommended Formulations ..................................... 235 10.10.1 Model Formulations ......................................................... 235 10.10.2 Recommended Formulations ......................................... 250 References .......................................................................................... 257 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 215–258 © 2005 William Andrew, Inc.

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10.1 Microencapsulation: A Delivery Method for Unstable Actives Throughout history, the principal objective of the cosmetic industry has been to provide products that prevent premature aging of the skin, promote skin regeneration, and help maintain a younger, healthier looking skin.[1] To attain these goals, formulators incorporate active ingredients with specific biological effects into their formulations. Examples of such actives include vitamins, antioxidants, and antibacterial and whitening agents. Similarly, the pharmaceutical industry is dependent on the presence of active ingredients with specific biological activity. Such actives form the essential component of formulations used in dermal preparations. While actives are highly useful and desirable, they generally are inherently unstable over time. Such instability shows up during preparation of various formulations, especially when stored in the finished product formulations. The content of active ingredients in cosmetic and dermal formulations may be adversely affected by exposure to light, pH, temperature, oxidation, and chemical reactions with other components of the formulations. Tests have shown that, in many commercial cosmetic and pharmaceutical formulations, the actual concentration of active ingredients (e.g., vitamins) rapidly declines over time. This decline in concentration is concomitant with the appearance of the harmful oxidized forms of the initial active ingredient.[2] In general, the instability of bioactive ingredients in products destined for skin care leads to undesirable results in the end product. Examples include: • Undefined physical parameters • Undefined chemical composition • Undefined biological activity • Degradation of other components in the formulation • Shortened shelf-life In order to avoid degradation of the bioactive ingredients and to control their delivery and release onto the skin, controlled drug delivery technology is employed. This technology represents one of the frontier areas of science. It involves a multi-

disciplinary scientific approach, and is instrumental in contributing to bettering human health care.[3] These controlled delivery systems offer numerous advantages when compared to conventional dosage forms. Examples include improved efficacy, reduced toxicity, and better patient compliance, along with improved convenience. Such systems often use macromolecules as carriers for the drugs. By doing so, treatments that would not otherwise be possible are now in conventional use. The field of pharmaceutical technology has grown and diversified rapidly in recent years. Controlled delivery systems usually consist of biopolymers and synthetic polymers used as carriers for drugs. Lack of understanding of current methods of controlled release, and the range of new polymers available, can be a barrier for non-experts. Although the introduction of the first clinical controlled-release systems occurred more than 25 years ago, sales of controlled drug delivery systems in the year 2000, for the U.S. alone, were $13.8 billion.[4] The widespread interest in controlled release systems is expected to result in sales reaching $19.6 billion by 2005. Hence, a brief introduction to the modern aspects of producing controlled delivery systems would be very useful for any expert or would-be-expert in formulations of both pharmaceutical and personal care products. Inserting drugs into a polymer-based device is a common technique. In this approach, drug release is regulated either by diffusion through an external polymer barrier, or by erosion of the polymer matrix.[5]–[7] A wide range of suitable polymers have been synthesized for this purpose.[8][9] In broad terms, such polymers may be classified as either biodegradable (polyesters, polyanhydrides, polyamides), or nonbiodegradable (vinyl-based polymers). In the realm of degradable polymers, there exists yet another level of classification based upon the mechanism of erosion. The term degradation specifically refers to bond cleavage within the polymer coating, whereas the term erosion refers to a physical depletion of the polymer material. In contrast to degradation, which is a chemical process, erosion is a physical phenomenon and reliant on both dissolution and diffusion processes. Within the scope of biodegradable systems, biopolymers, and particularly those in the polysaccharide family (e.g., starch, cellulose, and chitosan), are vigorously being investigated.[8][9]

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES Due to their attractive degradation properties, polymer microcapsules occupy a unique position in the variety of modern controlled delivery systems available.[5][10] Preliminary evaluation of the effectiveness of microcapsules incorporated into final formulations and study of key aspects of formulation development provide important information related to the design of effective systems. This chapter discusses the effects of the formulations and the variations of formulation conditions such as pH, temperature, mixing and pre-mixing rate, and product compatibility, etc.

10.2 Contemporary Microencapsulation Techniques The term microcapsule is defined as a spherical particle varying in size between 1 µm and 1 mm and containing a core substance that is usually bioactive. Microspheres are, in a strict sense, empty spherical containers. However, both terms, microcapsules and microspheres, are often used synonymously. In addition, some other related terms are used as well. For example, microbeads and beads are also used alternatively. Spheres and spherical particles are also terms of art that are employed for microspheres with large size and rigid morphology. The process of microencapsulation offers a variety of advantages, but two of these are the most beneficial. First, microcapsules are capable of protecting unstable (oxidative) substances from degradation processes while providing a means for the controlled release of desired active substances.[5][10] Second, microencapsulation enables the conversion of liquids to powder form. This approach is effective in isolating substances that may react with each other when in contact. Microcapsules usually consist of a polymeric shell (envelope) and an encapsulated active product located within the shell. The polymeric shell is frequently made of a wall-forming material. It serves as a membrane for the encapsulated substance, and thereby provides sustained release capability. Microencapsulation is suitable for drugs, vitamins, and food supplements since the process is easily adaptable by varying the solvents and/or polymers

217

employed in the manufacturing process. Microencapsulation technologies are capable of yielding microcapsules having a desirable size, spherical shape, and surface smoothness. These properties are important for achieving the desired level of controlled release as well as homogenous delivery of stable active substances to the target area. Two main classes of microencapsulation methods have evolved to date—chemical and physical. The first class provides polymerization during the process for preparation of the capsules. Examples in this class are based on interfacial polymerization, or in situ polymerization.[5][10] The second class relies on the controlled precipitation of a polymeric solution, wherein physical changes usually occur.[5]–[10] Classification of the various methods is briefly shown in Table 10.1 and is described in accordance with the large body of published data in this field. Classification is sometimes difficult to describe because specific techniques can be hybrids of two or more methods. Generally speaking, methods of producing nanocapsules are similar; one exception is monomolecular encapsulation by formation of inclusion complexes of cavitands like clathrates formed by cyclodextrins.[11]–[13] In this chapter, we focus on the processes of microencapsulation themselves and exclude such monomolecular encapsulation techniques. The interfacial polymerization technique of microencapsulation involves the condensation of one, or two different monomers at the interface of an organic and aqueous phase. Polyalkylcyanoacrylate[14]–[16] and polyacrylamide[7][17] microcapsules formed from their respective monomers are good examples of such systems. The interfacial polymerization of monomeric surfactants is an advanced method of this type of technique used for the preparation of nanocapsules.[18][19] A water-inwater emulsion technique has been applied by surface cross linking methacrylated dextran by means of radical polymerization of the dextran-bound methacryloyl groups.[20]–[22] This method renders microspheres with a hydrogel-like character. In such systems, the cross-link density of the hydrogel can be controlled by the water content and degree of grafting of the dextran. The resulting hydrogel particles can absorb enormous quantities of active substance, thereby swelling and forming an aqueous environment for diffusion of active from the core.

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Table 10.1. Classification of Microencapsulation Methods

Process

Coating Material

Suspending Medium (External Phase)

Interfacial polymerization

Water-soluble and water-insoluble monomers

Aqueous/organic solvents

Polymerization in bulk

Water-soluble and water-insoluble monomers

Aqueous/organic solvents

Complex coacervation

Water-soluble polyelectrolytes

Water

Simple coacervation

Hydrophobic polymers

Organic solvents

Thermal denaturation (precipitation)

Proteins

Organic solvents

Salting-out

Water-soluble polymers

Water

Solvent evaporation (double emulsion)

Hydrophilic and hydrophobic polymers

Aqueous/organic solvents

Hot melt

Hydrophilic and hydrophobic polymers

Aqueous/organic solvents

Solvent removal (emulsion solvent extraction)

Hydrophilic and hydrophobic polymers

Organic solvents

Spray-drying

Hydrophilic and hydrophobic polymers

Air, nitrogen

Phase separation

Hydrophilic and hydrophobic polymers

Aqueous/organic solvents

Principally new methods of enhancing interfacial polymerization are dendritic encapsulation, and cross-polymerization of allyl methacrylates followed by formation of the spongy-like microparticles. This approach is actually a polymerization of monomers in bulk. The geometric encapsulation of a core moiety by dendritic wedges ideally gives rise to a sphere with a radius determined by the size of the core, as well as the number of dendrons (topologically uniform sectors of dendrimer) surrounding it.[23] Dendritic shielding actually amounts to an encapsulation that can create a distinct microenvironment around the core moiety, hence affecting delivery properties.

types of actives without any chemical reaction. This can be accomplished by freezing and thawing of microdroplets of high molecular polyvinyl alcohol dispersed in oil and suspended in an aqueous external environment. This is then followed by the formation of elastic, porous microparticles that are fixed by a system of H-bonds.[25][26] With this method, both micro- and nanoparticles are obtainable.[27] Desired actives are then loaded into the spongy-like systems through a combination of capillary suction and their affinity for the polymer matrix. Such affinity has been characterized previously by techniques such as solubility parameter, for example.

Crosspolymers can be prepared from allyl methacrylates and other monomers containing allyl groups by suspension polymerization.[19][24] The ability of the obtained spongy-like microparticles to absorb both water-soluble and water-insoluble compounds in the same particle is a unique feature of this technology. Similar spongy-like systems can be prepared for both

Another technique of encapsulation, which uses the complex coacervation process, employs the interaction of two oppositely charged polyelectrolytes in water to form a polymer-rich coating solution called a coacervate.[28]–[30] This solution engulfs the liquid or solid active substance being encapsulated, thereby forming an embryo capsule. Cooling

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

219

the resulting system causes the coating solution to gel via a network formation and the barrier strength of the polymer gel coating can be altered by control of the degree of cross linking. Gelatin is the primary polymer component of most such complex coacervation systems.

potential problem with this process is the possibility of incorporating a relatively high concentration of the salt in the final capsule wall. This is undesirable because of the real menace of diffusion of salt into the formulation along with changing the salt balance and ionic strength.

Simple coacervation, yet another method for microencapsulation, employs the common phenomenon of polymer-polymer incompatibility in order to form microcapsules.[5] The polymer that is to become the capsule wall-forming material is dissolved in a solvent. To the obtained solution, a second polymer, called the phase inducer, is then introduced. Because these two polymers are mutually incompatible, two distinct polymer-rich phases are formed. If a loaded substance is then introduced into this system, one phase, rich in the desired coating polymer, engulfs the active substance being encapsulated, thereby forming the embryo capsules. The formation of chitosan microparticles by phase separation of chitosan from an aqueous solution is a good example of this technique. The separation is triggered by a counterion, or a positively charged macromolecule.[31][32]

In spray drying technology, the evaporation of solvent is achieved by means of a special temperature-controlled cyclone.[31][35][36] This method leads to the formation of good quality beads. However, fairly high temperatures must be applied with this technique and these are not appropriate for unstable active substances.

Preparation of microcapsules by another technique, called “precipitation,” has many variations. One of them includes the precipitation of watersoluble polymers such as gelatin, with water-miscible solvents such as isopropanol. Other examples of this method include the precipitation of ethyl cellulose from cyclohexane by cooling, the gelation of sodium alginate with aqueous calcium salt solutions,[33][34] and thermally induced precipitation of a protein to form microspheres. In all such cases, the objective is to precipitate the preformed polymer around the core. Although useful for certain applications, this method has a deficiency in that the capsules obtained in the coacervation technique are made of a water-permeable material (e.g., polysaccharides, alginate gel, and gelatin). Unfortunately, these polymers do not prevent diffusion into and out of the capsule in a cosmetic formulation. As a result of this deficiency, oxidation of active ingredients is not completely prevented in water-based formulations. The salting-out technique of preparing microcapsules involves the addition of a salt to an aqueous polymer solution thereby ultimately causing the polymer to phase-separate from the solution.[5] One

Phase separation is a new method of encapsulation. It involves a one-step precipitation of two polymers, or more then the two, and produces doublewalled microspheres.[37] Solvent evaporation[33][35]–[43] is the most popular way to accomplish encapsulation. In this method, core material, and a capsule wall-forming material are both dissolved into a water-immiscible volatile organic solvent. The resulting solution is then emulsified in an aqueous solution. The solvent is allowed to evaporate, thereby producing solid capsules or particles. Another version of this process involves the formation of a double emulsion wherein an aqueous solution of core material is first emulsified in a volatile, somewhat polar, organic solvent solution of polymer.[40] The resulting water-in-oil emulsion is then emulsified in water thereby generating a double emulsion (i.e., water-in-oil-in-water). Evaporation of the volatile solvent then yields a solid microcapsule with an aqueous core.[44] In a modified version of the solvent evaporation method, a water-soluble solvent such as acetone or methanol, along with a water-insoluble solvent, like dichloromethane or chloroform, have been used as the oil phase.[45][46] Due to the spontaneous diffusion of the water-soluble solvent, an interfacial turbulence is created between two phases. This process leads to the formation of considerably smaller particles. In order to avoid the use of chlorinated and other organic solvents throughout the encapsulation process, the hot-melt encapsulation technique was developed.[47] In contrast with the solvent evaporation technique, a modification of this method was developed that employed the use of organic solvents as the extracting medium.[48] In general, physicochemi-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

cal principles of phase separation and wall formation by both of these approaches are the same. However, the method of solvent removal differs considerably from that of the hot melt technique. Solvent removal techniques provide milder conditions for solvent extraction and this protects unstable active substances from destruction. The solvent removal method technique is widely used for the encapsulation of the water-insoluble drugs, vitamins, and oils within envelopes of waterinsoluble polymers.[49][50] Generally, in such a process, the desired polymer is first dissolved in a suitable organic solvent. This action is followed by the addition of the active substance to be encapsulated. The active is either dissolved or dispersed in the organic solvent. The resulting organic solution/dispersion is then dispersed into an aqueous phase. This results in the formation of an oil-in-water emulsion wherein oily microparticles are dispersed in the aqueous phase. Upon complete removal of the solvent from the microparticles by means of extraction, the walls of the microcapsules are consolidated, and microcapsules formed. A basic prerequisite for the solvent removal method is the use of a solvent that is able to efficiently dissolve the active substance to be encapsulated as well as the wall-forming material.[5][10] This solvent has to be only partially soluble in water, thereby giving rise to emulsification of an organic phase in the continuous aqueous phase. Chlorinated solvents such as dichloromethane, chloroform, or their mixtures with other solvents are widely used since they facilitate the microencapsulation process. In view of the well-known toxicity of such chlorinated solvents, all the microencapsulation technologies based on chlorinated solvent systems are not applicable for food, cosmetic, and pharmaceutical applications. The toxicity properties of the solvents do prevent microcapsules made by this method from meeting FDA and other regulations since residual amounts of chlorinated solvents may be retained in the microcapsules. Simple vacuum or heat drying does not sufficiently lower any such chlorinated solvent content. Therefore, it has been essential to improve upon the chlorinated solvent method in order to encapsulate vitamins, food supplements, oils, or pharmaceutical agents.

10.3 Preparation of Microcapsules for Skin Applications The solvent removal technique requires use of a solvent that can efficiently dissolve both the active substance to be encapsulated and the wall-forming material. This solvent must also be only partially soluble in water thereby giving rise to emulsification of the organic phase in a continuous water phase. While prior solvent removal methods rely on the use of chlorinated solvents to meet these requirements, the use of chlorinated solvent impurities is problematic, as discussed above. Based on the development of an innovative modification of the solvent removal technique, Tagra Biotechnologies, Ltd., has developed novel microencapsulated products for skin applications.[51] This technology uses non-chlorinated solvents and, therefore, can be universally applied for the stabilization of both the degradable oil-soluble and oil-dispersible active compounds employed in the cosmetic and pharmaceutical industries. The method is far superior to prior art processes based upon the use of toxic and, therefore, undesirable solvents. Tagra’s innovative modification of the solvent removal technology consists of the following four stages. Stage 1: Preparation of emulsion. An emulsion is produced from two phases: an organic phase, which includes the active ingredient, polymers, plasticizers, etc., and an aqueous phase, which includes emulsifiers, preservatives, etc. Mixing or homogenizing the organic and aqueous phases forms an emulsion. The size of droplets in this emulsion depends on a variety of mixing conditions. These include, primarily, the geometry of the reactor, the temperature, and the equilibrium that develops between the two phases. This method provides good control of droplet size and is capable of producing capsules with a defined size ranging from 10 µm to 200 µm. Stage 2: Extraction. The liquid droplets obtained in the first stage of the process are composed of the active component entrapped in a thin layer of a polymer that has been dissolved in the organic solvent. By means of extraction, the organic solvent is removed from the liquid droplets. It is then collected

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

10.4 Microencapsulation of Unstable Lipophilic Actives

within a coexisting second phase that is formed by water or a mixture of different solvents. The polymer hardens during the extraction process and envelops the capsules thereby forming a thin solid wall surrounding the bioactive core.

It has been estimated that almost $2 billion worth of vitamins are consumed by the cosmetic, pharmaceutical, and food industries today.[1] Thus, there is a widespread need for the effective incorporation of vitamins such as A, E, and F (essential unsaturated fatty acids) into cosmetic, personal care, and dermatological formulations.

Stage 3: Separation. At this stage, separation of the soft capsules from the suspension takes place. Special equipment is used for this process because the capsules are fragile at this stage and can be easily destroyed. The resulting capsules are then filtered, and washed with water to remove any remains of solvents, emulsifiers, etc. A wet bulk batch of capsules is thereby obtained.

Of the bioactive ingredients that are employed in the cosmetic industry, vitamin A is among the most popular.[52][55] This is a ubiquitous anti-aging and antiacne active agent that is also a skin nutrient agent. However, it must be noted that all the compounds that have a vitamin A activity, such as retinol, retinal, retinoic acid, retinol palmitate, and others, are unstable and extremely sensitive to the high temperatures and exposure to light. The oxidized forms of these molecules do not possess the initial biological activity and have a negative effect on the skin, which can result in irritation. By contrast to the free form of vitamin A, its microencapsulated version, Tagravit A, provides the skin with stable vitamin A in its active form. Thus, Tagravit A prevents the oxidation of vitamin A and eliminates skin irritation.

Stage 4: Drying. The nature of the active ingredients employed determines the specific process parameters to be used during the drying stage. For example, if vitamins are used, which are unstable at high temperatures, the process is carried out at a temperature that does not exceed 20°C. The drying processes are performed under appropriate conditions with special equipment. While drying, the capsules harden and thereby become a free-flowing powder which is then sifted. Typical microphotographs of microcapsules containing vitamin A (Tagravit™ A), or Hippophae oil (Tagravit™ H) are shown in Fig. 10.1a and b. The microcapsules are spherical and have an average diameter of 40 µm and a narrow size distribution. A scanning electron micrograph (SEM) of a fractured Tagravit™ microcapsule, shown in Fig 10.1c, clearly demonstrates its shell morphology.

(a)

221

Vitamin E (α-tocopherol) is the well-known antioxidant and anti-aging agent that scavenges free radicals and thereby provides cell membrane protection.[52]–[54][56] Vitamin E is readily absorbed by the skin and exerts a wide range of activities in the

(b)

(c)

Figure 10.1 Representative microphotographs of microcapsules containing: (a) retinol palmitate, Tagravit™ A, 750× magnification, or (b) Hippophae oil, Tagrol™ H, 100× magnification, and (c) SEM of a fractured Tagravit™ microcapsule, 3,000x magnification.

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epidermis. It significantly reduces wrinkle amplitude and skin roughness. Vitamin E enhances blood circulation in the skin by reducing platelet adhesion and stimulating the formation of certain prostaglandins. It inhibits lipase, which is responsible for releasing arachidonic acid (precursor for inflammatory eicosanids such as leukotrien B4) from the cell membrane. This vitamin also has a beneficial effect on the water retention properties of the skin. However, with all of these potential benefits, vitamin E is well known to degrade rapidly in cosmetic formulations and induce undesirable pro-oxidant activity. By contrast to free form of vitamin E, its microencapsulated form, Tagravit E, allows the vitamin E to retain its antioxidant and anti-aging activity on the skin, as well as to provide protection of cell membranes. Additionally, Tagravit E prevents the formation of prooxidant derivatives. Vitamin F is a group of essential fatty acids, EFA, (polyenoic acids) that promote growth and good health.[52][55] EFA is a generic term which historically has been applied to both the linoleate- and linolenoate-type of organic acids. Vitamin F is, however, highly unstable due to the existence of double bonds in these molecules. These molecular zones of unsaturation are sensitive to oxidation, especially when vitamin F is incorporated into cosmetic formulations. The oxidation of vitamin F in formulated personal care products causes a loss of activity, and a distinct malodor. By contrast with the neat form of vitamin F, its microencapsulated form Tagravit F contains a stable form of both the linoleic and linolenic acids and provides an active and odorless system of EFA. Vitamins A, E, and F may be used in the restructuring of skin, and in both skin and hair care products for treating phenomena related to aging, hyperpigmentation, skin dryness or skin disease, etc. As mentioned previously, these vitamins are highly unstable in solution. They are sensitive to various factors that result in their rapid decomposition and loss of biological activity. Since the resulting decomposition products have negative biological effects, encapsulation of these vitamins protects them and retains their biological efficacy. In order to achieve the benefits of encapsulation, it is essential to produce such vitamin-containing microcapsules of vitamins A, E, and F without any traces of harmful solvents. It is equally important to guarantee the effec-

tive, controlled release of these active components from the microcapsules onto the skin during the application of products formulated with them. Tagra Biotechnologies, Ltd., has developed a powerful new method of providing stability, efficacy, and controlled release properties for vitamins and other active ingredients. This method allows production of microencapsulated actives that conform to global cosmetic industry regulations. It has been found that Tagra’s microencapsulated vitamins (Tagravit A, E, and F) are ideally suitable for use in topical and dermal treatments. In response to the growing demand for such high performance and stable ingredients, Tagra’s technology offers both formulators and consumers several distinct advantages:[51] • The technology may be applied for the protection of water-insoluble compounds. • It provides a significant increase in stability of the active ingredient. • Microcapsules are similar in size and shape. • Microcapsules may be homogeneously dispersed in all types of formulations. • Microcapsules are not destroyed in the course of the mixing processes typically employed during incorporation into formulations. • The microcapsular system provides controlled release of actives. Microcapsule walls are made using a proprietary type of polymer. This polymer provides a rigid barrier for the first seventy-two hours in a waterbased formulation. This allows the microcapsules to remain rigid and not be broken down during their incorporation into a formulation. After this period, the polymer membrane becomes plastic and soft. As a result of this transformation, it is only when applying the end product to the skin that the microcapsules collapse and thereby release 95%–97% of the active ingredients onto the target area. • All the materials used in Tagra’s technology are CTFA approved (Table 10.2).[57] Besides the effective encapsulation of vitamins, Tagra also produces high quality, stable, microencapsulated natural oils using similar technology.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

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Table 10.2. CTFA Names and Numbers of Ingredients Used in Formulations of Tagravit™ A, E, and F[57]

Product

Cas No.:

EINECS No.:

Retinol palmitate

79-81-2

201-228-5

Tricaprylin

538-23-8

208-686-5

BHT

128-37-0

204-881-4

Poly(methyl methacrylate)

9011-14-7

-

Tocopherol

2074-53-5

218-197-9

Poly(methyl methacrylate)

9011-14-7

-

BHA

2513-16-5

246-536-8

Tricaprylin

538-23-8

208-686-5

Linoleic acid

60-33-3

200-470-9

Linolenic acid

463-40-1

207-334-8

Poly(methyl methacrylate)

9011-14-7

-

BHA

2513-16-5

246-536-8

Mineral oil

8012-95-1

232-384-2

Tagravit™ A

Tagravit™ E

Tagravit™ F

These oils include Evening Primrose, Borage, and Hippophae oils. This product line is known as Tagrol™ and is useful for personal care, cosmetic, and dermal applications. Tagrol microencapsulated oils offer the advantage of significantly increasing shelf-life of essential oils in personal care products and maintaining the oils’ original efficacies. They also prevent oxidation of unstable compounds and generation of malodor.

10.5 Stability Determination of Microencapsulated Vitamins in Various Formulations Stability of vitamins protected by Tagra microcapsules incorporated into various creams and gels was characterized via a HPLC method described previously in Ref. 51. A condensed description of this method of analysis is shown below.

Twenty milligrams of standard retinol palmitate (Fluka), α-tocopherol (Sigma), or mixture of linoleic and linolenic acids (Aldrich) were weighed in a 100ml volumetric flask, and 5 ml of dichloromethane (HPLC grade) were added as a solvent. A flask was then filled up to a level mark with methanol (HPLC grade). One milliliter of this solution was then transferred and mixed in a 10-ml volumetric flask filled with methanol. Prepared solutions were used as standards. In order to extract active ingredients either from microcapsules or formulations, 0.2 g of analyzed microcapsules or 2.0 g of each selected formulation were weighed in a 15-ml centrifuge tube, and 5 ml of dichloromethane were then added. The system was mixed thoroughly for two minutes in order to enable the extraction of actives. The resulting phases were then separated by centrifugation (5 min, 6,000 rpm). The lower phase was transferred to a 25-ml volumetric flask and the extraction process was then repeated. The dichloromethane phases were thereafter combined in the 25-ml volumetric flask and filled up to the level mark with methanol.

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An HPLC analysis was performed at 25°C with a Knauer C-18 column (25 cm, diameter 4 mm) by means of HPLC Jasco Pump PU-1580 instrument. The flow rate for the isocratic system was 1 ml/ min. Model phases applied were as follows: retinol palmitate—75% methanol/25% THF; α-tocopherol—100% methanol; EFA—95% methanol/5% of 0.1% solution of phosphoric acid. Both the standard and sample solutions were sequentially injected in an amount of 20 µl each. The resulting peak areas were then measured with a UV detector, UV-975, at 330 nm for retinol palmitate, 279 nm for α-tocopherol, and 204 nm for EFA.

10.6 Model Formulations Developed for Stability Testing of Tagravit™ Microencapsulated Products 10.6.1 Stability Variables Several sets of model formulations were developed. These were designed to investigate the effect of their composition on the stability of encapsulated vitamins A, E, and F and compare them to performance in their free (non-encapsulated) states. A number of independent variables were studied. Oil-phase concentration. The oil-phase concentration (i.e., the percent of the oil-phase ingredients relative to the total content of all ingredients) was varied. The oil-phase ingredients and their ratios kept constant. Formulation ingredients. The type of oil phase was varied while the total oil-phase percentage was kept constant. Oil-in-water versus water-in-oil emulsions. Various types of emulsions were investigated. These included oil-in-water (o/w) type as well as waterin-oil (w/o) type emulsions. The percentage of oil in both types of emulsion was kept constant. Formulation pH and viscosity. The pH of formulations that did not contain the oil phase (i.e., gels) was varied in a range between 4.0 and 7.5. Result-

ing viscosity of the formulations varied between 1,000 and 20,000 cP as measured by a Brookfield viscometer at 6 rpm. Oil-soluble ingredients. The presence or absence of an oil phase in the formulation was compared. A comparison was also made between a gel which had no oil phase, and an emulsion of silicone oil.

10.6.2

Effects of Stability Variables

Investigations of Tagravit A, Tagravit E, and Tagravit F in various model formulations (Formulations 10.1–10.12 at the end of this chapter) served as a guide to enable optimization of the formulation’s composition. Effect of varying oil phase concentration (Formulations 10.1 – 10.4). This set included four formulations consisting of 32 similar components. While the composition of the oil phase was kept constant, the total percent of the oil-soluble components in Formulations 10.1–10.4 was varied and included 12, 24, 32, and 40 wt%, respectively. Test results enabled conclusions to be drawn regarding the influence of the oil phase constituent on vitamin stability in oil-in-water emulsion-based formulations. Results provided guidelines for the use of encapsulated vitamins, the desirable content of microcapsules in formulations, and optimal parameters of microcapsules such as composition, size, and active substance content. Conclusions drawn during these tests were also important for determining the optimal formulation recommendations for final products. For example, formulations with a higher oil-phase percentage (32– 40 wt%) are recommended for use in products for very dry skin and specific areas of the body (e.g., feet and hand protection creams). These products are useful in world regions with a cold climate, and are therefore widely popular in most European markets. By contrast, formulations with a low oil-phase percentage (up to 20 wt%) are primarily used for baby and teenager cosmetics, in hair products, makeup-removers, and decorative cosmetics. Low oil-content products are found to be preferable in countries having a hot and wet climate such as Mediterranean basin, and the Far East, etc.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES Effect of formulation ingredients. This set included four model formulations (Formulations 10.1, 10.5–10.7). The overall percentage of the oil-phase ingredients was kept constant (12 wt%), but the type of ingredients, and their composition, was varied (see compositions of Formulations 10.1, 10.5, 10.6 and 10.7). Tests performed with this set of model formulations established the impact of formulation ingredients on vitamin stability. These tests allowed conclusions to be drawn as to preferable ingredients and also enabled identification of undesirable ones for further formulation development. For example, addition of α-tocopherol as an antioxidant for an oil phase in Formulation 10.5 significantly decreased the stability of vitamin A. On the other hand, a high content of dimethicone (12 wt%) in Formulation 10.7 had no effect on stability of vitamin A. This set of experiments established that composition of the oil phase affects the physical properties of the obtained formulations: texture, velocity of absorption, formation of a protecting film on the skin, etc. Moreover, certain principles of the formulation design and the use of various ingredients were seen to be specific and applicable to certain regional markets. The main goal of the investigation of this formulation set was to determine the formulation ingredients that affected the stability of the encapsulated vitamins. Negative effects on vitamin stability generally occurred by one of two mechanisms: (a) extraction into the formulation, or (b) radical oxidation of an active ingredient because of a pro-oxidative action. Comparison of oil-in-water and water-in-oil emulsions containing equal amounts of oil phase (Formulations 10.4 and 10.12). This set of experiments consisted of two formulations, each of which contained 40 wt% of the oil-phase constituent. The formulations represented comparison of two types of common emulsions: oil-in-water (o/w), Formulation 10.4, and water-in-oil (w/o), Formulation 10.12. This comparison resulted in guidelines for the optimal use of Tagravit encapsulated actives. Conclusions were drawn not only for their use in traditional products such as baby hygiene, cosmetics, and sunscreen products, but also in products for hypersensitive, dry, and withered skin. Useful data also emerged as to optimal use for selected regions of the skin, e.g., eyelids.

225

Influence of pH and viscosity on stability of encapsulated versus non-encapsulated vitamins (Formulations 10.8–10.10). This experimental set included three model gel formulations with various pH and viscosity characteristics, as follows. Formulation

Gel

pH

Viscosity, cP

Formulation 10.8

1

6.0–7.0 15,000–20,000

Formulation 10.9

2

4.0–4.5

Formulation 10.10

3

7.2–7.5 10,000–10,500

1,000–1,500

The purpose of comparing this set of three gels was to study the influence of pH of the external medium on the stability of non-encapsulated and encapsulated vitamins. It also enabled choice of the most effective protection factors for vitamins over a wide range of pH. The pH variation is important, for example, in systems containing α-hydroxy acids. These are used in formulations for peeling and anti-acne cosmetics and typically have a pH in the range of 3.5 to 4.5. On the other hand, the pH of depilatory products equals or even exceeds 7.5. Usually, the functional effect of such products is accompanied by various undesirable side effects such as irritation and damage to the skin. However, these helpful actives are generally degraded in alkaline media. This set of data also allowed some comparison of the effect of viscosity variation in formulations containing microcapsules. For example, the model Formulation 10.9, with a low viscosity, corresponds to the viscosity of typical hair products (e.g., shampoos, conditioners) as well as to that of body lotions and face cleaning lotions. Formulations 10.8 and 10.10, with a particularly high viscosity, correspond to products used for face and hair masks and to certain kinds of functional creams and products for depilation. Effect of oil-soluble ingredients on stability of encapsulated and non-encapsulated vitamins (Formulations 10.7 and 10.11). Two model formulations, an oil-in-water emulsion (Formulation 10.7) and a skin gel (Formulation 10.11) were investigated. This comparison was useful to clarify the effect of various oil-soluble ingredients on the stability of both encapsulated and non-encapsulated vitamins. Formulation 10.7 contained silicone oil as an inert oil phase. Comparison of microcapsules stored in the silicone oil (at a concentration of 50 wt% microcapsules in oil dispersion) with microcapsules

226

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

stored in a powder form (microcapsules themselves) showed identical stability. Homogeneity of the microcapsule distribution in formulations was studied just after their incorporation, as well as during their storage at 25°C. The viscosity of these two formulations was found to be almost the same (3,000– 4,000 cP). It was also found that the initial homogeneous distribution of microcapsules in the formulations, after a one-year storage period, remained unchanged.

10.7 Effect of Formulation on Stability of Microencapsulated Vitamins Formulation composition and preparation conditions for various creams, gels, and other cosmetic forms can affect the stability with respect to oxidation of incorporated microencapsulated vitamins. These factors may either decrease, or even increase, this stability in some instances.[58]–[60] The effect of formulation variables was studied by comparing the use of Tagravit A containing retinol palmitate, Tagravit E containing α-tocopherol, and Tagravit F containing a mixture of linoleic and linolenic acids. These studies addressed and answered several important questions: • Does encapsulation increase stability of active ingredients in various formulations? • Is the stability of Tagravit microcapsules affected by formulation composition? • Is the stability of Tagravit microcapsules affected by microcapsule composition variables such as the presence and kind of plasticizer in the microcapsular wall, and the amount of encapsulated active ingredient? • Does the stability of Tagravit microcapsules depend on their concentration in the formulation? These questions were addressed by comparing results obtained with the model oil-in-water emulsion formulations (Formulations 10.1–10.7), gels 1–3 (Formulations 10.8–10.10), skin gel (Formulation 10.11), and water-in-silicone oil emulsions (Formulation 10.12). Each of these is described in detail

in the Model Formulations section (Formulations 10.1–10.12).

10.7.1

Increased Stability of Microencapsulated Retinol Palmitate

Figure 10.2 demonstrates the increased stability of the microencapsulated form of retinol palmitate, Tagravit A (shown in Fig. 10.1a), in comparison with the non-encapsulated retinol palmitate, both incorporated into creams (Formulations 10.1–10.4). This experimental set shows that, in general, the half-life (a period measuring 50% degradation) of Tagravit A was significantly increased and was more then one order of magnitude longer than the non-encapsulated retinol palmitate. The ratio of half-life periods, calculated for the encapsulated to the non-encapsulated active substance, is called the protection factor. This protection factor depends on the parameters of the test system including formulation composition, vitamin concentration, test conditions, etc. Testing was performed in darkness at 40°C. The final concentration of the non-encapsulated retinol palmitate, as well as retinol palmitate introduced as Tagravit A in various formulations, was identical, 0.1 wt%. Figure 10.2 shows that increasing the content of the oil phase (in creams) leads to an increase of the protection factor. At oil-phase concentrations of 12, 24, 32, and 40 wt%, the following protection factors resulted, respectively, 10, 16, 42, and 32. Thus, we can conclude that the stability of the microencapsulated retinol palmitate, Tagravit A, increases with increasing the oil-phase content in the formulation up to about 32 wt%.

10.7.2

Increased Stability of Microencapsulated α αTocopherol

A stabilization effect similar to that obtained with retinol palmitate was also observed with microencapsulated α-tocopherol, Tagravit E, formulated in gels 1–3 (Formulations 10.8–10.10) as demonstrated in Fig. 10.3. It is seen that even after seven months of storage at 40°C, the remaining amount of α-tocopherol in gel-formulated microcapsules did not fall

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

227

Detected amount of retinol palmitate (remained %wt

100 90 80 70 c

60 50 b

40 30 20 c,d

a

10 0 0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

Days

Figure 10.2 Comparison of the degradation kinetics of retinol palmitate (RP) (the remaining amount of retinol palmitate was measured) encapsulated in Tagravit A (– – –) vs non-encapsulated retinol palmitate (––––) at 40°C, formulated in Formulations 10.1–10.4 with the oil-phase content of 12%, Formulation 10.1, (a, diamonds), 24 %, Formulation 10.2, (b, circles), 32%, Formulation 10.3, (c, squares), and 40%, Formulation 10.4, (d, triangles).

Detected amount of α -tocopherol (remained %)

100 90 80 70 60 50 40 30 20 10 0 0

20

40

60

80

100

120

140

160

180

200

220

Days Figure 10.3 Comparison of the degradation kinetics of α-tocopherol (the remaining amount of α-tocopherol was measured) encapsulated in Tagravit E (– – –) vs non-encapsulated α-tocopherol (––––) at 40°C, formulated in gels 1 (circles), 2 (triangles), and 3 (diamonds).

228

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS (Fig. 10.5a) to 40°C (Fig. 10.5b) leads to a dramatic degradation of retinol palmitate for all formulations except Formulations 10.4 and 10.7. The latter two formulations showed a very low stability of the nonencapsulated retinol palmitate over range of temperatures investigated. Retinol palmitate was found to be more stable in the skin gel. This is not surprising since it was incorporated into a water-in-oil emulsion system, which has a limited ability to dissolve air oxygen. Investigations of changing the oil-phase content in the formulation set A showed that the optimal level of oil phase for non-encapsulated retinol palmitate was in the range of 12–24 wt% (Formulations 10.1 and 10.2).

bellow 80%–90% of the initial value. This conclusion was the same for variations in pH of media in the range of 4.0–7.5 and in gels with viscosity in the range of 1,000–20,000 cP. At the same time, the half-life in the non-encapsulated α-tocopherol was much shorter, and lasted only 5–22 days for gels 1– 3 (Formulations 10.8–10.10).

10.7.3

Increased Stability of Microencapsulated Vitamin F

Figure 10.4 demonstrates the degradation process of vitamin F (mixture of linoleic and linolenic acids) in cream (Formulation 10.7) and skin gel (Formulation 10.11) model formulations at 40°C. In this case, it is seen that the protection factor of encapsulated form Tagravit F was 10.5 times higher than of non-encapsulated vitamin F for both cream and gel formulations.

10.7.4

Effect of Plasticizers in the Microcapsular Wall on Stability of Active

Effects of introduction of a plasticizer into the microcapsular wall are depicted in Fig. 10.6. It is clearly seen that the protection factor of retinol palmitate increases in the plasticizers’ order as follows: ipropylmyristate (c), tricaprylin (b), paraffin oil (a). An increase of the retinol palmitate loading into microcapsules from 6 wt% to 13 wt% (with application of tricaprylin as plasticizer) leads to a decrease

In order to estimate the influence of formulation and temperature of exposure on vitamin stability, the non-encapsulated retinol palmitate was formulated in the formulation set A (Formulations 10.1 – 10.4 with various content of the oil phase), B (Formulation 10.5), C (Formulation 10.6), D (Formulation 10.7), and skin gel (Formulation 10.11). Figure 10.5 shows that increasing the temperature from 25°C

Detected amount of vitamin F (remained %)

' & % $

=

#

>

" !

>

=

0

40

80

120

160

200

240

280

320

360

Days

Figure 10.4 Comparison of the degradation kinetics of vitamin F (the remaining amount of the sum linoleic and linolenic acids was measured) encapsulated in Tagravit F (– – –) vs non-encapsulated vitamin F (––––) at 40°C, formulated in cream Formulation 10.7 (circles) and skin gel (triangles).

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

229

70 68

60

50 45

42

Days

40

30

20 31

20

10

18

12

5

5

5

10

5

10 5 5

0

12%B

12%C

12%D

5

a 12%A

24%A

b

32%A

40%A

Skin gel

Figure 10.5 Half-life of non-encapsulated retinol palmitate incorporated in various formulations (see caption of Fig. 10.2) at (a) 25°C and (b) 40°C.

40

Protection Factor

30

20

10

a

0

b 12%B

12%C

12%D

c 12%A

24%A

32%A

d 40%A

Gel

Figure 10.6 Protection factor at 40°C of retinol palmitate (RP) encapsulated in Tagravit™ microcapsules that differ by type of plasticizer after introduction into Formulations 10.1–10.4 (12%, 24%, 32%, and 40% of the oil phase), Formulations 10.5–10.7 (12% of the oil phase), and skin gel; a: paraffin oil (Tagravit A, 6% retinol palmitate in microcapsules), b: tricaprylin (Tagravit A, 6% retinol palmitate in microcapsules), c: i-propylmyristat (Tagravit A, 6% retinol palmitate in microcapsules), and d: tricaprylin (Tagravit A, 13% retinol palmitate in microcapsules).

230

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 10.7.5

in stability (Fig. 10.6, graphs b and d). Figure 10.6 also shows that the protection factor of retinol palmitate depends on the amount of oil phase in a given formulation. For example, the optimal content of the oil phase in the formulation set A provided maximal oxidative stability of 32 wt% for all the tested plasticizers. In general, the same conclusion could be drawn for the other cream formulations B (Formulation 10.5), C (Formulation 10.6) and D (Formulation 10.7). As is seen in Fig. 10.6, the protection factor of retinol palmitate in microcapsules incorporated into gel is significantly lower then in cream formulations A. Surprisingly, an application of the reverse emulsions of the water/silicone-oil type (not shown in Fig. 10.6) increases stability of the encapsulated retinol palmitate significantly.

Effect of Loaded Amount of Encapsulated Retinol Palmitate on its Stability in Formulation

It was of interest to determine whether the loaded amount of encapsulated retinol palmitate affects its resistance to oxidation after being incorporated into a formulation. This experiment was performed with Tagravit A containing tricaprylin as a plasticizer. Figure 10.7 shows that increasing the loading of the encapsulated retinol palmitate, from 0.17 to 0.55 wt%, into Formulation 10.2 leads to a significant decrease of stability. The protection factor of retinol palmitate increases only by a factor of 1.6 if a twofold decrease in the content of retinol palmitate in microcapsules occurs (Fig. 10.6). This suggests that increasing the retinol palmitate content by increasing its loading in the microcapsules,

9.5

10 9

7.8

8 5.6

Protection Factor

7 6

5.7

4.8

5 4

3.8

3

0.17%

2

0.28%

1 0

0.55% A2 6%RP 24%A

A2 13%RP 24%A

Figure 10.7 Protection factor at 40°C of retinol palmitate (RP) encapsulated in Tagravit™ A in amount of 6% and 13% (containing tricaprylin as plasticizer) incorporated into the cream Formulation 10.2 (24% of the oil phase) with the various final concentrations of retinol palmitate in creams, 0.17 %, 0.28 % and 0.55 %.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES or increasing the concentration of microcapsules with retinol palmitate in a formulation, leads to the same effect. It is believed that the stability of retinol palmitate declines, in both cases, for two reasons. First, the total surface area of the microcapsules increases through swelling or by increasing their number. This results in an increase of the probability of penetration by the contained oxidizing agents inside the microcapsules. Second, increasing the retinol palmitate content in an individual microcapsule may lead to an accumulation of undesirable products of oxidation in the closed volumes of microcapsules (cage effect). This promotes a destructive auto-oxidation mechanism for the retinol palmitate. We conclude that compartmentalization of non-stable active substances in smaller microcapsules, as in the case of microcapsules containing 6 wt% of retinol palmitate, is an optimal way of providing additional antioxidant stability for the active substance. In summary, we point out that microencapsulation of vitamins A, E and F improves their resistance to oxidative degradation in the various selected formulations. Stability of the encapsulated retinol palmitate increases with the increasing oil-phase content in oil-in-water emulsion formulations, and is optimal at 32 wt%. Paraffin oil is an optimal plasticizer for the microcapsular wall, since it provides a sufficient retinol palmitate stability level. Stability of encapsulated retinol palmitate decreases when increasing its concentration in a formulation. It is suggested that compartmentalization of any non-stable active substance into smaller microcapsules can provide its additional stabilization. Taking into account all of the above-mentioned factors will guarantee a high stability of formulated microcapsules containing bioactive compounds that are sensitive to oxidation.

10.8 Incorporation of Tagravit/ Tagrol™ Microcapsules into Cosmetic Formulations 10.8.1

Basic Principles

All the products of the Tagravit/Tagrol line have been designed to be solid, powdered materials since

231

this physical state is of great benefit to formulators. In general, the incorporation of active ingredients (vitamins, essential fatty acids, caratenoids) into formulations presents a significant challenge. This is so because all the above-mentioned active ingredients are oil-soluble. Therefore, providing a homogeneous distribution of hydrophobic actives in formulations is typically problematic regarding both preparation and storage. Further, these active ingredients are generally heat-sensitive, and their incorporation into a formulation may only be carried out at temperatures which do not exceed 40°C–50°C. As a consequence, one cannot be certain that actives in the resulting formulation will retain the desired physical and chemical stability. In view of these issues, a powder form of active ingredients is certainly advantageous. This study revealed that microcapsules containing vitamins or natural oils in powder form (i.e., Tagravit/ Tagrol) can be homogeneously dispersed in many common cosmetic formulations such as creams, gels, lotions, etc. In low-viscosity formulations such as shampoos, the use of a suspension aid, or rheology modifier, may be required to insure homogeneous dispersion and long term stability relative to undesirable sedimentation. The stability of the encapsulated active ingredients studied is independent of pH, and Tagravits/ Tagrols can be used in formulations ranging in pH from 2 to 10. This result allows Tagravit/Tagrol microcapsules to be used, for example, with high pH formulations typically employed for peeling and depilation creams. This solution to the problem of stability in high pH media is a powerful new tool for the incorporation of active ingredients such as antioxidants and regenerating agents in the manufacturing of such products. It was established that emulsifiers, inorganic ions, and surfactants do not affect the stability of Tagravit/ Tagrol in formulations. This fact is essential for the design of new products incorporating novel active ingredients. As an example, cosmetic products for makeup contain large amount of salts that are typically able to dissociate and produce metal cations of variable affinity (so-called d-elements, e.g., iron, cobalt, nickel, copper). These cations are able to catalyze redox reactions, thereby resulting in the chemical degradation of active ingredients. On the other hand, the development of multifunctional products, such as makeup compositions with vitamins,

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

can be regarded as a fruitful line of inquiry in this branch of cosmetics when Tagravit/Tagrol microcapsules are employed. Such undesirable situations exist in formulations containing high concentrations of surfactants (e.g., soaps, body washes, and hair rinse aids). The use of Tagravit/Tagrol microencapsulated actives enhances the function of such products and insures stability of active ingredients. Use of Tagravit/Tagrol must be carefully evaluated for any new application.

solvents. It is also useful around the eyes as a makeup remover. The majority of typical prior-art formulations used in wet-tissue production differs fundamentally from Formulation 10.17 because they are prepared in the form of lotions which contain solvents. The main advantage of Formulation 10.17 is that it provides both a possibility for adjusting the parameters of the microcapsules used and the formulation itself, applicable to the wet tissue production equipment.

Since the barrier envelope of the microcapsule is formed by a thin layer of polymer, release of the active substance from the microcapsule into a formulation can occur if high enough concentrations of solvents such as ethanol, propylene glycol (more than 10%), allyl alcohol (as a fragrance solvent), and others are used. It is strongly recommended, therefore, that the use of such undesirable components be minimized or eliminated in formulations containing Tagravit/Tagrol microcapsules. As always, experimental determination of formulation stability should be carried out by appropriate analytical methods to provide proof of retained efficacy.

The specific functionality of an active ingredient can be provided. As an example, Formulation 10.15 provides a regenerative action after a depilation stress on the skin by high pH systems. This approach requires the use of antioxidants (Tagravit E, Tagrol B, Tagrol EPO) as well as use of a regenerative agent (Tagrol H). A synergistic action of active components is supplied by the combination of vitamins recommended. For example, the combination of encapsulated vitamins A and E increases efficiency on skin by providing an anti-aging complex as described by use of Formulation 10.14 for neck and eye creams.

As a result of studies on model formulations (Formulations 10.1–10.12) containing Tagravit/Tagrol microcapsules we have identified commercially useful formulations with high stability (Formulations 10.13– 10.18) and recommended them for use in various areas of cosmetics and personal care products. Some of these formulations are described below. These systems are ingenious and novel in the following aspects.

The choice of components in a formulation is of high importance. The main criteria for choice of ingredients used in the recommended formulations were their availability, and permission for use. Frequently used components, as well as the International regulatory aspects were also taken into consideration. For example, a number of complementary active components (panthenol, allantoin, zinc oxide) and a variety of softening compounds (beeswax, Shea butter, octyl palmitate) were used in the preparation of Formulation 10.16 for baby cream. As a result, this formulation is in full accordance with the contemporary international requirements for baby care products. Formulation 10.13 meets all current requirements in the field of sun protection products. It provides multifunctional benefits such as high SPF (through the presence of sunscreen agents), soothing properties, and a flow behavior suitable for high absorption.

Useful for a wide range of products. Tagravit/ Tagrol microcapsules are useful for the manufacture of a wide range of end products such as hair care (Formulation 10.18), wet tissues (Formulation 10.17), sun protection cosmetics (Formulation 10.13), and baby care products (Formulation 10.16). They can be used, as well, for skin (Formulation 10.15), lip, and eye care (Formulation 10.14). These formulations provide a wide choice of composition, texture, viscosity, rate of absorption, etc. Nontraditional harnessing of the encapsulated products is available. Formulation 10.17 is a representative example of an emulsion useful for wet tissues designed by Tagra Biotechnologies, Ltd., that contains no aggressive agents such as organic

The formulations described in this chapter will enable the development and expansion of new, beneficial tools for the formulators incorporating Tagravit/Tagrol microcapsules.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES 10.8.2 Application of Tagravit™/ Tagrol™ Microcapsules Incorporation process. Tagravit/Tagrol microcapsules should be added to formulations after homogenization and filtration procedures, and when the temperature of the formulation reaches 30°C–50°C. Optimal temperatures will depend on the viscosity of the formulation and its variation with temperature. The optimal temperature range is one where there will be no damage to the active substances applied. After incorporation of the microcapsules, the formulation should be mixed well by a regular mixer in order to obtain a homogeneous dispersion. High-shear mixing, however, should be avoided. This is especially true after seventy-two hours of contact between the microcapsules and aqueous media, because the elastic shell preventing contact between the active and other ingredients of formulation can be destroyed. If the shell is destroyed, undesirable oxidation of the active ingredient will then occur. Active substance release process. Following incorporation into a formulation, the microcapsular wall becomes elastic after approximately seventytwo hours. Once the microcapsule walls became elastic, the microcapsules enable mechanical release of the active substance upon rubbing during application onto a target area. Evaluation of a formulation’s final texture should take place after the above-mentioned period, but all other quality tests, as well as packaging may be performed during this period. Pre-production storage of microcapsules as a raw material. As a raw material, unopened Tagravit/Tagrol containers can be stored at 25°C in dry, dark conditions. Under such conditions the shelf life of the product exceeds one year. Opaque packaging is highly recommended for end products containing Tagravit A and Tagrol H since this approach will greatly increase stability.

10.9 Conclusions During the last three decades, polymeric microcapsules have become important instruments for controlled active delivery systems. They are especially effective as a means for preventing the degradation of non-stable components. Significant markets for

233

such materials have opened in the cosmetic and pharmaceutical formulation area since such microcapsules not only prevent the degradation of useful actives, but they also provide a desirable release mechanism. Tagra Biotechnologies, Ltd., has developed an innovative solvent removal technology. Microencapsulated products based upon this technology eliminate the need for chlorinated solvents in the microencapsulation process. This technology may be universally applied for stabilization of degradable oilsoluble and oil-dispersible actives in both the cosmetic and pharmaceutical industries. It was found that Tagra’s ranges of microencapsulated vitamins, Tagravit™, and natural oils, Tagrol™, are ideally suitable for topical and dermal treatment since they offer both formulators and consumers several distinct advantages. The most important advantage is a significant increase in stability of the active ingredient. This increase in stability is evident for raw microcapsular materials as well as in formulations containing these microcapsules. Other advantages include high uniformity of microcapsule size, their powder form, and their ability to be homogeneously dispersed in all types of formulations without destruction during processing or upon aging. Microencapsulation of vitamins A, E, and F by Tagra’s novel technology increases their resistance to oxidative degradation by a factor of ten to forty when incorporated in various formulations. Importantly, it has been demonstrated that the formulation itself can influence stability of the active ingredient contained within the microcapsules. For example, the stability of encapsulated retinol palmitate increases with increasing the silicone oil phase content in formulations, and has been found to be optimal at 32 wt%. Paraffin oil was found to be an optimal plasticizer for the microcapsular wall. It was also established that the stability of retinol palmitate increases as its concentration in formulations is decreased. This observation suggests that compartmentalization of non-stable active substances into smaller microcapsules can provide additional stabilization. Overall, taking into account the above-mentioned factors will guarantee high stability of the formulated microcapsules containing active compounds that are sensitive to oxidation.

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Several examples of formulations based on Tagravit/Tagrol microcapsules are recommended for use in various areas of cosmetics and personal care products. These formulations are applicable for the manufacture of a wide range of personal care end products such as sun protection cosmeceuticals, skin, hair, lips and eye care, including baby care, and wet tissues production and use. Tagravit/Tagrol microcapsules provide formulators with a powerful new

tool for the design of cosmetic products having a wide range of specific characteristics and improved efficacy. The behavior of microencapsulated, oxidatively sensitive actives, in fully formulated products is complex and provides a considerable intellectual challenge. The technology offers a significant opportunity regarding its ability to enhance health care, and provides the consumers with novel products.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

10.10 Model and Recommended Formulations 10.10.1 Model Formulations Model (base) formulations (Formulations 10.1– 10.12) were developed in order to discover the opti-

235

mal balance of their components for the best compatibility with Tagravit/Tagrol microcapsules. Tagra Biotechnologies, Ltd., is not responsible for any changes in the composition of ingredients or their replacement in the proposed base formulations made by a customer; nor is Tagra Biotechnologies, Ltd., responsible for the use of any ingredient covered by someone else’s patent.

Formulation 10.1: Base Formulation A12 (Tagra Biotechnologies, Ltd.)

Phase

A

B

Ingredients

Function

Water (aqua)

Solvent

Glycerin

Humectant

0.60

Allantoin

Anti-irritant

0.03

Propylene glycol

Humectant

0.60

Methylparaben

Preservative

0.09

Imidazolidinyl urea

Preservative

0.06

Xanthan gum

Thickener

0.12

Dow 350

Emollient

0.24

Decyl oleate

Emollient

1.80

Dioctyl adipate

Emollient

1.50

Myristyl myristate

Emollient

0.75

Steareth-21

Emulsifier

0.72

Steareth-2

Emulsifier

1.08

PPG-15 stearyl ether

Emollient

0.90

Cetyl alcohol

Emulsifier

0.45

BHA

Antioxidant

0.015

Dow 1503

Emollient

0.60

Stearyl dimethicone

Emollient

0.45

Oleoyl erucate

Emollient

0.30

Octyl palmitate

Emollient

2.40

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

C D

Weight % Up to 100

0.18

Propylparaben

Preservative

0.06

Sepigel 305

Thickener

0.30

Fragrance

Perfume

0.30

Lauryl pyrrolidone

Wetting agent

0.60

Aluminum starch octenyl succinate

Binder

0.90 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.1: (Cont’d.)

Phase

E

Ingredients

Function

Weight %

Chlorohexidine digluconate

Preservative

0.30

Ammonium lactate

Moisturizer

0.18

Lactic acid

Acidifier

0.09

Sodium hyaluronate

Moisturizer

0.03

Glyceryl polymethacrylate (and) propylene glycol (and) copolymer PVM/MA

Conditioner

0.06

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance (Phase C) at 45°C. 6. Prepare Phase D by pre-slurry of ingredients lauryl pyrrolidone and chlorohexidine digluconate in the ingredient aluminum starch octenyl succinate at room temperature. 7. You can use a small quantity of the lotion, as a pre-slurry carrier. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs. 8. Add ingredients of Phase E, one by one, at 40°C.

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237

Formulation 10.2: Base Formulation A24 (Tagra Biotechnologies, Ltd.)

Phase

A

B

C D

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

1.20

Allantoin

Anti-irritant

0.06

Propylene glycol

Humectant

1.20

Methylparaben

Preservative

0.18

Imidazolidinyl urea

Preservative

0.12

Xanthan gum

Thickener

0.24

Dow 350

Emollient

0.48

Decyl oleate

Emollient

3.60

Dioctyl adipinate

Emollient

3.00

Myristyl myristate

Emollient

1.50

Steareth-21

Emulsifier

1.44

Steareth-2

Emulsifier

2.16

PPG-15 stearyl ether

Emollient

1.80

Cetyl alcohol

Emulsifier

0.90

BHA

Antioxidant

0.03

Dow 1503

Emollient

1.20

Stearyl dimethicone

Emollient

0.90

Oleoyl erucate

Emollient

0.60

Octyl palmitate

Emollient

4.80

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

0.36

Propylparaben

Preservative

0.12

Sepigel 305

Thickener

0.60

Fragrance

Perfume

0.60

Lauryl pyrrolidone

Wetting agent

1.20

Aluminum starch octenyl succinate

Binder

1.80 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.2: (Cont’d.)

Phase

E

Ingredients

Function

Weight %

Chlorohexidine digluconate

Preservative

0.60

Ammonium lactate

Moisturizer

0.36

Lactic acid

Acidifier

0.18

Sodium hyaluronate

Moisturizer

0.06

Glyceryl polymethacrylate (and) propylene glycol (and) copolymer PVM/MA

Skin conditioner

0.12

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance (Phase C) at 45°C. 6. Prepare Phase D by pre-slurry of ingredients lauryl pyrrolidone and chlorohexidine digluconate in the ingredient aluminum starch octenyl succinate at room temperature. 7. You can use a small quantity of the lotion as a pre-slurry carrier. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs. 8. Add ingredients of Phase E, one by one, at 40°C.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

239

Formulation 10.3: Base Formulation A32 (Tagra Biotechnologies, Ltd.)

Phase

A

B

C D

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

1.60

Allantoin

Anti-irritant

0.08

Propylene glycol

Humectant

1.60

Methylparaben

Preservative

0.24

Imidazolidinyl urea

Preservative

0.16

Xanthan gum

Thickener

0.32

Dow 350

Emollient

0.64

Decyl oleate

Emollient

4.80

Dioctyl adipinate

Emollient

4.00

Myristyl myristate

Emollient

2.00

Steareth-21

Emulsifier

1.92

Steareth-2

Emulsifier

2.88

PPG-15 stearyl ether

Emollient

2.40

Cetyl alcohol

Emulsifier

1.20

BHA

Antioxidant

0.04

Dow 1503

Emollient

1.60

Stearyl dimethicone

Emollient

1.20

Oleoyl erucate

Emollient

0.80

Octyl palmitate

Emollient

6.40

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

0.48

Propylparaben

Preservative

0.16

Sepigel 305

Thickener

0.80

Fragrance

Perfume

0.80

Lauryl pyrrolidone

Wetting agent

1.60

Aluminum starch octenyl succinate

Binder

2.40 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.3: (Cont’d.)

Phase

E

Ingredients

Function

Weight %

Chlorohexidine digluconate

Preservative

0.80

Ammonium lactate

Moisturizer

0.48

Lactic acid

Acidifier

0.24

Sodium hyaluronate

Moisturizer

0.08

Glyceryl polymethacrylate (and) propylene glycol (and) copolymer PVM/MA

Skin conditioner

0.16

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool while mixing down to 50°C. 5. Add fragrance (Phase C) at 45°C. 6. Prepare Phase D by pre-slurry at room temperature of ingredients lauryl pyrrolidone and chlorohexidine digluconate in the ingredient aluminum starch octenyl succinate. You can use small quantity of the lotion as a pre-slurry carrier. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs. 7. Add ingredients of Phase E, one by one, at 40°C.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

241

Formulation 10.4: Base Formulation A40 (Tagra Biotechnologies, Ltd.)

Phase

A

B

C D

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

2.00

Allantoin

Anti-irritant

0.10

Propylene glycol

Humectant

2.00

Methylparaben

Preservative

0.30

Imidazolidinyl rrea

Preservative

0.20

Xanthan gum

Thickener

0.40

Dow 350

Emollient

0.80

Decyl oleate

Emollient

6.00

Dioctyl adipinate

Emollient

5.00

Myristyl myristate

Emollient

2.50

Steareth-21

Emulsifier

2.40

Steareth-2

Emulsifier

3.60

PPG-15 stearyl ether

Emollient

3.00

Cetyl alcohol

Emulsifier

1.50

BHA

Antioxidant

0.05

Dow 1503

Emollient

2.00

Stearyl dimethicone

Emollient

1.50

Oleoyl erucate

Emollient

1.00

Octyl palmitate

Emollient

8.00

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

Propylparaben

Preservative

0.20

Sepigel 305

Thickener

1.00

Fragrance

Perfume

1.00

Lauryl pyrrolidone

Wetting agent

2.00

Aluminum starch octenyl succinate

Binder

0.60

3.00 (Cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.4: (Cont’d.)

Phase

E

Ingredients

Function

Weight %

Chlorohexidine digluconate

Preservative

1.00

Ammonium lactate

Moisturizer

0.60

Lactic acid

Acidifier

0.30

Sodium hyaluronate

Moisturizer

0.10

Glyceryl polymethacrylate (and) propylene glycol (and) copolymer PVM/MA

Skin conditioner

0.20

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add Phase B to Phase A slowly, while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance (Phase C) at 45°C. 6. Prepare Phase D by pre-slurry of ingredients lauryl pyrrolidone and chlorohexidine digluconate, in the ingredient aluminum starch octenyl succinate at room temperature. You can use a small quantity of the lotion as a pre-slurry carrier. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs. 7. Add ingredients of Phase E, one by one, at 40°C.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

243

Formulation 10.5: Base Formulation B12 (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

D

E

Ingredients

Function

Weight. %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

2.00

Cetearyl alcohol (and) sodium cetearyl sulfate

Emulsifier

2.00

Propylene glycol

Humectant

2.00

Methylparaben

Preservative

0.30

Imidazolidinyl urea

Preservative

0.20

Octyl methoxycinnamate

Sunscreen

1.00

Dow 350

Emollient

0.90

Cetyl alcohol

Emulsifier

2.00

Cetearyl alcohol (and) PEG-20 stearate

Emulsifier

2.00

Octyl palmitate

Emollient

5.00

Propylparaben

Preservative

0.20

Fragrance

Perfume

0.50

Aloe Barbadensis gel

Humectant

0.30

Witch Hazel (Hamamelis Virginiana) distillate

Botanical

0.30

Tocopherol (vitamin E)

Active

1.00

2-Bromo-2-nitropropane-1,3-diol

Preservative

0.04

Mixing Procedure: 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance at 45°C. 6. Prepare Phase D by pre-slurry of ingredients aloe Barbadensis gel and tocopherol (vitamin E) in the ingredient Witch Hazel (Hammamelis Virginiana) distillate at room temperature. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs.

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Formulation 10.6: Base Formulation C12 (Tagra Biotechnologies, Ltd.)

Phase

A

Ingredients

Function

Weight %

Water (aqua)

Solvent

Glycerin

Humectant

2.00

Cetearyl alcohol (and) sodium cetearyl sulfate

Emulsifier

2.00

Propylene glycol

Humectant

2.00

Methylparaben

Preservative

0.30

Imidazolidinyl urea

Preservative

0.20

Octyl methoxycinnamate

Up to 100

1.00

Dow 350

Emollient

0.90

Cetyl alcohol

Emulsifier

2.00

Cetearyl alcohol (and) PEG-20 stearate

Emulsifier

2.00

Octyl palmitate

Emollient

5.00

Propylparaben

Preservative

0.20

C

Fragrance

Perfume

0.50

D

Aloe Barbadensis gel

Humectant

0.30

Witch Hazel (Hamamelis Virginiana) distillate

Astringent

0.30

2-Bromo-2-nitropropane-1,3-diol

Preservative

0.04

B

E

Mixing Procedure 1. Combine Phase A and heat up to 75°C 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance at 45°C. 6. Prepare Phase D by pre-slurry of ingredients aloe Barbadensis gel and 2-bromo-2-nitropropane1,3-diol, in the ingredient Witch Hazel (Hammamelis Virginiana) distillate at room temperature. Add slowly Phase D.

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245

Formulation 10.7: Base Formulation D12 (Tagra Biotechnologies, Ltd.)

Phase

A

B

C D

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

2.00

Cetearyl alcohol (and) sodium cetearyl sulfate

Emulsifier

2.00

Propylene glycol

Humectant

2.00

Methylparaben

Preservative

0.30

Imidazolidinyl urea

Preservative

0.20

Dow 350

Emollient

12.00

Cetyl alcohol

Emulsifier

0.50

Cetearyl alcohol (and) PEG-20 stearate

Emulsifier

2.00

Propylparaben

Preservative

0.20

Fragrance

Perfume

0.50

Aloe Barbadensis gel

Humectant

0.30

Witch Hazel (Hamamelis Virginiana) distillate

Astringent

0.30

2-Bromo-2-nitropropane-1,3-diol

Preservative

0.04

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Add fragrance at 45°C. 6. Prepare Phase D by pre-slurry of ingredients aloe Barbadensis gel and 2-bromo-2-nitropropane1,3-diol, in the ingredient Witch Hazel (Hammamelis Virginiana) distillate at room temperature. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs.

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Formulation 10.8: Base Formulation Gel 1 (Tagra Biotechnologies, Ltd.)

Phase

A

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Xanthan gum

Thickener

1.00

DMDM hydantoin

Preservative

0.20

Methylparaben

Preservative

0.10

Citric acid

Acidifier

Up to pH 6.0–7.0

Viscosity 15,000–20,000 cP Mixing Procedure 1. Dissolve ingredients in water. Heat slightly up to 45° C. 2. Adjust pH as necessary.

Formulation 10.9: Base Formulation Gel 2 (Tagra Biotechnologies, Ltd.)

Phase

A

B

Ingredients

Function

Weight %

Water

Solvent

Up to 100

Sodium methylparaben

Preservative

0.15

Natrosol Plus 250 HBBR

Thickener

0.80

Keltrol T

Thickener

0.20

PVP K-30

Conditioner

0.50

Glydant

Preservative

0.30

TEA/lactic acid

Acidifier/neutralizer

Up to pH 4.0–4.5

Viscosity 1,000–1,500 cP

Mixing Procedure 1. Dissolve ingredients sodium methylparaben and glydant in water. 2. Disperse ingredients Natrosol Plus 250 HBBR, Keltrol T, and PVP K-30 in water through strong agitation. Let them hydrate until uniformly and completely dispersed. Heat slightly, up to 45°C. 3. Add TEA/lactic acid using moderate agitation and homogenize until uniform state occurs. 4. Adjust pH as necessary.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

247

Formulation 10.10: Base Formulation Gel 3 (Tagra Biotechnologies, Ltd.)

Phase

A

B

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Sodium methylparaben

Preservative

0.15

Natrosol Plus 250 HBBR

Thickener

0.80

Keltrol T

Thickener

0.80

PVP K – 30

Conditioner

0.50

Glydant

Preservative

0.30

TEA/lactic acid

Acidifier/neutralizer

Up to pH 4.0–4.5

Viscosity 10,000–10,500 cP Mixing Procedure 1. Dissolve ingredients sodium methylparaben and glydant in water. 2. Disperse ingredients Natrosol Plus 250 HBBR, Keltrol T and PVP K-30 in water through strong agitation. Let them hydrate until uniformly and completely dispersed. Heat slightly up to 45°C. 3. Add TEA/lactic acid using moderate agitation and homogenize until uniform state occurs. 4. Adjust pH as necessary.

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Formulation 10.11: Base Formulation Skin Gel (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

D

Ingredients

Function

Weight %

Water

Solvent

Up to 100

Propylene glycol

Humectant

6.00

Allantoin

Anti-irritant

0.30

Potassium sorbate

Preservative

0.20

Sodium methylparaben

Preservative

0.15

Natrosol Plus 330 CS

Thickener

0.30

Jaguar HP – 105

Thickener

0.35

PVP K-30

Conditioner

0.20

Sepigel 305

Thickener

3.20

PEG -40 Castor Oil

Solubilizer

0.50

Phenonip

Preservative

0.15

Chlorohexedine digluconate

Preservative

0.15

Ammonium lactate

Moisturizer

5.00

Lactic acid

Acidifier

2.50

Fragrance

Perfume

0.15

TEA/lactic acid

Acidifier/neutralizer

Up to pH 4.0–5.0

Mixing Procedure

1. Dissolve ingredients propylene glycol, allantoin, potassium sorbate, and sodium methylparaben in water. 2. Disperse ingredients Natrosol Plus 330 CS, Jaguar HP–105, and PVP K-30 in water with strong agitation. Let them hydrate until being uniform and completely dispersed. Heat slightly up to 45°C. 3. Add the Phase B ingredients using moderate agitation and homogenize until uniform state occurs. 4. Add the ingredients in Phase C–D using moderate agitation and homogenize until uniform state occurs.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

249

Formulation 10.12: Base Formulation Water-in-Oil – 40 (Tagra Biotechnologies, Ltd.)

Phase

A

B

Ingredients

Function

Weight %

Cyclomethicone

Emollient

11.0

Dow Corning 5225C Formulation Aid

Emulsifier

10.0

Isostearyl isosterarate

Emollient

4.0

Caprylic/capric triglyceride (and) stearalkonium hectorite (and) propylene carbonate

Thickener

2.0

Dimethicone/vinyldimethicone crosspolymer

Skin conditioner

1.0

Cetyl dimethicone copolyol

Emulsifier

0.5

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

0.8

Fragrance

Perfume

0.1

Water (aqua)

Solvent

Glycerin

Humectant

3.5

Dead Sea Water (Maris Sal and Aqua)

Moisturizer

2.0

Glycerin (and) butylene glycol (and) water (aqua) (and) hydrocotyl (centella asiatica) extract

Botanical

1.0

Aloe Barbadensis gel

Humectant

1.0

Butylene glycol (and) water (aqua) (and) Calendula Officinal (Calendula officinalis) extract

Botanical

1.0

Panthenol

Moisturizer

0.5

Saccharide isomerate

Moisturizer

0.5

Propylene glycol (and) (water) (and) zizyphus jububa (and) algae (and) sclerotium gum

Botanical

0.5

Bisabolol

Anti-inflammatory

0.3

Carob Bean (Cerafonica Siliqua) gum

Skin conditioner

0.3

Allantoin

Anti-irritant

0.3

Sodium hyaluronate

Moisturizer

0.1

Up to 100

Mixing Procedure 1. Combine Phase A and heat up to 35° C. 2. Combine Phase B and heat up to 40° C. 3. Add slowly Phase B (water) to Phase A (oil) while homogenizing. Continue homogenizing for 5 minutes.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

10.10.2 Recommended Formulations Recommendations (Formulations 10.13–10.18) were made (from base model Formulations 10.1– 10.12) for the incorporation of Tagravit/Tagrol microcapsules into commercial formulations. Tagra Bio-

technologies, Ltd., is not responsible for any changes in the composition of ingredients or their replacement in the proposed base formulations made by a customer; nor is Tagra Biotechnologies, Ltd., responsible for the use of any ingredient covered by someone else’s patent.

Formulation 10.13: Moisturizing Cream (SPF 15) (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

D

Ingredients

Function

Weight %

Water (aqua)

Solvent

43.00

Sodium methyl paraben

Preservative

0.20

Propylene glycol

Humectant

4.00

Benzophenone-4

Sunscreen

0.90

Na-PCA

Moisturizer

2.00

TEA

Neutralizer

0.40

Tetrasodium EDTA

Chelant

0.10

Magnesium aluminium silicate

Suspending

0.20

Xanthan gum

Thickener

0.40

Steareth-21

Emulsifier

4.00

Glyceryl stearate N/E

Emulsifier

2.00

Steareth-2

Emulsifier

3.00

Stearyl alcohol

Emulsifier

1.50

Phenoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

1.20

Caprylic/Capric triglyceride

Emollient

3.00

Octyl methoxycinnamate

Sunscreen

6.75

Benzophenone-3

Sunscreen

0.45

Octyl salicylate

Sunscreen

0.90

Isodecyl neopentanoate

Emollient

3.00

BHA

Antioxidant

0.05

C12-15 alkyl benzoate

Emollient

9.50

Z–Cote HP–1

Sunscreen

2.40

Dow 344

Emollient

3.00

Fragrance

Perfume

0.50 (Cont’d.)

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

251

Formulation 10.13: (Cont’d.)

Phase

E

Ingredients

Function

Weight %

Tagravit™ E

Active

1.00

Tagravit™ F

Active

1.00

Tagrol™ B

Active

1.00

Tagrol™ EPO

Active

1.00

Aluminum starch octenyl succinate

Binder

2.00

Glycerin (and) urea (and) saccharide hydrolyzate (and) magnesium aspartate (and) glycine (and) alanine (and) creatine

Moisturizer

1.00

Na-hyluaronate

Moisturizer

1.00

Glyceryl polymethacrylate (and) propylene glycol (and) copolymer PVM/MA

Skin conditioner

0.20

Chlorohexidine digluconate

Preservative

0.20

Iodopropynyl butylcarbamate

Preservative

0.10

Mixing Procedure 1. Combine Phase A and heat up to 75°C. Disperse and mix ingredients magnesium aluminium silicate and xanthan gum until complete dissolution occurs. 2. Combine Phase B and heat up to 80°C. Disperse thoroughly ingredient Cote–HP-1 in Phase B. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 50°C while mixing. 5. Combine Phase C and add at 50°C. 6. Prepare Phase E by pre-slurry of ingredients Tagravit E, Tagravit F, Tagrol B and Tagrol EPO in the ingredient aluminum starch octenyl succinate at room temperature. 7. Add slowly Phase D at 40°C. Mix gently till complete dissolution occurs. 8. Add other ingredients of Phase E, one by one, at 40°C.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.14: Eye and Neck Cream (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

Ingredients

Function

Weight %

Water

Solvent

Up to 100

Panthenol

Moisturizer

0.5

Glycerin

Humectant

3.5

Dead Sea Water

Moisturizer

2.0

Pentavitin

Moisturizer

0.5

Centella asiatica extract

Botanical

1.0

Aloe Vera Gel

Humectant

1.0

Calendula officinalis extract

Botanical

1.0

Butcher’s broom extract

Botanical

1.0

Bisabolol

Anti-inflammatory

0.3

Phytoluronate

Moisturizer

0.3

Allantoin

Anti-irritant

0.3

Sodium hyaluronate

Moisturizer

0.1

Dow 344

Emollient

11.0

Dow 5225

Emulsifier

10.0

Isostearyl isostearate

Emollient

4.0

Dow 9556

Skin conditioner

1.0

Abil EM90

Emulsifier

0.5

Bentone Gel GTCC

Thickener

2.0

Phenochem

Preservative

0.8

Fragrance

Perfume

0.1

Tagravit™ E

Active

1.0

Tagravit™ F

Active

1.0

Tagrol™ EPO

Active

1.0

Tagrol™ B

Active

1.0

Tagravit™ A

Active

1.0

Mixing Procedure: 1. Combine Phase A and heat to 35°C. 2. Combine Phase B and heat to 40°C. 3. Add slowly Phase A (water) to Phase B (oil) while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 30°C while mixing. 5. Add fragrance (Phase C) at 30°C. 6. Prepare Phase C by pre-slurry of ingredients allantoin, sodium hyaluronate, and Dow 344 in a small amount of the cream at room temperature. Add slowly Phase C at 40°C. Mix gently (300 rpm) till complete uniform dissolution occurs.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

253

Formulation 10.15: After-Depilatory Lotion (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

D

E

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerin

Humectant

3.00

Cetearyl alcohol (and) sodium cetearyl sulfate

Emulsifier

2.00

Propylene glycol

Humectant

3.00

Methylparaben

Preservative

0.30

Imidazolidinyl urea

Preservative

0.20

Isohexadecane

Emollient

1.00

Dow 350

Emollient

0.80

Cetyl alcohol

Emulsifier

2.00

Cetearyl alcohol (and) PEG-20 stearate

Emulsifier

3.00

Octyl palmitate

Emollient

5.00

Propylparaben

Preservative

0.20

Fragrance

Perfume

0.50

Menthyl lactate

Cooling agent

0.50

Tagtavit™ E

Active

1.00

Tagrol™ H

Active

1.00

Aluminum starch octenyl succinate

Binder

1.00

Tagrol™ B

Active

1.00

Tagrol™ EPO

Active

1.00

Aloe Barbadensis gel

Humectant

1.00

Witch Hazel (Hamamelis Virginiana) distillate

Astringent

0.50

2-Bromo-2-nitropropane-1,3-diol

Preservative

0.04

Mixing Procedure 1. Combine Phase A and heat up to 75°C. 2. Combine Phase B and heat up to 80°C. 3. Add slowly Phase B to Phase A while homogenizing. Continue homogenizing for 5 minutes. 4. Cool down to 45°C while mixing. 5. Add fragrance (Phase C) at 45°C. The base of lotion is ready after this stage. 6. Prepare Phase D by premixing its ingredients at room temperature. Alternatively, a small quantity of the base of lotion may be used as a pre-slurry carrier through its premixing to Phase D. Add slowly Phase D at 40°C. Mix gently until complete dissolution occurs. 7. Add ingredients of Phase E, one by one, at 40°C.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.16: Baby Cream/Paste (Tagra Biotechnologies Ltd.)

Phase

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Glycerine

Humectant

6.0

Magnesium sulfate

Stabilizer

1.0

Panthenol

Moisturizer

0.5

Methylparaben

Preservative

0.3

Imidazolidinyl urea

Preservative

0.2

Allantoin

Anti-irritant

0.1

Dow 350

Emollient

0.5

Shea Butter (Butyrospermum Parkii)

Emollient

5.0

Cera alba

Emollient

Cetyl dimethicone copolyol

Emulsifier

3.0

Polyglyceryl-4-isostearate

Emulsifier

1.0

Octyl palmitate

Emollient

5.0

Penoxyethanol (and) methylparaben (and) butylparaben (and) ethylparaben (and) propylparaben

Preservative

0.2

C

Calamine

Skin conditioner

D

Fragrance

Perfume

0.5

Octyl palmitate

Emollient

2.0

Tagravit™ E

Active

1.0

Tagrol™ B

Active

1.0

Bisabolol

Antiinflammatory

0.5

Tagrol™ H

Active

1.0

Tagrol™ EPO

Active

1.0

Tagravit™ A

Active

1.0

A

B

E

10.0

Mixing Procedure 1. Combine Phase A and heat up to 45° C. 2. Combine Phase B and heat Phase B up to 50° C. 3. Disperse Calamine in Phase B. 4. Add slowly Phase A to Phase B while homogenizing. Continue homogenizing for 15 minutes. 5. Cool down while homogenizing to 35° C. 6. Add fragrance at 35° C. 7. Prepare Phase E by pre-slurry of ingredients Tagravit E, Tagrol B, Bisabolol, Tagrol H, Tagrol EPO, and Tagravit A in the ingredient octyl palmitate at room temperature. Add slowly Phase E at 35° C. Mix gently until complete homogeneity occurs.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

255

Formulation 10.17: Wet Tissues Makeup Remover (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

Ingredients

Function

Weight %

Octydodecanol

Emollient

3.0

Cetyl stearyl alcohol

Emulsifier

1.0

Steareth 20

Emulsifier

1.0

Hexadecyltrimethylammonium chloride

Preservative

0.5

Disodium PEG-5 laurylcitrate sulfosuccinate; sodium laureth sulfate

Surfactant

2.0

PEG-7 glyceryl cocoate

Emollient

1.0

Sodium polystyrene sulfonate

Surfactant

1.0

Water

Solvent

Sodium methylparaben

Preservative

0.1

Glydant Plus

Preservative

0.1

Fragrance

Perfume

0.2

Saccharide isomerate

Moisturizer

0.5

Tagravit™ E

Active

0.2

Mixing Procedure 1. Mix Phase A and heat up to 70°C. 2. Mix Phase B and heat up to 70°C. 3. Add Phase B to Phase A and homogenize while stirring. 4. Add Phase C at 30°C– 40°C.

Up to 100

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 10.18: Cream for Hair Dressing (Tagra Biotechnologies, Ltd.)

Phase

A

B

C

Ingredients

Function

Weight %

Water (aqua)

Solvent

Up to 100

Panthenol

Moisturizer

0.5

Methylparaben

Preservative

0.3

Imidazolidinyl urea

Preservative

0.2

Emulsifying wax

Emulsifier

10.0

Mineral oil (Paraffinum Liquidum)

Emollient

5.0

Crodamol OP

Emollient

5.0

Magnifera Indica (Mango) Butter

Conditioner

5.0

Propylparaben

Preservative

0.2

Fragrance

Perfume

0.5

Tagravit™ E

Active

1.0

Tagrol™ B

Active

1.0

Tagrol™ EPO

Active

1.0

Mixing Procedure 1. Heat Phase A up to 75° C. 2. Heat Phase B up to 75° C. 3. Add Phase A to Phase B while homogenizing. Continue homogenizing for 10 minutes. 4. Cool down to 45° C while mixing. 5. Add Phase C.

KVITNITSKY, LERNER, SHAPIRO: TAGRAVIT™ MICROCAPSULES AS DRUG DELIVERY DEVICES

References 1. De Polo, K. F. A Short Textbook of Cosmetology. Verlag für Chem. Ind. H. Ziolkowsky GmbH: Augsburg, 1998, pp. 335, 399. 2. Halliwell, B., Gutteridge, J. M. C., Free Radicals in Biology and Medicine, 2nd ed. Oxford University Press, Oxford, 1998, pp. 36109. 3. Handbook of Pharmaceutical Controlled Release Technology. Ed. by D. L. Wise. M. Dekker, Inc.: New York, 2000. 4. Advanced Drug Delivery Systems: New Developments, New Technologies. Business Communications Co., Inc. U. S., 2001. 5. Encyclopedia of Controlled Drug-Delivery. Vol. 1-2. Ed. by E. Mathiowitz. John Wiley: New York, 1999. 6. Jalil, R., Nixon, J. R. J. Microencaps. 7, 297325 (1990). 7. Conti, B., Pavanetto, F., Genta, I. J. Microencaps. 9, 153-166 (1992). 8. Uhrich, K. E., Cannizzaro, S. M., Langer, R. S., Shakesheff, K. M. Chem. Rev. 99, 31813198 (1999). 9. Jagur-Grodsinski, J. J. Reactive and Functional Polymers. 39, 99-138 (1999). 10. Ravi Kumar, M. N. V. J. Pharm. Pharmaceut. Sci. 3 (2), 234-258 (2000).

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18. Shapiro, Yu. E., In: Encyclopedia of Nanoscience and Nanotechnology, Ed. by I. A. Schwarz, C. Contescu, K. Putyera, M. Dekker: New York, 2004, pp. 2339-2354. 19. Shapiro, Yu. E., Pykhteeva, E. G. Appl. Biochem. and Biotech. 74, 67-84 (1998). 20. Stenekes, R. J. H., Franssen, O., van Bommel, E. M. G., Grommelin, D. J. A. Hennink, W. E. Pharm. Res. 15, 555-559 (1999). 21. Franssen, O., Hennink, W. E. Int. J. Pharm. 168, 1-7 (1998). 22. Franssen, O., Stenekes, R. J. H., Hennink, W. E. J. Contr. Release 59, 219-228 (1999). 23. Hecht, S., Frechet, J. M. J. Angew. Chem. Int. 40, 74-91 (2001). 24. Spindler, R., Sojka, M. Luteri, G., Cureton, K. Cosmetics and Toiletries Manufacture Worldwide. 174-177 (2002). 25. Shapiro, Yu. E. J. Colloid and Interf. Sci. 212 (2), 453-465 (1999). 26. Shapiro, Yu. E. Colloids and Surfaces, A: Physicochem. and Eng. Aspects. 164 (1), 71-83 (2000). 27. Li, J. K., Wang, N., Wu, X. S. J. J. Contr. Release. 56, 117-126 (1998). 28. Kaplan, D. L. et al. In Biomedical Polymers, Ed. by S. Shalaby, Hansen: Cincinnati, OH, 1994.

11. Szejtli, J. Chem. Rev. 98, 1743-1753 (1998).

29. Mathiowitz, E., Cohen, M. D. J. Membr. Sci. 40, 1-86 (1989).

12. Uekama, K., Hirayama, F., Irie, T. Chem. Rev. 98, 2045-2076 (1998).

30. Chan, L. W., Heng, P. W. S. J. Microencaps. 15, 409-420 (1998).

13. Duchene, D., Ponchel, G., Wouessidjewe, D. Adv. Drug Delivery Rev., 39, 29-40 (1999).

31. Kas, H. S., J. Microencaps. 14 (6), 689-711 (1997).

14. Al-Khiuri Fallouch, N., Robbot-Treupel, L., Fessi, J. P., Devissaguet, J. P., Puesieux, F. Int. J. Pharm. 28, 125-132 (1986).

32. Lim, L. Y., Wan, L. S. C. J. Microencaps. 15 (3), 319-333 (1998).

15. Soma, C. E., Dubernet, C., Bentolila, D., Benita, S., Couvereur, P. Biomaterials 21, 17 (2000). 16. Sommerfeld, P., Sabel, B. A., Schroeder, U. J. Microencaps. 17 (1), 69-79 (2000). 17. Lowe, P. J., Temple, C. S. J. Pharm. Pharmacol. 40, 547-552 (1994).

33. Gohel, M. C., Amin, A. F. J. Contr. Release 53, 115-122 (1998). 34. Lee, B.-J., Choe, J. S., Kim, C.-K. J. Microencaps. 15, 775-787 (1998). 35. Lorenzo-Lamosa, M. L., Remunan-Lopez, C., Vila-Jato, M. J. A. J. Contr. Release 52, 109118 (1998). 36. Ile, P., Davis, S. S., Illum, L. J. Microencaps. 16 (3), 343-355 (1999).

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37. Pekarek, K., Jacob, J., Mathiowithz, E. Nature 367, 258-260 (1994).

50. Mathiowithz, E., Dor, P., Amato, C., Langer, R. J. Polymer 31, 547-555 (1990).

38. Vanichtanunkul, D., Vayumhasuvan, P., Nimmanit, U. J. Microencaps. 15, 752-759 (1998).

51. Shapiro, Yu. E., Kvitnitsky, E., Babtsov, V., Cosmetic and Toiletries Manuf. Worldwide, 183-189 (2001).

39. Scholes, P. D., Coombes, A. G. A., Illum, L., Davis, S. S., Vert, M., Davies, M. C. J. Contr. Release 25, 145-153 (1993).

52. The Vitamins. Ed. by W. H. Sebrell and R. S. Harris. Vol. 1-5. Acad. Press: New York, London, 1972.

40. Zambaux, M. F., Bonneaux, F., Gref, R., Maicent, P., Dellacherie, E., Alonso, M. J., Labrude, A., Vigneron, C. J. Contr. Release 50, 31-40 (1998).

53. Free Radical Damage and Its Control. Ed by C. A. Rice-Evans and R. H. Burdon. Elsevier: Amsterdam, London, New York, and Tokyo, 1994.

41. Kidchob, T., Kimura, S., Imanishi, Y. J. Contr. Release 54, 283-292 (1998).

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55. Carotenoids In Human Health. Ann. New York Acad. Sci. Vol. 691. Ed. by L. M. Canfield, N. J. Krinski and J. A. Olson. New York, 1993.

43. Chiou, S.-H., Wu, W.-T., Huang, Y.-Y. Chung, T.-W. J. Microencaps. 18 (5), 613-625 (2001). 44. Brannon-Peppas, L. Int. J. Pharm. 116, 1-9 (1995). 45. Niwa, T., Takeuchi, H., Hino, T., Kunou, N., Kawashima, Y. J. Contr. Release 25, 89-98 (1993). 46. Wehrle, P., Magenheim, B., Benita, S. J. J. Pharm. Biopharm. 41, 19-26 (1995).

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11 Phase-Change Materials A Novel Microencapsulation Technique for Personal Care Todd Elder Ciba Specialty Chemicals Tarrytown, New York Andrew Bell Ciba Specialty Chemicals Basel, Switzerland

11.1 11.2 11.3

Introduction ................................................................................... 260 History of Ciba Encapsulation Technology ................................... 260 Review of Ciba Encapsulation Techniques .................................. 260 11.3.1 Capsule Particle Size ....................................................... 261 11.4 Skin Temperature Regulation via Phase-Change Materials ......... 261 11.4.1 The “Eureka!” Moment ...................................................... 262 11.4.2 Selection of Melting Point of Encapsulated Wax ............... 262 11.5 Phase-Change Materials .............................................................. 263 11.5.1 Preparation of Encapsulated PCMs ................................. 263 11.5.2 Application of PCMs in Personal Care Formulations ........ 265 11.5.3 Potential Applications ........................................................ 265 11.5.4 Future Work ...................................................................... 265 11.6 Conclusions .................................................................................. 265 11.7 Formulations ................................................................................. 267 Acknowledgments ................................................................................... 272

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 259–272 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

11.1 Introduction In recent years, a significant effort has been made to microencapsulate cosmetic materials. The delivery of useful cosmetic actives to specific sites is a challenge that is being addressed by a wide number of suppliers, personal care formulators, and finished goods marketers. The delivery of desirable actives can be achieved either through targeted selection of an active site (i.e., skin or hair) or by means of “triggers” that release the active under specific stressors (i.e., pH, sweat, shear, etc.). In addition to the area of delivery systems for actives, another outlet for microencapsulation technology is the permanent entrapment of actives. This approach is useful, for example, in cosmetic colors, which have been entrapped in large beads to provide a visual cue to consumers as well as product recognition awareness. Combinations of UV absorbers have also been encapsulated in order to provide enhanced stability in sunscreen formulations. While Ciba Specialty Chemicals maintains an active program to evaluate the many uses of microencapsulation, one recent advance in this area has been to demonstrate the use of phase-change materials (PCMs) as a microencapsulation technique for personal care products. The utility of PCMs in such products is discussed in Sec. 11.5.

11.2 History of Ciba Encapsulation Technology In the 1980s, Allied Colloids (which subsequently became Ciba Water and Paper Treatment in 1998) became involved in encapsulation through the development and sale of color-former encapsulates for carbonless copy paper. These products were sold as Alcapsol™ 144 and 170. This accomplishment established Ciba’s reputation and experience in the art and science of microencapsulation. In 1990, the company, along with Novo-Nordisk (Denmark), the world’s largest producer of industrial enzymes, and the University of Thessaloniki in Greece, began a joint project funded by the European Community to investigate enzyme confinement in liquid detergents.

Since this joint project began, many programs and microencapsulation techniques have been undertaken by Ciba and have led to a significant expansion of science and technology in this area. At the most fundamental level, cosmetic actives may be encapsulated by at least two general techniques. These are physical methods and chemical synthesis techniques. A combination of the two approaches is also possible. For example, physical methods include spray drying, spray coating, and granulation. By contrast, chemical methods involve the reaction of a variety of monomers, polymers, and reactive species to form a polymeric shell, or barrier, around an active substrate. This chemical approach relies not only on the shell material, but also on a chemical and colloid technological foundation employed to control the process. Ciba’s core competency in encapsulation centers on the chemical approach. It stems from its fundamental use and expertise in polyacrylate chemistries. Many of the company’s customers are familiar with Ciba’s Water and Paper Treatment business segment. The company has an excellent reputation in utilizing polyacrylate chemistries for flocculation, sedimentation, and separation of solids from liquids. Such separation processes are widely used in industry for waste-water treatment, etc. As a result of this reputation, Ciba was approached by a number of companies who asked if the same “chemistries” could be utilized to encapsulate key cosmetic actives. As a result of this market pull, Ciba subsequently investigated the encapsulation of a wide variety of potentially useful personal care materials. These ranged from colors and fragrances to antioxidants and enzymes. The trade name “Encapsulence” was chosen for Ciba’s commercially encapsulated products. Application for Encapsulence™ trademark registration has been made on a worldwide basis.

11.3 Review of Ciba Encapsulation Techniques While addressing the needs of Ciba’s customers for microencapsulation technology, a range of distinct functions has emerged. These include, for example:

ELDER AND BELL: PHASE-CHANGE MATERIALS • Controlled release • Targeted delivery • Segregation of components • Protection of active ingredients • Protection from active ingredients • Changing physical form • Aiding formulation • Differentiating product lines from competition Each of these technological distinctions within the broad class of microencapsulation technology offers profound opportunities for companies interested in providing new and improved products and performance. Ciba’s polymeric encapsulates can be tailored to achieve the criteria described above by using a variety of proprietary chemical and physical techniques in order to modify the microcapsule structure.

11.3.1

Capsule Particle Size

Capsule particle size can be described by a variety of methods and these can be confusing to the uninitiated. It should be noted that, in the general microencapsulation literature, particles with size below 1,000 microns tend to be coded as “microcapsules” while those with sizes above 1,000 microns are often described as “macrocapsules.” Quite another set of definitions exists in the personal care market. In this area, encapsulates below 1 micron are termed “nanocapsules,” those below 1,000 microns are called “microcapsules,” and those above 1,000 microns are described as “millicapsules!” Thus it is very important to be aware of these differences in nomenclature so that all parties are talking about the same particle size. This is especially true as certain particle size ranges are very difficult to achieve by some techniques. To simplify this variety of descriptive terminology, Ciba has developed its own terminology to define specific capsule size ranges for its Encapsulence™ line. Larger capsules (greater than, say, 200 µm) are termed macrocapsules. By contrast, capsules below about 100 µm are called microcapsules. Additionally, most humans can sense, either tactually or visually, particles greater than 100 µm. The size range between the macro and micro types have been left nameless at present.

261 Along with the confusion of particle size “name” variations, other descriptors have emerged in the encapsulation industry in an attempt to characterize important variations in process and final product form. For example, microcapsules are products that have a polymeric shell that surrounds a liquid or solid core containing the active. A suitable analogy for this would be the Lindt® truffle, where the truffle core contains the active and the chocolate shell is the polymer coating providing the encapsulation. On the other hand, microspheres are polymeric beads that contain the encapsulated material physically entrapped within the porous polymer matrix. A good example of this approach would be the way a sponge (the polymer matrix) can absorb and retain water (i.e., the active). Ciba has developed technology and practical experience in both of these techniques.

11.4 Skin Temperature Regulation via PhaseChange Materials One recent advance at Ciba Specialty Chemicals has been the utilization of encapsulated phasechange materials (PCMs) into personal care formulations. PCMs are substances that have the capability of absorbing or releasing thermal energy. A phasechange material will reduce or stop the flow of thermal energy through a substrate during the time it is absorbing or releasing heat. This property enables a localized area to maintain a more uniform temperature during extreme thermal variations. Typically, this ability to absorb thermal energy occurs during the material’s change of phase. This action is transient. The phase-change material will be effective as a barrier to thermal energy until the total latent heat of the temperature stabilizing material is absorbed or released during the heating or cooling process. Changes in the local environment can result in thermal energy being stored in, or removed from, the phase-change material. In this way, the phasechange material can effectively be recharged by a source of heat or cold. PCMs have found utility in the textile industry where PCM encapsulates are either incorporated into a textile fiber, or are coated onto a fabric. Sports clothing such as skiing or hiking equipment take ad-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

vantage of the thermal regulating effect PCMs provide and can be found under the name Outlast®. PCMs have also found their way into bedding such as blankets and pillows to allow for thermal comfort while sleeping. Indeed, Ciba Specialty Chemicals manufactures encapsulated PCMs for Outlast that go into a wide range of textile products (www.outlast.com).

11.4.1

The “Eureka!” Moment

Within Ciba, the technology transfer for PCMs from textile applications to personal care emerged as our Personal Care segment was looking for new effects to provide the customer. We observed, for example, that when fabric swatches were coated with PCMs and held in the hand, an expected cooling sensation was observed. This observation led us to question whether the same cooling sensation would be observed if the PCMs were applied to the skin from a typical personal care cream. A simple experiment demonstrated that we were correct and that, indeed, a cooling sensation did actually result. This led us to further investigate the possible uses of PCMs in personal care. A review of the literature showed that personal care products that provide thermal effects are well known. For example, alcohol-containing aftershave lotions provide cooling effects. Evaporation of the alcohol provides a short-term, irreversible cooling effect. While this is an interesting sensory change, the phenomenon does not provide any lasting treatment to counteract the burning sensation from the razor. Further, it would not provide a feeling of warmth should the skin become too cold. In light of these consumer perceivable deficiencies, an unfilled need emerges for personal care products. Such products would be capable of modulating fluctuations in skin-surface temperature by supplying either a cooling effect, or a feeling of warmth, as needed. Ciba’s research has shown that personal care or cosmetic formulations that contain an effective amount of a PCM are capable of achieving these results. Although the normal human body temperature is relatively constant at about 37°C, the skin temperature of various parts of the body can vary considerably even at room temperature (i.e., from about 29°C to 37°C). Additionally, on very hot or cold days,

the extremities can differ even more considerably from the core body temperature. In principle, any material that undergoes a phase change from solid to liquid at a temperature that is close to such skin temperatures would be suitable as a phase-change material for personal care or cosmetic compositions. For this reason, the materials were selected for evaluation if they had a melting range between 29°C and 39°C. However, preference was given to microparticulate phase-change materials comprising a core of a hydrophobic material contained within a shell of a polymeric material. In one embodiment, the hydrophobic material comprises a blend of one or more paraffinic hydrocarbons. Alternatively, other types of phase-change materials exist, such as salt hydrates. These materials can also be microencapsulated. Skin-surface temperature will have a direct impact on whether a cooling effect will be observed when a phase-change material encapsulate is initially applied. In one set of experiments, skin-surface temperature was measured on four healthy adults, at four different areas of the body, where phase-change material encapsulates might be utilized. The individuals were engaged in office work (room temperature 21.7°C) for approximately one hour prior to being tested. Skin temperatures were measured (°C) and are shown in Table 11.1.

11.4.2

Selection of Melting Point of Encapsulated Wax

It is understood that skin-surface temperature will vary depending on a number of factors including level of activity, environment, and time of day. Thus, the melting point of the encapsulated wax must be carefully selected for the particular application. Paraffinic hydrocarbons suitable for use in the personal care formulations described in this chapter, and covered by Ciba’s patent application, include those shown in Table 11.2. It is noted that the number of carbon atoms in such materials is directly related to their respective melting points. Additionally, blends of compounds such as those listed in the table, including isomer blends, can be employed in order to provide specific melting points or a range of melting points.

ELDER AND BELL: PHASE-CHANGE MATERIALS

263

Table 11.1. Skin Surface Temperature Measured on Four Healthy Adults at Four Different Areas of the Body

Individual

Back of Hand

Forearm

Forehead

Underarm

Male #1

30.6

33.3

34.1

36.0

Male #2

30.2

31.9

34.0

35.6

Female #1

30.7

33.8

34.1

36.1

Female #2

30.2

33.2

33.4

36.4

30.4 ± 0.3

33.1 ± 0.8

33.9 ± 0.3

36.0 ± 0.3

Average

Table 11.2. Melting Points of Various Selected Aliphatic Hydrocarbon Waxes that can be Encapsulated

Hydrocarbon

Carbon Chain Length

Melting Point Peak, (°C)

n-Heneicosane

21

40.5

n-Eicosane

20

36.8

n-Nonadecane

19

32.1

n-Octadecane

18

28.2

n-Heptadecane

17

22.0

11.5 Phase-Change Materials 11.5.1

Preparation of Encapsulated PCMs

A representative process for preparing PCM encapsulates is described here. An oil phase is prepared by mixing 331 grams methyl methacrylate, 142 grams methacrylic acid, 2.3 grams butanediol diacrylate, 1,102 grams octadecane, and 4.7 grams lauroyl peroxide. The oil phase is added to a stirred, nitrogen degassed vessel at 70°C containing 3,235 grams water, 175 grams polyvinyl alcohol (Gohsenol GH-20), and 7.1 grams acrylamido methyl propane sulphonic acid sodium salt. The contents are allowed to exotherm, after which the temperature is maintained at 85°C for an

additional hour prior to being cooled and filtered. The resulting capsule dispersion contains polymeric particles, each of which is comprised of a polymeric shell encapsulating the octadecane wax and having a solids content of 35%. The average particle size is 2 µm. A scanning electron micrograph of the PCM encapsulates made by the above procedure is shown in Figure 11.1. A fairly uniform size distribution can be observed. Increasing the magnification gives some visual insight as to the encapsulate shell structure. Figure 11.2 shows the differential scanning calorimetry (DSC) of a typical PCM encapsulate manufactured at 35% solids. The DSC shows both the melting point (top) and the freezing point (bottom) of the PCM encapsulate.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 11.1 Scanning electron micrographs of various PCM encapsulates. The scale bar across the top of each micrograph provides an indication of particle size. The scale bars (from left to right) represent 10 µm, 2 µm, and 0.1 µm.

Figure 11.2 Differential scanning calorimetry of PCM encapsulates showing the melt (top) and freeze points (bottom).

ELDER AND BELL: PHASE-CHANGE MATERIALS 11.5.2

Application of PCMs in Personal Care Formulations

As a starting point for personal care formulation investigation, PCMs containing octadecane were incorporated into several formulations. This was done in order to determine whether any cooling effects could be observed. Octadecane has a melting point below the skin-surface temperature on the body sites that were measured and described Table 11.1. A localized cooling effect would be expected as energy from the skin is utilized to melt the PCM. A skin cream formulation was prepared as shown in Formulation 11.1 (see Sec. 11.7). A blind study was conducted whereby the control cream was applied to one forearm and the cream containing the microencapsulated phase-change material was applied to the other forearm. The panelists were then asked to observe if an immediate cooling effect was observed on one forearm more than on the other forearm. They were then polled ten minutes later to determine if any effect was still observable. The results of the panel test are shown in Table 11.3. In Table 11.3, a positive cooling effect is designated with a plus sign. If no observable difference was felt between the control cream and the PCMcontaining cream, this was designated by a minus sign. In the study shown in Table 11.3, eight of the panelists described a significant cooling sensation within sixty seconds of application as compared to the control. In addition, the cooling effect remained consumer perceivable for the entire ten-minute test period. The other three panelists were unable to discern a distinctive cooling effect with either formulation. In another evaluation, a shave cream was prepared and a similar panel test was conducted. The control shaving cream was applied to one half of the face and, simultaneously, the shaving cream containing the phase-change material (Formulation 11.2) was applied to the other half of the face. The test formulations were again applied and the panelists

265 were asked to identify a cooling effect before and during shaving. Four out of the five male panelists felt a cooling sensation on the treated side containing the PCMs. This sensation was perceived to last throughout the shaving experience.

11.5.3

Potential Applications

There are a variety of personal care formulations that may benefit from the incorporation of PCM encapsulates. Some of the potential applications are listed in Table 11.4

11.5.4

Future Work

Ciba is actively involved in other areas of encapsulation research designed to enhance the effects of various cosmetic actives. Some actives of interest include fragrances, colorants, and cosmetically useful oils. The overall intention of this research is to utilize microencapsulation technology to expand the capabilities a cosmetic formulator can draw upon when formulating cosmetic actives into delivery systems.

11.6 Conclusions Ciba has developed a new class of delivery systems for personal care applications. The process employs specially designed microencapsulation technology known as phase-change material (PCM). The technology is based on the use of novel materials that change phase at body temperatures. The new technique appears to be an important new tool for personal care formulation chemists interested in providing novel consumer-perceivable benefits and claims.

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Table 11.3. Panel Results: Sensory Test of a Phase Change Material Cream vs Control

Individual

Left Forearm (°C)

Right Forearm (°C)

Observed Cooling

Male #1

31.0

31.6

-

Male #2

33.5

32.7

-

Male #3

+

Male #4

+

Female #5

32.3

32.5

+

Female #6

31.5

31.8

+

Female #7

31.5

31.7

+

Male #8

+

Male #9

+

Female #10

32.0

31.8

+

Male #11

33.8

33.5

-

Testing conditions: Room Temp. = 21.2°C, Formulation at Room Temp.

Table 11.4. Potential Applications for PCM Encapsulates

Market

Formulations

Shaving preparations

shaving soap, foaming shaving creams, non-foaming shaving creams, foams and gels, pre-shave preparations for dry shaving, aftershaves, and aftershave lotions

Skin-care preparations

skin emulsions, skin oils, and body powders

Cosmetic personal care preparations

facial makeup in the form of day creams or powder creams and face powder (loose or pressed)

Foot-care preparations

foot powders, foot creams or foot balsams, special deodorants and antiperspirants, and callous-removing preparations

Light-protective preparations

suntan lotions, creams and oils, sun blocks, and pre-tanning preparations

Burn treatment preparations

lotions, creams, and oils

Underarm products

deodorant/antiperspirant sprays, pump-action sprays, deodorant/antiperspirant gels, sticks and roll-ons

Hair-removal preparations

hair-removing powders, liquid hair-removing preparations, cream- and paste-form hair-removing preparations, hairremoving preparations in gel form and aerosol foams

ELDER AND BELL: PHASE-CHANGE MATERIALS

267

11.7 Formulations

ited to just these. These examples are courtesy of Ciba; the information given is based on the present state of our knowledge. These formulations show, without liability on our part, the some potential uses of our products.

Formulations 11.1–11.4 are provided to show examples of potential applications that are mentioned in Table 11.4. These examples cover a range of personal care products but the use of PCMs is not lim-

Formulation 11.1: Skin Cream Formulation Containing Micro-PCMs

Phase

A

B

C

INCI Name

Trade Name

Supplier

Deionized water

Deionized water

N/A

Magnesium aluminum silicate

Veegum granules

V.T. Vanderbilt

Methylparaben, USP

Nipagin M

C12-15 alkyl ethylhexanoate

Function Vehicle

Control Weight %

PCM Weight %

64.35

53.46

Thickener

1.30

1.00

Clariant

Preservative

0.30

0.30

Hetester FAO

Bernel

Emollient

5.00

4.00

Trioctyldodecyl citrate

Pelemol TGC

Phoenix, Inc.

Emollient

5.00

2.00

Ethylhexyl isononanoate

Pelemol 89

Phoenix, Inc.

Emollient

5.00

1.00

Glyceryl stearate

Lipo GMS-450

Lipo

Surfactant

3.50

2.00

Stearic acid

Emersol 132, NF

Cognis

Emulsifier

2.50

0.00

PEG-7 glyceryl cocoate

Cetiol HE

Cognis

Emollient

2.50

0.00

Cetyl palmitate

Cutina CP

Cognis

Conditioner

2.00

0.00

Isostearyl neopentanoate

Ceraphyl 375

ISP

Conditioner

2.00

0.00

Persea gratissima oil

Avocado oil

Desert Whale

Emollient

1.00

0.00

Butyrospermum parkii

Shea Butter

Desert Whale

Emollient

0.20

0.00

Sorbitan oleate

Span 80

Uniqema/ ICI

Surfactant

0.80

0.80

Polysorbate 80

Tween 80

Uniqema/ ICI

Surfactant

0.15

0.15

Propylparaben, USP

Nipasol M

Clariant

Preservative

0.10

0.10

Deionized water

Deionized water

N/A

Vehicle

2.00

2.00

Triethanolamine 99%, USP

Triethanolamine

Dow Chemical

Adjust pH

1.00

1.00

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 11.1: (Cont’d.)

Phase

INCI Name

Supplier

Function

Control Weight %

PCM Weight %

0.00

28.57

PCM (35% Active)

Ciba Specialty Chemicals

Provides phase change thermal control

Deionized water

Deionized water

N/A

Vehicle

1.00

1.00

Diazolidinyl urea

Germall II

ISP

Preservative

0.30

0.30

D

E

Trade Name

Total

100.00

100.00

Procedure The Veegum is dispersed in the water portion of Phase A using a homogenizer. The mixture is then heated to 80°C–85°C and the methylparaben is then added. Phase B is heated to 80°C–85°C in a separate vessel; then added to Phase A using a homogenizer, and the temperature is maintained for 15 minutes. The mixture is then gradually cooled. The pre-mixed Phase C is added to the mixture at 65°C using a homogenizer. Homogenization is stopped and side sweep mixing with a Lightening Mixer is then begun. The pre-mixed Phase D is then added to the mixture of A, B, and C at 45°C. Mixing is stopped when the mixture has cooled down to 30°C or room temperature. The information given is based on the present state of our knowledge. It shows without liability on our part the uses to which our products can be put.

ELDER AND BELL: PHASE-CHANGE MATERIALS

269

Formulation 11.2: Shave Cream Formulation Containing Micro-PCMs

Phase

A

INCI NAME

Trade Name

Supplier

Deionized water

Deionized water

N/A

Polyquaternium -7

SALCARE SC 10

Purpose

30.54

21.97

Ciba Specialty Skin Chemicals conditioner

6.00

6.00

Glycerin

Glycerin 96%, USP Dow Chemical Humectant

7.00

7.00

Disodium EDTA

Edeta BD

BASF

Chelator

0.10

0.10

Sodium chloride

Sodium chloride

Fisher

Viscosity adjuster

0.50

0.50

Sodium coco sulfate Mackol CAS-100F McIntyre

Surfactant

5.00

5.00

Citric acid (10% solution)

Adjust pH

0.46

0.46

0.00

28.57

50.00

30.00

0.40

0.40

100.00

100.00

10% Aqueous solution

Fisher

Vehicle

PCM Control Weight Weight % %

Provides phase Ciba Specialty PCM (35% Active) change Chemicals thermal control

B

C

Disodium lauryl sulfosuccinate

D

Phenoxyethanol (and) methylparaben (and) ethylparaben (and) butylparaben Phenonip (and) propylparaben (and) isobutylparaben

Mackanate LO

McIntyre

Surfactant

Clariant

Preservative

Total Procedure

The Polyquatemium-7 is dispersed in the water portion of Phase A by heating to 40°C and mixing with Lightning Mixer using a small side-sweep blade. The glycerin, the disodium EDTA and the sodium chloride are added in the order stated. The solution is heated to 65°C and mixed well until properly dispersed. The sodium is heated to 65°C and mixed well until properly dispersed. The sodium coco sulfate is added to the above mixture at 65°C and mixed well until properly dispersed. The pH is adjusted by adding the citric acid 10% solution. Phase B is added to Phase A slowly using moderate agitation. The solution is then mixed well until homogenous; then is cooled to 45°C. Phase C is heated to 45°C in a separate vessel until it liquefies. Phase C is added to the above mixture slowly using moderate agitation. Phase D is then added to this mixture at a temperature of 45°C or below and mixed well. The product is cooled to 30°C. The white liquid solution increases in viscosity within 24 hours to a creamy texture. The information given is based on the present state of our knowledge. It shows without liability on our part the uses to which our products can be put.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 11.3: After-Sun Lotion Formulation Containing Micro-PCMs

Phase

A

B

C

D

INCI Name

Trade Name

Supplier

Purpose

Parts

Octoxynol-11 (and) polysorbate 20

Solubilisant Gamma 2420

Gattefosse

Surfactant

1.00

Persea gratissima (Avocado) Oil

Lipovol A

Lipo

Emollient

2.00

Simmondsia chinensis (Jojoba) seed oil

Lipovol J

Lipo

Emollient

2.00

Tetradibutyl pentaerithrityl hydroxyhydrocinnamate

TinogardtTM TT

Ciba Specialty Chemicals

Antioxidant

0.10

Sodium acrylates copolymer (and) Paraffinium liquidum (and) PPG-1 Trideceth-6

Salcare SC 91

Ciba Specialty Chemicals

Thickener

2.00

Deionized water (aqua)

Water

N/A

Vehicle

Aqua & tocopheryl acetate & polysorbate 80 & caprylic/capric triglyceride & lecithin

TinodermTM E

Ciba Specialty Chemicals

Antioxidant

5.00

Phenoxyethanol (and) methylparaben (and) ethylparaben (and) butylparaben (and) propylparaben (and) isobutylparaben

Phenonip

Clariant

Preservative

0.70

Propylene glycol

Propylene Glycol, USP

Dow Chemical

Humectant

1.50

Citric acid

Citric acid (20% solution)

N/A

Adjust pH

0.20

Ciba Specialty Chemicals

Provides phase change thermal control

E

PCM (35% actives)

Total

56.93

28.57

100.00

Procedure Phase A is heated to 80°C and mixed well. Phase C is mixed separately at room temperature. Phase A is added to Phase C with continuous stirring. Slowly, Phase B is added to the mixture and mixed well. The pH is adjusted with Phase D. Phase E is added to this mixture slowly using moderate agitation. The solution is mixed well until homogenous. The information given is based on the present state of our knowledge. It shows without liability on our part the uses to which out products can be put.

ELDER AND BELL: PHASE-CHANGE MATERIALS

271

Formulation 11.4: First Aid Cream for Burns

Phase

A

INCI Name

Trade Name

Purpose

Parts

Deionized water

Water

N/A

N/A

Hydroxypropyl methylcellulose

Methocel

Amerchol

Thickener

0.50

Palmitamidopropyl trimonium chloride

Varisoft PATC

Witco

Thickener

0.60

Rona

Antimicrobial

0.30

Cetylpyridinium chloride

B

Supplier

59.20

Cetyl alcohol

Lanette 16

Cognis

Emulsifier

5.00

Glyceryl stearate

Lipo GMS 450

Lipo

Emulsifier

5.00

Isopropyl myristate

Dermol IPM

Alzo

Emollient

5.00

Stearyl alcohol

Crodacol S-95

Croda, Inc.

Thickener

2.00

Synthetic beeswax

Beeswax, synthetic

Ross Waxes

Thickener

1.00

PCM (50% Actives)

Ciba Specialty Chemicals

Provides phase change thermal control

20.00

D

E

Trisodium phosphate

Amresco, Inc.

Chelating agent

0.20

F

Benzyl alcohol

Quest Internat.

Preservative

1.20

Total

100.00

Procedure In a vessel the Methocel is dispersed in the water portion of Phase A using a homogenizer. The mixture is heated to 75°C and the rest of the ingredients of Phase A are added. The solution is mixed well until homogenous. In a separate vessel Phase B is heated to 75°C and stirred well until a homogenous solution is obtained. Phase B is added to Phase A using a homogenizer. Homogenization is maintained for 15 minutes at 75°C Homogenization is stopped and side-sweep mixing with a Lightening Mixer is started. Phase D is added to the mixture at 65°C and cooling is begun. At 45°C Phase E is added to the mixture, which is subsequently cooled to 30°C or room temperature. The information given is based on the present state of our knowledge. It shows without liability on our part the uses to which our products can be part.

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Acknowledgments The authors thank and acknowledge the assistance of Rachel Weston and Howard Dungworth, both of Ciba Specialty Chemicals, Water Treatments,

in the Acrylic Polymer Research Department, and Christina Andrianov, Ciba Specialty Chemicals, Home & Personal Care. Their support in the development of the microencapsulation process and preparation of microPCM samples is highly appreciated.

12 Topical Delivery Systems Based on Polysaccharide Microspheres Maurizio V. Cattaneo IVREA Laboratories, Inc. Quincy, Massachusetts 12.1 Background .................................................................................. 273 12.2 Acceptable Cosmetic Delivery Systems ...................................... 274 12.2.1 Good Skin Tolerance ......................................................... 274 12.2.2 Stability of the Active Ingredient ......................................... 277 12.2.3 No Ghosting ...................................................................... 278 12.2.4 Biodegradability ................................................................. 279 12.3 Chitosphere™ Topical Delivery Technology ................................. 279 12.4 Conclusions .................................................................................. 280 12.5 Formulation ................................................................................... 281 References .......................................................................................... 282

12.1 Background The main issues today facing formulators of cosmetic products, and anti-aging products in particular, include minimizing toxicity and prolonging stability of active ingredients. These issues have increasingly been addressed successfully through the use of topical delivery systems. Topical delivery systems are designed to carry active ingredients to the cells of the stratum corneum. For cases where the actives may be irritating, such delivery systems render these actives less irritating. Ideally, topical delivery systems should not allow the active past the outer skin layers, thereby eliminating systemic exposure.

Historically, a reduction in toxicity or skin irritation has been dealt with largely by encapsulating the active ingredient. Encapsulation produces an enhanced stability of the active relative to exposure to oxidative reactions, moisture, and light. It also provides sustained release of the active, as well as a reduction in the vaporization of volatile substances. Finally, isolation of the active by means of the barrier of the capsule wall allows the separation of incompatible substances within a single formulation. This capability greatly eases the burden of the formulator as he or she seeks to incorporate many useful actives. Capsules are particles that contain an active agent surrounded by a coating layer or shell.

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 273–282 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Capsule terminology is defined according to size and structure. Capsules smaller than 1 µm are called nanocapsules. Those with sizes between 1 µm and 1 mm are called microcapsules, and those with particle sizes larger than 1 mm are called millicapsules or macrocapsules. Capsules may also have a variety of shapes ranging from spherical to irregular. They may also have one or more cores and multiple layers, or coatings. Some qualities desirable in an acceptable cosmetic delivery system include: • Good skin tolerance (e.g., reduced irritation) • Stability of the active • No residue left on the skin after application (no ghosting) • Biodegradability (initiated by the enzymes contained in the skin layer) Each of these factors is discussed in the following sections.

12.2 Acceptable Cosmetic Delivery Systems 12.2.1 Good Skin Tolerance Irritation of the skin has been attributed, in part, to an overload resulting from a systemic absorption of the active ingredient.[1] Compared to oral administration, topical delivery increases the concentration of the active in the dermal compartment 10- to 100-fold.[1] In view of this high concentration, various methods have been employed to minimize the potential irritation of active ingredients. A good example of this approach is demonstrated with a porous particulate delivery system known as Microsponge®.[2] This material is capable of reducing percutaneous penetration, or systemic absorption, as measured by means of a Franz cell apparatus.[3] Such absorption can be reduced by a factor of two without interfering with the amount of an active such as retinoic acid taken up by the skin.[2] Bead-entrapped retinoic acid formulations have been shown to exhibit reduced irritancy when compared to free retinoic

acid. These results have been confirmed in a 14day cumulative irritancy study in humans in which both types of formulations were tested.[2] Slow release of actives using biopolymer matrices. Slow release of irritating actives can also be achieved by entrapping the active ingredient in a high viscosity biopolymer matrix such as chitosan.[4] The term chitosan refers to a family of polymers having a high percentage of glucosamine (normally 80%–99%) and N-acetylated glucosamine (1%– 20%). These structures form a linear polysaccharide chain of molecular weight up to about 800,000 Daltons (Fig. 12.1). Chitosan is derived from chitin. It is normally extracted from the exoskeleton of shellfish, mushrooms, or algae and has previously been described as a promoter of wound healing.[5][6] Controlled release properties have been achieved with chitosan by increasing the viscosity of the biopolymer matrix.[4] Skin permeability studies demonstrating this effect were obtained by the author with Franz diffusion cells using gel formulations containing either free retinoic acid or biopolymer-entrapped retinoic acid. The ability to release all-trans-retinoic acid (ATRA) from the biopolymer was found to be highly dependent upon the low shear viscosity of a solution of the polymer in acetic acid. This parameter ranged from 552 cP for a 1% biopolymer solution in 1% acetic acid (measured using a Brookfield LVT viscometer at 25°C with appropriate spindle at 30 rpm) to an estimated viscosity of 200,000 cP for a 3% biopolymer solution. The latter was calculated from the Philipof equation: V = (1 + KC)8 In this equation, V is the viscosity in cP, K is a constant that is evaluated by using known viscosityconcentration measurements obtained at low shear rate, and C is the weight percent concentration expressed as a fraction.

Figure 12.1 Structure of chitosan.

CATTANEO: TOPICAL DELIVERY SYSTEMS BASED ON POLYSACCHARIDE MICROSPHERES Skin permeability studies were performed using skin explants with formulations containing transretinoic acid, at 0.1 wt% concentration, in gels containing either the free retinoic acid or the chitosan-entrapped retinoic acid. The apparatus consisted of six Franz diffusion cells (PermeGear Inc.) operating in parallel and maintained at a constant temperature of 37°C. Approximately 200 mg/ cm2 of each formulation containing 0.04 µCi of 3HATRA was applied to the epidermal side of the skin sample (1 cm2). Each formulation was tested in triplicate. The dermal surface of the skin was perfused with receptor solution consisting of buffered saline containing 0.05% Volpo (Croda, Inc.). At daily intervals, 500 µL of the receptor solution was sampled in order to obtain kinetic data. At the end of a 200 hour run, a surface wash consisting of 2 × 500 µL aliquots of a 1% acetic acid solution in absolute ethanol was applied to the skin surface. The skin sample was then digested overnight in 4 mL of Solvable (Packard Instruments). The entire contents of the receptor volume (5 mL), the surface wash, and digested skin layer were then mixed with Ultima Gold scintillation fluid (Packard Instruments) for 3H counting.[2] Analysis of the test data showed the formulations containing free retinoic acid delivered a large amount of the drug through the skin in the first 50 to 120 hours while, after an initial lag, the chitosan-entrapped formulation delivered the retinoic acid at a much slower, and constant rate. The effect of the chitosan biopolymer concentration on percutaneous transport was also investigated and was found to level off above a concentration of over 2 wt% (Fig. 12.2). At the end of the skin permeability study, when the distribution of the retinoic acid active in the different skin compartments was evaluated, it was seen that the amount of drug which penetrated percutaneously from the chitosan biopolymer matrix formulation, was 40% lower than that obtained when using the free drug formula. When the skin layers were compared for drug content, however, there was

275

not significant difference in the concentration of the drug (Fig. 12.3). These results indicate that the chitosan-based delivery system was able to reduce systemic absorption by 40%. However, it did not interfere with the amount of retinoic acid taken up by the skin at the site of therapeutic action. Based on these results, the chitosan-entrapped retinoic acid formulation is expected to exhibit reduced irritancy compared with formulated free retinoic acid systems. (This is also confirmed in the irritancy testing trials that were conducted, see Table 12.2.) Other ways to reduce systemic absorption exist besides increasing biopolymer concentration and achieving controlled release properties. These techniques include crosslinking and coacervation. Crosslinking, complex precipitation, and coacervation. Crosslinking methods to inter-couple chitosan chains via their free amino groups include the use of glutaraldehyde, or of negatively charged ions such as polyphosphate. These techniques have been used to increase the viscosity and trap active molecules in the chitosan matrix. This approach has been shown to provide controlled release properties.[7] In a process called complex precipitation, oil microcapsules have been prepared by using anionic emulsifiers to precipitate the chitosan in the form of a membrane surrounding the active.[8][9]

Figure 12.2 ATRA permeation through a skin explant model using Franz diffusions cells for free retinoic acid (open squares) or chitosan-entrapped retinoic acid (full triangles or diamonds) as a function of the concentration of high molecular weight chitosan (HMW).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS and capable of entrapping a variety of oil-soluble active agents.[4][12][13] Skin irritation by surfactants and secondary emulsifiers. Skin irritation by actives has also been attributed to the use of surfactants, or secondary emulsifiers, used in standard formulations such as creams or gels. These emulsifiers can cause the disruption of skin lipids, or induce excessive percutaneous penetration of the active ingredient. The increased penetration induced by surfactants is largely due to their strong interaction with components of the stratum corneum. In particular, it has been shown that binding of keratin filaments to surfactants induces denaturation of the proteinaceous matrix.[14] Denaturation has also been shown to be a result of solubilization and removal of the intercellular lipids by surface active agents.[15]

Figure 12.3 Skin distribution of all-trans-retinoic acid (ATRA) after 200 hours.

Complex coacervation also yields stable delivery systems that can successfully entrap active substances. In this process, precipitation of the polymer encapsulating the active ingredient is brought about by the addition of an oppositely charged polymer.[10] Complex coacervation is generally applied to the encapsulation of lipophilic materials emulsified in an aqueous solution of polymers. Such solutions are employed to form the wall of the resulting microcapsules. It is generally possible to produce, by complex coacervation, capsules with sizes ranging from 10 to 100 µm. Alginic acid has been used to form complex coacervates with chitosan and form highly stable microcapsules.[11] This process involves the use of a high viscosity chitosan solution, which is first combined with oil soluble active agents and then dispersed in a suitable solvent to form a matrix. This matrix can then be precipitated, under vigorous stirring conditions, in the presence of anionic polymers, and at higher pH values in order to form micron size particles (Fig. 12.4). The resulting microcapsules produced by this method contained a highly viscous core. They were found to be highly stable,

A particulate delivery system was developed without the need for surfactants, or emulsifiers, in a gel system. Chitosan particles containing retinoic acid (0.05%) were made using a Model 110Y Microfluidizer (Microfluidics Corp., Newton, MA) and suspended in a standard gel formulation.[13] Standardized in vivo toxicity tests were performed to measure irritation and edema using the scoring system shown in Table 12.1. In vivo toxicity tests indicated a significant decrease in both erythema and edema for the chitosan particles containing retinoic acid compared with the free retinoic acid formula as shown in Table 12.2. Patch testing on humans also confirmed the relative safety of the chitosan-based delivery system within a standard Carbopol® gel formulation.[4]

Figure 12.4 Encapsulation of active ingredients in a chitosan coacervate matrix.

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Table 12.1. Scoring System for Irritation and Edema

Level

Irritation

Edema

0

No erythema

No edema

1

Very slight erythema

Barely perceptible edema

2

Well defined erythema

Slight edema

3

Moderate to severe erythema

Moderate edema

4

Severe erythema

Severe edema

Table 12.2. Average Erythema and Edema Scores at Ten Days Post Treatment

Group Number

Average Erythema (n = 8)

Average Edema (n = 8)

Comment

1. Vehicle

0.125

0

No erythema/edema

2. Vehicle + chitospheres

0

0

No erythema/edema

3. Vehicle + chitospheres + ATRA (100 human dose)

0.125

0

No erythema/edema

4. Vehicle + chitospheres + ATRA (500 human dose)

0.875

0.25

Very slight erythema; no edema

5. Positive control (free ATRA) (500 human dose)

2.125

1.875

Well defined erythema; slight edema

12.2.2 Stability of the Active Ingredient Retinol, also known as vitamin A, is a fat-soluble isoprenoid. The advantages of retinol in skin care have been known for some time. These effects are largely attributable to the fact that retinol promotes the growth, differentiation and preservation of epithelial tissue.[16] Accordingly, the use of retinol-containing materials, particularly in so-called anti-aging products like Vichi’s “Reti-C Concentre with Vitamin C” or Roc’s “Retinol-concentre bi-actif with AHA” is very popular. A disadvantage of retinol, when used by itself, is its photochemical instability. Under the influence of light, especially at elevated temperatures, the material is rapidly degraded. In the cosmetics field, attempts have been made to solve the problem of retinol’s inadequate stability in a variety of ways. These include, for example, storage of the material under inert conditions, addi-

tion of antioxidants such as vitamin E or BHT, and the use of lightproof packs. However, it has been found that only encapsulation of retinol in a matrix has proved to be of any practical value. Comparison of different matrix materials has shown that a chitosan matrix is ideal for preparing retinol-containing microcapsules that are clearly superior to known products. Retinol delivery, using chitosan-based microspheres, provides significantly more active retinol to the skin than other commercially available retinol delivery systems. Chitosan-based systems have been shown to be superior to phospholipid-based liposomes (Sphere Tech), collagen-based Thalaspheres® (Coletica), and sphingolipid-based sphingosomes (Lipotec). When chitosan-based microspheres are employed as a delivery system for retinol, skin care preparations also show significantly greater activity than products containing commercially available retinol microcapsules.

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As shown in Fig. 12.5, retinol entrapped in 3% high molecular weight (HMW) chitosan was highly stable at 40°C. In this work, the concentration of retinol was measured by HPLC using UV detection at 328 nm. Similar results to retinol were obtained with alltrans-retinoic acid (ATRA) (Fig. 12.6).

12.2.3

No Ghosting

Long-acting porous particulate formulations generally leave an undesirable residue after topical

application. This residue is commonly referred to as ghosting. One way to eliminate ghosting is to use bioadhesive polymers that enable the particles to attach to the skin tissue. Bioadhesiveness results from ionic or hydrophobic interactions between the polymer and the proteins and lipids which compose the stratum corneum. In addition, bioadhesive delivery systems may prolong the contact between the drug and the stratum corneum, and thereby enhance the “reservoir” effect. The reservoir effect is a result of the stratum corneum acting as a reservoir for compounds that have penetrated into the stratum corneum but have not been further absorbed into the body. Albumin, starch, diethylaminoethyl (DEAE)-dextran, and chitosan are some of the polymers which have been used to enhance the bioadhesive properties of particulate delivery systems. Use of such materials increases bioadhesiveness and allows transmucosal delivery of peptides and proteins that do not normally cross the mucosal membrane of the skin.[17]–[19]

Of the several types of cationic polysaccharides, chitosan is unique in that it possesses both nonionic hydrophobic functionality as well as a hydrophilic cationic charge. Chitosan, through its cationic glucosamine groups, interacts with keratin, an anionic protein found in the skin. This interaction confers Figure 12.5 Stability of retinol encapsulated in a high bioadhesive characteristics to systems that employ viscosity chitosan matrix (3% HMW) at 40°C as it. In addition, when not deacetylated, the acetamino measured using UV absorbance at 328 nm. groups of chitosan are an interesting target for hydrophobic interaction with the skin lipids. This type of interaction also contributes, in some degree, to its observed bioadhesive characteristics.[20] Complex coacervates of chitosan and anionic surfactants have also been used to prepare microcapsules with strong bioadhesive properties. [8] Unexpectedly, chitosan microcapsules containing retinol, or retinoic acid, have been shown to provide a higher degree of fusion with the skin when the particle size of the microcapsules is reduced. Such considerable size reduction to form nanocapsules (“bio-vectors”) is typically obtained by means of an extrusion Figure 12.6 Stability of ATRA at 40°C in a 3% high molecular weight using a Microfluidizer, or a high-

(360,000 Dalton) chitosan matrix.

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279

pressure homogenizer.[13] Lancome has recently introduced a cosmetic product called “Primordiale” based on vitamin E nanocapsules. This product is made by the Eurand Company who claims to achieve deeper skin penetration.[24]

12.2.4

Biodegradability

Natural and synthetic polymers that are biodegradable may offer advantages over nonbiodegradable polymers for cosmetic delivery vehicles. In one study, a hyaluronic acid biopolymer was shown to penetrate and disseminate through all layers of intact skin in both mice and humans. Results showed the biopolymer reached the dermis within thirty minutes of application in mice.[21] In this work, cellular uptake of [3H-Hyaluronan] was also observed in the lymphatic endothelium. Whether nonbiodegradable polymers can also penetrate the skin is not known at this time. It is believed that no mammalian enzymes exist that are capable of degrading such polymers and, therefore, the polymers could accumulate in the various body tissues. It is possible that some nonbiodegradable polymers may be retained by the reticuloendothelial system, with uncertain long-term consequences such as occlusion of blood vessels. Unlike nonbiodegradable polymers, a biodegradable polymer would be advantageous as a cosmetic delivery system when used alone, or complexed with other biodegradable polymers. Chitosan is a fully biodegradable natural polymer of marine origin. It is degraded internally by mammalian enzymes such as lysozyme, glucosaminidases, and lipases into glucosamine and N-acetylglucosamine fragments.[22][23] As such, use of this polymer, in the described delivery system, offers an excellent opportunity to formulators willing to go beyond traditional techniques of incorporating functional actives in cream and gel emulsions.

12.3 Chitosphere™ Topical Delivery Technology Chitosphere™ is an encapsulation technology based on chitosan. It is designed to entrap hydrophobic substances when used alone, or dispersed in an oil phase (Fig. 12.7).

Figure 12.7 Microscopic observation of Chitospheres™ containing retinoic acid and soybean oil (average size = 50–150 µm).

One advantage of Chitospheres is their ability to separate lipophilic components from aqueous ones. This capability prevents unwanted side reactions. Examples of these include oxidation and degradation processes that can compromise the formulation stability. In addition, this novel technology allows formulators to deliver desired active ingredients from skin and hair treatment products without using traditional emulsion product forms. As a benefit of this approach, the need for surfactants, or secondary stabilizers, is eliminated. Further, inherent problems associated with the use of such surface active agents, such as disruption of skin lipids, or excessive transport of irritating topical ingredients, are also avoided. Chitospheres are completely resistant to the high shear rate typically imposed during manufacturing. They are stable when exposed to both high temperatures and to a wide range of pH values. The products are easily absorbed by the skin and do not leave a ghosting residue. There are several variations of Chitospheres available commercially. These include, for example, Chitospheres containing vitamins and their derivatives (such as vitamins A, E, K) as well as Chitospheres containing antioxidants (such as alphalipoic acid), UV absorbers (such as octylmethoxycinnamate), and fragrance oils (such as mint). Formulators seeking to have their favorite lipophilic active incorporated in Chitospheres can have them prepared up to a level of 10%, on a custom basis.

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12.4 Conclusions Chitospheres™ are cosmetic delivery systems. They are biodegradable, have a good cosmetic feel, do not produce “ghosting” and provide reduced skin irritation side effects that may result from certain actives. This novel delivery system enhances the stability of the active ingredient without the use of

surfactants or emulsifiers. Chitosphere technology is a promising new step beyond the traditional emulsion techniques. Chitospheres offer one example of an acceptable cosmetic delivery system that can be easily incorporated into formulations and provide customers with distinct product improvements and differentiation from competitors.

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281

12.5 Formulation

vitamin in chitospheres, its stability is greatly increased.

Formulation 12.1 is a vitamin E moisturizer. Vitamin E in its native form is an excellent antioxident and free radical scavenger. The main drawback with vitamin E is its poor stability. By incorporating this

Disclaimer: IVREA Laboratories does not guarantee the performance of the final product since minor changes in the formulation’s procedures will affect the final outcome.

Formulation 12.1: Vitamin E Moisturizing Gel

Phase

A

Ingredient

Weight %

Deionized water

86.8

Disodium EDTA

0.1

Sodium alginate (Protanal LF10/60; FMC biopolymer)

1.0



Aloe Barbadensis (Activera 100-200C; active organics)

0.5

Xanthan gum (Keltrol T; CP Kelco)

0.5

B

Triethanolamine

0.1

C

Vitamin E Chitosphere

D

Preservatives

10.0 1.0 Total

100.0

Mixing Procedure 1. Weigh the Phase A ingredients into a suitable vessel equipped with a mixer. Dissolve the mixture at room temperature until uniform. 2. Add Phase B to adjust the pH to 7.0. 3. Separately add the Phase C ingredient under vigorous stirring conditions until a homogenous mixture is formed. 4. Mix Phase D for the final preparation. Disclaimer This formulation is provided courtesy IVREA Laboratories, Inc. The information contained in this formulation is for illustrative purposes only. The author is not responsible for ingredients protected under patent for which licensing from the manufacturer may be required.

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References 1. G. Siegenthaler, et al., Topical Retinaldehyde on Human Skin: Clinical and Biological Observations, Retinoids: From Basic Science to Clinical Applications, p. 329, Birkhauser Verlag, Basel, Switzerland (1994) 2. R. Won, et al., U.S. Pat. 5,955,109 (1999) 3. P. A. Lehman, et al., J. Invest. Dermatol., 91:56-61 (1988) 4. M. V. Cattaneo and M. F. Demierre, Drug Del. Technol., 1, 45 (2001) 5. L. L. Balassa, U.S. Pat. 3,632,754 (1972); L. L. Balassa, U.S. Pat. 3,903,268 (1975) 7. J. Akbuga and N. Bergisadi, J. Microencapsulation, 13, 161 (1996) 8. S. Magdassi, et al., U.S. Pat. 5,753,264 (1998) 9. V. Sovilj, et al., J. Colloid Interface Sci. 158(2), 483 (1993) 10. C. Thies, Polym Mater. Sci. Eng. 63, 243 (1990) 11. O. Gaserod, et al., Biomaterials 20, 773 (1999) 12. M. V. Cattaneo and M. F. Demierre, U.S Pat Appl. 20030206958 (2003)

13. M. V. Cattaneo, Abstract No. 3031, AAPS National Biotech Conference, Boston, MA, (May 16-19, 2004) 14. M. M. Breuer, J. Soc. Cosmet. Chem., 30, 41 (1979) 15. M. K. Bahl, J. Soc Cosmet. Chem., 36, 287 (1985) 16. J. Varani, et al., J. Invest. Dermatol., 114, 480 (2000) 17. L. Illum, et al., Pharm. Res., 11, 1186 (1994) 18. L. Illum, et al., Int. J. Pharm., 39:189 (1987) 19. L. Illum, U.S. Pat. 5,554,388 (1996) 20. R. A. A. Muzzarelli, et al., Chitin and Chitinases, p. 251, Birkhauser Verlag Publ., Basel, Switzerland (1999) 21. T. J. Brown, et al., J. Invest. Dermatol., 113, 740 (1999) 22. H. Onishi, and Y. Machida, Biomaterials, 20, 175 (1999) 23. H. Sashiwa, et al., Chitin Enzymology, p. 177, Atec, Grottamare (1993) 24. Product of the Eurand Company: French agents for the cosmetic industry: SEDERMA

Part V Liposomes

Liposomes in Personal Care Products

LIPOSOMES

Interactive Vehicles in Synergistic Cosmeceuticals: Advances in Nanoencapsulation, Translocation, Transfer and Targeting

13 Liposomes in Personal Care Products Vitthal S. Kulkarni DPT Laboratories, Ltd. San Antonio, Texas

13.1 Introduction ................................................................................... 285 13.2 The “Lip-O-Somes” ...................................................................... 286 13.3 Lipids and their Self-Assembly ..................................................... 287 13.4 Liposomes: Production Methods .................................................. 288 13.5 Encapsulation/Loading of Actives in Liposomes .......................... 290 13.6 Characterization of Liposomes .................................................... 292 13.7 Formulating with Liposomes ........................................................ 295 13.8 Liposomes: Applications in Personal Care Products ................... 297 13.9 Liposomes: Future Trends ........................................................... 298 References .......................................................................................... 299

13.1 Introduction The term “lipids” encompasses a broad range of fatty organic compounds of plant or animal origin. Generally, these compounds are soluble in organic solvents and their physical state is that of oils or waxes. The lipids can be broadly classified into four categories: • Simple lipids: that include long chain fatty acids, -alcohols, -esters, -amines and sterols. • Phospholipids: glycerol based lipids which are abundant in the cell membranes.

• Sphingolipids: sphingosine based lipids that have very distinguished structural and functional roles. • Complex or miscellaneous lipids which consist of bacterial membrane lipids, polymeric lipids, and others. The bacterial membrane lipids have unusual properties and functions that help bacteria to survive in extreme environments. However, commercial applications of bacterial lipids are as yet vastly unexplored.

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 285–302 © 2005 William Andrew, Inc.

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13.2 The “Lip-O-Somes” Although the discovery of lipids dates back to 1811, it was recognized in 1930s–1940s that the phospholipids are the basic building blocks of cell membranes and that they are systematically organized in a bilayer form.[1] Alec Bangham and his group at Babraham Institute of Animal Physiology, Cambridge, England, was intrigued by the peculiar properties of aqueous dispersions of ultrapure lecithin. During 1961–1963, Bangham and his team examined such phospholipid dispersions using an electron microscope. It was soon clear that phospholipids in water formed “bag-like” structures that conformed very closely to what they had envisioned. One of their most dramatic electron micrographs encouraged them to believe that the phospholipid dispersions could be a good model for a cell membrane. The electron microscope experiments by Bangham and his team indicated that simple shaking of pure lecithin in water would ensure the spontaneous formation of an unlimited number of closed membranes. Their now famous article on this subject was published in 1965. In this article, they claimed that over a wide range of variables such as composition, concentration, temperature and pressure, ultrapure lecithin in aqueous systems spontaneously formed concentric-bimolecular layers wherein each layer was separated by an aqueous compartment. This article later received the “Citation Classic” award.[2] In the summer of 1964, Dr. Gerald Weissmann (New York University) went to Dr. Bangham’s laboratory in England to investigate whether agents like steroids and lytic toxins that disrupted lysosomes in cells would also disturb the “closed bag-like” structures formed by lipids in aqueous media. The results were very encouraging and indicated that the steroids and toxins interacted in a similar manner with the hydrated lecithin structures just as they would with the lysosomes. Later that summer, during a lunch with Dr. Bangham at a pub in Cambridge, Dr. Weissmann came up with a name and called the “closed bag-like” structures “liposomes.” The first syllable of this term is pronounced like lip as in upper lip; not like lye as in lysosome.[3] However, it took several years for Dr. Weissmann to get the name “liposomes” accepted by the scientific community. The first formal reference to “liposomes” appears in a 1968 paper entitled “Phospholipid spherules (li-

posomes) as a model for biological membranes” authored by Dr. Weissmann and his post-doctoral colleague Grazia Sessa. The paper was published in the Journal of Lipid Research.[4] The liposomes are generally classified by grouping them based upon their lamellarity, size, charge, and functionality. Suspensions of pure lecithin in water typically yields liposomes with concentric bilayers (lamellae) wherein each bilayer is separated from the next one by an aqueous region and are termed multilamellar vesicles (MLV). When small vesicles are trapped within the large vesicles, the complexes are known as multivesicular vesicles (MVV). Liposomes consisting of only one bilayer are called unilamellar vesicles. The unilamellar vesicles with a diameter of 20–100 nm (due to geometric constraints, liposomes <20 nm can not exist) are often referred to as small unilamellar vesicles (SUV). The unilamellar vesicles of 100–1000 nm size are known as large unilamellar vesicles (LUV) and LUV with >1000 nm are called giant unilamellar vesicles (GUV). Giant liposomes of up to 100-µm size have been reported.[5][6] The LUV can be further grouped into four subcategories based upon their functionality. These include conventional liposomes, stealth liposomes, cationic liposomes, and targeted liposomes. Conventional liposomes are the most common type. These consist of phospholipids with “cargo” (i.e., the actives) encapsulated in the internal aqueous compartment. Liposomes coated with certain proteins, or polymers such as polyethylene glycol, are known as stealth liposomes. Liposomes with cationic charge at the surface are called cationic liposomes and these have shown good potential as gene delivery systems. Unilamellar liposomes consisting of certain special lipids, including glycosphingolipids such as gangliosides (or other headgroup-modified lipids) in the outer monolayer bind to specific cells. Liposomes engineered in this manner are known as targeted liposomes and utilized for preferentially targeting certain cells. Liposomes were first envisioned as safe delivery vehicles probably because of their three main characteristics. They are typically small in size and fall in the range of about 25 to 1000 nm and easily disperse in the aqueous medium. Second, their closed bilayer structures are capable of encapsulating water-soluble drug molecules in their aqueous core and

KULKARNI: LIPOSOMES IN PERSONAL CARE PRODUCTS oil-soluble active ingredients in the hydrophobic region of the bilayer. The third characteristic is that they closely resemble the cells and cell membranes there by suggesting little intrinsic toxicity. Probably based on these attributes, in early 1970s it was thought that liposomes could be used as drug delivery vehicles.[7] In 1980, Mezei and Gulasekharam[8] suggested for the first time that liposomes could also be used as topical delivery vehicles for use in skin care. Several researchers around the world have investigated liposomes and reported that liposomes are efficient drug delivery systems for topical applications in cosmetic or dermatological products.[9][10] Liposomes based on marine-derived lipids have been explored for cosmetic applications.[11] Recent review by Baca-Estrada,[12] et al., suggests that liposomes have good potential as vaccine delivery systems. Scientists are also experimenting on liposomes in the context of the space age. The effects of microgravity on the formation of liposomes has been studied and results suggest that liposomes prepared at low gravity in space by a detergent dialysis method, were much smaller (<150 nm) than those prepared during the space flight by the same method.[13] These experiments may one day lead to the better engineered liposomes.

287

13.3 Lipids and their SelfAssembly As noted earlier, phospholipids are the building blocks of cell membranes. In order to better understand the structure of liposomes we will first begin with a description of a typical phospholipid molecule, which is shown in the Fig. 13.1. The molecule has a “headgroup” which is hydrophilic in nature (water-loving) and a hydrophobic (water-hating) “tail” consisting of two acyl chains. When one of the acyl chains of the phospholipid molecule is clipped, the resulting lipid molecule is known as a “lyso-lipid.” Since the two opposing types (hydrophilic and hydrophobic) of groups are present on a single molecule, such molecules are generally termed as “amphiphiles.” This term implies that both water-hating and water-loving moieties are present on the same molecule. Surfactants, detergents, lipids, cholesterol, bile acids, and similar synthetic molecules are included in amphiphiles. Aqueous solubility of an amphiphile depends on both the length of the hydrophobic tail and the affinity of the headgroup to water. Pure lipids with each acyl chain containing 14 or more carbons in the form of a straight chain (unbranched) with saturated C–C

Figure 13.1 A typical phospholipd (1,2 diacyl phosphatidylcholine) molecule. The “head group” is the water loving (hydrophilic) part of the molecule while the “tail” is the water hating (hydrophobic) part.

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bonds are water insoluble. Table 13.1 provides the critical micelle concentration (CMC) of a few lipids and common surfactants. The table indicates that as the acyl chain-length of the lipids increases, the CMC decreases rapidly. The table also shows that the CMC of common, naturally occurring lipids is extremely low compared to that of common surfactants. The very low CMC observed for naturally occurring lipids suggests that, for the practical purposes, the concentration of individual phospholipids in an aqueous system is negligible. As a result of the presence of the both hydrophobic and hydrophilic groups, all amphiphiles in an aqueous phase self-assemble into one of several possible forms of microstructures. The shape of the resulting microstructure depends upon the type of the amphiphile. An approximate correlation between the geometrical shape of an amphiphilic molecule and the corresponding shape of the self-assembled microstructures is shown in the Table 13.2. Although, the geometrical shapes of amphiphiles contribute to the final shape of the selfassembled microstructures, the real driving force behind the formation of self-assembled structures is the molecular interactions between amphiphile-surrounding-aqueous-media and interactions between amphiphile-and-amphiphile.[15] Kulkarni, et al.,[16] have reported that a small change in the chemical structure of a lipid can cause major changes in the resulting self-assembled microstructures.

Upon hydration, phospholipids having acyl chains of 12 or more carbon atoms are observed to instantly self-assemble into closed bilayers called vesicles or liposomes. As described previously, the crude dispersion of liposomes can be in form of multilamellar vesicles (MLV) and multivesicular vesicles (MVV) of varying size. Further processing is required to produce unilamellar liposomes of uniform size.

13.4 Liposomes: Production Methods There are three general methods employed to produce liposomes on small scale for research purposes. These are typically known as: • Hydration of dry lipid film: Hydrate dry lipid film formed on walls of the flask using appropriate buffer solution. • Ethanol injection: Inject ethanolic solution of lipids into rapidly stirred aqueous buffer phase. • Detergent dialysis: Use a suitable detergent, such as octyl glucoside, to solubilize the dry lipid in buffer solution followed by dialysis to remove the detergent.

Table 13.1. The Critical Micelle Concentration (CMC) of a Few Lipids and Common Surfactants (Data obtained from Jones and Chapman [14])

CMC (mM)

Phospholipids (lecithins) with phosphatidylcholine head group

Surfactants (in water at 20°C–25°C)

Dibutanoyl lecithin (di C4)

80

Dihexanoyl lecithin (di C6)

14.6

Diheptanoyl lecithin (di C7)

1.42

Dioctanoyl lecithin (di C8)

0.265

Dinonanoyl lecithin (di C9)

2.87 × 10-3

Dipalmitoyl lecithin (di C16)

2.0 × 10-8

Sodium n-octylsulphate (anionic)

130

n-Dodecyltrimethylammoniumbromide (cationic)

14.8

n-Octyl β-D-glucopyranoside (nonionic) Triton X-100 (nonionic)

23 0.24

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Table 13.2. A General Correlation Between the Geometrical Shapes of Amphiphilic Molecules and the Corresponding Shapes of Self-assembled Microstructures

Amphiphiles

Geometrical Shapes of the Amphiphiles

Types of Microstructures Formed Upon Hydration

Single chain surfactants

Spherical micelles

Double chained amphiphilic molecules like di-acylphosphatidylcholine

Bilayer vesicles (liposomes) or planer bilayers

Phospholipids with small head group like diacyl phosphatidylglycerol or diacyl (PG) phosphatidylethanolamine (PE)

Diacyl PE forms Inverted hexagonal phases (HII) at high temperature

Note: This correlation is rather crude and may work with only pure surfactant molecules. Impurities or mixtures of the surfactants may not follow the predicted pattern. Formation of the microstructure self-assembly strongly depends on the intermolecular interactions between the amphiphiles and amphiphiles-surround-aqueous-media, not merely on the geometrical shapes.

For small scale research work, typically lipids are first dissolved in an organic solvent and the solution is placed into a round bottom flask. Using a rotary evaporator, the solvent is removed. This process leaves a uniform film of lipid on the walls of the flask. By subjecting the flask to high vacuum, this film is further dried in order to remove the traces of organic solvents. The dried lipid film is then hydrated with an aqueous phase (a suitable buffer; typically 10 mM phosphate buffer at pH 6.5), which is held above the gel-liquid crystalline phase transition temperature of the lipid (refer to Table 13.4). This procedure will instantly produce a heterogeneous mixture of MLV and MVV. Dispersions thus obtained are subjected to five to ten freeze-thaw cycles (thaw-

ing to a temperature greater than the phase transition temperature; see Table 13.4). This procedure helps to uniformly distribute the buffer solutes across the bilayers. The resulting crude dispersion of liposomes can then be subjected to extrusion through a membrane of known pore size or subjected to probe sonication in order to produce LUV or SUV, respectively. There are two other commonly used methods for the laboratory scale production of liposomes. One of the methods is injection of an ethanolic solution of lipids into a rapidly stirring aqueous phase. Alternatively, in the detergent dialysis method, lipids are first dissolved in an aqueous phase using a surface active agent such as octyl glucoside. Then

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removal of the detergent by dialysis produces liposomes in the dialysis bag. These laboratory methods of liposome production have limited scope and are not useful for large-scale industrial production. Recently, however, liposome extruders of 800 ml capacity have been introduced to the market by Lipex Biomembranes, Inc., Canada. Another company, Harvard/AmiKa Liposomes, has introduced a continuous dialysis unit called a “Liposomat.” A more suitable method for large-scale production of liposomes is “microfluidization.” This process is similar to the “French Press” method.[17]-[19] The microfluidization process has the advantage of being capable of continuous mass production of liposomes. High concentrations of lipids in aqueous phase can be used in the process and it requires no organic solvent to dissolve the lipids. As a result, microfluidization is highly applicable for use in cosmetics and food technology applications. In this method, slurry-like concentrated lipid/water dispersions are introduced into the microfluidizer which then pumps it at a very high pressure (10,000 to 20,000 psi) through filters of 1–5 µm pore size. The fluid moving at a very high velocity is split into two streams by forcing them through two defined microchannels. The two streams are then made to collide together at right-angles at very high velocity. The tremendous energy imparted by the high pressure and high velocity causes the lipids to self-assemble into liposomes. The fluid collected at the end is re-passed until a homogeneous-looking dispersion is obtained. The microfluidization technique typically produces unilamellar liposomes of 50 to 500 nm diameter. The size of the liposomes can be roughly controlled by the processing pressure at which a microfluidizer is operated. Liposomes of larger size may be obtained by reducing the processing pressure.[19] However, the microfluidization method also has its own limitations. It has a high production cost since it requires expensive equipment. Certain active ingredients, particularly proteins/enzymes or similar biological actives, may break down under the high processing pressure which makes the microfluidization technique unsuitable for such actives. Further, because very high energy is imparted on the lipids during microfluidization, this method of liposome production may not be suitable for producing multilamellar liposomes. Methods of preparation of different types of liposomes, along with general characteristics of each category of liposomes, are summarized in Table 13.3.

The table shows the major types of liposomes (lipid vesicles) based on their sizes, general methods of preparation, corresponding approximate encapsulation volume, encapsulation efficiency, and calculated number of POPC (1-palmitoyl, 2-oleoyl phosphatidylcholine) molecules in the different types and sizes of liposomes made from POPC. The actual captured volume or encapsulation efficiency varies depending on the method of preparation of liposomes, type of the lipid, and the active itself. The type and amount of the payload influences the stability of the liposomes. The encapsulation efficiency of the oilsoluble actives is nearly 100% because these actives reside in the hydrophobic region of the bilayer. However, the payload of the oil-soluble active may not exceed 2%–5% of the total formula weight including active, lipid, and aqueous phase. The last column in the table shows the calculated number POPC molecules per POPC liposome of specific size. However, Hauser[1] has reported the molecular weight of SUV (size not specified) of egg PC (which is enriched with POPC) to be 2.5 × 106 to 2.7 × 106 Da. Assuming that only the phospholipid molecules contributed to the molecular weight of the liposome, the experimentally determined molecular weight will roughly correspond to 3 × 103 to 4 × 103 phospholipid molecules per liposome which is slightly higher than the calculated value of POPC SUV provided in the table. The data in Table 13.3 were compiled from Walde and Ichikawa,[20] and Puisieux and Poly.[21]

13.5 Encapsulation/Loading of Actives in Liposomes Both hydrophobic and hydrophilic actives can be encapsulated into liposomes. If water-soluble actives are encapsulated during the process of liposome preparation, it is known as “passive loading.” It can be achieved by pre-dissolving the hydrophilic active(s) in a buffer that is to be used for hydration of the dry lipid. Any non-encapsulated active can thereafter be removed by dialyzing against the blank buffer, or by passing the dispersion through a Sephadex™ gel column. For most cosmetic and personal care products, removal of non-encapsulated actives is not considered critical since there is a high cost associated with such processing, and cosmetic

Table13.3. Methods of Preparation, Characteristics, and Calculated Number of POPC (1-palmitoyl, 2-oleoyl phosphatidylcholine) Molecules of Major Types of Lipid Vesicles (Data Compiled from Walde and Ichikawa,[20] and Puisieux and Poly[21])

Type of Liposomes (Vesicles)

Methods of Preparation

Encapsulation volume µl/µmole lipid

Encapsulation efficiency, % active encapsulated (water soluble)

Calculated number of POPC molecules in the POPC liposomes

0.2 to 0.5

up to 15

SUV: 2.4 × 103 (20 nm)

2–7

up to 50

LUV: 8.1 × 104 (100 nm), 3.4 × 105 (200 nm)

up to 60

MLV: 7.2 × 107 (1 µm w/10 layers), 3.2 × 108 (2 µm w/10 layers)

up to 60

GUV: 3.5 × 106 (1 µm), 3.5 × 107 (2 µm), 3.5 × 109 (20 µm)

Probe sonication followed by ultracentrifugation to collect vesicles of 20–50 nm Small Unilamellar Vesicles (SUV); 20–100 nm

Ethanol injection or detergent dialysis followed by extrusion through <100 nm membrane and ultracentrifugation French Press or microfluidization and harvesting by ultracentrifugation

Large Unilamellar Vesicles (LUV); 100–1000 nm

Ethanol injection or detergent dialysis followed by extrusion French Press or microfluidization Hydration of dry lipid film followed by 3–10 freezethaw (thawing to >Tm) cycles

Multilamellar Large Vesicles (MLV); 100–1000 nm Dehydration-Rehydration Vesicles (DRV): liposomes are stored freeze dried , rehydrated when required

2.5–6

Reverse-phase Evaporation Vesicles (REV): lipid is dissolved in organic solvent that is immiscible with water to make an emulsion followed by removal of the organic solvent under vacuum results in vesicles of >1 µm size Giant Unilamellar Vesicles (GUV); >1000 nm

Interdigitated-Fusion Vesicles (IFV): ethanol is added to SUV prepared using saturated long chain PC like DPPC which leads to the formation of lamellar sheets characterized by interdigitated acyl chains. Upon cycling the temperature (>Tm to 1 µm are formed

as high as 720

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actives are theoretically non-toxic at the levels they are commonly used. By contrast with the hydrophilic actives, which are entrapped within the core of the liposomes, hydrophobic actives are typically entrapped in the hydrophobic region of the lipid bilayers. The process involves a partitioning method wherein the hydrophobic actives are dissolved in a suitable organic solvent, along with the lipid. Thereafter, the solvent is removed by drawing a vacuum, then followed by hydration of the lipid. If the active is soluble in ethanol, it can be dissolved along with the lipid in the ethanol; liposomes are then produced by the ethanol injection method. In “active loading,” also referred to as “reverse loading,” a pH or ionic gradient is first generated between the inside and outside of the liposomes. “Blank” (empty) liposomes are first prepared in a low pH (citrate buffer, pH = ~4). Thereafter, a high pH (pH = ~7.4) buffer containing the active (e.g., weak organic acid) is then added to the blank liposomes. As a result of pH gradient, actives such as weak acids partition in the internal core.

the properties of the active to be encapsulated are also important factors that contribute to the encapsulation efficiency. Both water-soluble payloads (due to interactions with the lipid headgroups), and hydrophobic payloads (due to interactions with the fatty acyl chains of the bilayer membrane) influence the molecular packing of the lipid bilayer. Ultimately, these factors impact the stability of liposomes. The concentration of active encapsulated inside liposomes is an important parameter, particularly in pharmaceutical applications. “Capture-volume capacity” of liposomes is measured in µl/mmole of lipid (see Table 13.3), and encapsulation efficiency is described in terms of the percentage (i.e., percent encapsulated compared to the total amount of active used for encapsulation). Among the several methods reported to determine the capture-volume capacity of liposomes,[22] the fluorescence method reported by MacDonald’s group [23] is quite useful in view of its simplicity and the fact that the separation of non-encapsulated dye is not required.

There are several methods to load enzymes in lipid vesicles and these have been reviewed by Walde and Ichikawa.[20] They include detergent dialysis, solvent evaporation, and dehydration-rehydration techniques. However, most of the methods listed by these authors have only been evaluated on a laboratory scale (usually a few milliliters). The encapsulation and stability of enzymes beneficial for skin care products (e.g., antioxidants including superoxide dismutase, glutathione peroxidase, and metallothionein), is considered worthy of future investigations. Although topical treatment by delivering DNA to skin is far from a routine practice, it is well established that cationic liposomes can be efficient vectors for delivering DNA to cells. DNA fragments can be loaded on the cationic liposomes by simple hand-shaking of DNA and liposome solutions. The DNA attaches to the surface of the positively charged liposomes and may not, necessarily, penetrate inside the liposomes. Such liposome-DNA complexes are termed lipoplexes.

Liposomes may be characterized for their size, lamellarity, capture volume capacity, and chemical integrity of the lipids. Chemical analysis of liposomes sheds light on the purity of lipids and can quantitatively reveal the absence or presence of degradation products formed by unintended lipid hydrolysis or peroxidation. The hydrolysis of lipids leads to the formation of lyso-lipids. As the concentration of lysolipid increases in a given solution of liposomes, the bilayer structure of the liposome is eventually disintegrated and the undesirable formation of micelles takes place. The hydrolysis of lipids depends on the pH of the media employed. Reported data indicate that, at pH 6.5, lipid hydrolysis is minimal.[24] This suggests that a pH of 6.5 is the most ideal for preparation of liposomes with optimal stability.

Factors that influence encapsulation efficiency of actives include lipid composition used for liposome preparation, type of liposomes (SUV/LUV/MLV), method of liposome preparation, and liposome charge. Buffer strength (buffers of higher strength reduce the amount of resulting encapsulation) and

Lipids with unsaturated acyl chains tend to oxidize due to the presence of oxidizing agents present in the media. This process results in fragmented acyl chains which contribute to the destabilization of the bilayer structure of the liposomes. It is, therefore, very important to provide an optimum pH range as

13.6 Characterization of Liposomes

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well as the presence of antioxidants in liposome products in order to reduce foreseeable hydrolysis and oxidation. Ultraviolet (UV) spectra of an ethanolic solution of a lipid can reveal if the lipid is oxidized. An absorbance at 230 nm will suggest the presence of conjugated dienes, while absorbance between 270 and 280 nm will indicate the presence of conjugated trienes and this suggests that degradation of the lipid has occurred.[25] Other commonly used methods of lipid analysis include thin-layer chromatography (TLC),[26] high-performance liquid chromatography (HPLC),[27] gas chromatography,[28] nuclear magnetic resonance (NMR) spectroscopy, and differential scanning calorimetry (DSC). HPLC, using an evaporative light scattering detector, can quantitatively separate lipids with different headgroups (e.g., phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, and phosphatidyl ethanolamine), lipids with different acyl chains but with common headgroups, and the lyso-lipids. Gas chromatography analysis provides characterization of acyl chain composition of lipids. Fatty acyl chains of lipids are extracted by hydrolysis and converted to methyl esters then analyzed using gas chromatography. Lipid content in a given dispersion of liposomes is usually characterized by the phosphorus content following Bartlett assay for quantitative determination of phosphorus in the solution.[29] This method is very sensitive and measures phosphorus concentration as low as 30 nmol/ml.

require no fracturing or staining of the sample. Sample preparation for cryo-TEM is different than the freeze-fracture TEM method. For cryo-TEM, the liposome suspension is frozen on a TEM grid coated with a holey carbon film, in liquid ethane or propane and examined in the TEM using a cryostage held at liquid-nitrogen temperature. Another commonly used method for liposome size determination is light scattering (including low-angle light scattering and photon correlation spectroscopy, PCS) which is a relatively simple and rapid method compared to TEM, and it is commonly applied by quality control labs for characterization and generating specifications of liposomes in the cosmetic and pharmaceutical industries. For SUV or LUV types of liposomes, the PCS method is preferred over the lowangle light scattering method.

The size of liposomes are commonly characterized by two different methods: transmission electron microscopy (TEM) and light scattering. TEM (negative stain method and cryo-TEM) images allow accurate measurement of the liposome diameters (size) while the freeze-fracture TEM sheds light on lamellarity and surface morphology of the liposomes. Although TEM is a lengthy, tedious, and expensive technique, it provides compelling evidence for lamellarity, size, shape, and morphology of the liposomes through its ability to provide high-resolution images. In freeze-fracture TEM, a small quantity of liposome solution is rapidly frozen in liquid ethane or propane. This frozen sample is then fractured under high vacuum at liquid-nitrogen temperature and coated with a carbon/platinum film in a freeze-fracture unit (such as Balzers). The replica is, thereafter, floated on a water surface and cleaned before transferring it onto a TEM grid for examination. Cryo-TEM provides high-resolution images that

Nuclear magnetic resonance (NMR) provides a very useful tool for the study of liposomes. The 31P NMR of liposome solutions can precisely and quantitatively determine the amount of lipid in a bilayer phase as well as in a micellar phase.[30] It can also differentiate between different lipid-headgroup moieties and the other phases (such as cubic or hexagonal types) present in a suspension. Lipid thermal behavior is studied using a differential scanning calorimeter. Lipids (both dry or hydrated) exhibit unique thermal phase transition(s). The main thermal phase transition temperature (Tm) of a lipid is a very important parameter for choosing the type of lipid employed for the formation of liposomes. It is also useful for determining proper storage conditions of the liposomes. Spontaneous formation of liposomes takes place only when the temperature of the lipid/water dispersion is above the main phase transition temperature (Tm ). Below the Tm, lipids are in the gel state and above the Tm, they are in a liquid crystalline state. In the gel state, the lipid molecules are tightly packed; this suggests that in this state the hydrophobic tails of the lipids are highly ordered. By contrast with their orientation and close packing in the gel state, at temperatures greater than the main phase transition temperature, lipid molecules in the bilayer are loosely packed. At these elevated temperatures, the lipid hydrophobic tails have a higher degree of freedom than in the gel state. The thickness of the bilayer in the liquid crystalline state is relatively smaller than the bilayer thickness seen in the gel

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state. Permeability of the bilayer is higher in the liquid crystalline state than in the gel state. The thermal phase behavior of lipids reflects intermolecular interactions in the bilayer. The Tm of common phospholipids ranges from –4°C to 50°C, and depends upon chain length, degree of unsaturation in the acyl chains and the headgroup.[31] A higher Tm suggests the presence of stronger attractive inter-lipid interactions in the bilayer. Certain sphingolipids, including skin ceramides, have a very high Tm. This suggests that the ceramides have strong intermolecular interactions. Phospholipids with saturated acyl chains have a higher Tm than those hav-

ing the same number of carbon atoms with unsaturated acyl chains. The cell membranes (lipid bilayers) are generally in a liquid crystalline state which is achieved by selecting the right combination of different types of lipids, including cholesterol. The main phase transition temperatures (Tm) of some common lipids are provided in Table 13.4. In summary, testing of liposomes for lipid-hydrolysis, lipid-peroxidation, size distribution, and thermal phase transition behavior are the important factors in determining the stability, storage conditions, and the shelf-life of liposomes. The “Guidance for Industry: Liposome Drug Products,” published by

Table 13.4. Thermotropic Phase Transition Temperature (Tm) of Various Hydrated Lipids (Data from Cevc,[32] *Rinia, et al.,[33] **Tanikawa and Miyajima,[34] and Wegener, et al.[35])

Tm, oC

Lipid 1,2-C16:0 PC (DPPC)

41.5

1,2-C16:0 PE (DPPE)

65

1,2-C18:0 PC (DSPC)

55.5

1,2-C16:1c∆9 PC (DOPC)

-21

1-C16:0, 2-C18:1c∆9 PC (POPC)

0 to -5

Egg yolk PC (major acyl chains are C16:0 and C18:1c∆9)

-5 to -15

Hydrogenated egg yolk PC Soybean PC, (major acyl chains are C18:2cc∆ C18:1c∆9)

46 9,12

, C16:0 and

-10 to -20

Hydrogenated soybean PC

51

Egg sphingomyelin (n-acyl chain enriched with C16:0)*

38

Ceramide-IV (a type of skin ceramides)**

89 (anhydrous), 77.5 to 81 (hydrated)

Note: DPPC = di-palmitoyl phosphatidylcholine; DPPE = di palmitoyl phosphatidylethanolamine; DOPC = di-oleoyl phosphatidylcholine and POPC = 1-palmitoyl, 2-oleoyl phosphatidylcholine. Nomenclature: PC = phosphatidylcholine Cn:m = carbon chain length of n carbon atoms with m number of double bonds c∆x,y = cis double bond(s) at carbon position(s) x (and y) (counting from carboxyl terminal of the fatty acid)

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the Food and Drug Administration in 2002, suggests testing physicochemical properties to ensure the quality of liposome drug products. The tests, including lipid integrity, particle size, morphology of liposomes, phase transition temperature, and drug release rates, are suggested for stability study of liposome products. HPLC to determine the lipid integrity and PCS for particle size distribution are commonly employed in the pharmaceutical industry to characterize the liposomal products.

dispersions of certain commonly used cosmetic oils. Examples of such oils include polysynlane, silicone oil fluid, or hydrogenated polyisobutenes. The surface tension of water is only slightly reduced (~5–8 mN/m) when the nanodispersions of such oils are dispersed (at 1%) in water. On the other hand, when a conventional emulsion, prepared using common surfactants, is dispersed in water (at 1%), the surface tension of water is considerably reduced by 30–40 mN/m. This suggests that nanodispersions are practically free of surfactant-like molecules. Such preformed nanodispersions are demonstrated to be compatible with liposomes and will not damage their integrity. 31P NMR data of such systems showed that the 1:1 mixture of nanodispersions-to-liposomes did not disturb the integrity of the liposomes.[37] This approach of using pre-formed nanodispersions, followed by addition of appropriate thickeners in order to produce finished products, considerably enhanced the stability of liposomes. It is hypothesized (as depicted in Fig. 13.2) that the evenly distributed nanodispersion particles, which are of similar size to that of liposomes, act as “padding” between colliding liposome particles. This padding reduces direct collisions between liposome particles and thereby reduces the chances of liposome-liposome fusion. Providing a suitable polymeric matrix to the media in which the liposomes are suspended, by thickening, can further reduce the chances of liposome-liposome fusion.

13.7 Formulating with Liposomes In skin care or cosmetic products, liposomes are formulated in an appropriate matrix such as serums, lotions, gels, or creams. It is well established that liposomes consisting of phospholipids are not stable in the presence of surfactants,[36] therefore, it is challenging to formulate liposomes in personal care products since surfactants are commonly used in the preparation of personal care products. The major destabilizing factors for liposomes include surfactants, temperature, pH, and lipid peroxidation; however, proper formulation may help to enhance the stability of liposomes. The lipid molecules in bilayer membranes (liposomes) maintain a dynamic equilibrium. They move laterally in the monolayer plane and flipflop from inner monolayer to outer monolayer and viceversa. Thus, dynamic membrane processes lead to fusion of liposomes when they are in close proximity and this fusion can result in larger liposomes. The process of liposome fusion can be retarded by storage at low temperature and/or by increasing the viscosity of the (a) external media. Kulkarni, et al.,[37] have reported a novel approach of preparing topical personal care products containing liposomes using pre-formed nano-

(b)

Figure 13.2 Stabilization of liposomes with nanodispersions and appropriate thickeners. (a) The presence of nanodispersion particles (N) between the liposomes (L) reduces the chances of liposomes fusing with each other. (b) The polymeric thickeners are hypothesized to reduce the dynamics of the liposome particles thereby reducing the chances of liposome-liposome fusion, consequently extending the shelf-life of liposomes.

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Surfactants are known to vary in their ability to destabilize the integrity of liposomes and surfactant structure plays an important role in this regard. In general, nonionic surfactants are likely to be most compatible with liposomes.[38] In a study that is not directly relevant to the cosmetic applications of liposomes, London and Brown[39] have shown that detergent-resistant membranes are enriched with sphingolipids compared with detergent soluble membranes. Their results appear to suggest that liposomes made of phospholipids mixed with sphingolipids (e.g., sphingomyelin) may show greater resistance to surfactant attack than the liposomes made of phospholipids alone. The effect of the vehicle chosen for topical formulations containing liposomes has been studied by Foldvari.[40] This study showed that when liposomes were mixed at 1:1.9 (base:liposomes; w/w) in a white petrolatum cream, a dermatologically acceptable and stable dosage form was achieved. In this system, it is reported that the liposomes were uniformly distributed and their structures were preserved.[40] In a separate study, using freeze-fracture electron microscopy, Williams, et al., have shown that liposomes are stable in 2% Carbopol® gel for up to two years at 20°C.[41] However, their photomicrographs are not quite conclusive and further systematic study of the stability of liposomes in a Carbopol gel are essential. Gels prepared using 2% Carbopol are quite viscous and may not be suitable for certain types of personal care preparations such as lotions, creams, and sprays. Liposome stabilization can also be achieved through freeze-drying. The freeze-dried liposomes may then be rehydrated in order to obtain multilamellar liposomes. This process for producing liposomes is known as dehydration-rehydration vesicles (DRV). It is most suited for use with lipophilic (oilloving) actives that are encapsulated in the lipid bilayer. Water-soluble actives tend to leak out of such systems after rehydration of the freeze-dried liposomes. The efficiency of entrapment (after rehydration of freeze-dried liposomes) is reported to be dependent upon the initial size of the liposomes. Crommelin, et al.,[24] have reported that after freezedrying, 25% of the carboxyfluorescein (a watersoluble fluorescent dye) was encapsulated in liposomes of 130 nm diameter, whereas only 7% of the

dye remained encapsulated when the liposome size was much larger (280 nm). A major concern for using freeze-dried liposomes in personal care formulations is the high cost of processing. For the stabilization of liposomes in finished personal care formulations, the following parameters should be carefully considered by formulators. • Use liposomes prepared from pure lipids because impure lipids (oxidized/hydrolyzed or lipids suspended in oil/triglycerides) tend to destabilize the liposomes. • Avoid using harsh surfactants (ionic surfactants) in the preparation of the base or the vehicle in which liposomes are to be added. It is reported that creams prepared using phospholipids-based emulsifiers do not destabilize the liposomes.[41] • Use of pre-formed nanodispersions for making finished products containing liposomes is worth considering because the nanodispersions not only help to stabilize the liposomes but they also provide considerable flexibility in producing various types of finished formulations such as sprays, lotions, and creams.[37] • Avoid high temperature (> 40°C) while preparing finished products containing liposomes. Liposomes may be added to the base at the end, when temperature of base is less than 40°C. • In order to achieve optimal liposomal stability, use of antioxidants and chelating agents is recommended. • Keep the pH of the product close to neutral because it is reported that the rate of lipid hydrolysis is lowest at a pH of 6.5. • Liposome-containing products should be ideally stored at refrigeration temperatures. However, if the finished product is made sufficiently viscous using appropriate (neutral) gums or thickeners, such products may then be stored at room temperature. • The container in which the product containing liposome is to be stored should be opaque in order to avoid/reduce photodamage to the liposomes.

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13.8 Liposomes: Applications in Personal Care Products

Many dermatological studies have indicated that deeper and more rapid penetration of actives is achieved when they are encapsulated in liposomes, compared with non-liposomal formulations of the same actives. Liposomal tretinoin gel (prepared with Carbopol 934) has produced a significant improvement in the treatment of acne. This suggests a strong potential for commercial liposomal products to treat acne.[45][46] Wolf, et al.,[47] have shown that a liposomal formulation can be used for topical intracellular delivery of small proteins to human skin. This suggests that the DNA repair enzymes may provide a novel method for photoprotection against certain forms of ultraviolet-induced skin damage.[47]

Controlled release, reduced toxicity, increased stability (for certain actives), and increased bioavailability are just a few benefits of liposomal formulations. There is a considerable interest in the use of liposomes for products that retard premature aging of skin, or prevent photoaging. Antioxidants along with natural botanical extracts are commonly used in anti-aging products and encapsulation of vitamins in liposomes has been shown to enhance the stability of the vitamins. Stabilization of retinol has been achieved by encapsulating it in liposomes. Lee, et al.,[42] have shown that encapsulation of retinol in multilamellar liposomes made of soy phosphatidylcholine extended the shelf life of the retinol under different conditions including temperature, pH, and ambient light. Their data indicates that the stability of retinol encapsulated in the liposomes is highly dependent on pH. Their study indicated that the retinol degraded much faster at pH 3 than at pH 7 or pH 11. Obesity, or excess fat, is a concern for a significant portion of the human population in developed countries. Recently, Tholon, et al.,[43] have prepared liposomes (called slimming liposomes) from soy phospholipids in the presence of extract of Centella asiatica (a potent veinotonic), L-carnitine (a major lipolysis stimulator), and other actives. Their in-vivo data indicates that a daily topical application of 3% slimming liposomes to thighs reduced thigh circumference by 10 mm in 28 days (for >20% of the subjects). This noteworthy study suggests a lipolitic effect is achieved by the topical use of slimming liposomes. Applications of liposomes in wound care are also reported. A combination of povidone-iodine (PVPI) with liposomes has been shown to provide a unique activity for wound healing. Liposomal eye drops (isotonic with tear fluid at pH 6), containing 2.5% and 5% PVP-I in animal studies, showed broad spectrum antibiotic activity.[44] It is also reported that, PVP-I liposomes formulated in hydrogels have shown high efficacy and tolerability in treating deep dermal burn wounds.[44] These results suggest a significant commercial potential for liposomal formulation in hydrogels used for wound care.

Enhanced skin penetration is one of the major interests for dermatological treatments and liposomes have shown a good potential to achieve the goal.[48] Based on results obtained with confocal laser scanning microscopy, van Kuijk-Meuwissen, et al.,[49] have concluded that liposomes are more favored than micellar solutions for achieving increased drug penetration into the skin. Their study also reports that when a lipophilic substance applied to skin via liposomes in liquid-crystalline state penetrated deeper into skin than the same substance applied in the gel state of liposomes.[49] These data suggest that the thermodynamic state of liposomes can influence skin penetration. Shoemaker and Vanderlick[50] have studied the elastic behavior of liposomes prepared from mixtures of 1-palmitoyl 2-oleoyl phosphatidylcholine (POPC) and dipalmitoyl phosphatidylcholine (DPPC). Their study indicated that mechanical characteristics of the liposomes were markedly different in the liquid-crystalline state compared with that in the liquid-crystalline-gel coexisting region. In the liquid-crystalline state, the liposomes were elastic whereas in liquid-crystalline-gel coexisting region, liposomes were non-elastic.[50] Foo, et al.,[51] have studied thermal effects on mechanical deformation and viscous drag of lipid vesicles. Their data indicate that lipid bilayers (liposomes) are less rigid with increasing temperature, and that the deformation of liposomes is reversible and strongly depends on the thermotropic phase transition of liposomes. Jain, et al.,[52] have reported that the addition of appropriate amounts of certain nonionic surfactants to phospholipids enhances the elasticity of the resulting liposomes. Such “elastic” lipo-

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somes are suggested to be suitable for transdermal delivery.[52] It is known that addition of nonionic surfactants or lyso-lipids to a lipid bilayer disrupt the molecular packing of lipids in the bilayer, which decreases the thermal phase transition of the bilayer. Because the molecular packing of lipids in a bilayer in the liquidcrystalline state is less compact, it is suspected to provide mechanical deformability compared to the compactly packed bilayer structure in the gel state. The intermolecular interactions of lipids in a bilayer are, therefore, suspected to influence the elasticity of a bilayer (liposomes). However, it is important to know that the ratio of surfactant-to-lipid has to be optimized so that the resulting liposomes have reasonable elasticity and stability for their intended shelf life. Van den Bergh, et al.,[53] have shown that topical application of empty elastic liposomes made of octaoxyethylenelaurate-ester (PEG-8-L) enhanced the skin penetration of marker 3H2O compared to the rigid liposomes prepared from sucrose stearate-ester. In general, there seems to be agreement among researchers that liposomes provide deeper penetration of an active into the skin than that achieved without the liposomes. By transmission electron microscopic examination, Betz, et al.,[54] have shown the presence of intact liposomes in the stratum corneum lipids. However, the data in this study was not conclusive nor is it widely accepted that liposomes remain intact when they penetrate into skin layers. It is accepted, however, that the marker dyes encapsulated in liposomes do indeed penetrate to the dermis. This suggests that the drug molecules encapsulated in the liposomes may also penetrate to the dermal level.[54] There are three different skin penetration routes for liposomes. These include intercellular diffusion, the transcellular route, and follicular penetration. In the past, the intercellular route has been considered the predominant pathway of skin penetration. Hair follicles and sweat glands account for approximately only 1% of the skin surface and, therefore, the follicular route was not previously considered to represent a significant route of penetration. Surprisingly, however, recent in-vitro and in-vivo studies suggest that the follicular route is the major route of skin penetration.[55]

Schramlova, et al.,[56] have provided electron microscopic evidence to show the penetration of liposomes through skin layers. Their study showed that liposomes smaller than 600 nm penetrated skin while liposomes larger than 1,000 nm did not penetrate. They also suggest that the major route of skin penetration for liposomes is along the hair sheaths.[56] Similarly, Agarwal, et al.,[57] have also suggested that the pilosebaceous route is the pivotal route of topical drug delivery using liposomes. Physical factors that affect the efficiency of skin penetration by liposomes not only include lipid composition,[58] the thermotropic state (liquid crystalline or gel), elasticity, size, and charge of liposomes, but also the nature of the encapsulated active. Ogiso, et al.,[59] have investigated the effect of liposomal charge on the ability to penetrate the skin. Their study indicates that negatively charged liposomes travel more rapidly through the stratum corneum than positively charged liposomes, and they diffuse into the dermis as well as the lower part of hair follicles.

13.9 Liposomes: Future Trends Maintenance of healthy skin is becoming increasingly important in view of environmental insults such as UV radiation and atmospheric pollution. Current literature reveals that mere application of existing sunscreens is not sufficient to protect the skin from premature photodamage. It is well documented that exposure to UV radiation induces premature skin aging thereby causing immunosuppression and photocarcinogenesis which, in some cases, can lead to skin cancer. The reported concerns about the existing sunscreens are that they provide incomplete spectral protection, they have some toxicity issues, and they are used inadequately.[60] As a natural defensive system, the skin uses antioxidants to protect itself from photodamage. Use of antioxidants along with sunscreens is emerging as a new trend. As a result of this trend, a considerable growth is anticipated for anti-aging or sun care products containing antioxidants. Liposomes have been proven to protect certain antioxidants, increase their bioavailability, and provide release in sustained manner. As a natural outgrowth of these features and benefits, a remarkable growth in novel antioxidant products is anticipated, particularly centered around liposomal-

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encapsulated antioxidants for topical use. An example of this approach is the use of photolyase, a xenogenic repair enzyme. When encapsulated in liposomes, this enzyme may have broad use as an active ingredient in modern sun care products.[61]

skin than cationic liposomes. These results encourage new experiments to test the possibility that mixing blank anionic liposomes with personal care formulations will improve transdermal penetration.

Although liposomes have been used in skin care products, there are few existing liposomal products in the oral care area. Liposomal encapsulation of antibacterial actives for oral bacteria has been reported by Jones and his group who have suggested the possibility of such liposomal applications in oral hygiene.[62][63] Another area for topical liposomal formulations is in nail care. Delivery of antifungal agents by encapsulating them in liposomes may address the current existing problems of poor delivery for nail fungal treatment. Delivering genes to hair follicles has recently interested the dermatology community. Cotsarelis and his group at the University of Pennsylvania, have investigated gene delivery to hair follicles using liposomes.[64][65] Hoffman and others have also reported on the liposomal targeting of hair follicles.[66][67] These studies have shown encouraging results and may become a practical way of treating hair disorders by means of DNA treatment. The successful targeting of actives via hair follicles using liposome delivery systems is expected to open doors for cosmetic applications as well. Introducing hair growth promoters or hair growth retardants through liposomal formulations may also be a practical approach. Efforts continue to improve the stability of liposomes in cosmetic formulations. Recently, a new type of liposome gel has been reported.[68] Polymers such as PEG 800 Chol2 , PEG 800, or PEG 800-distearate have been used in the preparation of liposomes along with the phospholipids. It is reported that these polymers crosslink and tie the liposomes to each other. The resulting structure is envisioned as if the beads (i.e., liposomes) are connected by a thread (i.e., cross-linked polymer).[68] By tying the liposomes to one another, the rate of liposome-liposome fusion is likely to be reduced, providing extended stability to the liposomes. Hui and his group have suggested that use of empty anionic liposomes will enhance skin penetration by electroporation.[69] These results are consistent with the findings by Ogiso, et al.,[59] who have indicated that anionic liposomes penetrate faster in

Although it took almost nine years to report the first liposome-based topical delivery application after the first liposomal drug delivery system was reported, the topical delivery of liposomes is anticipated to have wide applicability in areas ranging from cosmetics to dermatological products. Topical delivery of actives using liposomes may prove to be a remarkable advancement if topical gene delivery or topical vaccine delivery by means of liposomes becomes practical. Use of liposomes holds a great potential for the improvement of personal care products. They are expected to play a key role in topical formulations for the next generation of skin protectants, especially in anti-aging, antioxidant, and wound care products containing proteins and enzymes.

References 1. Hauser, H., Phospholipid Vesicles, Phsopholipid Handbook (G. Cevc, Ed.), pp. 603–637, Marcel Dekker, New York (1993) 2. Bangham, A. D., Liposomes: the Babraham Connection, Chem. Phys. Lipids, 64:275–285 (1993) 3. Kulkarni, V. S., personal correspondence with Dr. Weissmann (2002) 4. Sessa, G., and Weissmann, G., Phospholipid Spherules (Liposomes) as a Model for Biological Membranes, J. Lipid Res., 9:310–318 (1968) 5. Moscho, A., Orwar, O., Chiu, D. T., Modi, B. P., and Zare, R. N., Rapid Preparation of Giant Unilamellar Vesicles, Proc. Natl. Acad. Sci., USA, 93:11443–11447 (1996) 6. Oku, N., Scheerer, J. F., and MacDonald, R. C., Preparation of Giant Liposomes, Biochim. Biophys. Acta, 692:384–388 (1982) 7. Gregoriadis, G., and Ryman, B. E., Liposomes as Carriers of Enzymes or Drugs: a New Approach to the Treatment of Storage Diseases, Biochem J.,124(5):58P. ?? (1971)

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8. Mezei, M, and Gulasekharam, V., Liposomes—A Selective Drug Delivery System for the Topical Route of Administration. Lotion Dosage Form. Life Sci., 26(18):1473– 1477 (1980) 9. Weiner, N., Lieb, L., Niemiec, S., Ramachandran, C., Hu, Z., and Egbaria, K., Liposomes: A Novel Topical Delivery System for Pharmaceutical and Cosmetic Applications, J. Drug Target, 2(5):405–410 (1994) 10. Lasic, D. D., Novel Applications of Liposomes, Trends Biotechnol., 16(7):307–321 (1998) 11. Moussaoui, N., Cansell, M., and Denizot, A. Marinosomes, Marine Lipid-based Lposomes: Physical Characterization and Potential Application in Cosmetics, Int. J. Pharm., 242(12):361–365 (2002) 12. Baca-Estrada, M. E., Foldvari, M., Babiuk, S. L., Babiuk, L. A., Vaccine Delivery: Lipidbased Delivery System, J. Biotechnol., 83(12):91–104 (2000)

20. Walde, P., and Ichikawa, S., Enzymes Inside Lipid Vesicles: Preparation, Reactivity and Applicatons, Biomol. Eng., 18:143–177 (2001) 21. Puisieux, F., and Poly, P. A., Problemes Technologiques Poses par l’Utilisation des Liposomes Comme Vecteurs de Substances Medicamenteuses. Encapsulation, Sterilization, Conservation, Les Liposomes applications therapeutiques (F. Puisieux and J. Delattrte, Eds.), pp. 73–113, Technique et Documentation-Lavoisier, Paris (1985) 22. Perkins, W. R., Minchey, S. R., Ahl, P. L., and Janoff, A. S., The Determination of Liposome Captured Volume, Chem. Phys. Lipids, 64:197–217 (1993) 23. Oku, N., Kendall, D. A., and MacDonald, R. C., A Simple Procedure for the Determination of the Trapped Volume of Liposomes, Biochim. Biophys. Acta, 691:332–340 (1982)

13. Claassen, D. E. and Spooner, B. S., Liposome Formation in Microgravity, Adv. Space Res., 17(6-7):151–160 (1996)

24. Crommelin, D. A. J., Talsma, H., Grit, M., Zuidam, N. J., Physical Stability on Long Term Storage, Phsopholipid Handbook (G. Cevc, Ed.), pp. 335–348, Marcel Dekker, New York (1993)

14. Jones, M. N., and Chapman, D., Micelles, Monolayers, and Biomembranes, WileyLiss, New York (1985)

25. New, R. R. C., (Editor), Liposomes: A Practical Approach, pp. 113–116, IRL Press, Oxford, UK (1990)

15. Fuhrhop, J. H., and Koning, J., Membranes and Molecular Assemblies: The Synkinetic Approach (J. F., Stoddart, Ed.), The Royal Society of Chemistry, London (1994)

26. Touchstone, J. C., Practice of Thin Layer Chromatography, John Wiley & Sons, Inc., New York (1992)

16. Kulkarni, V. S., Boggs, J., and Brown, R.E. “Modulation of nanotube formation by structural modification of sphingolipids” Biophys. J. 77:319–330 (1999) 17. Barenholz, Y., Amselem, S., Lichtenberg, D. A New Method for Preparation of Phospholipid Vesicles (Liposomes)—French Press, FEBS Lett., 99:210–214 (1979) 18. Vulllemard, J. C., Recent Advances in the Large Scale Production of Lipid Vesicles for Use in Food Products: Microfluidization, J. Microencapsul., 8:547–562 (1991) 19. Zheng, S., Alkan-Onyuksel, H., Beissinger, R. L., and Wasan, D. T., Liposome Microencapsulations Without Using Any Organic Solvent, J. Disper. Sci. Technol., 20:1189–1203 (1999)

27. Arnoldsson, K. C., and Kaufmann, P., Lipid Class Analysis by Normal Phase High Performance Liquid Chromatography Development and Optimization Using Multivariate Methods, Chromatographia, 38:317–324 (1994) 28. Kim, H. Y., and Salem, N., Liquid Chromatography-Mass Spectrometry of Lipids, Prog. Lipid Res., 32:221–245 (1993) 29. Bartlett, G. R. J., Phosphorus Assay in Column Chromatography, J. Biol. Chem., 234: 466–468 (1959) 30. Ulrich, A. S., Biophysical Aspects of Using Liposomes as Delivery Vehicles, Biosci. Rep., 22:129–150 (2002) 31. Marsh, D. CRC Handbook of Lipid Bilayers, CRC Press, Boston, MA (1990)

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32. Cevec, G. (Editor), Phospholipid Handbook, pp. 939–956, Marcel Dekker, Inc., New York (1993)

tions, (G. Cevc and F. Paltauf, Eds.), pp. 181–188, AOCS Press, Champaign, IL (1995)

33. Rinia, H. A., Snel, M. M. E., van der Eerden, J. P. J. M., and de Kruijff, B., Visualizing Detergent Resistant Domains in Model Membranes with Atomic Force Microscopy, FEBS Letters, 501:92–96 (2001) 34. Tanikawa, S., and Miyajima, K., Calorimetric and Infrared Spectroscopic Study of Phase Behavior of Hydroxyceramides/Cholesterol3-Sulfate System, Chem. Phys. Lipids, 77:121–130 (1995) 35. Wegener, M., Neubert, R., Rettig, W., and Wartewig, S., Structure of Stratum Corneum Lipids Characterized by FT-Raman Spectroscopy and DSC, I, Ceramides Int. J. Pharm., 128:203–213 (1996) 36. Nomura, F., Nagata, M., Inaba, T., Hiramatsu, H., Hotani, H., and Takiguchi, K., Capabilities of Liposomes for Topological Transformation, Proc. Natl. Acad. Sci. U.S.A., 98(5):2340– 2345 (2001) 37. Kulkarni, V. S., Ross, M., Brockway, B., Wilmott, J., and Hayward, J. A., Novel Method of Formulating Skin Care Products with Liposomes, J. Cosmet. Sci., 53:297–298 (2002) 38. de la Maza, A., Lopez, O., Coderch, L., and Parra, J. L., Solubilization of Phosphatidylcholine Liposomes by the Amphoteric Surfactant Dodecyl Betaine, Chem. Phys. Lipids, 94(1):71–79 (1998) 39. London, E., and Brown, D. A., Insolubility of Lipids in Triton-X100: Physical Origin and Relationship to Sphingolipid/Cholesterol Membrane Domain (Rafts), Biochim. Biophys. Acta, 1508:182–195 (2000) 40. Foldvari, M., Effect of Vehicle on Topical Liposomal Drug Delivery: Petrolatum Bases, J. Microencapsul., 13(5):589–600 (1996) 41. Williams, W. P., Perrett, S., Golding, M., and Arnaud, J-P., The Pro-Liposome Method: A Practical Approach to the Problem of the Preparation and Utilization of Liposomes Suitable for Topical Applications, Proc. 6th Int. Colloq. Phospholipids: Characterization, Metabolism, and Novel Biological Applica-

42. Lee, S. C., Yuk, H. G., Lee, D. H., Lee, K. E., Hwang, Y. I., and Ludescher, R. D., Stabilization of Retinol through Incorporation into Liposomes, J. Biochem. Mol. Biol., 35(4):358– 363 (2002) 43. Tholon, L., Neliat, G., Chesne, C., Saboureau, D., Perrier, E., and Branka, J. E., An In Vitro, Ex Vivo, and In Vivo Demonstration of the Lipolytic Effect of Slimming Liposomes: An Unexpected a2-Adrenergic Antagonism, J. Cosmet. Sci., 53:209–218 (2002) 44. Reimer, K., Fleischer, W., Brögmann, B., Schreier, H., Burkhard, P., Lanzendörfer, A., Gümbel, H., Hoekstra, H., and BehrensBaumann, W., Povidone-Iodine Liposomes— An Overview, Dermatology, 195(2):93–99 (1997 ) 45. Patel, V. B., Misra, A., and Marfatia, Y. S., Topical Liposomal Gel of Tretinoin for the Treatment of Acne: Research and Clinical Implications, Pharm. Dev. Technol., 5(4):455– 464 (2000) 46. Patel, V. B., Misra, A., and Marfatia, Y. S., Preparation and Comparative Clinical Evaluation of Liposomal Gel of Benzoyl Peroxide for Acne, Drug Dev. Ind. Pharm., 27(8):863– 869 (2001) 47. Wolf, P., Maier, H., Müllegger, R. R., Chadwick, C. A., Hofmann-Wellenhof, R., Soyer, H. P., Hofer, A., Smolle, J., Horn, M., Cerroni, L., Yarosh, D., Klein, J., Bucana, C., Dunner, K., Jr., Potten, C. S., Hönigsmann, H., Kerl, H., and Kripke, M. L., Topical Treatment with Liposomes Containing T4 Endonuclease V Protects Human Skin In Vivo from Ultraviolet-Induced Upregulation of Interleukin-10 and Tumor Necrosis Factor-a, J. Invest. Dermatol., 114:149–156 (2000) 48. Braun-Falco, O., Korting, H. C., and Maibach, H. I., Liposome Dermatics, Springer Verlag, Germany (1992) 49. van Kuijk-Meuwissen, M E. M. J, Mougin, L., Junginger, H. E., and Bouwstra, J. A., Application of Vesicles to Rat Skin In Vivo: A Confocal Laser Scanning Microscopy Study, J. Control. Rel., 56:189–196 (1998)

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50. Shoemaker, S. D., and Vanderlick, K., Material Studies of Lipid Vesicles in the La and LaGel Coexistence Regimes, Biophys. J., 84:998–1009 (2003) 51. Foo, J. J., Liu, K. K., and Chan, V., Thermal Effect on a Viscously Deformed Liposome in a Laser Trap, Ann. Biomed. Eng., 31(3):354– 362 (2003) 52. Jain, S., Jain, P., Umamaheshwari, R. B., and Jain, N. K., Transfersomes—A Novel Vesicular Carrier for Enhanced Transdermal Delivery: Development, Characterizatrion, and Performance Evaluation, Drug Dev. Ind. Pharm., 29(9):1013–1026 (2003) 53. van den Bergh, B. A. I., Bouwstra, J. A., Junginger, H. E., and Wertz, P. W., Elasticity of Vesicles Affects Hairless Mouse Skin Structure and Permeability, J. Control. Rel., 62:367–379 (1999) 54. Betz, G., Imboden, R., and Imanidis, G., Interaction of Liposome Formulations with Human Skin In Vitro, Int. J. Pharm., 229:117–129 (2001) 55. Lademann, J., Otberg, N., Richter, H., Weigmann, H-J., Lindemann, U., Schaefer, H., and Sterry, W., Investigation of Follicular Penetration of Topically Applied Substances, Skin Pharmacol. Appl. Skin Physiol., 14(1):17– 22 (2001) 56. Schramlova, J., Blazek, K., Bartackova, M., Otova, B., Mardesicova, L., Zizkovsky, V., and Hulinska, D., Electron Microscopic Determination of the Penetration of Liposomes through Skin, Folia Biol. (Praha), 43:165–169 (1997) 57. Agarwal, R., Katare, O. P., and Vyas, S. P., The Pilosebaceous Unit: A Pivotal Route for Topical Drug Delivery, Methods Find. Exp. Clin. Pharmacol., 22(3):129–133 (2000) 58. Kirjavainen, M., Urtti, A., Jaaskelainen, I., Suhonen, T. M., Paronen, P., ValjakkaKoskela, R., Kiesvaara, J., and Monkkonen, J., Interaction of Liposomes with Human Skin In Vitro—The Influence of Lipid Composition and Structure, Biochim. Biophys. Acta 1304:179–189 (1995) 59. Ogiso, T., Yamaguchi, T., Iwaki, M., Tanino, T., and Miyake, Y., Effect of Positively and Negatively Charged Liposomes on Skin Per-

meation of Drugs, J. Drug Target, 9(1):49– 59 (2001) 60. Pinnell, S. R., Cutaneous Photodamge, Oxidative Stress, and Topical Antioxidant Protection, J. Am. Acad. Dermatol., 48:1–19 (2003) 61. Stege, H., Effect of Xenogenic Repair Enzymes on Photoimmunology and Photocarcinogenesis, J. Photochem. Photobiol. B, 65:105–108 (2001) 62. Jones, M. N., Song, Y. H., Kaszuba, M., and Reboiras, M. D., The Interaction of Phospholipid Liposomes with Bacteria and Their Use in the Delivery of Bactericides, J. Drug. Target, 5:25–34 (1997) 63. Robinson, A. M., Creeth, J. E., and Jones, M. N., The Use of Immunoliposomes for Specific Delivery of Anatimicrobial Agents to Oral Bacteria Immobilized on Polystyrene, J. Biomater. Sci. Polym. Ed., 11:1381–1393 (2000) 64. Domashenko, A., Gupta, S., and Cotsarelis, G., Efficinet Delivery of Transgenes to Human Hair Follicle Progenitor Cells Using Topical Lipoplexe, Nature Biotechnol., 18:420– 423 (2000) 65. Gupta, S., Domashenko, A., and Cotsarelis, G., The Hair Follicles as a Target for Gene Therapy, Eur. J. Dermatol., 11(4):353–356 (2001) 66. Hoffman, R. M., Topical Liposome Targeting of Dyes, Melanins, Genes, and Proteins Selectively to Hair Follicles, J. Drug Target., 5:67–74 (1998) 67. Li, L., and Lishko, V., Method for Delivering Beneficial Compositions to Hair Follicles, US Patent # 6,224,901 (2001) 68. Diec, K. H., Sokolowski, T., Wittern, K. P., Schreiber, J., and Meier, W., New Liposome Gels by Self Organization of Vesicles and Intelligent Polymers, Cosmetics and Toiletries, 117(8):55–62 (2002) 69. Sen, A., Zhao, Y-L., and Hui, W., Saurated Anionic Phospholipids Enhance Transdermal Transport by Electroporation, Biophys. J., 83:2064–2073 (2002)

14 Interactive Vehicles in Synergistic Cosmeceuticals Advances in Nanoencapsulation, Transportation, Transfer, and Targeting Elishalom Yechiel Elsom Research Co., Inc. San Antonio, Texas 14.1 14.2 14.3 14.4

Introduction ................................................................................... 304 What Can Be Claimed? ................................................................ 304 What Can Be Named? ................................................................. 304 What Can Be Explained? ............................................................. 305 14.4.1 Vehicles For Overcoming Obstacles in Actives’ Performance ..................................................................... 305 14.4.2 Interactions, Mobilization, and Transport of Actives: Across the Barriers ........................................................... 305 14.4.3 Drug Delivery Technology Rejuvenates Old Drugs and Gives Them New Applications ................................... 308 14.4.4 Topical and Injectable Vehicles ......................................... 308 14.4.5 Synergistic Effects ............................................................ 310 14.4.6 Side Effects ...................................................................... 314 14.4.7 Nanoemulsion-Based Vehicles ......................................... 314 14.4.8 Nanosomes™ and Double Emulsion-based Vehicle Technologies ..................................................................... 314 14.4.9 Intra-Dermal and Trans-Dermal Vehicles ......................... 314 14.5 Formulations ................................................................................. 316 14.5.1 Moisturizing Wrinkle Cream with Green Tea and Vitamins ... 316 14.5.2 Face Cream with Jojoba, Aloe Vera, and Vitamin E ......... 316 14.6 Conclusions .................................................................................. 316 References .......................................................................................... 319

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 303–320 © 2005 William Andrew, Inc.

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14.1 Introduction

14.2 What Can Be Claimed?

Cosmeceutical development has been expanding rapidly to cover a desperate need for new and accessible effective products. This need cannot be satisfied by drug development under the present legal requirements in the United States. The placement of cosmeceuticals under the larger category of cosmetics is thought, due in part to its relatively moderate level of regulation, to allow comparatively inexpensive and rapid development of new, exciting, and beneficial ingredients and formulae. Unlike the development of cosmetics, innovation in drug development is severely crippled by the heavy cost and slow pace imposed by stricter regulations; this makes the development of a new drug a comparatively rare event.[1] Only about two decades old, cosmeceuticals as a field of study is relatively young. However, inspired by mounting restrictions and heavy regulation of drug development, cosmeceuticals are gaining recognition and individual status within the general skin care field, under the regulatory umbrella of cosmetic products.

Activity in medicinal and cosmetic formulations. Medicine comes in a variety of forms, including oral, injectable, and topical. Cosmetics are limited to the topical form (i.e., applied to the surface of the skin). That is the most obvious difference between drugs and cosmetics. In addition, there are legal differences, well explained in Huff’s “The Legal Distinction in the United States Between a Cosmetic and a Drug,”[2] and in publications by the US Food and Drug Administration (FDA), including their searchable website at http://www.fda.gov/.[3] FDA regulations identify certain ingredients as drugs, and certain claims for ingredients’ activity (such as the treatment or cure of disease) as medicinal. Any formulation containing a drug or claiming medicinal activity is regulated by the FDA as a medicine. By definition, cosmetics may alter appearance but not cure disease. This means that cosmetics are not drugs and do not claim to have medicinal activity, so they are subject to lighter regulatory standards by the FDA.

Innovations in delivery systems, previously almost exclusive to injectable and oral drug regimens, are now implemented in topical formulations. Topical delivery systems for drugs and actives are gaining high esteem in the pharmaceutical and the cosmetic industries. Active ingredient is a legal term defining an ingredient with a drug activity in a medicinal preparation. Active is used to describe an ingredient with beneficial non-medicinal properties. However, their mechanisms in delivery systems are similar, so the terms are used interchangeably in this chapter. With cosmeceuticals at the frontier of new topical delivery systems development, modern medicine is aiming toward topical applications such as nicotine patches, contraceptive patches, topical antiinflammatories, and many others. Modern cosmetics is aiming at intra-dermal penetration. The rationale behind the development of topical delivery systems is, in many aspects, similar to that of injectable and oral delivery systems. However, topical applications have some specific considerations to address, which are unique to topicals but not relevant to oral or injectable actives. In addition, considerations derived from regulatory considerations for development of topical delivery systems for drugs are different from those intended for cosmetics.

14.3 What Can Be Named? Defining a category for a formulation. Cosmetics cannot claim to have medicinal activity. However, no matter what they can legally claim, there are topical cosmetic formulations which seem to improve something deeper than the appearance. The impulse to describe such cosmetics led to the coining of the term cosmeceutical in the 1980s[4] and the growing recognition of that term today. What is it that cosmeceuticals do, and how do they do it? Additional terms such as active cosmetics and functional cosmetics are used in the continuing struggle to define whatever it is that, unrecognized by the FDA, has so many consumers convinced that the products they apply to their skin are responsible for real change in their well-being.[5] The available legal and linguistic definitions are inadequate, but the biochemical description of cosmeceuticals’ activity makes it possible to understand their mechanisms and appreciate their possibilities. Cosmeceuticals can be formulated with delivery systems.[6] Just as delivery systems carry medicines into cells or remove undesirable material from cells, so can de-

YECHIEL: INTERACTIVE VEHICLES IN SYNERGISTIC COSMECEUTICALS livery systems in cosmeceuticals deliver actives into, and remove undesirable materials from, the skin. Chapter 5 of this book contains a discussion of the natural origins and long history of delivery systems. Cosmetics, including cosmeceuticals, cannot contain any material classified as a drug. If the material they delivered to the skin were classified as a drug, then cosmeceuticals would be called drug delivery systems and would themselves be classified as drugs rather than cosmetics. Non-drug materials can be carried in and out of skin by cosmeceutical delivery systems. The operation of these delivery systems can be clearly understood by reference to mechanistic models described and illustrated in this chapter.

14.4 What Can Be Explained? 14.4.1

Vehicles For Overcoming Obstacles in Actives’ Performance

A material transported into the skin for its activity, medicinal or non-medicinal, is referred to as active or active ingredient interchangeably in this chapter. Actives often: • Are immiscible in the media in which they are intended to be formulated. • Are too poisonous if they are distributed throughout the body. • Have a short circulation life time in the body and are readily expelled, biodegraded, or metabolized after application. • Have little or no ability to cross biomembranes, skin, or other biological obstacles. Encapsulation of an ingredient and formulating it into a vehicle: • Can solve problems of immiscibility. • Can contain the poisonous effect of the ingredient to the body. • Can protect the ingredient from biodegradation and increase its circulation life. • Can improve transportation via biological obstacles.

305

14.4.2 Interactions, Mobilization, and Transport of Actives: Across the Barriers Actives start their journey in the body at an application site which may not be the desired site of action. Their activity may be undesirable at the application site, or conditions at the site may be inhospitable, bringing about their inactivation and destruction. Actives have to cross barriers which block their journey to the target zone. This is the process of transportation. Figures 14.1a, b, and c show the transportation of an active through a water barrier. Figures 14.2a, b, and c show a similar process of transportation across an oil barrier. Figure 14.3 shows an amphipathic barrier made of phospholipids which are the building blocks of both cell membranes and liposomes. The skin’s outer layers have a bilayer structure and can be accessed by liposomes which also have a bilayer structure. The bilayer structure of skin makes liposomes a rational candidate to be used as a intra-dermal and trans-dermal transporter of active in topical formulations. Indeed, many studies confirm the ability of liposomes to penetrate into the skin’s outer layers. The active, and the vehicle carrying it, must travel a distance to its site of action. This is called mobilization. They may encounter incompatibility with the medium in which they travel. Mechanical barriers, as shown in Fig. 14.4, can prevent an active from traveling to its site of action. Chemical barriers may also prevent mobilization of actives to their site of action even if they are mechanically compatible. This is shown in Fig. 14.5. Even if the actives can move freely in the medium, they are subject to attack by the immune system (Fig.14.6), or they may be metabolized into inactive molecules by biochemical processes (Fig.14.7) or simply expelled from the body. Actives must be directed to their site of action so they are not diluted in traveling to other organs. They must not harm other organs through which they are traveling. Controlling the mobilization of an active so that it does not have contact with organs on which it may have undesirable side effects, or on which it may simply be wasted as it will be unable to achieve desirable effects, is called targeting. Reaching the site of action does not guarantee success. When actives reach their site of action they may face limitations at that site resulting from incompatibility in the proximity of the site of action.

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Hydrophobic active molecule

Hydrophilic active molecule

Hydrophobic active cannot cross water barrier

Hydrophilic active cannot cross lipid barrier

water barrier

lipid barrier

(a)

(a)

Surfactant type transporter has:

Surfactant type transporter has:

1. Hydrophobic region

1. Hydrophobic region

2. Hydrophilic region

2. Hydrophilic region

(b)

(b)

Hydrophobic region of surfactant interacts with hydrophobic active.

Hydrophilic region of surfactant interacts with hydrophilic active.

Hydrophilic region of surfactant is submerged in water.

Hydrophobic region of surfactant is submerged in lipid.

Step 1

Step 1

Step 2 Surfactant flips and transports the hydrophobic molecule across the water barrier.

Surfactant flips and transports the hydrophilic molecule across the lipid barrier.

Step 2

(c)

(c)

Figure 14.1 Crossing a water barrier: (a) hydrophobic molecule faces hydrophilic barrier, (b) transporter is simultaneously hydrophilic and hydrophobic, and (c) transporter enables hydrophobic active to cross hydrophilic barrier.

Figure 14.2 Crossing an oil barrier: (a) hydrophilic molecule faces hydrophobic barrier, (b) transporter is simultaneously hydrophilic and hydrophobic, and (c) transporter enables hydrophilic active to cross hydrophobic barrier.

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Figure 14.3. Amphipathic barrier. Phospholipid bilayer is a semi-permeable barrier to both hydrophobic and hydrophilic actives.

active

Immune system

narrow passage

active

Figure 14.4 Mechanical barrier (narrow path type barrier). Active is too large to pass through the barrier and is unable to reach its target molecule which is behind the barrier and the desired result cannot be produced.

Figure 14.6 Deactivation by immune system. Deactivation may be triggered by cross-linking or immune system. When an active is not protected by a capsule or a carrier molecule it can be attacked by the immune system and become immobilized and deactivated.

charged passage active active

Figure 14.5 Chemical barrier (charged passage restricts movement of charged active). Active and barrier are both charged with positive and negative charges. Active can be oriented towards barrier entrance in only two ways: similar charges in active and barrier deflect each other and the active cannot enter the barrier; and opposite charges in active and barrier attract each other and the active is arrested at the entrance to the barrier. Unable to cross the barrier, the active is unable to reach its target molecule which is behind the barrier and the desired result cannot be produced.

biological degradation system

(a)

(b)

Figure 14.7 Activity loss during transport. (a) Biological degradation imposes a time limit on active lifespan; active ingredient must find target while still alive. (b) Biodegradation process changes actives into different molecules that do not retain their activity. Active ingredient may be secreted by the body even without prior biodegradation.

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Development of delivery systems deals with identifying and finding solutions to such problems. It is a field filled with the opportunity to tailor solutions for transfer of actives from the application site to the site of action. Delivery systems for drugs were developed first; recently, the body of research that originated with drug delivery systems is being applied to cosmeceuticals. This technology transfer is a growing phenomenon. As the successful transfer of technology from textiles to hair care has become more and more apparent, the analogy exists for technology transfer from the world of drug delivery systems to that of cosmetics and cosmeceuticals.

14.4.3 Drug Delivery Technology Rejuvenates Old Drugs and Gives Them New Applications Drug delivery systems are well known in modern medicine. The expectation of extreme expenditures of cost and time for new drug development has been instrumental in encouraging rediscovery of old drugs.[1][7][8] New uses for existing materials can be approved much more expediently than can the first use of a new material. Applying new formulation technologies such as delivery vehicles, encapsulation technology, and innovative formulation methods to familiar drugs can reduce undesired side effects associated with those drugs, increase their activity, reduce the effective therapeutic dose, increase the drug’s concentration at desired organs, and reduce drug concentration in healthy organs that do not require the drug. Applications of delivery vehicles and encapsulation technologies in cosmeceuticals create an opportunity to improve skin penetration by beneficial actives.

14.4.4

Topical and Injectable Vehicles

The differences between topical vehicles applied to the skin and injectable vehicles injected into the bloodstream are found at two major levels. Injectables require vehicles that can survive the environment into which they are injected. They must release the actives or drugs at the site of action. They must be degradable by the body in a reasonable time after injection. Topical vehicles must have the ability to penetrate the skin. Topical cosmetics

are formulated for problems of appearance and comfort at the skin level. Since the outer layers of skin are “dead,” such products are not expected to interact with live cells. Topical medicinals are formulated for problems of health in the live cell layers under the surface which are in contact, or in proximity of, the outer skin level. They are applied directly to their target site, the skin itself. For cosmetics, there is no need to prove that the vehicle separates from its contents at the target site. In fact, a new technology can be used that can change not only the activity of ingredients but induce new activities not obtainable before from the same ingredients. This technology is called “turtle head encapsulation” and involves semi-encapsulated actives that can act while encapsulated. Figure 14.8 shows a cyclodextrin molecule suitable for use in “turtle head encapsulation.” Cyclodextrin (Fig. 14.8c) is formed around a hollow center. When a molecule of an active such as retinol (Fig. 14.8a) or retinyl palmitate (Fig. 14.8b) is encapsulated in cyclodextrin, the bulk of the molecule is embedded within the core of the cyclodextrin. The active site of the retinol molecule can, in some cases (depending on the formulation), perform its activity even when in encapsulated form and does not require release at the site of action. Vehicles are active ingredients’ carriers. Combining active ingredients into vehicles is the art of encapsulation. Vehicles can: • Enhance ingredients’ activity. • Transport across biological obstacle. • Increase active lifetime. • Improve ingredients’ solubility in the desired media. • Protect the body from possible poisonous effects of ingredients. • Concentrate active ingredients in the desired biological target area. Vehicle performance with a certain active ingredient can be rated by the following criteria: • Facilitated transport to the site of action. • Differential concentration of actives at the site of action. • Enrichment of the proximity of the target molecules at the site of action with actives . • Orientation of actives toward target molecules at the site of action.

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area while restricting spread of that ingredient to other areas of the body.

(a)

(b)

Proximity is a factor when a vehicle enables, or significantly increases, concentration of active ingredient molecules around molecules at the site of action. Figure 14.9 illustrates the role of proximity in enabling successful delivery of actives. Orientation is modified when a vehicle enables, or significantly alters, alignment of active ingredient molecules so that the active ingredient molecule and the target molecule form a desired angle for interaction. The importance of orientation in successful delivery can be seen by comparing Fig. 14.10a, a successful orientation, and Fig. 14.10b, an unsuccessful orientation. Accessibility is enabled when a vehicle significantly improves the shape or the charge of the site of action of active ingredients or the target molecule so that large inactive chemical side-groups will not create steric hindrance preventing the final interaction. Steric hindrance ( Fig. 14.11) occurs when physical features of one molecule prevent it from interacting with another. Vehicles can change the stereochemistry of an active ingredient to make it compatible with its target molecule at the site of action.[9] In some cases, this will result in increasing the reactivity of an active ingredients’ site of action and enhance its activity. Vehicles can remove steric hindrance from the proximity of a site of action of an active ingredient,

(c) Figure 14.8 Nanoencapsulation in cyclodextrin, turtle head encapsulation: (a) retinol, (b) retinyl palmitate, and (c) beta cyclodextrin capsule.

target molecule active molecule

• Accessibility of target molecules to actives and overcoming of hindrance at the site of action. Facilitated transport occurs when a vehicle enables, or significantly accelerates, intra-dermal and trans-dermal transport of an active or its penetration across any other biological obstacle. Differential concentration exists when a vehicle enables, or significantly increases, concentration of an active ingredient at the biological target organ

Figure 14.9 Limitations at site of action: proximity. The active arrives to close proximity (very close distance in molecular range size) of the target molecule. However, compatible orientation, “lock and key” structural and chemical compatibility, and hindrance-free space is required before the active and the target molecule can snap together and interlock, and produce the desired result.

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active molecule

target molecule

compatible, illustrates that a minor change of molecular shape may cause more than a minor change in the quality of a reaction. A minor change of shape may determine whether there is a reaction at all.

(a) target molecule active molecule

(b) Figure 14.10 Limitations at site of action: orientation. Contact between active molecule and target molecule must be in a specific orientation to perform desired activity. (a) Effective orientation: the active and the target molecules are aligned with each other in “lock and key” orientation. The active and the target molecule can now snap together and interlock, and produce the desired result. (b) Ineffective orientation: the active and the target molecules cannot snap together and interlock and the desired result cannot be produced.

14.4.5 Synergistic Effects Synergistic effects are nonlinear cumulative effects of two active ingredients with similar or related outcomes of their different activities, or active ingredients with sequential or supplemental activities. For example, vitamin E is an antioxidant and vitamin C may help to recycle oxidized vitamin E into active vitamin E, thus, a synergistic[10] effect may be possible between the two. The series of illustrations in Fig. 14.13 shows a mechanism by which the alterations produced by two materials may combine to produce an effect that is larger than the simple sum of the effects of which each is individually capable.

active molecule

active molecule

(a)

target molecule

Figure 14.11 Limitations at site of action: steric hindrance. Though otherwise compatible in their “key and lock” structure, steric hindrance represented by the symbol (o) will prevent the active and target molecules from interlocking, and the desired result cannot be produced.

target molecule

target molecule

active molecule

(b) enabling its activity at molecular targets that are resistant to that same active ingredient if it were not encapsulated in a vehicle. Vehicles may affect active ingredients’ shape and reactivity so that they gain accessibility and synergistic activity with molecular sites of action. A comparison of Fig. 14.12a, which depicts an incompatible conformation between two molecules, and Fig. 14.12b, which shows the same conformation slightly adjusted and, therefore,

Figure 14.12 Conformational compatibility. (a) Incomplete conformation: the structure of the active and target molecules is incompatible as “key and lock.” This will prevent the active and target molecules from snapping together and interlocking and the desired result cannot be produced. (b) Compatible conformation: active molecule and target molecule snap together and interlock, and the desired activity is performed.

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star-shaped black thick line represents a folded vessel wall spring-shaped lines represent anchors which keep the vessel wall folded internal dark circle represents the actual free flow volume in the vessel

(a)

(b) factor B

factor A

(c)

(d)

spring-shaped anchor barriers

star-shaped folded vessel wall

factor B

factor A

(e)

(f)

Figure 14.13 Synergy: (a) constricted fluid path in a constricted vessel with star-shaped folded walls (side view), (b) constricted fluid path, fluid can flow only in gray area (front view), (c) Factor A is represented by a scissorsshaped symbol, (d) Factor B is represented by a “Z” shaped symbol, (e) Factor A has specific affinity to the spring-shaped anchor barriers, (f) Factor B has specific affinity to the star-shaped folded vessel wall, (g) changes induced by adding Factor A: when Factor A is added to the liquid material flowing inside the restricted vessel volume, it interacts with the spring-like anchor barriers and dissolves them, which allows flow of the liquid material into the previously inaccessible areas (Factor A is cleared from the system after dissolving the spring shaped barrier); (h) changes induced by adding Factor B: Factor B has specific affinity to the spring shaped anchors; when Factor A is added to the liquid material flowing in the restricted vessel volume, it removes the spring-like anchor barriers which allows flow of the liquid material into the previously inaccessible areas; and (i) changes induced by synergy of Factors A and B: when Factors A and B are added together, Factor B permeates the vessel wall so that Factor A can penetrate and interact with the spring-shaped barrier located outside the folded vessel.

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→

→

Add Factor A

→

Factor A removes the barriers and clears the vessel

1. Limited flow

→

2. Increased flow the result of the action of Factor B

(g)

Add Factor B

→

→

1. Limited flow

→

2. Increased flow the result of the action of Factor B

(h) Figure 14.13 (Cont’d.)

→

Factor B permeates the star-shaped wall to the liquid material and clears the vessel

YECHIEL: INTERACTIVE VEHICLES IN SYNERGISTIC COSMECEUTICALS

→

Add Factor A + B

→

The sum of ingredients Factor A dissolves the spring-shaped anchor barriers located within the star-shaped folded vessel wall. Factor B permeates the star-shaped folded wall to the liquid in the vessel and also to Factor A. Factor A penetrates via the permeated star-shaped wall and accesses the outside spring-shaped anchor barriers which were not previously accessible to Factor A. The flow rate increases as the sum of the action of Factors A+B.

→

1. Limited flow

313

→

2. The sum of ingredients: increase in flow reflects combined contribution of Factors A & B.

1. Unfold vessel wall 2. Full volume vessel flow 3. Factor A dissolves external spring-shaped anchor barriers

More than the sum of ingredients Factor A accesses the outer spring-shaped anchor barriers and dissolves them. The star-shaped folded vessel wall stretches to its maximum ability. The volume of the flow in the vessels increases several folds over the combined fractional increase in flow contributed by the relative increase in flow of Factors A+B

(i) Figure 14.13 (Cont’d.)

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Interactive vehicles are vehicles which can deliver and extract ingredients in exchange with their biological targets. They can interact with different barriers with some shape-shifting abilities and can effectively cross those barriers. For example, very small liposomes (a term coined and trademarked as Nanosomes™) can encapsulate and carry watersoluble and oil-soluble ingredients. These liposomes can exchange entrapped molecules, including phospholipids and cholesterol, with cell membranes. When liposomes in water face an oil barrier they can transport material or even entire liposomes via that medium. Complex morphological and conformational changes of phospholipids, as well as liposomal and cell membrane changes, take place during their interactions.[11]

to clog pores and can be formulated with encapsulated actives. Dispersicles™ are an example of an emulsion-like nano-vehicle with extremely low detergentibility.

14.4.6 Side Effects

14.4.9 Intra-Dermal and Trans-Dermal Vehicles

Side effects are in the eyes of the beholder. What may be a desirable effect to one may be an undesirable effect to the other. For example, encapsulation of vitamin A with a vehicle of the cyclodextrin family may increase vitamin A activity against wrinkles.[12] At the same time, the dark brown color and the vivid medicinal odor of vitamin A are great deterrents to its use. Color and odor are important manufacturing concerns. Less than effective concentrations of vitamin A in anti-wrinkle or anti-aging skin care are, therefore, used in order to avoid unpleasant color and odor in many preparations. Encapsulation of vitamin A in a cyclodextrin vehicle drastically reduces color and odor of topical formulations enriched with vitamin A. The benefits may be tripled, including increased activity and concentration of vitamin A and increased aesthetic performance (Fig. 14.7).

14.4.7

Nanoemulsion-Based Vehicles

Delivery systems can be formulated into nanoemulsions which provide very diversified templates for advanced cosmeceuticals. Nanoemulsion particulates have more surface area to volume than large emulsions; they also allow more actives to interact with skin at the surface of emulsion particulates for fast and effective interaction. Nanoemulsions are not likely to be comedogenic since they are too small

14.4.8 Nanosomes™ and Double Emulsion-based Vehicle Technologies Double emulsion technology is another delivery system/template technology that allows two emulsion/encapsulation types such as Nanosomes™ (nano-liposomes) and nanoemulsion to coexist and act together synchronously or synergistically.[13] Our Dispersosomes™ are an example of a double emulsion co-formulated with Nanosomes™ and Dispersicles™.

A recent and most exciting research trend for the advancement of cosmeceuticals involves incorporating ingredients into intra-dermal (in the cosmetics category) and trans-dermal (in the topical overthe-counter and prescription drug category) delivery vehicles. Such vehicles are supposed to improve penetration of actives into the skin. The bilayer structures of liposomes and skin cell membranes do have similar bilayer structures, which makes liposomes excellent vehicles for delivery of actives into the skin. The series depicted in Fig. 14.14 shows that the alignment of phospholipids to form liposomes (Fig. 14.14a) and cell membranes (Fig. 14.14b) are similar, as are the fully-formed liposome (Fig. 14.14c) and cell membrane (Fig. 14.14d). A three-dimensional structure of a Nanosome is shown in Figure 14.14e, which illustrates the spherical shape of a small liposome, its core, and its wall. Nanosomes are structurally capable of encapsulating and transporting both water-soluble ingredients in their central polar cavity and oil-soluble ingredients in their hydrophobic double wall. A multilamellar liposome, as illustrated in the cross section in Fig. 14.14f, is spontaneously formed when phospholipids are mixed in water. A multilamellar liposome is probably the simplest form of liposome and its creation does not involve significant technological challenges. A multilamellar liposome may contain several layers of liposomes entrapped within each other, each capable

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(a)

315

(b)

(c)

(d)

(f)

(e)

(g)

Figure 14.14 Encapsulation: Interactive liposomes. Interactive liposomes are liposomes which can participate in surface-to-surface interactions with cell membranes and exchange materials between the cell membranes and the liposomes. Liposomes have many similarities with cell mambranes. (a) very small liposome (Nanosome™) formation, (b) cell membrane formation, (c) very small liposome (Nanosome™), (d) cell membrane, (e) liposomes can encapsulate and transport water-soluble ingredients in their polar cavity and oil-soluble ingredients in ther hydrophobic cavity, (f) multilamellar liposome, and (g) interactions between liposomes and cells.

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of encapsulating compatible ingredients. Even without encapsulation, liposomes can create changes in cell membranes.[14]–[16] As Fig. 14.14f shows, if a liposome is small enough and is made of suitable phospholipids, as Nanosomes are, a liposome can exchange molecules from its own outer barrier with molecules from the cell membrane. This makes it possible for the liposome to remove sphingomyelin, present in large amounts in aged cell membranes, from the cell membrane and replace it with phosphatidylcholine from the liposome itself. Young cell membranes are characterized by higher concentrations of phosphatidylcholine. Providing the cell membrane with a phosphatidylcholine-rich chemical structure via exchange with the liposome returns the cell membrane to the structure it had in its youth. The “Lipid Replacement Therapy” patent[17][18] is based on accomplishing this structural change; a treatment based on this patent has undergone Phase I human trials.

14.5 Formulations

14.5.1 Moisturizing Wrinkle Cream with Green Tea and Vitamins This is a very simple recipe for an emulsionbased moisturizing cream cosmeceutical, combining water-based and oil-based ingredients. Based on these ingredients alone, such an emulsion would ordinarily not form. To combine the ingredients and hold the emulsion together, a chemical emulsifier (such as glyceryl monostearate, cetearyl alcohol, or sodium stearoyl lactylate) would be required to stop the oil and water phases from separating. Sellers of chemical emulsifiers, such as AquaSapone’s AS102, advertise that their use adds a “slick” feel to the finished product. If the natural texture of the combined oil and water phase ingredients is desired, while avoiding harsh emulsifiers, an alternative emulsification technology is needed. Using nanoemulsification technology available from Elsom Research, oil and water phases can be combined into stable,

ultra-fine droplet emulsions without the use of chemical emulsifiers. In addition, the tiny droplets (Dispercicles™) produced by nanoemulsification are fast absorbing and too small to clog pores, a problem likely to occur with oil-based formulations. Other options include encapsulated vitamin A. Elsom Research can provide proprietary nanoencapsulated vitamin A in vehicles including cyclodextrin and in Nanosomes. (See Formulation 14.1)

14.5.2

Face Cream with Jojoba, Aloe Vera, and Vitamin E

This is a very simple recipe for an emulsionbased moisturizing cream cosmeceutical, combining water-based and oil-based ingredients. Based on these ingredients alone, such an emulsion would ordinarily not form. To combine the ingredients and hold the emulsion together, a chemical emulsifier (such as cetyl alcohol, Polysorbate 60, or Sorbitan Stearate) would be required to stop the oil and water phases from separating. If the natural texture of the combined oil and water phase ingredients is desired, staying away of harsh emulsifiers, an alternative emulsification technology is needed. Using nanoemulsification technology available from Elsom Research, oil and water phases can be combined into stable, ultra-fine droplet emulsions without the use of chemical emulsifiers. In addition, the tiny droplets (Dispersicles) produced by nanoemulsification are fast absorbing and too small to clog pores, a problem likely to occur with oil based formulations. (See Formulation 14.2.)

14.6 Conclusions The above advancements in cosmeceuticals makes them the forerunners for both topical medicinals and cosmetics in their sophistication, complexity, elegance, and state of the art delivery systems and encapsulation technology invested in these formulae.

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Formulation 14.1: Moisturizing Wrinkle Cream with Green Tea and Vitamins

Phase

Ingredient Water

1 - Water

152

Green tea extract

2

4

Vitamin C

5

10

Vitamin A

3 - Preservative

Weight (grams)

76

Grapeseed, apricot kernel, and sweet almond oil

2 - Oil

Weight (%)

22 0.2

43.6 0.4

Rosemary oil extract (preservative and antioxidant): 1 drop 15 drops Grapefruit seed extract (natural antiseptic)

Mixing Procedure: 1.

The procedure for combining oil and water phases with the help of a chemical emulsifier is simple: heat both phases to melt the emulsifier, then let the combination cool, then add the preservative, mix, and pour into jars.

2.

The procedure for creating a stable, fine emulsion without chemical emulsifiers is also simple. Use Elsom Research nano-emulsion technology to combine the water and oil phases into Dispercicles™, then adjust pH and the thickness of the cream to your preference. Supplement with preservative if you increase the volume of the cream, mix, and pour into jars.

3.

In addition to the advantages of natural texture that is not dominated by that of the emulsifier, and a droplet size that does not clog pores, this makes it possible to include materials in the oil and water phases that might be evaporated or otherwise damaged by exposure to heat.

Yield: 200 grams

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Formulation 14.2: Face Cream with Jojoba, Aloe Vera, and Vitamin E

Phase

Ingredient

1 - Water

2 - Oil

3 - Optimizers

Amount

Warm Aloe Vera Gel

85 ml

Xanthan gum

0.6 g

Sorbitol

5 ml

Natural Jojoba

10 ml

Triglyceride

10 ml

Shea Butter

1.6 g

Ceramide

2.5 ml

Vitamin E Acetate

1.3 ml

Grapefruit seed extract (natural antiseptic)

20 drops

Essential oils (examples): Chamomile

5 drops

Neroli

4 drops

Mixing Procedure: 1. Pre-mix Phase 1 by sprinkling the xanthan gum into the water and mixing on high speed. 2.

Add Phase 2 into a heat resistant glass jar and warm it in a hot water bath to maximum 150°F, 67°C.

3.

Add Phase 1 to Phase 2 and mix it thoroughly until it is a homogenous cream.

4.

After the temperature has dropped below 100°F (35°C), add phase 3 and stir again.

Yield: 114 grams

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References 1. Hara, T., Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development, Cheltenham, UK: Edward Elgar Publishing, Inc. (2003) 2. Hutt, P. B., The legal distinction in the United States between a cosmetic and a drug. Cosmeceuticals: Drugs vs. Cosmetics, pp. 223– 240 (P. Elsner, and H. I. Maibach, eds.) Marcel Dekker, Inc., New York (2000) 3. U. S. Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors, Is it a Cosmetic, a Drug, or Both? (or Is It Soap?), (http:// www.cfsan.fda.gov/~dms/cos-218.html) (Jul. 15, 2002) 4. Kligman, A. M., Cosmeceuticals: Do We Need a New Category? Cosmeceuticals: Drugs Vs. Cosmetics, (H. I. Maibach, ed.) Cosmetic Science and Technology Series; Vol. 23, Marcel Dekker, Inc., New York (2000) 5. Aust, L. B., Cosmetic Claims Substantiation. Cosmetic Science and Technology Series; Vol. 18, Marcel Dekker, Inc., New York (1998) 6. Magdassi, S., and Touitou, E., eds. Novel Cosmetic Delivery Systems, Cosmetic Science and Technology Series; Vol. 19, Marcel Dekker, Inc., New York (1999) 7. Heemskerk, J., Tobin, A. J., and Bain, L. J., Teaching old drugs new tricks, Trends in Neurosciences, 25(10):494–496 (Oct. 1, 2002) 8. Bodor, N., and Buchwald, P., Drug Targeting by Retrometabolic Design: Soft Drugs and Chemical Delivery Systems, Drug Targeting Technology: Physical · Chemical · Biological Methods; (H. Schreier, ed.) Drugs and the Pharmaceutical Sciences, 115:163–187, Marcel Dekker, Inc., New York (2001)

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9. Tomlinson, E., Theory and practice of site-specific drug delivery, Adv. Drug. Del. Rev., 1:87 (1987) 10. Peyrat-Maillard, M. N., Bonnely, S., Rondini, L., and Berset, C., Effect of Vitamin E and Vitamin C on the Antioxidant Activity of Malt Rootlets Extracts, Lebensmittel-Wissenschaft und-Technologie, 34(3): 176–182 (May 2001) 11. Gaudioso, J., and Sasaki, D. Y., Nanostructure and Dynamic Organization of Lipid Membranes, Dekker Encyclopedia of Nanoscience and Nanotechnology, Marcel Dekker, Inc., New York (2004) 12. Yechiel, E., Turtle Head Encapsulation, novel nano-encapsulation of Vitamin A and its potentiation as anti-wrinkle and anti-acne treatment, Unpublished data. 13. Yechiel, E., Dispersosomes™, a novel hybrid liposome, Unpublished data. 14. Yechiel, E., and Barenholz, Y., Relationships between membrane lipid composition and biological properties of rat myocytes, J. Biol. Chem., 260:9123–9131 (1985) 15. Yechiel, E., Barenholz, Y., and Henis, Y. I., Lateral mobility and organization of phospholipids and protein in rat myocyte membranes, J. Biol. Chem., 260:9132–9136 (1985) 16. Yechiel, E., and Edidin, M., Micron scale domains in fibroblast plasma membranes, J. Cell. Biol., 705:755–760 (1987) 17. Yechiel, E., and Barenholz, Y., Lipid Replacement Therapy, for treatment of age-related disorders. U.S. Patent No. 4,812,314 (1989) 18. Yechiel, E., Method of Reducing Age-Related Changes in Heart Muscle Cells, for treatment of age-related disorders, U.S.Patent No. 6,348,213 (2002)

Part VI Particles

Porous Entrapment Spheres as Delivery Vehicles

Practical Application of Fractal Geometry for Generation of Ultra High Surface Area Personal Care Delivery Systems

PARTICLES

Nanotopes: A Novel, Ultrasmall Unilamellar Carrier System for Cosmetic Actives

Polymeric Porous Delivery Systems: Polytrap™ and Microsponge™

Chronospheres: Controlled Topical Actives Release Technology

15 Porous Entrapment Spheres as Delivery Vehicles Anthony Ansaldi Presperse Inc., Somerset, New Jersey

15.1 Introduction ................................................................................... 323 15.2 Before Cosmospheres ................................................................. 323 15.2.1 Microcapsules ................................................................... 323 15.2.2 Liposomes ........................................................................ 325 15.3 Porous Entrapment System Technology ...................................... 326 15.3.1 What are Cosmospheres? ............................................... 326 15.4 Conclusion .................................................................................... 327 15.5 Formulations ................................................................................. 328 References .......................................................................................... 332

15.1 Introduction The need to deliver active materials to specific areas of the body has led to a new discipline. Over the years, many of the technologies and systems developed for delivering health care actives have been adapted to the cosmetics industry. While not all systems can be applied to all products, segments of the cosmetic industry have adopted specific delivery systems that have been found to perform well in various personal care and cosmetic markets. The development and application of “porous entrapment spheres” (cosmospheres) is one such delivery system. This chapter initially describes the technology of microcapsules and liposomes that were

among the first such systems introduced to the cosmetic industry. Thereafter, the technology of the cosmospheres and their applicability in personal care formulations is described.

15.2 Before Cosmospheres 15.2.1 Microcapsules Encapsulation technology essentially deals with the incorporation of a commercially useful “active” material into a protective system that can deliver

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 323–332 © 2005 William Andrew, Inc.

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the active to a specific site at a later time; one such example is termed “microcapsule.” There are four typical mechanisms by which the active (core) material may be released from a microcapsule. These are: 1) mechanical rupture of the capsule wall or “shell,” 2) dissolution of the wall, 3) melting of the wall, and 4) diffusion through the wall. Microcapsules, which range in size from one micron (one-thousandth of a millimeter) to seven millimeters, release their contents at a later time by means appropriate to the application. Applications of microcapsules. Two wellknown applications of microencapsulated products rely on mechanical rupture of the shell to release the active (core) contents. These are represented by scratch-and-sniff fragrance advertisements and carbonless paper. Scratch-and-sniff products involve the use of tiny, perfume-filled microcapsules, which are coated onto the magazine page. When scratched, the shell walls of the microcapsules rupture, releasing the fragrance. Carbonless copy paper utilizes the same release mechanism as the scratch-and-sniff perfume. In this application, small capsules, about 1–20 microns in diameter, coat the underside of the top sheet of paper. When exposed to pressure, the microcapsules rupture and release their ink supply. For most microcapsules, the shell material is usually one of several types of organic polymers; however, waxes and fats have also been used, particularly in food and drug applications where the shell must meet U.S. Food and Drug Administration specifications. Examples of some useful organic polymers include: polyvinyl acetate, polyethylene, carrageenan, dextrin, and sodium alginate. Preparation of microcapsules. The successful preparation of a microencapsulated product involves a number of steps. An optimal process is critical to the preparation of such microcapsules. Consider, for example, the process called “complex coacervation.” In complex coacervation, the active substance to be encapsulated must first be dispersed and emulsified as very fine droplets in an aqueous solution of a polymer such as gelatin. For this process to be successful, the active core material must be immiscible in the aqueous phase. Assessment of miscibility is usually accomplished by means of laboratory testing, but predictive methods using solubility parameter data may also be used prior to actual experimentation. Emulsification of the active liquid

is usually achieved by mechanical agitation, and the size distribution of the droplets is governed by the shear pattern and the work input obtained by the selected mixing device. A second water-soluble polymer, such as gum arabic, is then added to this emulsion. After mixing, dilute acetic acid is added to adjust the pH of the final system. Though both polymers used are water-soluble, addition of the acetic acid results in the spontaneous formation of two incompatible liquid phases. One phase, called the coacervate, has a relatively high concentration of the two polymers. The other phase, called the supernatant, has a much lower concentration. The resulting concentration of both polymers in each of these two phases is a result of complex physical chemical phenomena. Optimization of such systems usually involves considerable experimental work to arrive at commercially useful systems. If the materials are properly chosen, the coacervate preferentially adsorbs onto the surface of the dispersed core droplets, forming the desired microcapsules. The physical chemistry and thermodynamics involved in the process dictate whether or not the coacervate adsorbs onto the core material. The complex phenomena of this process are governed by the solubility of the coacervate in the aqueous media as well as the wetting and spreading ability of the materials as determined by the various surface tensions and spreading coefficients of the components involved. A two-step process usually hardens the capsules’ shells. The first step involves cooling via heat transfer, while the second step involves a chemical reaction through the addition of a cross-linking agent such as formaldehyde (polymer chemistry). The release characteristics of the microcapsules are governed by materials science (mechanical), heat transport (thermal release), and mass diffusion (diffusion through the wall). Each aspect of the encapsulation process plays a key role in the properties of the final product. For example, the thermodynamics of the phase separation process affects the composition of the shell material, and this in turn affects not only the ability of the shell material to wet the core phase, but it also is critical in determining the resulting barrier properties and release characteristics.

ANSALDI: POROUS ENTRAPMENT SPHERES AS DELIVERY VEHICLES Despite extensive research to fully comprehend the coacervation process, it has been almost impossible to study the influence of each of these factors on an individual basis. Furthermore, answers to some questions remain qualitative and are only achieved via experimentation; examples include: How fast should the pH be lowered? How can undesirable agglomeration and formation of free coacervates be avoided? What are the effects of rapid cooling?[1] Benefits of microcapsules. Visual Impact: Colored microcapsules create an attractive presentation that can catch a consumer’s “eye” in a wide range of personal care products. Tactile Impact: The size and hardness of the microcapsules can be modified to produce a bead, which provides a specific or special desirable sensory effect. Stabilization: Microcapsules can be used to isolate and protect those materials that present stability problems or are incompatible in a specific formulation. Targeted Delivery: The encapsulated ingredients are released upon the breaking of the capsules. This is typically achieved by a shearing action wherein pressure is applied to the capsules, causing the outer membrane to rupture and release the active (core). The process provides a targeted delivery of functional actives to the intended area of release.

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15.2.2 Liposomes Overview. Liposomes are microscopic spherical vesicles that form when phospholipids are hydrated. In water, under low-shear mixing conditions, the phospholipids arrange themselves in “sheets” in which the molecules align themselves side-by-side in like orientation. A “heads” up and “tails” down configuration typically results. In this orientation, the “head” is the hydrophilic portion of the molecule and the “tail” is the hydrophobic portion. These sheets form a bilayer membrane by orienting themselves in a head-to-head–tail-to-tail arrangement (Fig. 15.1). The resulting structure encloses some of the water in a phospholipid sphere. A multilamellar structure of concentric phospholipid spheres separated by layers of water will form during which time several clusters of these vesicles (diminishing in size) associate. Liposomes have a long history in the study of biological membranes. Recently, they have been evaluated as delivery systems for drugs, vitamins, and cosmetic materials. The fact that liposomes can be custom-designed for almost any need by varying the lipid content, size, surface charge and method of preparation offers significant potential for their use with a variety of personal care actives in a wide range of commercially interesting products.

Properties of microcapsules. Form: Microcapsules are normally supplied in the form of an aqueous slurry with a typical composition of 60% total solids, 40% water plus preservative (as required). Size: The complex coacervation technology allows for producing microcapsules that range in particle size from 10 to 2,000 microns. Loading: The payload of the active (core) material inside the coacervate capsules can be as high as 95%. Wall Strength: By controlling the thickness of the microcapsule walls, a variety of tactile properties can be achieved. These properties range from soft capsules that can disappear upon rubbing, to resilient capsules that yield a more distinctive sensory impact.

Figure 15.1 Typical liposome structure showing headto-head, tail-to-tail arrangement.

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Advantages. Liposomes have the unique property of being able to encapsulate both water-soluble and water-insoluble materials. This property allows both types to be used together in a formulation without the use of surfactants or other emulsifiers. Of particular interest are water-soluble actives, which are incorporated into the liposomes by first dissolving them in the water containing the hydrated phospholipids. The resulting material is then trapped in the aqueous center when the liposomes form. The liposome wall is generally a fluid phospholipid membrane and is capable of holding fat-soluble materials such as oils that have similar structural characteristics to the phospholipids. The resulting liposomes hold the normally immiscible materials together in a lamellar structure, which allows for controlled release of the encapsulated active ingredients as the structure loses water and disassembles. This disassembling takes place in cosmetic applications as the water in the liposome is drawn into the skin. The characteristics of liposomes also yield a variety of other formulation benefits. These include: • Controlled delivery system • Biodegradable, nontoxic properties • Ability to carry both water- and oil-soluble payloads

15.3 Porous Entrapment System Technology The development of cosmospheres by Pelletech, an affiliate of Spirig Ltd., Switzerland, first emerged in the pharmaceutical industry. The initial application for these products was in the area of oral drug delivery. Cosmospheres were developed to offer controlled-release characteristics on the basis of controlled dissolution and thus controlled availability in a biological system. As the dissolution of a drug from a solid substrate is, in part, dependent on the surface area exposed to the dissolving medium, spherical particles are ideal since they present the lowest surface-area to volume ratio. This factor can be effectively used to reduce the dissolution rate of active substances. After extensive development and testing, it was determined that there was also a wide spectrum of personal care applications where these pellets would also be suitable. Based on the considerable potential for the use of cosmospheres in the personal-care market, an association between Presperse, Inc., and Pelletech was formed. Cosmospheres represent a novel alternative to the currently used delivery systems (microcapsules and liposomes) for the personal-care formulator.

• Prevention of oxidation • Controlled hydration Types. Conventional: • Stabilized natural lecithin mixtures • Synthetic identical-chain phospholipids • Glycolipid-containing liposomes Specialty: • Bipolar fatty acids • Antibody directed • Methyl/methylene cross linked • Lipoprotein coated • Carbohydrate coated • Multiple encapsulated • Emulsion compatible

15.3.1

What are Cosmospheres?

Essentially, cosmospheres are beads (Fig. 15.2) based on cellulose and lactose. The beads appear as small, dry spheres that hydrate and swell in aqueous media resulting in small, optically colored beads that are visible to the naked eye. A major difference between the cosmospheres and either microcapsules or liposomes is the lack of a shell wall. Since the cosmosphere beads have no shell wall, they disappear completely when rubbed into the skin! Cosmospheres have the following benefits/ features: • They have no shell wall. • They are supplied in dry form. • They can be loaded with a variety of substances (e.g., colored pigments, vitamins, plant extracts, sunscreens, etc.).

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manufacture of a narrow particle-size distribution, thereby eliminating the formation of undesirable fines, which can present a dusting problem for the enduser. The basic ingredients used to produce the cosmospheres are microcrystalline cellulose and lactose. Both of these materials are USP grade and suitable for personal-care applications.

Figure 15.2 Typical appearance of cosmospheres.

• They are available in different sizes (0.5– 2.0 mm) and are visible to the naked eye. • They are emulsifier-free and leave no residue after application. • They provide a superb aesthetic after-feel. • They provide excellent visual effects to finished products. The development of the process for manufacturing cosmospheres is covered by U.S. Patent 5,292,461 and is based on the special processing “know-how” of Pelletech. Using Pelletech’s proprietary technology, common pharmaceutical excipients can be processed into porous spheres. This allows for the incorporation of sensitive actives to be entrapped in the porous spheres using gentle processing techniques. The use of gentle processing enables the entrapment of ingredients that may be sensitive to high temperatures. The size of the cosmospheres produced can be predetermined by the process. This allows for the

Cosmosphere applications. Cosmospheres can be incorporated into a variety of product forms for personal care. These include: skin care, hair care, and bath and body products, etc. Cosmospheres are used in personal care to deliver actives, colors and/ or fragrances to the skin. Most typically, in the personal-care industry, cosmospheres are utilized to deliver oil-soluble materials from aqueous systems. A variety of formulations using cosmospheres that serve to demonstrate their utility in selected personal care formulations. The most aesthetically pleasing formulations are the clear systems. These can take advantage of the size and color of the cosmospheres to add a visual dimension to the finished product. In several cases, the cosmospheres are used only to produce a visual effect and are, therefore, incorporated as unloaded beads.

15.4 Conclusion As a delivery system, cosmospheres offer a useful alternative to the coacervate-based microcapsules and liposome technology. They are especially useful for the growing number of clear products being introduced into the personal-care market.

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15.5 Formulations Formulation 15.1: Bath and Body Gel

Phase

Ingredients

Function

Weight %

Deionized Water

Diluent

Carbomer 940

Thickener

0.40

Zilgel® SM

Thickener

8.00

Butylene Glycol

Solvent

2.00

Dissolvine NA-3T

Chelator

0.15

Tween 20

Emulsifier

0.25

DC 193 Surfactant

Emulsifier

0.40

FD&C Blue #1 (0.1%)

Colorant

0.02

FD&C Yellow #5 (0.1%)

Colorant

0.01

FD&C Red #28 (0.1%)

Colorant

0.03

C

Germaben II

Preservativ e

1.00

D

Triethanolamine 99%

Neutralizer

0.75

E

Flonac MS-60C

Pearl Pigment

0.10

F

Cosmosphere BN w/Ultramarine Blue

Delivers Color

1.00

A

B

85.59

Mixing Procedure: Slowly add the Carbopol resin into a vortex of water, using low shear agitation, and disperse completely. Slowly add the rest of Phase A ingredients in sequence, mixing each addition well. Add the color. Mix well. Add Phase C to Phases A and B mixtures. Slowly add Phase D to the batch. Mix until uniformly dispersed. Slowly add Phase E in a circular rotation until evenly dispersed. Then pass through homomixer until Phase E ingredient is smoothly and fully dispersed. Slowly add Phase F into the batch. Mix well until fully dispersed. Keep in an appropriate container.

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Formulation 15.2: Scented Hair Styling Gel

Phase

A

Ingredients

Function

Weight %

Deionized Water

Diluent

45.40

Carbopol 940 (2% solution)

Thickener

25.00

Deionized Water

Diluent

0.60

Triethanolamine 99%

Neutralizer

0.60

Zilgel® SM

Thickener

15.00

PVP/VA E-735

Styling Aid

10.00

Deionized Water

Diluent

1.00

Germall II

Preservative

0.30

Tween 20

Fragrance Solubilizer

1.00

B

C

D

Fragrance E

Cosmosphere BRT w/Ultramarine Blue / Tocopherol Acetate / Retinyl Palmitate

0.10

Delivers Vitamins

1.00

Mixing Procedure: Disperse Carbomer in water with good agitation to create a vortex. Mix until fully hydrated. Slowly add pre-mixed Phase B ingredients. Add Phase C ingredients in sequence very slowly using paddle-like mixer, starting from outside toward center, to minimize trapping the air bubbles into the batch. Add the pre-mixed Phase D to the batch. Mix to uniformity. Add in sequence Phase E to the mixtures of Phases A, B, C, and D. Mix well. Fill at room temperature.

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Formulation 15.3: Face Scrub

Phase

A

B

Ingredients

Function

Weight %

Deionized Water

Diluent

60.70

Carbopol 940 (2% solution)

Thickener

10.00

Glycerine, USP

Solvent / Moisturizer

2.00

Arlacel 165 Permethyl® 102A

Emulsifier

6.00

Emollient

5.00

Liponate NPGC-2

Emulsifier

8.00

Stearic Acid

Emulsifier

3.00

Lipocol S

Emollient

1.00

C

Cosmosphere BM50-L3 Delivers Exfoliator w/Polyethylene

3.00

D

Triethanolamine 99%

Neutralizer

0.30

E

Germaben II

Preservative

1.00

Mixing Procedure: Combine Phase A materials with propeller mixing and heat to 70°C. Combine Phase B materials and heat to 75°C. Add Phase B to A with propeller mixing. Hold at 72°–75°C for 15 minutes. Add Phase C to the batch. Mix until uniform. Add Phase D. Mix until uniform. Cool to 40°C. Add Phase E. Mix until uniform. Cool to 25°–28°C. Store in suitable containers.

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Formulation 15.4: Cooling Gel

Phase A

B

Ingredients

Functions

Weight %

Zilgel® VV

Thickener

40.00

Deionized Water

Diluent

42.00

Codiavelane BG Enteline 2®

Moisturizer

2.00

Moisturizer

2.00

Germaben II

Preservative

1.00

C

Alcohol SDA 40-2 (190º)

10.00

D

Cosmosphere ML w/Menthyl Delivers Cooling Lactate Agent

3.00

E

Color

Q.S.

Mixing Procedure: Place Phase A in a suitable kettle equipped with a side-wiping and counter-rotating mixer. Slowly add Phase B to Phase A with moderate mixing. Mix until uniform. Slowly add Phase C to the batch with moderate mixing. Mix until uniform. Sprinkle in Phase D. Mix until uniform. Store in appropriate containers.

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Formulation 15.5: Glittering Clear Gel

Phase

Ingredients

Function

Weight %

Deionized Water Zilgel® SM

Diluent

53.40

Thickener

32.50

Butylene Glycol Zilgel® Oil

Solvent

6.50

Moisturizer

5.00

B

Flonac MS-10C

Pearl Pigment

0.10

C

Cosmospheres GTI w/3% Tocopherol Acetate

Delivers Vitamin E

1.50

D

Germaben II

Preservative

1.00

A

Mixing Procedure: Charge de-ionized water into a main kettle and start mixing under propeller mixer. Add the remaining ingredients in sequence while mixing into the batch. Mix the batch very gently and slowly to avoid air entrapment. Add Phase B into Phase A and agitate gently in circular motion until the powder is thoroughly dispersed. Homomix the Phases AB mixtures until the batch is smoothly homogenized. Add Phase C into Phases AB mixtures. Mix gently until the beads are uniformly suspended into the batch. Add Phase D to Phases ABC mixtures. Mix gently until uniform. Store or fill appropriate containers.

References 1. Franjione, J., and Vasishtha, N., The Art and Science of Microencapsulation, Technology Today, Southwest Research Institute 2. Private communications with Pelletech

16 Polymeric Porous Delivery Systems: Polytrap and Microsponge Subhash Saxena Cardinal Health – Topical Technologies, Somerset, New Jersey Sergio Nacht Riley-Nacht, LLC., Las Vegas, Nevada

16.1 Introduction ................................................................................... 334 16.1.1 Needs in Skin Care ........................................................... 334 16.1.2 Entrapments: General Description ................................... 334 16.2 Polytrap® Technology .................................................................... 334 16.2.1 What is a Polytrap Polymer? ............................................ 334 16.2.2 How are Polytrap Polymers Made? .................................. 335 16.2.3 How Can They Be Loaded? .............................................. 335 16.2.4 Mode of Action .................................................................. 335 16.2.5 Main Applications .............................................................. 335 16.2.6 Strengths and Limitations ................................................. 337 16.3 Microsponge® Technology ............................................................ 338 16.3.1 What is a Microsponge® Polymer? ................................... 338 16.3.2 How are Microsponge® Polymers Made? ......................... 338 16.3.3 How are They Loaded? ..................................................... 339 16.3.4 Mode of Action .................................................................. 340 16.3.5 Main Applications .............................................................. 341 16.4 Summary and Conclusions .......................................................... 344 16.5 Formulations ................................................................................. 345 References .......................................................................................... 351

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 333–352 © 2005 William Andrew, Inc.

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16.1 Introduction

16.1.2

16.1.1 Needs in Skin Care

The term “entrapment” is used throughout this chapter to describe the process of incorporating an ingredient into a porous polymeric matrix. This type of system is quite different from the typical microencapsulation process that employs an ingredient that is literally surrounded by a continuous, and usually non-permeable, membrane.

In the last ten years we have seen an ever-increasing interest by the consumer (primarily the female) in skin treatment products. These contain active ingredients first termed “cosmeceuticals” by A. M. Kligman, M.D. This interest has been fostered by the widespread use of ingredients like alpha-hydroxy acids (AHAs) and vitamins in topical products that can induce perceivable and demonstrable benefits—especially in aging or photo-damaged skin. While quite useful, in many instances these ingredients may produce irritancy. Such irritancy can be perceived as burning, stinging or redness, and particularly occurs in individuals with sensitive skin. Recognizing this problem, formulators have attempted to deal with this problem in one of two ways. They have reduced the concentration of such ingredients but, in the process, sacrificed efficacy. They have also modified the vehicle in order to make the product more emollient or “skin-compatible.” However, this approach, in many cases, also reduces the overall beneficial effects of the final product. Since the early 1970s, the pharmaceutical industry has developed special delivery system methodologies to minimize the undesirable effects of systemic drugs while maintaining their efficacy. These delivery systems usually release the drug at a predictable rate over a more or less prolonged time. In this way, the body is able to absorb the pharmacological agents gradually and avoid the “peak concentrations” that may cause undesirable side effects. In the last fifteen years, new polymeric systems have been developed to provide predictable rates of skin absorption for topical active agents. Such systems have been employed for both pharmaceutical and cosmetic products and have resulted in a new generation of very well tolerated, and highly efficacious, novel products. These products are typically presented to the consumer in conventional forms, like creams, gels, or lotions, and they contain relatively high concentrations of the active ingredient. In this chapter, two such novel polymeric systems are described: Polytrap® and Microsponge®.

Entrapments: General Description

In a typical entrapment process, a porous polymeric structure is first synthesized using an appropriate procedure. The active ingredient may then be incorporated into the final polymer in one of two ways. Incorporation can be accomplished at the time of synthesis, or the active may be post-loaded into the pre-formed structure. In general, the latter procedure consists of a facilitated diffusion process wherein the porous polymer structure is mixed with the pure active ingredient, or with a concentrated solution of the active in a suitable solvent. Different technologies can produce a variety of polymers with a broad range of chemical compositions, particle sizes, porosity (void volumes), pore openings, and surface areas. This range of capabilities can result in vast differences in payload efficiencies and release rates of the active substance. Therefore, to maximize the benefits of such polymeric transport systems, it is imperative to carefully match the desired active ingredient with the appropriate polymeric structure in order to obtain an optimal rate of delivery from the porous, polymeric delivery system to the skin.

16.2 Polytrap® Technology 16.2.1 What is a Polytrap Polymer? The Polytrap® technology was originally developed and patented by R. C. Chromecek, et al., in 1990.[1][2] Dow Corning later acquired the company and broadened the commercialization of these polymers through its worldwide network of distributors and representatives. Following a series of further corporate acquisitions, this technology is now owned by AMCOL Health & Beauty Solutions.

SAXENA, NACHT: POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® AND MICROPSONGE® 16.2.2 How are Polytrap Polymers Made? As described in the Chromecek patents,[1][2] useful polymers are synthesized by the suspension polymerization of lauryl methacrylate and ethylene glycol dimethacrylate using a peroxide as a catalyst. The polymerization conditions lead to the formation of amorphous micro-aggregates. The size of these aggregates is about 25 µm in diameter and within their structure is a high degree of crosslinking (Fig. 16.1). By modifying the synthesis process, different porous polymeric materials can be obtained and these can be loaded with a variety of active substances useful in skin care products.

335

16.2.3 How Can They Be Loaded? The Polytrap polymers can adsorb a significant amount (up to 70% w/w) of added compounds like silicone oils and the like. As a result, they are ideal carriers for such lipophilic actives and provide a unique method for incorporating them into water based or oil-in-water formulations without resulting in a greasy after-feel. Thus, Polytrap polymers are useful formulation aids that permit the development of unusual product forms. These include, for example, skin protectant body powders containing high levels of petrolatum and/or dimethicone. Other ingredients of potential interest can easily be loaded into a Polytrap matrix by gently mixing the ingredient (as a pure liquid, or in a suitable nonaqueous solvent solution) with the polymer until all the liquid phase has disappeared and a free flowing powder is obtained.

16.2.4

Mode of Action

As a result of their macroporous open structure, when the finished product (i.e., the active + Polytrap polymer + vehicle) is applied to the skin, these porous networks will promptly release the entrapped ingredient, thereby rendering it easily available to the skin. Figure 16.1 Scanning electron micrograph: polytrap particles.

In addition to the carrier property resulting from the reservoir formed by the porous network, these polymers are extremely lipophilic and hydrophobic. These attributes make the Polytrap family of compounds ideal for the control of skin oiliness. They will absorb up to six times their own weight of sebaceous secretions but will not pick up moisture from the skin. This property allows the Polytrap polymeric family to be nondrying as well as efficacious regarding absorption of sebum. While the lipophilic nature of the Polytrap polymers holds value, this property must be kept in mind when formulating these raw materials into emulsions in order to avoid potential disruption of the formulation during aging.

16.2.5

Main Applications

Polytrap® technology can be used in a variety of ways. In view of its extraordinary lipophilic properties, its widest use is as an oil absorber modality on skin. Beyond the oil absorption property and use, however, the technology has also been used to entrap lipophilic active ingredients and deliver them to the skin. In one commercial approach, special large Polytrap particles that physically disintegrate with the typical shear forces of application have been created for use in scrubs. Oil absorption. Polytrap polymers are prepared from lauryl methacrylate and ethylene glycol dimethacrylate monomers. The lauryl methacrylate makes the internal surface area of the finished polymer very lipophilic and very hydrophobic. The combination of resulting low surface energy and high surface area make the oil absorption potential of

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these particles exceptional. In an in vitro experiment, the absorption potential of these porous polymers was compared to other conventional cosmetic ingredients used for oil absorption such as talc, bentonite, and cornstarch. When artificial sebum was used as the substrate, Polytrap absorbed nearly six times its own weight (Fig. 16. 2), and this was a much higher ratio than seen for any of the other ingredients tested. On the other hand, when water sorption was measured in these experiments, there was practically no adsorption by the Polytrap particles (Fig. 16.3).

These attributes make Polytrap ideal for inclusion in moisturizers, foundations, and other skin care products designed for oily or combination skin since Polytrap will absorb the excess oil from the skin without dehydrating it. Because these polymers are free-flowing powders, they have also been incorporated in compressed powders to absorb excess oil. Formulation 16.1 (see Sec. 16.5) presents an example of a prototype moisturizing formulation that can control skin oiliness without dehydrating it. Sunscreens can also be added to this formulation to obtain a product with an SPF 15 without having an undesirable oily after-feel.

Figure 16.2 Comparison of oil absorbance potential of Polytrap® particles vs other raw materials used as oil absorbers for sebum.

Figure 16.3 Comparison of water removing potential of Polytrap® particles vs other raw materials used as oil absorbers for sebum.

SAXENA, NACHT: POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® AND MICROPSONGE® Delivery of actives. Though not a primary use of this technology at present, Polytrap has great potential for use in the entrapment and delivery of lipophilic actives. Materials such as cyclomethicone, petrolatum, or mineral oil can easily be loaded into the polymeric structure with very high payloads, up to 80% w/w. Since the particles are not porous, the material is held on the surface of and between the particles and, even with these high payloads, the material remains a free-flowing powder. Other actives, such as hydroquinone, have also been successfully loaded onto the polymer. The loading process is rather simple with the polymer and active. This is typically accomplished by means of a solution of the active or, if it is a liquid, in the neat form, being brought together at predetermined ratios and mixed under controlled conditions for easy and even loading. The loading may be done under any temperature condition depending upon the properties of the active. Scrub applications. Regular Polytrap particles are about 1µm in diameter though they tend to form loosely bound clusters of about 25 µm in size. Though the individual particles themselves do not break when rubbed, the clusters do come apart exposing the high surface area of the individual particles to the skin. Special Polytrap particles have been created that are much larger than these clusters and range from about 200 µm to 400 µm (Figs.16.4 and 16.5). The special Polytrap particles are different from regular Polytrap particles in three ways, other than their size. They are porous, they contain dimethicone

337

Figure 16.5 Scanning electron micrograph: Polytrap® microporous macrobead after rubbing.

(30% w/w), and they break when rubbed on the skin. Such polymers have been used to create gentle skin scrubs. Conventionally, ground apricot, walnut pits, aluminum oxides, or polyethylene granules have been used in such scrubs. However, in view of their irregular shape, these materials can be rather irritating to the skin. By contrast with conventional materials used in scrubs, the large Polytrap particles are spherical particles with no edges. When rubbed on the skin, they rapidly break down into very small spherical particles and are, therefore, mild and self-limiting. During the breakdown process they release dimethicone, which can act as a skin protectant. In consumer tests, scrubs containing these large Polytrap materials were found to be as efficacious as other commercial scrubs, but they were highly preferred since they were much gentler to the skin (Fig. 16.6). An example of a formulation for a gentle exfoliating cleanser containing these large Polytrap particles is shown in Formulation 16.2.

16.2.6

Figure 16.4 Scanning electron micrograph: Polytrap® microporous macrobead before rubbing. Particle diameter is approximately 200 µm.

Strengths and Limitations

A significant feature of the Polytrap polymers is their ability to absorb very high amounts of sebum. Since they are free-flowing powders, they can easily be incorporated in all types of formulations. These include gels, lotions, creams, ointments, and powders, all of which are designed to absorb oil exuded by the

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Figure 16.6 Scrub preference of scrub containing Polytrap® macrobeads vs scrub containing polyethylene beads.

skin. Depending upon the amount added, they can be employed to create a long-lasting matte appearance and reduce or eliminate undesirable sheen from the skin. Small amounts of Polytrap polymers are usually needed, and typically 0.5%– 2.0% w/w is sufficient, although higher amounts can easily be incorporated. The lipophilic properties of the Polytrap polymers also make them suitable to deliver relatively high loads of lipophilic materials. Because the individual particles are spherical and small in size, (<1 µm), they can impart a smooth, silky feel to the skin. Their high surface area has been employed to stabilize certain types of emulsions. One limiting aspect of Polytrap polymers is the fact that they are so lipophilic that loading of hydrophilic materials onto the polymer is quite difficult. Dispersion of Polytrap in emulsions must be aided by mechanical agitation, and in the presence of a mild surfactant. These polymers do not wet very easily without a surfactant. Since the active is adsorbed onto the surface of, and in-between, the particles, the time or gradual release benefits are limited and less subject to control than results obtained with porous particles like Microsponge® polymers.

16.3 Microsponge® Technology 16.3.1

What is a Microsponge® Polymer?

This technology was developed by Won in l984[3] and then expanded in 1987.[4] The original patents were assigned to Advanced Polymer Systems, Inc. This company developed a large number of variations of the technology and applied them to cosmetic products as well as OTC and prescription pharmaceutical products. At the present time, this interesting technology has been licensed to Cardinal Health, Inc., for use in topical products.

16.3.2

How are Microsponge® Polymers Made?

While Microsponge polymers are also prepared by suspension polymerization techniques, both the conditions of synthesis, as well as the monomers used, are quite different from those employed with Polytrap materials. The Microsponge products can be made using either styrene and divinylbenzene or

SAXENA, NACHT: POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® AND MICROPSONGE® methyl methacrylate and ethylene glycol dimethacrylate, as starting materials. Depending upon the choice of monomers and crosslinkers, two different families of compounds can be created. While both families consist of porous microspheres, their physical-chemical properties are quite different. In addition, the Microsponge manufacturing process allows products to be made with a wide range of particle size, porosity (void volume), pore diameter (openings on the surface), and surface area. Thus, an almost unlimited number of variations can be obtained. This permits the customization of the polymer to the active ingredient to be entrapped. It also allows design and control of the required release rate and maximization of beneficial effects on the skin.

16.3.3 How are They Loaded? Ingredients can be entrapped in Microsponge polymers either at the time of synthesis (one step process)[3] or, if too labile to withstand polymerization conditions, they can be post-loaded after the microsphere structure has been preformed (two-step process).[4] In general, the latter process is the preferred mode since many cosmetic ingredients, and most pharmaceutical ones, would decompose at the temperatures employed for polymerization. As depicted in Fig. 16.7, the microspheres resulting from this process closely resemble spherical sponges. However, while they behave like these materials in many aspects, they differ considerably by being practically non-compressible. This is a re-

Figure 16.7 Scanning electron micrograph: Microsponge® particles.

339

sult of a high degree of crosslinking in the polymeric structure that imparts them significant rigidity. When a cross-section of a single particle is observed by scanning electron microscopy (SEM) (Fig. 16.8) a structure of amazing complexity is perceived. Typical Microsponge spheres of about 15 µm in diameter contain a multitude of submicron nanospheres, surrounded by a membrane riddled by pores. A significant amount of empty space is seen to exist in between the nanospherical particles. This structure defines the void volume or total porosity of the particle and, therefore, the maximum potential payload concentration of the entrapped ingredient within the Microsponge particle. Microsponge particles can be loaded by diffusion in a manner quite similar to regular sponges. The entrapped ingredient can then be gradually released when the polymer is placed in contact with the skin. The rate of active release will ultimately depend not only on the partition coefficient of the entrapped ingredient between the polymer and the vehicle (or the skin), but also on some of the parameters that characterize the microsphere. Examples of these include surface area and primarily, mean pore diameter.[5] The gradual release of entrapped ingredient over time not only extends the duration of the beneficial effects of the active, but also minimizes its potential undesirable effects.[6] In some instances, this can also be achieved by avoiding the use of harsh solvents in the vehicle since the technology, by prepackaging the active in the polymer, facilitates formulating a gentler final product.[7]

Figure 16.8 Scanning electron micrograph: crosssection of a single Microsponge® particle showing inner structure and void spaces where the loaded material is held.

340 16.3.4

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Mode of Action

The hypothetical mechanism of action for the Microsponge system is shown in Fig. 16.9. The active ingredient is added to the vehicle in the entrapped form. Since the Microsponge particles have an open structure (i.e., they do not have a continuous membrane surrounding them), the active is free to move in and out from the particles into the vehicle until equilibrium is reached when the vehicle becomes saturated. Once the finished product is applied to the skin, the active that is already in the vehicle will be absorbed into the skin, depleting the vehicle, which will become unsaturated, therefore disturbing the equilibrium. This will start a flow of the active from the Microsponge particle into the vehicle and, from it, to the skin until the vehicle is either dried or absorbed. Even after that, the Microsponge particles retained on the surface of the stratum corneum will continue to gradually release the active to the skin providing prolonged release over time.

The Microsponge particles themselves are too large to be absorbed into the skin and this adds a measure of safety to these materials. As shown in Figs. 16.10 and 16.11, the particles can reside on the surface of the skin and in its fine lines and crevices, thereby delivering the active over a prolonged time. This proposed mechanism of action highlights the importance of formulating vehicles appropriate for use with Microsponge entrapments. If the active is too soluble in the desired vehicle, it will leach out of the entrapment into the vehicle during compounding of the finished product, or while it sits on the shelf. If this occurs, the product will not provide the desired benefits of gradual release. Instead, it will behave as if the active was added to the vehicle in the free (unentrapped) form. Therefore, when formulating with Microsponge entrapments, it is important to design a vehicle which has minimal solubilizing power for the actives. This principle is contrary to the conventional formulation principles usually applied to topical products. For these conventional

Figure 16.9 Schematic showing the distribution of loaded material (active) on skin: skin depletes vehicle concentration, and Microsponge® releases active in response to vehicle depletion.

Figure16.10 Confocal microscopic picture of Microsponge® particles residing on the skin.

Figure 16.11 Confocal microscopic picture of Microsponge® particles residing in the fine lines and wrinkles of the skin.

SAXENA, NACHT: POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® AND MICROPSONGE® systems, it is normally recommended to maximize the solubility of the active in the vehicle. When using Microsponge entrapments, some solubility of the active in the vehicle is acceptable because the vehicle can provide the initial loading dose of the active until release from the Microsponge is activated by the shift in equilibrium from the polymer into the carrier. Examples of results obtained with properly and improperly formulated systems are shown in Figs. 16.12 and 16.13. In the unoptimized form, there is no difference in the in-vitro release profiles of vitamin A obtained with a formulation containing free vitamin A and another one having entrapped vitamin A. On the other hand, when the vehicle is properly formulated, the rate of release is significantly slower from the entrapped version, as expected. Another way to avoid undesirable premature leaching of the active from the Microsponge polymer is to formulate the product with some free and some entrapped active so the vehicle is pre-saturated and equilibrium is pre-established. In this case, there will not be any leaching of the active from the polymer during compounding, or while the product is sitting on the shelf.

Figure 16.12 In vitro release of vitamin A from a nonoptimized formulation containing vitamin A entrapped in Microsponge® particles.

16.3.5

341

Main Applications

The Microsponge polymers are used in a large number of commercial cosmetic and pharmaceutical products. Examples of pharmaceutical applications include Retin-A® Micro®* (containing tretinoin), Carac®† (with 5-fluorouracil), and the Exact®‡ line of anti-acne medications which contain benzoyl peroxide or salicylic acid. In the cosmetic area, a significant number of products containing entrapped Retinol as well as other vitamins have been enabled by the use of this technology. Useful active materials for personal care are easy to load onto the polymer because they simply require the addition of an active solution, or liquid to the polymer under controlled conditions. Prescription topical products. Microsponge technology has been successfully applied to a large number of topical products including cosmetics, cosmeceuticals, over-the-counter drugs, and prescription drugs. To date, there are four prescription products on the market that utilize this technology. Three of these have been the subject of New Drug Applications and have received approval from the U.S. Food and Drug Administration. These include:

Figure 16.13 In vitro release of vitamin A from an optimized formulation containing vitamin A entrapped in Microsponge® particles.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

• Retin-A® Micro® (0.1% tretinoin) for the treatment of acne vulgaris. • Retin-A® Micro® (0.04% tretinoin) for the treatment of acne vulgaris. • Carac® (0.5% fluorouracil) for the treatment of actinic keratoses. • The fourth Rx product is a 4% hydroquinone Cream (Epiquin®§) for the treatment of postinflammatory hyperpigmentation and melasma. All these formulations were designed to minimize skin irritation. For example, tretinoin is well known to be very irritating to the skin and often causes dryness, flaking, and erythema. With such negative side effects, subjects generally stop using the products. The capabilities of the Microsponge technology allowed tretinoin to be formulated in an aqueous gel without the use of alcohol or organic solvents. Heretofore, such solvents have been irritating to the skin but were considered essential in previous formulations in order to dissolve the active ingredient. By contrast, since the Microsponge particles containing the active can readily be suspended in an aqueous gel, no solvent was used in the RetinA Micro formulation thereby making it far gentler to the skin. By virtue of the gradual release of the tretinoin from the Microsponge, the formulation is rendered even milder. Due to the proprietary nature of these formulations, it is not possible to list their quantitative formula. However, the qualitative formula of Retin-A Micro is described in Formulation 16.3. The gentleness of Formulation 16.3 was proven in clinical studies.[8] In a half-face, double-blind clinical study, the Retin-A Micro formulation was compared with the conventional Retin-A formulation, both of which contained 0.1% tretinoin. Twenty-five women selected for having sensitive skin applied one product to one cheek and the second product was applied to the other cheek for fourteen days. Based on the irritation perceived and other subjective parameters like burning and stinging, the women were

then asked for their product preference. As seen in Fig. 16.14, an overwhelming majority of the women (23 out of the 25) found the Microsponge-containing formulation gentler than the conventional RetinA® formulation. These observations were confirmed in the Phase III clinical safety and efficacy studies. Similar results have been seen with a 0.5% fluorouracil (5-FU) formulation. Once again, the irritation of the product was reduced while still maintaining its efficacy. With conventional 5-FU formulations, not only is irritation very severe, but also the recovery time is lengthy, with resulting irritation and erythema taking several weeks to subside. The Carac® cream formulation (Formulation 16.4) containing Microsponge polymer was also shown to minimize in-use irritation, as well as shorten the recovery period.[9] The qualitative formula is shown in Formulation 16.4. The Microsponge technology can also be used to bring two or more relatively incompatible materials together in the same formulation. An example of this is the 4% hydroquinone formulation used in Epiquin. It is well known that hydroquinone and Retinol are usually chemically incompatible. However, the possibility of incorporating both in the same formula could provide many benefits to the skin. The primary benefit from such a combination in the same formulation is the cosmetic effect of Retinol for reducing the appearance of fine lines and wrinkles. To demonstrate this capability, two different Microsponge entrapments were used in the formulation: one of which contained hydroquinone while the other contained Retinol. The qualitative base formula is shown in Formulation 16.5. This rather complex vehicle formulation was needed to minimize the solubility of both the Retinol and the hydroquinone. In this way, the premature leaching of the actives was prevented, thereby insuring their stability. By such means, a product with a shelf life of more than 24 months was obtained.

* Retin-A® Micro® is a registered trademark of Johnson & Johnson, Inc., New Brunswick, NJ. † Carac® is a registered trademark of Dermik Laboratories, Inc., Berwyn, PA. ‡ Exact® is a registered trademark of Cardinal Health, Dublin, OH, or one of its subsidiaries. § Epiquin® is a registered trademark of SkinMedica, Inc.

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Figure 16.14 Subject preference of formulation containing tretinoin entrapped in Microsponge® particles vs a conventional formulation containing free tretinoin.

OTC products. Using the same strategy and rationale as employed for the prescription products described, several proprietary OTC formulations were developed containing useful personal care actives entrapped in a Microsponge polymer. These actives included benzoyl peroxide (at various concentrations),[10] salicylic acid, and hydroquinone (at typical OTC concentration). An example of a 5% benzoyl peroxide vanishing cream formulation is shown in Formulation 16.6. This formulation has been shown to have less irritancy potential than comparable conventional OTC formulations[6] while providing excellent antiacne efficacy. One interesting aspect of these acne formulations is that as the Microsponge particles deliver the acne active (e.g., benzoyl peroxide or salicylic acid), they tend to absorb excess sebum from the skin. Since excess sebum is a contributing factor in acne, reducing skin oiliness is highly desirable and addresses an important need of the typical acne sufferer.

Cosmeceuticals. Although not an officially defined FDA category, cosmeceuticals have become the fastest growing category in the skin care business. Cosmetic ingredients such as alpha-hydroxy acids (AHAs), Retinol, and vitamin K are examples of cosmetic actives that fall in this category. While able to provide unusual features and benefits, use of such materials is accompanied by similar side effects to those associated with pharmaceutical ingredients such as tretinoin (e.g., peeling, drying, erythema, etc.). In view of this, formulating with such cosmeceutical ingredients entrapped in Microsponge polymers becomes a viable alternative. Perhaps no single entity more so than Retinol demonstrates the advantages of formulating with the Microsponge system. Retinol is chemically quite unstable oxidatively, is irritating to the skin, and is not easy to formulate with. Entrapment of Retinol in the Microsponge system successfully addresses all of these issues. Formulations containing Retinol entrapments have been

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made in aesthetically pleasing moisturizing bases. These have been shown to be shelf stable for 2 to 3 years and retain more than ninety percent of their initial concentration. Clinical studies have shown them to be safe and effective in reducing the appearance of fine lines and wrinkles, and in improving the overall condition of prematurely aged skin.[11] A typical qualitative formulation is shown in Formulation 16.7. Formulations containing Retinol entrapment, in combination with other cosmeceutical agents such as vitamin K (phytonadione) (also in the entrapped form) improve the appearance of dark circles under the eyes.[12] Entrapment of the actives has made these formulations milder and, therefore, suitable for daily use, yet retaining their activity for more than two years. Formulation flexibility. Microsponge technology allows the formulation of products that can contain two or more entrapments which have mutually incompatible actives (e.g., hydroquinone and Retinol), thereby allowing the formulator greater flexibility. Also, aqueous gels can be made containing lipophilic materials without the use of any emulsifying agents. This is because the entrapped materials are inside the Microsponge particles and these are easily wetted and suspended in the aqueous phase. On the other hand, very lipophilic formulations can be prepared with hydrophilic materials being added in the entrapped form, again without surfactants or emulsifying agents since the Microsponge particles are easily “wetted” and suspended in the lipid phase due to the amphiphilic nature of the polymer. A similar rationale can be used to prepare formulations with actives that have limited solubility in the desired vehicle. Using this principle, several commercial formulations have been prepared in soft gelatin capsules where the anhydrous vehicle is siliconebased. Retinol, vitamin K, vitamin C, and combinations of these agents, are just some of the entities

that have successfully been incorporated into formulations filled in soft-gelatin capsules using Microsponge entrapments.

16.4 Summary and Conclusions The two patented polymeric technologies discussed in this chapter are unique and have brought a much-needed tool to the skin care field. Historically, while much effort was being placed on improving the delivery and safety of systemic drugs (including the use of transdermal patches), there was a conspicuous absence of such efforts in the delivery of actives where the skin itself was the target organ. Microsponge® and Polytrap® were the first two technologies developed in the 1980s to fill this void. They are simple and practical to use because they can be incorporated into the conventional dosage forms such as creams, lotions, and gels. Such product forms are normally employed by the user to cover wide areas of the skin. By providing a gradual release of actives to the skin, these technologies offer a means of reducing the possible side effects that some active ingredients may cause such as overdrying, irritation, and erythema. In addition, since the techniques enable the formulator to compound products with less technical limitations, they facilitate the development of novel product forms and, in many cases, enable the development of more cosmetically pleasing products for the consumer. Finally, from a marketing standpoint, Microsponge and Polytrap have provided a means of extending the life cycle of commercial products because both technologies, as well as formulations containing various active ingredients, are broadly patented.

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16.5 Formulations All formulations listed in this chapter are prototype formulations. No claim is made about the stability, efficacy, safety, and toxicity of the formula-

tions and/or of the specific ingredients used in them. Formulations 16.1 through 16.7 may only be used as guidelines when developing other formulations.

Formulation 16.1: Oil Control Moisturizer

Ingredient

Function

Water

% w/w 71.70

®

Carbomer 941

Thickener

0.20

Glycerin

Humectant

4.00

Propylene glycol

Skin conditioner

4.00

Panthenol

Skin conditioner

0.30

Green tea extract

Antioxidant

2.00

Methylparaben

Preservative

0.20

Disodium EDTA

Chelating agent

0.05

Polyoxyethylene (100) Stearate

Emulsifying agent

1.25

Cetyl alcohol

Emulsifying agent

2.00

Triclosan

Preservative

0.30

Tocopheryl acetate

Antioxidant

0.05

Glyceryl stearate

Emollient

0.75

Octyl methoxycinnamate

Sunscreen

7.50

Propylparaben

Preservative

0.10

Dimethicone

Skin protectant

2.00

Cyclomethicone

Skin conditioner

1.00

Lauryl methacrylate/glycol dimethacrylate crosspolymer

Oil absorber

2.00

Triethanolamine

pH adjuster

0.30

Imidazolidinyl urea

Preservative

0.30

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 16.2: Gentle Exfoliating Cleanser with Large Polytrap Particles

Ingredient

Function

Water

% w/w 62.14

Lauryl methacrylate/glycol dimethacrylate crosspolymer (and) dimethicone

Exfoliant and skin protectant

4.00

Polyglyceryl-3 diisostearate

Emulsifying agent

7.00

PEG-7 Glyceryl cocoate

Emollient

5.00

Milkamidopropyl betaine

Skin conditioner

3.00

Cocoamidopropyl betaine

Skin conditioner

3.00

Sodium cocyl isothionate

Cleansing agent

2.50

Disodium cocoglucoside sulfosuccinate

Cleansing agent

5.00

Cetrimonium silicone carboxy complex

Skin conditioner

1.00

TEA-cocyl glutamate

Cleansing agent

4.00

Preservative

Preservative

1.00

Sodium hydroxide

pH adjuster

0.20

Hydroxypropyltrimonium chloride

Skin conditioner

1.00

Citric acid (10%)

Buffer

0.85

Disodium EDTA

Chelating agent

0.01

Fragrance

0.30

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Formulation 16.3: Qualitative Composition of Tretinoin Formulation Using a Microsponge Polymer

Ingredient

Function

Tretinoin in methyl methacrylate/glycol dimethacrylate crosspolymer Purified water Carbomer 934P

Viscosity (gel) agent

Glycerin

Humectant

Disodium EDTA

Chelating agent

Propylene glycol

Skin conditioner

Sorbic acid

Preservative

PPG-20 methyl glucose ether distearate

Skin conditioner

Cyclomethicone and dimethicone copolyol

Skin conditioner

Benzyl alcohol

Preservative

Trolamine

pH adjuster

BHT

Antioxidant

Formulation 16.4: Qualitative Composition of a 5-Fluorouracil Formulation Using a Microsponge Polymer

Ingredient

Function

Fluorouracil in methyl methacrylate/glycol dimethacrylate crosspolymer Carbomer 940

Viscosity (gel) agent

Dimethicone in methyl methacrylate/glycol dimethacrylate crosspolymer

Skin conditioner

Glycerin

Humectant

Methyl gluceth-20

Skin conditioner

Methylparaben

Preservative

Octyl hydroxy stearate

Skin conditioner

Polyethylene glycol 400

Emulsion stabilizer

Polysorbate 80

Emulsifying agent

Propylene glycol

Skin conditioner

Propylparaben

Preservative

Purified water Sorbitan monooleate

Emulsifying agent

Stearic acid

Emulsifying agent

Trolamine

pH adjuster

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 16.5: Qualitative Formula of a Hydroquinone/ Retinol Combination

Ingredient Hydroquinone in methyl methacrylate/glycol dimethacrylate crosspolymer

Function Skin bleaching agent

Water Caprylic/Capric triglyceride

Skin conditioner

Emulsifying wax

Emulsifier

Dimethicone

Skin protectant

Glycerin

Humectant

C10-30 cholesterol/lanosterol esters

Skin conditioner

Cetyl alcohol

Emulsifying agent

Cetyl ricinoleate

Skin conditioner

Retinol in methyl methacrylate/glycol dimethacrylate crosspolymer

Skin conditioner

Tocopheryl acetate

Antioxidant

Ascorbic acid

Antioxidant

Ascorbyl palmitate

Antioxidant

Bisabolol

Skin conditioner

Cyclomethicone

Skin conditioner

PEG-10 Soy sterol

Skin conditioner

Polyacrylamide

Film former

C13-14 isoparaffin

Solvent

Laureth-7

Emulsifying agent

Magnesium aluminum silicate

Viscosity increasing agent

TEA-stearate

Emulsifying agent

Cetyl phosphate

Emulsifying agent

BHT

Antioxidant

Disodium EDTA

Chelating agent

Benzyl alcohol

Preservative

Methylparaben

Preservative

Phenoxyethanol

Preservative

Triethanolamine

pH adjuster

Sodium metabisulfite

Antioxidant

SAXENA, NACHT: POLYMERIC POROUS DELIVERY SYSTEMS: POLYTRAP® AND MICROPSONGE® Formulation 16.6: Qualitative Composition of a Benzoyl Peroxide Anti-acne Product

Ingredient Benzoyl peroxide in methyl methacrylate/glycol dimethacrylate crosspolymer

Function Anti-acne

Water Glycerin

Humectant

Sorbitol

Skin conditioner

Cetyl alcohol

Emulsifying agent

Glyceryl dilaurate

Emollient

Stearyl alcohol

Emulsifying agent

Sodium laurylsulfate

Surfactant

Magnesium aluminum silicate

Viscosity increasing agent

Sodium citrate

Buffer

Silica

Bulking agent

Citric acid

Buffer

Methylparaben

Preservative

Xanthan gum

Thickener

Propylparaben

Preservative

349

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 16.7: Qualitative Formulation of a Retinol Cream with Microsponge Polymer

Ingredient Retinol in methyl methacrylate/glycol dimethacrylate crosspolymer

Function Skin conditioner

Water Caprylic/Capric triglyceride

Skin conditioner

Emulsifying wax

Emulsifier

Glycerin

Humectant

C10-30 cholesterol/lanosterol esters

Skin conditioner

Cetyl ricinoleate

Skin conditioner

Cetyl alcohol

Emulsifying agent

Dimethicone

Skin protectant

Tocopheryl acetate

Antioxidant

Ascorbic acid

Antioxidant

Ascorbyl palmitate

Antioxidant

Bisabolol

Skin conditioner

Cyclomethicone

Skin conditioner

PEG-10 Soy sterol

Skin conditioner

Magnesium aluminum silicate

Viscosity increasing agent

Stearic Acid

Emulsifying agent

BHT

Antioxidant

Disodium EDTA

Chelating agent

Benzyl Alcohol

Preservative

Methylparaben

Preservative

Phenoxyethanol

Preservative

Triethanolamine

pH adjuster

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References 1. Chromecek, R. C., et al., US Patent # 4,962,133

Porous Microsphere Polymeric System can Reduce Topical Irritancy, J. Am. Acad. Dermatol., 24:720–726 (l99l)

2. Chromecek, R. C., et al., US Patent # 4,962,170

7. Froix, M., et al., US Patent # 5,851,538

3. Won, R., US Patent # 4,690,825

8. PDR 57, pp. 2449–2450 (2003)

4. Won, R., US Patent # 5,145,675

9. PDR 57, pp.1216–1218 (2003)

5. Embil, K., and Nacht, S., The Microsponge Delivery System (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives, J. Microencapsulation, 13:575–588 (l996) 6. Wester, R. C., Patel, R., Nacht, S., Leyden, J. J., Melendres, J., and Maibach, H. I., Controlled Release of Benzoyl Peroxide from a

10. Katz, M., et al., US Patent # 5,879,716 11. Kligman, L. H., and Gans, E. H., Re-emergence of Topical Retinol in Dermatology, J. Derm. Trtmnt., 11:47–52 (2000) 12. Elson, M. L., and Nacht, S., Treatment of Periorbital Hyperpigmentation with Topical Vitamin K/ Vitamin A, Cosmetic Dermatol., pp. 32–34 (Dec. 1999)

17 Chronospheres®: Controlled Topical Actives Release Technology James V. Gruber, Louis Punto, and Peter Dow Arch Personal Care South Plainfield, New Jersey

17.1 Introduction ................................................................................... 353 17.2 Chemistry and Historical Development ........................................ 354 17.3 Functional Properties.................................................................... 355 17.4 Formulary Guidelines.................................................................... 356 17.5 Manufacturing Process ................................................................. 357 17.6 Formulations ................................................................................. 358 Acknowledgements ................................................................................. 359 References .......................................................................................... 364

17.1 Introduction The emergence of various new and unique topical delivery systems has expanded the realm of cosmetic and topical therapeutic sciences significantly. This book summarizes the broad field of delivery systems useful for personal care actives and heightens the awareness of readers as to the wide range of such systems available to the cosmetic formulating chemist. Sometimes the decision as to which particular delivery system is most appropriate is daunting.

In this chapter, the reader is introduced to novel polymeric delivery systems known as Chronospheres®. Chronospheres are powdered delivery systems that can incorporate lipophilic and hydrophilic actives and deliver them to the skin in a diffusion-controlled fashion. Chronospheres have the INCI adopted name of acrylates/carbamates copolymer. Empty Chronospheres (i.e., Chronospheres that do not contain an active ingredient) are known as Chronosphere® MT.[1] Chronospheres that have incorporated actives typically carry the tradename plus the active ingredient as a blend. For example, a Chronosphere with glycolic acid would be known as Chronosphere® glycolic acid.

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 353–364 © 2005 William Andrew, Inc.

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17.2 Chemistry and Historical Development There is no desire to overwhelm the reader with the intricacies of the chemistry of Chronospheres, as this does little to help understand whether Chronospheres may be the right choice in a particular formulation. However, it is essential that the chemistry be briefly summarized so that chemists interested in using Chronospheres for new actives can understand the scope of the technology. Chronospheres were developed in the pharmaceutical and medical device industry. They have their roots in polyurethane biomaterial devices and are some of the most well-known, biocompatible medical polymers available. Originally, Chronosphere-type products had their origins as flexible sheets called ChronoFlex®. [Eq. (17.1)] The equation was derived from the reaction of a polyether (1) with a difunctional isocyanate (2), to form a polyurethane prepolymer (3). The polyurethane prepolymer was then reacted with a polyalcohol (4) to form the flexible polyurethane sheet. Eq. (17.1) HO———OH + OCN—R1—NCO → (1)

(2)

OCN–R1–NH–CO–O—O–OC–NH–R1–NCO (3)

+ HO—R2—OH → polyurethane (4)

The flexible polyurethanes, often referred to as polyurethane elastomers, have found unique medical applications in transdermal drug delivery and medical foams. The tradename ChronoFlex® is a registered trademark for CT Biomaterials, a subsidiary of CardioTech International.[3] Patents for the use of polyurethane foams as topical antifungal delivery devices were issued to Hydromer in 1988, and as perfume entrapment devices to Thermedics in 1989.[4][5] The Thermedics patent appears to suggest one of the first cosmetic applications for these polyurethane foams. While flexible polyurethane foams and sheets were practical for therapeutic applications, the use of foams and sheets of this type were limited in per-

sonal care applications. In 1992, a patent was issued to Polymedica Industries that described the use of actinic radiation to initiate the reaction of polyurethane prepolymers with polyols.[6] In order to carry out the photo-initiated reaction, it was essential that the polyols have “two terminal groups each of which contains an active hydrogen.” The presence of the active hydrogen allowed the polymerization of the polyurethane to occur through radiation-initiated crosslinking. This provided two important improvements in the technology: (1) rapid formation for the polyurethane sheets and, (2) the ability to capture hydrophilic medications. Previous art had taught that heat was required to drive the polymerization and, as a consequence of this, volatile actives and water-miscible actives were typically excluded from incorporation into the polyurethane matrix. Still, the art focused on the use of the polyurethanes as sheets, dressings, and foams, and this limited their applicability in cosmetics and personal care. Realizing that the use of foams and sheets was a limiting factor for the sale of the ChronoFlex technology in topical applications, in 1992, PolyMedica introduced a pulverized powdered version of the ChronoFlex technology that they called Chronospheres.[7] In order to manufacture Chronospheres, Polymedica had to modify the normal polyurethane elastomer technology so that more brittle polyurethanes could be made and they could be pulverized into powders. However, PolyMedica did not want to lose the unique benefits that came with radiation crosslinking, although the use of actinic radiation was limiting to the overall practicality of the products. To address this issue, Polymedica introduced the chemical modifications seen in Eq. (17.2) in order to make the polyurethane polymers more functional as powdered products. Eq. (17.2) CH2=CH–R3–O–CO–NH–R1–NH–CO–O–(R2–O–)n –CO–NH–R1–NH–CO–O–R3–CH=CH2 (5)

+R4–CO–R5 + (CH2=CH–CO–O–)x–R6 (6)

(7) UV light

+ Active Ingredient →→→ Chronosphere® Pulverization

GRUBER, PUNTO, DOW: CHRONOSPHERES®: CONTROLLED TOPICAL ACTIVES RELEASE TECHNOLOGY In the newly introduced technology, the active hydrogen component was replaced with acrylatebased polyurethane oligomers (5) and a liquid acrylate comonomer (7). To modify the chemistry further, a photoinitiator (6) was added at extremely low levels. This helped to initiate and accelerate the polymerization reaction. Through these changes, it was possible to now conduct the polymerization reaction in the presence of ultraviolet light, at wavelengths similar to those found in a typical tanning bed. The modifications also accelerated the polymerization reactions such that the entire composition including the active component, could be made in approximately one minute!

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17.3 Functional Properties Chronospheres are unique, biocompatible, temperature-stable polymeric matrices into which useful active cosmetic ingredients can be added. Inside the polymeric matrix, the actives are essentially protected from external threats such as oxygen and moisture. A scanning electron photomicrograph of a typical Chronosphere is shown in Fig. 17.1. The length of the dashes at the bottom of the figure represent 100 microns. One can see that the particles typically range between 5 and 20 microns. Typical Chronosphere powders are pulverized in such a way that 99% of the powder will pass through a 200mesh sifting screen.

As expected, the addition of the acrylate-based comonomers served to make the resulting polymers more brittle, effectively raising the glass transition temperature of the Chronospheres so that they could now be made into powders. As a result, the process to manufacture the Chronospheres Table 17.1. Oil-soluble and Water-soluble Actives That could be run in a nearly continuous fashion, as Can Be Incorporated into Chronospheres long as the initial unpolymerized liquid composition was available. Commercially, the process to manufacture Chronoshperes is more Water-soluble Oil-soluble Actives Actives batch process related. This is discussed in a later section (see Sec. 17.5). Ascorbic acid Dimethicone In 1995, PolyMedica relinquished the Fomblin HC Biopol OE trademark rights and product rights for (perfluorinated (Lactoglobulin sulfonate) polyethers) Chronosphere powders to Brooks Industries. Brooks Industries has been marketing these Collagen Methyl salicylate unique delivery systems for many years and Epidermal growth factor Mineral oil built up a considerable repertoire of oil-soluble (EGF) and water-soluble active ingredients that can Glycerin Octyl methoxycinnamate be incorporated into the Chronosphere polyGlycolic acid Olive oil mer matrix. A partial list of useful actives can be found in Table 17.1. Sodium hyaluronate Panthenol Planell oil (Olive oil Brooks Industries was acquired by Arch Lactic acid unsaponifiables) Chemical Company (Norwalk, CT) in 2001 and became part of Arch Chemical’s personal Para-aminobenzoic acid Retinol care division known as Arch Personal Care. Pyrrolidone carboxylic Arch Personal Care continues to market acid Chronospheres® and works closely with cusRosemary extract tomers to encapsulate unique active ingrediSalicylic acid ents specific for individual customer needs. Information on Arch Personal Care and their Superoxide dismutase multiple products, including Chronospheres, Tissue respiratory factor can be found at www.archpersonalcare.com. Vitazymes ACE

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS ders are encountered when the products are applied to the skin. Some of the critical information that a formulator needs to keep in mind regarding the encapsulation of active ingredients into Chronospheres includes the following: 1. Chronospheres are made through an ultraviolet light-initiated polymerization mechanism. While exposure to the UV light is rapid, the manufacturing process may degrade active ingredients that are susceptible to ultraviolet light degradation.

Figure 17.1 A scanning electron photomicrograph of a typical Chronosphere®. The dashes below represent 100 microns. One can see that the particles typically range between 5 and 20 microns.

The porous nature of the Chronospheres allows the active ingredients to escape from the interior through a first-order, diffusion-controlled rate, thereby allowing time-released delivery of the active ingredients. The lipids and/or moisture of the skin accelerate diffusion that influence the release of lipophilic (fat-loving) or hydrophilic (water-loving) actives. Release of active materials is first order, diffusion controlled as has been demonstrated in a number of isolated studies which have been compiled below (see Fig. 17.2). Elution of various actives from Chronosphere powder. Actives were eluted into PBS (phosphate buffer solution) at 25°C with constant stirring. The following actives were examined: (X) hyaluronic acid loaded at 0.5 wt% into Chronosphere,[8] (♦) benzocaine loaded at 1 wt% into Chronosphere,[9] (▲) para-amino benzoic acid loaded at 1 wt% into Chronosphere,[7] and (■) salicylic acid loaded at 20 wt% into Chronospheres.[10] Data are presented as percentages of total amount of available active eluted versus time in minutes. As shown in Fig. 17.2, the elution rate of the active ingredient varies depending on the active encapsulated. However, in each case, the active elutes following first order kinetics. Elution is driven by a desire for the active to move from an area of high concentration inside the Chronosphere to an area of low concentration in the water. Similar elution or-

2. The chemistry to form the Chronospheres is free-radical based through the acrylatebased oligomers and monomers. Active ingredients that possess reactive double bonds such as acrylates will probably not survive the polymerization process without becoming incorporated into the polymer matrix. If this happens, these materials cannot be released through diffusion control.

17.4 Formulary Guidelines Because delivery of the actives from Chronospheres is diffusion-controlled, and is influenced both by skin lipids and skin moisture, the following principals should guide formulators who intend to encapsulate and use actives in Chronospheres: 1. Water-soluble actives can be entrapped in Chronospheres and they can be suspended in an anhydrous cosmetic vehicle (see Formulation 17.1). 2. Oil-soluble actives can be trapped in Chronospheres and they can then be suspended in an aqueous cosmetic vehicle (see Formulation 17.2). 3. Water-soluble and/or oil-soluble actives entrapped within Chronospheres can be formulated into solid or powdered products (see Formulation 17.3). 4. Oil-soluble or water-soluble actives are incorporated into the Chronospheres and these compositions can be suspended in a vehicle in which an equal concentration of the same active is present in the sus-

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Figure 17.2 Elution of various actives from Chronosphere® powder into PBS at 25°C with constant stirring: (X) hyaluronic acid loaded at 0.5 wt% into Chronosphere,[8] (♦) benzocaine loaded at 1 wt% into Chronosphere,[9] (▲) para-amino Benzoic acid loaded at 1 wt% into Chronosphere,[7] (■) salicylic acid loaded at 20 wt% into Chronospheres.[10]

pending formulation (see Formulation 17.4). Water-soluble actives entrapped in Chronospheres should not be formulated into water-based products. Likewise, oil-entrapped actives should not be formulated into oil-based products. In both of these situations, the active will tend to diffuse out of the Chronosphere and into the surrounding medium on storage. The rationale for the final formulating tip above is that the Chronosphere diffusion delivery occurs by means of a concentration gradient from areas of high concentration to areas of lower concentration. A consequence of this concentration gradient requires formulation vehicles that contain an equal amount of the active as compared to the encapsulated concentration in the Chronosphere, so that the driving force for diffusion of the active out of the Chronosphere will not occur during storage. However, diffusion of the active out of the Chronosphere will only occur after the level of unencapsulated active on the skin decreases below a critical threshold. At this point and below, the active entrained in the Chronosphere will begin to be released. One exception to this principal would occur if an oilsoluble ingredient were not soluble in silicone oil such as cyclomethicone or dimethicone. In this circumstance, the oil-soluble encapsulated ingredients might remain inside the Chronosphere in a silicone-based formulation.

The level of incorporated active will tend to be dependent upon the nature of the active ingredient being encapsulated. Oil-soluble actives can be incorporated at levels as high as 20 wt%. Higher levels than this are sometimes possible, but must be examined on a case-by-case basis. Aqueous-based products typically cannot be formulated at greater than 10 wt% in Chronoshperes. However, if the aqueous-based ingredient can be incorporated in a powdered form, loading levels as high as 40 wt% can easily be achieved.

17.5 Manufacturing Process Chronospheres form when liquid blends of reactive prepolymers are polymerized by ultraviolet light. The converter shown in Fig. 17.3, originally designed for use in the pharmaceutical and medical device industry, has been configured to produce the brittle sheets from which the Chronospheres are formed. The apparatus allows thin films of unreacted liquid prepolymers to be drawn through banks of ultraviolet lamps on conveyor belts. While the Chronosphere manufacturing process has several steps and requires additional equipment than the converter shown in Fig. 17.3, the process is

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS knifebox, a removable trough shaped to fit up against two moving drive rollers, is depicted in Fig. 17.4. The rollers drive two transparent belts past the knifebox and through the light box. Each belt is siliconized and forms its own continuous loop. The knifebox meters the unreacted composition between two belts as they move toward the UV lights. Sandwiched between the belts, the liquid polymerizes in a matter of seconds. At the back of the converter, the now brittle sheet separates from the siliconized belts as the belts are redirected toward the front of the machine. To complete the process, the collected shards of encapsulated active are first ground and then milled into an fine powder.

Figure 17.3 Chronosphere® converter.

simple, and flexible enough to meet demanding production schedules for a wide range of products. Before going into production, each formula must be optimized in the laboratory. In addition to choosing the appropriate oligomer, the appropriate ratio of oligomer and acrylate comonomer must be determined for each active. The two reactive components, produce a liquid prepolymer, that then forms the delivery system upon polymerization. With the specific chemistry predetermined, the formulas are then ready for production.

The manufacturing process described allows for both near continuous and batch process operation for Chronosphere manufacture. The siliconized belts are easily replaced, and the knifebox can be easily cleaned so that a number of experimental batches, or pilot studies can be conducted in a day. The adaptation of this technology from the pharmaceutical and medical device industry into the personal care and cosmetics industry has provided both a novel and practical delivery system for formulators to consider.

The manufacturing process begins with the dispersion of both the active and the photoinitiator into the unreacted prepolymer composition. As can be expected, the blended composition may be either an emulsion or a dispersion, depending upon the specific active employed. This uniform composition is next pumped into the knifebox of the converter. The

Chronosphere formulations included here are intended to demonstrate typical formulations following the tips outlined earlier in the chapter. The rationales for the selection of the ingredients are described here.

Figure 17.4 The knifebox.

In Formulation 17.1, Chronospheres provide a formulator with the ability to add a heat-labile aqueous ingredient to an incompatible anhydrous product and also provide this ingredient protection from high processing temperatures. Sodium hyaluronate is a water-soluble polymer that absorbs ambient water vapor and transfers this moisture to the skin in topical products. It would be incompatible in this anhydrous system if not for the entrapment in Chronospheres. Also, the Chronospheres delivery system is heat-stable and protects the sodium hyaluronate from the extreme temperatures required to manufacture this product (80°C–90°C). Without this protective copolymer, sodium hyaluronate, a natural

17.6 Formulations

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biopolymer, would degrade. After product application, the Chronosphere hyaluronate begins to swell due to the moisture uptake of the sodium hyaluronate. This moisture is slowly released and absorbed by the stratum corneum, thus boosting skin moisturization. In this application, the Chronospheres provide the capability to add a water-soluble active to an anhydrous product and also indirectly enhance skin moisturization.

Chronosphere will desorb over an extended time period. If the applicator is dry and then used to apply the product, all of the lactic acid will desorb from the Chronosphere over an extended period of time. In this formulation, the Chronosphere allows for an immediate/sustained or sustained release of the active depending upon method of application. No deleterious skin effects occur with this system due to the sudden release of a potential irritant.

In Formulation 17.2, the Chronosphere encapsulates a beta-hydroxy acid exfoliating agent, salicylic acid. With chemical exfoliating agents, the potential for skin irritation increases with increasing concentration of the exfoliant applied to the skin as well as the sensitivity to such agent. The Chronosphere entrapment system ensures the salicylic acid is delivered to the skin in a controlled manner preventing possible erythema that can be caused by full exposure to the active if unencapsulated. Upon contact with the skin, epidermal oily secretions will slowly dissolve the salicylic acid, a lipophilic ingredient entrapped in the Chronosphere. This process allows the salicylic acid to become more bioavailable.

In Formulation 17.4, Chronosphere glycolic is contained in an aqueous formulation. Since glycolic acid is water soluble, diffusion of the glycolic acid into the aqueous media is expected to occur. If this were to occur, it would negate the purpose of the Chronosphere since release of the active should only occur upon skin contact and not in the formulation. To prevent premature release of the active, 0.3% glycolic acid is added to the system. This creates equilibrium in the formulation with the 0.3% glycolic acid contained in the Chronosphere (in Chronosphere glycolic, there is a 30% load of the glycolic acid). Therefore, glycolic acid diffusion from the Chronosphere will not occur in the formulation but will occur upon product application to skin.

Formulation 17.3 is designed for two-way application, wet or dry. The lactic acid is contained in the Chronosphere, allowing a water-soluble ingredient utilization in this anhydrous formulation. Release of the lactic acid to the skin can be controlled in two ways depending upon product application. If the applicator is wet with water and used to apply the product, partial release of the lactic acid to the aqueous media will occur and be immediately available to the skin. The remainder of the lactic acid in the

Acknowledgements The authors express their appreciation to Dr. Richard Shalvoy for providing the scanning electron photomicrograph and to Sarah Jindal for the photographs of the Chronosphere manufacturing machine.

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Formulation 17.1: Lipstick with Chronosphere Hyaluronate

Phase

A

B

C

Ingredient

INCI Nomenclature

Supplier

Weight %

Crystal O

Castor Oil

CasChem

35.30

Titanium dioxide FHC

Titanium dioxide and perfluoropolymethylisopropyl ether

Cardre Inc.

3.00

D&C Red #7 FHC

D&C Red #7 Ca lake and perfluoropolymethylisopropyl ether

Cardre Inc.

2.50

FD&C Yellow #6

FD&C Yellow #6 Al lake and perfluoropolymethylisopropyl ether

Cardre Inc.

2.00

Black iron oxide FHC

Iron oxides and perfluoropolymethylisopropyl ether

Cardre Inc.

0.50

Chronosphere HA

Acrylate/carbamate copolymer and sodium hyaluronate

Arch Personal Care Products

2.00

Candelilla wax

Candelilla wax

Koster Kuenen

7.70

Carnauba wax

Carnauba wax

Koster Kuenen

2.20

Ozokerite wax

Ozokerite

Koster Kuenen

1.65

Ceresin wax

Ceresin wax

Koster Kuenen

1.65

Planell oil

Squalene, squalane, glycolipids, phytosterol, and tocopherol

Arch Personal Care Products

5.00

Ivarbase 3210

Cetyl acetate/acetylated lanolin alcohol

Arch Personal Care Products

1.00

Ceraphyl 368

Octyl palmitate

ISP

4.00

Liquiwax IPL

Dicetearyl dilinoleate

Arch Personal Care Products

10.00

Ivarlan 3100

Lanolin oil

Arch Personal Care Products

5.00

Ivarlan 3001

Lanolin light USP

Arch Personal Care Products

10.00

Bio-Oil HBSL

Soyabean extract and Ceramide 3

Arch Personal Care Products

2.00

Mica

Mica

Mearl/Engelhard

4.00

Methylparaben

Methylparaben

Jeen Chemicals

0.30

Propylparaben

Propylparaben

Jeen Chemicals

0.10

BHA

BHA

Eastman

0.10

Mixing Procedure: 1. Using a three-roll mill, grind all pigments and Chronosphere® HA of Phase A in the castor oil. 2. Combine and heat the waxes and oils of Phase B and mix with a propeller mixer to 90°C. Hold for 20–30 minutes. 3. Add Phase A to Phase B and mix for 30 minutes. 4. Add the mica, methylparaben, propylparaben, and BHA of Phase C and mix well. 5. Cool the batch to 82°C and pour into the mold.

6. Chill the mold to -5°C and remove the product. Let stand at room temperature.

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Formulation 17.2: Lotion with Chronosphere SAL

Phase

A

B

C

Ingredient

INCI Nomenclature

Supplier

Weight %

Demineralized water

Demineralized water

74.85

Disodium EDTA

Disodium EDTA

0.05

Carbopol Ultrez

Carbomer

Noveon

0.30

Chronosphere SAL

Acrylate/carbamate copolymer and salicylic acid

Arch Personal Care Products

2.00

Stearic acid

Stearic acid

Brookswax D

Cetearyl alcohol and Ceteareth-20

Cetyl alcohol

Cetyl alcohol

Finsolv TN

C12-13 Alkyl benzoate

Finetex

1.00

Arlamol DOA

Dioctyl adipate

Alzo

1.00

Liponate NPGC-2

Neopentyl glycol dicaprylate dicaprate

Lipo

1.00

Loronate TMP-TC

Trimethylolopropane

Arch Personal Care Products

1.00

Ceraphyl 368

Octyl palmitate

ISP

1.00

Bio-Oil HBSL

Soyabean extract and Ceramide 3

Arch Personal Care Products

1.00

Gel Base Sil

Cyclomethicone and dimethicone

Arch Personal Care Products

1.00

Demineralized water

Demineralized water

2.50

TEA-99

Triethanolamine

0.30

Aloe vera gel

Aloe barbadensis

5.00

Chamomile extract

Chamomile extract

Arch Personal Care Products

1.00

Germaben IIE

Propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

ISP

1.00

D

1.00 Arch Personal Care Products

3.50 1.50

Mixing Procedure: 1. Disperse Ultrez, EDTA, and Chronosphere® SAL in water and heat to 70°C. 2. In a separate vessel, combine Phase B ingredients and heat the oil phase to 75°C. Add to the water phase and mix for 20 minutes. Begin cooling. 3. In a side kettle, pre-blend the water and TEA of Phase C. At 60°C add to the batch. Mix for 20 minutes. Continue cooling. 4. At 45°C add the Phase D ingredients. Mix for 30 minutes.

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Formulation 17.3: Wet/Dry Dual Face Powder

Phase

Ingredients

Supplier

Weight %

Cardre Talc FHC

Talc and perfluoropolymethylisopropyl ether

Cardre

59.80

Cardre Mica FHC

Mica and perfluoropolymethylisopropyl ether

Cardre

29.0

Cardre TiO2 FHC

Titanium dioxide and perfluoropolymethylisopropyl ether

Cardre

2.0

Cardre UF TiO2 FHC

Titanium dioxide and perfluoropolymethylisopropyl ether

Cardre

2.0

Cardre Yellow FHC

Yellow iron oxide and perfluoropolymethylisopropyl ether

Cardre

2.8

Cardre Red FHC

Red iron oxide and perfluoropolymethylisopropyl ether

Cardre

2.2

Cardre Black FHC

Black iron oxide and perfluoropolymethylisopropyl ether

Cardre

0.2

Chronosphere Lactic

Acrylates/carbamate copolymer and lactic acid

Arch Personal Care Products

1.0

Isopropyl isostearate

Isopropyl isostearate

A

B

INCI Nomenclature

Mixing Procedure: 1. Combine Phase A powders, colors, and Chronosphere® lactic to a suitable mixer. 2. Mix and blend batch until uniform. 3. Spray Phase B into the blended batch. 4. Pass batch through a micropulverizer. 5. Repeat Step 4 until the batch is uniform without undispersed color. 6. Press tables to a suitable hardness and texture.

1.0

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Formulation 17.4: Acne Serum

Phase A

B

C

D

Ingredient

INCI Nomenclature

Supplier

Weight %

Deionized water

Water

q.s to 100

Glycolic acid 99%

Glycolic acid

Chronosphere Glycolic

Acrylates/carbamate copolymer and glycolic acid

Arch Personal Care Products

1.00

Vanilla extract

Butylene glycol, water, and vanilla extract

Arch Personal Care Products

2.00

Germaben II

Propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

ISP

0.45

Sepigel 305

Polyacrylamide, C13-14 isoparaffin, and laureth-7

Seppic, Inc.

3.00

SMEC concentrate

Water, trimethylolpropane tricaprylate/tricaprate, glycerin, cetearyl alcohol, Ceteareth 20, glyceryl stearate, PEG 100 stearate, Steareth 2, dimethi- Arch Personal cone, Ceteth-24, Choleth-24, phospho- Care Products lipids, phenoxyethanol, methylparaben, butylparaben, ethylparaben, propylparaben, and disodium EDTA

0.30

46.11

Mixing Procedure: 1. Into the main kettle, combine the water and glycolic acid of Phase A. 2. Add the Chronosphere® glycolic, vanilla extract and Germaben II of Phase B and mix until uniform. 3. Slowly add the Sepigel 305 of Phase C and allow the product to thicken.

4. Add the SMEC concentrate of Phase D into the main kettle and mix for ½ hour with the propeller mixer until uniform.

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References 1. International Cosmetic Ingredient Dictionary and Handbook, 9th Ed., p. 29, (R. C. Pepe, J. A. Wenninger, G. N. McEwen, eds.), The Cosmetic, Toiletry, and Fragrance Association, Washington, DC (2001) 2. Szycher, M., Biostability of polyurethane elastomers: A critical review, J. Biomat. Appl., 3:297–402 (1988) 3. www.cardiotech-inc.com/biomatr.htm 4. Lorenz, D. H., and Creasy, W. S., US Patent # 4,769,013 (1988)

5. Szycher, M, and Rolfe, J., US Patent # 4,880,690 (1989) 6. Szycher, M., US Patent # 5,118,779 (1992) 7. Siciliano, A. A., Polymer entrapment powders for topical delivery, J. Biomat. Appl., 6:326– 339 (1992) 8. Arch Personal Care, Unpublished Internal Data 9. PolyMedica Industries: Chronosphere Technical Fact Sheet 10. Brooks Industries Technical Datasheet-Elution Study, Chronosphere® SAL

18 Nanotopes™ A Novel Ultra-Small Unilamellar Carrier System for Cosmetic Actives Werner Baschong, Bernd Herzog, Carl W. Artmann, Christine Mendrok, Sébastien Mongiat, and Joseph A. Lupia Ciba Specialty Chemicals Inc., Basel, Switzerland

18.1 Introduction ................................................................................... 366 18.1.1 The Nanotopes™ System ................................................ 367 18.1.2 Surfactant-Stability of Nanotopes™ Particles ................... 368 18.2 Nanotopes™: Stability in Formulation........................................... 368 18.2.1 Particle Stability in the Presence of Sodium Dodecyl Sulphate as Assessed by Dynamic Light Scattering (DLS) ............................................................... 368 18.2.2 Stability of Nanotopes™ and Liposomes in the Presence of Various Surfactants, as Assessed by Turbidity Measurements ............................................... 370 18.3 Nanotopes™: Performance .......................................................... 373 18.3.1 Influence of Nanotopes™ Encapsulation on Stability of Vitamin A Palmitate ........................................................... 373 18.3.2 In Vitro Performance of Aqueous Nanotopes™ Solutions on Human Skin ................................................................. 375 18.3.3 In Vitro Performance on Human Skin of Nanotopes™ in Cosmetic Formulations ................................................. 377 18.3.4 In Vivo Performance of Aqueous Nanotopes™ in Solutions . 379 18.3.5 In Vivo Performance of Formulated Nanotopes™ ............ 381 18.4 Conclusions .................................................................................. 382 18.5 Formulations ................................................................................. 383 Acknowledgement ................................................................................... 393 References .......................................................................................... 393

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 365–394 © 2005 William Andrew, Inc.

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18.1 Introduction Cosmetic actives comprise a wide range of useful materials in personal care products. These actives may be organic, natural or botanically derived. Typically, they are formulated into topical preparations, such as lotions, oil-in-water or water-in-oil emulsions. This approach is designed to permit enhanced permeation into the stratum corneum. The stratum corneum forms the barrier protecting the underlying, living skin from water-evaporation and environmental hazards. When applied to skin, these actives partition between the skin surface and the stratum corneum. Following absorption, a concentration gradient between the skin surface and the barrier lipids of the stratum corneum is usually established, where higher concentrations of reactives are found within the stratum corneum than at the skin’s surface. Various delivery system approaches have been designed to facilitate this process. A well-known approach is the use of “empty” carriers called vesicles. These are mainly phospholipid based and include examples such as liposomes, nanoparticles, or nanoemulsions. They may also include specific solubilizers that have been developed to achieve optimal delivery of cosmetic actives into the skin. Such solubilizers are believed to shift the gradient in favor of delivery of actives into the stratum corneum.

(a)

Liposomes are probably the most popular type of carriers used for cosmetic actives. They are formed by a phospholipid bilayer enclosing an aqueous core. The phospholipids consist primarily of lecithin made from soybean or egg yolk. These spherical vesicles can vary in size from some ten to about several hundred nanometers. Those used for cosmetics are usually in the size range between 150– 300 nm (Fig. 18.1). The membranes of these vesicles are not rigid structures; instead, they form a fluid type of envelope. They continuously break and reassociate at varying sites within the outer membrane in a dynamic equilibrium state. Interparticle exchange of the membrane constituents may lead to the formation of a range of particle sizes. Moreover, other ambiphilic molecules, such as surfactants may incorporate into the phospholipid bilayer; such incorporation may destabilize the vesicle, or even induce particle lysis. This also holds true for most nanoparticles or nanoemulsions. Ideally, a carrier for actives should remain intact in the presence of surfactants since many personal care formulations employ surfactants. Further, in the ideal system, the number and size of particulate active carriers should remain constant over time. Moreover, the particulate carriers should be as small

(b)

Figure 18.1 (a) Conventional liposomes (usual size range: 150–300 nm) vs (b) Nanotopes™ (size range: 20–40 nm) (cryo-electron microscopy).

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES as possible, in order to facilitate distribution and penetration of the active into the inner core. The smaller the particles, the better the distribution of the encapsulated material in the formulation. Small particle size is also critical for achieving desirable behavior on the skin surface, since this greatly increases the probability of successful absorption into the stratum corneum. The actual transport route into the epidermis, the site of cosmetic interest, is through the intercorneocyte pores of the stratum corneum. These pores have a width of about 50 nm.[1] Logic dictates that the smaller particles should require less membrane deformation for successful vesicle barrier penetration. Since membrane deformation decreases the contact area between the constituting molecules and thus the compactness of the liposome membrane, smaller particles undergoing less deformation may be less prone to deformation-based decay.

18.1.1 The Nanotopes™ System By comparison with conventional phospholipidbased membrane systems, monolayered Nanotopes™ particles, with their lipid core, have a membrane composed of a phospholipid (i.e., lecithin) and a co-surfactant.[2] In Nanotopes, these membrane constituents are present in a well-defined ratio. At some optimum ratio of phospholipid to cosurfactant, the co-surfactant intercalates between

(a)

367

the lecithin molecules and forms a continuous array extending from the lipid-core into the aqueous phase (Fig. 18.2a). By means of this arrangement, the Nanotopes’ particle size is determined by the maximal angles between the lipid molecules forming the membrane that still provides membrane-stability via van der Waals hydrophobic interaction forces (e.g., in liposomes); the angle is substantially smaller. As a result of the co-surfactant intercalation between the extending lecithin molecules, the Nanotopes system provides a stable particle-membrane at a much smaller core-diameter than in liposomes. The cylinder-cone approach to stabilizing the barrier membrane in the Nanotopes system allows for the production of ultra-small (20–40 nm) particles (Fig. 18.2b). These have been used to encapsulate cosmetic actives such as vitamin E[3][4] and vitamin A esters. Nanotopes containing vitamin E acetate dissolved in miglyol (caprylic/capric acid triglyceride) as a core lipid solution, and employing lecithin as the phospholipid with polysorbate-80 used as the co-surfactant, provide effective, small encapsulates as seen in the cryo-electron micrographs shown in Fig. 18.1b. Conventional liposomes of vitamin E acetate are represented in Fig. 18.1a. When contrasting liposome technology with that of Nanotopes technology, the smaller size and greater uniformity of the Nanotopes systems are clearly evident.

(b)

Figure 18.2 Modelling of Nanotopes™ architecture. (a) Co-surfactant intercalates between lecithin molecules. (b) Cylinder-cone structure stabilizes the barrier membrane in the Nanotopes™ system.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Due to the nature of the very small particle size, and the lipid co-surfactant interactions in the Nanotopes systems, other actives may have to be prepared in other cosmetically acceptable oils, or combined with other co-surfactants to achieve the same particle stability and size. Another factor, which can influence the overall stability and size of Nanotopes, is the preservative used. In view of this, if a specific active is to be encapsulated in a Nanotopes particle, the core-forming oil and the co-surfactants must be combined with a compatible preservative. Generally, this selection process is determined experimentally, by trial and error.

18.1.2

Surfactant-Stability of Nanotopes™ Particles

The surfactants present in cosmetic formulations can, and often do, interfere with the stability of the lipid membranes found in liposomes. By contrast with liposomes, the more compact membrane arrangement of Nanotopes is less susceptible to surfactant interaction and disruptions. This was confirmed experimentally via dynamic light scattering (DLS)[5] and turbidity measurements. The stability of both Nanotopes and liposomes were compared in the presence of increasing concentrations of various surfactants used in cosmetics formulations. Since nanosized particles scatter incoming light, the presence of opalescence was used to demonstrate this effect. This scattering phenomenon is, of course, a function of the diameter, size distribution, and concentration of the Nanotopes. It can be quantified by measuring light transmission in a photo-spectrometer at a wavelength at which light absorbance by the constituting substances is minimal. Stable particles should not alter their scattering behavior upon addition of surfactants, while surfactant-induced particle disruption will result in an increase in transmittance (i.e., a clearer solution). Surfactants may intercalate into the phospholipid membrane of both Nanotopes and liposomes. They may even solubilize the existing particles and form new particles out of both constituents (i.e., mixed micelles).[6] Moreover, the surfactants themselves can form a second population of particles (i.e., surfactant micelles). Dynamic light scattering (DLS), a technique which measures particle size distribution and discriminates between different

particle populations, was employed to monitor such surfactant-particle interactions. In a first set of experiments, the stability of Nanotopes was compared with that of liposomes by adding various concentrations of sodium dodecyl sulphate to the particle dispersions. The particle size and number was then monitored by means of DLS and turbidity measurements. In a second set of experiments, the phenomenon was investigated by means of the less laborious turbidity measurements method.

18.2 Nanotopes™: Stability in Formulation 18.2.1

Particle Stability in the Presence of Sodium Dodecyl Sulphate as Assessed by Dynamic Light Scattering (DLS)

In the absence of sodium dodecyl sulphate, DLS shows the presence of unimodal particle size distributions for both Nanotopes and liposomes (Figs. 18.3 and 18.4). Particle size distributions show peak maxima for Nanotopes corresponding to a particle diameter of 21 nm, as compared with much larger particle maxima observed for liposomes (i.e., 86 nm). Upon addition of sodium dodecyl sulphate to the Nanotopes solution, a second peak emerged at a particle diameter of 4.2 nm (Fig. 18.5). Its radius (i.e., 2.1 nm) compared well to the 2 nm length of a sodium dodecyl sulphate molecule, thus indicating this peak corresponds to the sodium dodecyl sulphate micelles. In confirmation, further addition of sodium dodecyl sulphate directly increased the volume fraction of the 4.2 nm diameter peak (not shown), which means that the Nanotopes were not affected. The particle size distribution of Nanotopes particles in the presence of sodium dodecyl sulphate peaked at a size maximum of 17 nm, instead of the 21-nm size seen in absence of sodium dodecyl sulphate (Figs. 18.3 and 18.5). This shrinking in particle diameter may be attributed to sodium dodecyl sulphate-molecules replacing membrane constituents, such as phospholipid or co-surfactant, extending into the aqueous phase, and, in turn, leading to smaller particles.

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In the liposome solution, the addition of 2.5% sodium dodecyl sulphate induced a second peak evolving at a particle diameter of 7.2 nm. Concomitantly, the particle size peak observed in absence of detergent at 86 nm (Fig. 18.4) was seen to decrease to a broad, and very small, signal exhibiting about the same maximum. This 7.2 nm peak represents the formation of the corresponding mixed micelles (Fig. 18.6).

Figure 18.3 Particle size distribution of Nanotopes™ without surfactants added, measured by dynamic light scattering (DLS) at a scattering angle of 90°, d(max.) = 21 nm.

Figure 18.4 Particle size distribution of liposomes without surfactants added, measured by DLS at a scattering angle of 90°, d(max.) = 86 nm.

Figure 18.5 Particle size distribution of Nanotopes™ at 1% lipid content in the presence of 2.5% SDS, measured by DLS at a scattering angle of 90°, d(max. micelles) = 4.2 nm, d(max. Nanotopes™) = 17 nm.

Particle stability is predictable based on the data acquired by DLS. If particles are stable, the number and size of the original particles will remain unchanged upon surfactant addition. By contrast, destruction of nanoparticles by surfactants will result in a reduction of the volume fraction Φ as determined from the DLS measurements. Ratios of volume fractions of ΦNT (Nanotopes) to ΦSDS (SDSmicelles) and Φlipo (liposomes) to ΦSDS (SDS-micelles) were calculated and compared with the values obtained experimentally by DLS. For stable particles, the volume fraction Φ of the different particles was estimated from the lipid concentration, the area of the head groups (assuming 0.75 nm2 for the phospholipid head and 0.6 nm2 for the sodium dodecyl sulphate head) and the respective radius of the particles as measured by electron microscopy (Fig. 18.1). The volume fraction ratios, calculated under assumption of particle stability, are listed together with the ratio’s determined experimentally by DLS (Tables 18.1 and 18.2), for Nanotopes themselves (i.e., no surfactant) and Nanotopes in the presence of up to 5% sodium dodecyl sulphate, the calculated

Figure 18.6 Particle size distribution of liposomes with surfactants added: measured by DLS at a scattering angle of 90°, d(max. mixed micelles) = 7.2 nm, d(max. liposomes) = 66 nm.

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Table 18.1. Volume Fractions Φ of Nanotopes™ and SDS-Micelles and Their Ratios, Obtained by Calculation and from DLS Measurements

SDS (%)

ΦNT (%)

ΦSDS (%)

ΦNT / ΦSDS calculated, (assuming particle stability)

ΦNT / ΦSDS experimental

0

3.0

0

–

–

2.5

2.6

2.0

1.30

1.3

5

2.6

4.0

0.7

0.8

10

2.6

8.0

0.3

0.1

Table 18.2. Volume Fractions Φ of Liposomes and SDS-micelles and Their Ratios, Obtained by Calculation and from DLS Measurements

Φlipo (%)

ΦSDS (%)

Φlipo /ΦSDS calculated (assuming particle stability)

Φlipo /ΦSDS experimental

0

4.2

0

–

–

2.5

4.2

2.0

2.1

0.014

5

4.2

4.0

1.1

0

10

4.2

8.0

0.5

0

SDS (%)

ratio of the volume fractions was in good agreement with that determined experimentally. However, at a presence of 10% sodium dodecyl sulphate, the Φ-ratio measured for the Nanotopes was about one third of the predicted value. This decrease of the number of particles indicates a partial particle decay. By contrast, liposomes exhibited in the presence of 2.5% sodium dodecyl sulphate, an experimental Φ ratio that was about 200 times lower than that predicted for stable particles. Obviously, the addition of 2.5% sodium dodecyl sulphate decreased the amount of liposomes, which, if stable, would occupy twice the volume of that occupied by surfactant micelles, by almost 200 times. At such a ratio the number of intact liposomes is marginal. (See Table 18.2.)

18.2.2 Stability of Nanotopes™ and Liposomes in the Presence of Various Surfactants, as Assessed by Turbidity Measurements In the set of experiments discussed Sec. 18.1, DLS revealed that Nanotopes particles remain unaffected by the presence of up to 5% sodium dodecyl sulphate. Only at a 10% concentration of sodium dodecyl sulphate the measured volume fraction of Nanotopes began to decrease. In contrast, the volume fraction of conventional liposomes had already strongly decreased in the presence of 2.5% of sodium dodecyl sulphate, indicating a substantial decay of these particles.

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES In a second series of experiments, the resistance of Nanotopes particles to the presence of other surfactants used in cosmetic formulations was investigated. Since DLS is experimentally rather demanding, the particle stability was assessed by means of a light scattering technique known as turbidity measurements.[7][8] This method is far less difficult to DLS in view of its experimental simplicity. The turbidity, τ, of a colloidal suspension can be expressed according to Hiemenz[9] as:

Eq. (18.1)

 m2 − 1  4 ⋅π  τ = 4 ⋅ d 3 ⋅ Φ ⋅  2  m + λ 2  

2

In Eq. (18.1), λ is the wavelength of the monochromatic incident light, d is the “particle” diameter, Φ is the volume fraction occupied in solution by particles, and m is the ratio of refractive index of the particles to that of the surrounding solvent. If Φ remains constant, for measurements made at a given wavelength, the turbidity depends only on the particle diameter and manifests itself as an apparent light extinction due to particulate light scattering. Turbidity measurements were carried out at a wavelength of 400 nm on suspensions of both Nanotopes and liposomes. These measurements were made both in the absence of and in the presence of a range of surfactant concentrations. At a wavelength of 400 nm, it was found that none of the molecular constituents of the solution showed significant light absorbance. When the turbidity, τ (c), of the liposome suspension was measured in the presence of increasing concentrations of sodium dodecyl sulphate, the normalized turbidity, τnorm (2), [i.e., the turbidity at a specific surfactant concentration, τ(c)], related to the turbidity in absence of surfactant τ(0), was observed to be well in accordance with the observations made by DLS:

Eq. (18.2)

τ norm =

τ (c ) τ (0 )

Already, the addition of 1% of sodium dodecyl sulphate to the liposome suspension almost abolished τnorm, and at a sodium dodecyl sulphate concentration of 5% the solution was clear, corroborating the

371

essential absence of liposome particles in presence of 5% sodium dodecyl sulphate as measured before via DLS. In contrast to DLS measurements, which documented Nanotopes stability up to a sodium dodecyl sulphate concentration of 7%, already the addition of 1% of sodium dodecyl sulphate decreased τnorm to 0.65 implying that 35% of the particles have disappeared at this concentration (Fig.18.7). This decrease seems not to depend on incubation time. For given surfactant concentrations, τnorm did not change between 30 minutes and 1 week (Fig. 18.8). On the other hand, DLS clearly documented that the volume fraction of particles (i.e., the Nanotopes population) was not affected by the presence of up to 7.5% of sodium dodecyl sulphate. However, the mean diameter d of the Nanotopes had shifted from 21 to 17 nm. According to Eq. (18.1), such a decrease of the particle diameter d by 4 nm will reduce turbidity τnorm by (17 nm)3/(27 nm)3 (i.e., by about 50%). Consequently, and in the following, the turbidity at a given surfactant concentration was replaced by τcrit (i.e., as the turbidity at which τnorm reaches 50%): Eq. (18.3)

τ crit = 0.5 ⋅ τ norm

Thus, τcrit corrects the effect of surfactant-induced particle shrinkage at least in part, though the volume fraction occupied by these smaller particles may also be smaller and thus affect turbidity accordingly. In consequence, the stability of liposomes and Nanotopes in the presence of cosmetically used surfactants was determined by turbidity measurements. The τnorm were determined for increasing concentration of surfactants. Then, τcrit was derived for each surfactant and carrier as indicated in Figs. 18.9 through 18.12 and listed in Table 18.3. The bottom line of the extensive work cited above is that Nanotopes can tolerate up to five times higher surfactant concentration than liposomes are able to tolerate. Thus, Nanotopes appear to solve a long-standing problem in personal care systems requiring delivery systems. Since such liposome-containing materials have therefore gathered a poor reputation, due to their lack of stability in the presence of surfactants, Nanotopes represent a powerful solution to the problem.

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Figure 18.7 The normalized turbidity of Nanotopes™ and liposome suspensions as function of SDS concentration.

Figure 18.10 Turbidity of Nanotopes™ and liposome suspensions as function of cocamidopropyl betaine concentration.

Figure 18.8 Turbidity of Nanotopes™ suspensions as function of SDS concentration after 30 minutes and after one week of incubation.

Figure 18.11 Turbidity of Nanotopes™ and liposome suspensions as function of trideceth-8 concentration.

Figure 18.9 Turbidity of Nanotopes™ and liposome suspensions as function of the concentration of laureth-11 carboxylic acid.

Figure 18.12 Turbidity of Nanotopes™ and liposome suspensions as function of PEG-20 hydrogenated tallow amine concentration.

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES

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Table 18.3. Critical Surfactant Concentration ccrit for Nanotopes™ and Liposomes

Surfactant

Critical Surfactant Concentration ccrit for Nanotopes™ (%)

Critical Surfactant Concentration ccrit for Liposomes (%)

Sodium dodecyl sulphate (SDS)

7

1

PEG-20 hydrogenated tallow amine

> 20

1

Laureth-11 carboxylic acid

6

1

> 20

4

10

2

Cocoamidopropyl betaine Trideceth-8

18.3 Nanotopes™: Performance 18.3.1

Influence of Nanotopes™ Encapsulation on Stability of Vitamin A Palmitate

Besides providing protection against surfactant disruption, Nanotopes are also expected to protect cosmetic actives from environmental stressors. This is especially important for encapsulated vitamin esters such as pro-vitamin A palmitate (VAP) or vitamin E acetate. These derivatives are less labile than their respective free vitamins. This hypothesis was tested by comparing the recovery rates of integrated vitamin A palmitate (the least stable of the pro-vitamins) with that of vitamin A palmitate encapsulated in Nanotopes™ (TINODERM® A, Ciba Specialty Chemicals Inc., Basel, Switzerland). The comparison was made in several cosmetic formulations. Corresponding amounts (i.e., 0.1% vitamin A palmitate and 5% TINODERM® containing 2% vitamin A palmitate) were formulated in several product forms. This included a liquid gel, a water-in-oil emulsion, and an oil-in-water emulsion. One-hundred-gram samples of each formulation were stored in clear glass bottles under a variety of conditions. These included: at ambient temperature (20°C) in the dark, 20°C at day lighting, and at 40°C in the dark. After 7 days, 1 month, 3 months, and 6 months of storage, 1-gram aliquots of each formulation were removed,

and the content of vitamin A palmitate was measured by high-pressure liquid chromatography (HPLC). Prior to sample removal, these formulations had been stirred at atmospheric conditions by a spatula, to mimic air-exposure. Thus, after 6 months, each bottle had been opened and closed a total of 5 times. Figures 18.13 through 18.15 illustrate the effect of Nanotopes encapsulation to formulated vitamin A palmitate. As expected, all vitamin A palmitate formulations exposed to light demonstrated complete decomposition within 90 days. However, formulations containing the Nanotopes encapsulated material demonstrated lower rates of the active’s decomposition (Fig. 18.13). In the absence of light and at room temperature (Fig. 18.14), all Nanotopes containing formulations considerably enhanced and improved the stability of the vitamin esters. In contrast, formulations containing unencapsulated vitamin A palmitate (formulated in a gel) had completely degraded after 3 months. Nanotopes-encapsulated vitamin A palmitate proved far more resistant to hydrolysis than vitamin A palmitate alone. The concentration of vitamin A palmitate decreased by about 30% in the first 4 weeks and then remained constant at this level for up to 6 months. Even more drastic changes were observed when comparing the oil-in-water emulsions made with

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS vitamin A palmitate and the Nanotopesencapsulated vitamin A palmitate. It was observed that the vitamin A palmitate system had lost most of its concentration within three months. However, the nanoencapsulated vitamin A palmitate-containing formulations retained more than 80% of vitamin A palmitate intact.

Figure 18.13 Recovery of encapsulated vs nonencapsulated vitamin A palmitate (VAP) over time (exposed to light).

Figure 18.14 Recovery of encapsulated vs nonencapsulated vitamin A palmitate (VAP) over time (stored in the dark at room temperature).

In the water-in-oil emulsion systems, vitamin A palmitate proved rather stable and 83% of the vitamin A palmitate and 100% of the encapsulated material were recovered after 6 months. This suggests that, like the Nanotopesbased systems, the water-in-oil emulsion systems had similar efficacy. However, Nanotopes provided overall value beyond that of water-in-oil emulsions because the oily core containing the active vitamin A palmitate is enclosed in the protective Nanotopes shell, which reduces direct contact of the active at the water-oil interface. In turn, environmental-prone oxidation should manifest itself as less harmful. Measurements made in systems at 40°C, in the dark (Fig. 18.15), demonstrated that formulated vitamin A palmitate completely lost their concentration after 6 months. By contrast, 60% of the nanoencapsulated material was recoverable from oil-in-water and water-inoil formulations and 40% was recoverable from the gel formulation. In conclusion, the use of Nanotopes encapsulates offers improved performance in all formulation types evaluated. Nanotopes-encapsulated vitamin A palmitate was found to be more resistant to environmental stressors than the non-encapsulated control. Stability was formulation dependent, where gels were found to be the least stable, water-in-oil were more stable than gels, and oil-in-water formulations were most stable.

Figure 18.15 Recovery of encapsulated vs nonencapsulated vitamin A palmitate (VAP) over time (stored in the dark, 40°C).

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES 18.3.2

375

In Vitro Performance of Aqueous Nanotopes™ Solutions on Human Skin

In general, carrier systems increase the transport of actives to the epidermis, which is the main zone of cosmetic interest. Carrier systems are of special importance for transporting the more stable, but inactive, ester-derivatives of vitamin A, C, or E[10]–[13] to specific esterases localized within the skin.[14] The esterases eventually hydrolyze these pro-vitamins to form the free, active vitamins.[15][16] Recently, the cleavage of vitamin E acetate to the free active vitamin E by skin-related esterases has been documented in a clear-cut fashion on excised human skin using plastic surgery techniques.[4][17] The crucial step in these experiments was the use of large-area penetration cells (PhaCo-Cells, PhaCos D-82131-Gauting). These cells have an application area that is almost 10 times larger than that of conventional Franz cells. As a result these modified Franz cells provide enough material for quantifying the deposited active in different skin layers by HPLC. Moreover, these cells are covered with a bell-shaped lid fitted with a cock, thus permitting application with or without exposure to the atmosphere (i.e., application under non-occlusive or occlusive conditions, respectively). In short, preparations containing 2% vitamin E acetate dissolved either in capric/caprylic acid (miglyol), or in water, and prepared by means of a solubilizer (Solubilizant, Wacker), or encapsulated in conventional liposomes or in the core of Nanotopes were applied as 5% suspensions onto excised human skin. The skin was mounted in these large-area Franz cell-like penetration cells introduced by Artmann (Fig. 18.16).[18] All experiments were carried out in triplicate. After 8 hours, under defined non-occlusive conditions, the skin surface was wiped-off, and the outer horny layer of the skin was removed by tape stripping. HPLC was employed to analyze actives in the wipe-off, the tape strips with the adhering horny layer, and in the underlying skin. These were extracted by HPLC and analyzed for both vitamin E acetate and free vitamin E. The recovery rate of vitamin Etotal (vitamin E acetate + free vitamin E) exceeded 90% in all experiments.

Figure 18.16 PhaCo-Cells.

As illustrated in Fig. 18.17, the Nanotopes (TINODERM® E) were most effective in depositing vitamin Etotal in the skin. Second runner up to the Nanotopes were the liposomes and the solubilizing system, which employed an oil solution that remained on both the skin surface and in the upper most layers of the horny layer. The same order of effectiveness held true under occlusive conditions. However, it was found that the carrier performance of all systems was slightly lower. The rate of bioconversion of vitamin E acetate to free vitamin E was found to increase with increasing effectiveness of active delivery to the viable skin below the dead cell layer of the stratum corneum (Table 18.4). In a second set of experiments, the PhaCo-Cells system was used to assess the performance of Nanotopes-encapsulated vitamin A palmitate. Ten mg/cm2 of either a non-diluted Nanotopes™ suspension containing 1.6% vitamin A palmitate (TINODERM® A) or of a 20-fold dilution of this system in water (5% TINODERM A) was applied

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onto the PhaCo-Cells, as described previously for vitamin E loaded Nanotopes. After 8 hours of open incubation, the wipe-off from the skin surface, the horny layer separated by tape stripping, and the underlying skin were then extracted with methanol. HPLC was employed to determine the content of vitamin A palmitate and free vitamin A in each ex-

tract. It was found that recovery rate of the initially applied vitamin A palmitate amounted to more than 90%. As illustrated in Fig. 18.18, approximately 50% of the applied vitamin A palmitate was recovered in the skin. Bioconversion of vitamin A palmitate was restricted just to the viable skin. While the amount of free vitamin A on the skin surface, and in the horny layer were negligible, about 10% of the initially applied vitamin A palmitate was recovered as free active vitamin A. This was seen for both of the concentrations applied.

Figure 18.17 Relative distribution (%) on the skin surface, in the horny layer, and in the viable skin of vitamin Etotal (E acetate+ free E) 8h after application as a 2% solution in TINODERM™ E; liposomes, solubilizer (solubilized by PPG-26-Buteth-26 and PEG-40 hydrogenated castor oil), or oil (in caprylic/capric acid triglyceride). All experiments performed in triplicate. Analysis by HPLC.

The deposition of vitamin A palmitate and of free vitamin A was comparable to that illustrated in Fig. 18.19 for vitamin E acetate (i.e., about 50% of the applied amount was recovered in the viable skin in both the vitamin A palmitate and vitamin E acetate cases). However, the rate of bioconversion of vitamin A palmitate was found to be about half that observed for vitamin E acetate. This difference may be due to the much bulkier palmitoyl-rest, which may be hydrolyzed less efficiently by the esterases than the smaller acetate-ester (e.g., in vitamin E acetate).

Table 18.4. Distribution of Vitamin Etotal in Skin: Comparison Between Different Delivery Systems under Non-Occlusive Conditions

Micrograms Detected Application: 6 mg Vitamin E Acetate /28 cm2

Surface

Horny Layer

Viable Skin

1460

1428

1613

62

60

1112

4925

781

3

67

8

–

Tinoderm® E Vitamin E acetate Free vitamin E

Control (Miglyol) - vitamin E acetate in caprylic/capric acid triglyceride Vitamin E acetate Free vitamin E

Amount of vitamin E acetate and free vitamin E measured by HPLC in extracts from the skin surface, the horny layer, and the viable skin. Experiments performed in triplicate.

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES 18.3.3

Figure 18.18 Bioconversion of vitamin A palmitate to free vitamin A. Localization of bioconversion of vitamin A palmitate in human skin. Relative distribution (%) of the vitamin A palmitate and free vitamin A at the skin surface, in the stratum corneum and in the viable skin, in relation to the initially applied amount of vitamin A palmitate by Nanotopes™ [i.e., a Nanotopes suspension containing 1.6% vitamin A palmitate (TINODERM™ A) and a 20-fold aqueous dilution containing 0.08% vitamin A palmitate (5% TINODERM A)].

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In Vitro Performance on Human Skin of Nanotopes™ in Cosmetic Formulations

The system used for measuring the distribution of actives in the various layers of human skin using Nanotopes emulsions[4] was also used for comparing the performance of both Nanotopes and liposome carriers when integrated into cosmetic formulations. Carriers containing equal amounts of vitamin E acetate were integrated into different types of formulations such as oil-in-water emulsions, water-in-oil emulsions, and gels. These formulations were subsequently applied to the human skin mounted in PhaCoCells and subjected to the set non-occlusive conditions previously described in Sec. 18.3.2.[17] It was found that each formulation retained more than 90% of the amount of vitamin E initially applied. As illustrated in Fig. 18.17 and summarized in Table 18.4, Nanotopes performed consistently better than liposomes. Both Nanotopes and liposomes performed much better than the controls without phospholipid carriers (Figs. 18.20 and 18.21).

Figure 18.19 Bioconversion of vitamin E acetate to free vitamin E. Relative distribution (%) of the vitamin E acetate and free vitamin E at the skin surface, in the horny layer and in the viable skin, in relation to the initially applied amount of vitamin E acetate by Nanotopes™ (i.e., an aqueous dilution of TINODERM® E with a final concentration of 2% of encapsulated vitamin E acetate).

The type of formulation (i.e., oilin-water emulsion, water-in-oil emulsion, and gel) had little influence on the performance of either Nanotopes or liposomes. However, the composition of the formulation itself proved crucial. Formulations were thus categorized empirically into ”carriercompatible” and “carrier-incompatible” systems. In our observations, silicone-based, ethoxylated polyhydroxystearate-based emulsifiers systems and some polyacrylate-based

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS thickeners practically blocked the carrier’s activity (Fig. 18.20). In these carrier-incompatible formulations, substantially less than 10% of the applied vitamin E acetate was recoverable from the viable skin penetrated and bioconversion was reduced accordingly.

Figure 18.20 Carrier performance in non carrier-compatible formulations. Delivery to viable skin. Distribution of vitamin E acetate and free vitamin E in the viable skin. The o/w emulsion was siliconebased, the w/o emulsion was based on ethoxylated polyhydroxystearate and the gel contained a polyacrylate-based thickener.[17]

Figure 18.21 Carrier performance in carrier-compatible formulations. Delivery to viable skin. Distribution of vitamin E acetate and free vitamin E in the viable skin. The o/w emulsion was based on a mixture of phosphate esters and fatty alcohols, the w/o emulsion on hydrogenated lecithin combined with a polyglycerol ester, and the gel contained a xanthan gum-based thickener.

By contrast, oil-in-water emulsions comprising mixtures of phosphate esters and fatty alcohols, water-in-oil emulsions composed of hydrogenated lecithin (combined with a polyglycerol ester), and gels containing xanthan gum-based thickeners were all highly efficient (Fig.18.21). In these carrier-compatible formulations, the deposition of the active in the viable skin and its bioconversion were at least comparable to that observed with the carrier alone (i.e., Table 18.4 and Fig. 18.19). In summary, it was observed that only an efficient carrier system such as Nanotopes or liposomes proved essential for the effective bioconversion of esterified prodrugs such as vitamin E acetate. The type of emulsifier system, or type of thickener used, strongly influenced the performance of the carrier system. By contrast, the type of formulation (i.e., oil-in-water emulsion, waterin-oil emulsion, or gel) seemed to be of minor importance. While it is difficult to draw wide generalizations from the small number of formulations tested, general rules for carrier performance in formulations are not clear cut at the present time. Future work should be directed to further understand the scientific underpinnings of this technology and further elucidation and identification of the key variables are recommended. At this stage in the development of such systems, trial and error seems to be the only way to success.

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES 18.3.4

In Vivo Performance of Aqueous Nanotopes™ in Solutions

Logic dictates that Nanotopes (i.e., these nanosized particles with a mean diameter below 30 nm) should be well suited to improve the delivery of cosmetic actives. One example of this is improving the passage of an active like D-panthenol (P) through the stratum corneum (i.e., the horny layer) and into the underlying skin. In order to confirm this hypothesis, a series of experiments was carried out on human volunteers, to compare the anti-inflammatory effect of D-panthenol (encapsulated in Nanotopes) as compared to a commercial preparation of Dpanthenol.[19] Experimental procedure. Individual minimal erythema doses (MED) were determined for each subject. Sites of measurement (each 6.25 cm2) were marked ambilateral to the dorsal spine. These areas were then exposed to 2 MED (40-60 mJ/cm2, Philips TL 0.1 - lamp, 100 W, UV-A and -B). Immediately after irradiation and twice daily, Nanotopes containing 5% D-panthenol (TINODERM P, from Ciba Specialty Chemicals) were compared with 10-fold (0.5% D-panthenol) and 100-fold (0.05% D-panthenol) aqueous dilutions. Empty Nanotopes (placebo control) were also employed (8 mg/cm2). The testing was carried out in a randomized double-blind fashion and all materials were applied to the designated sites on the back of each volunteer. For each treated area, an irradiated, non-treated area was randomly assigned as a control. Additionally, non-occlusive applications of a commercial preparation containing 5% D-panthenol (8 volunteers) and of a commercial ointment containing 0.1% hydrocortisone (16 volunteers) served as positive controls. The redness a* of treated-irradiated, untreatedirradiated, and non-irradiated areas was registered daily by a Minolta CM-508i spectrophotometer for determining the L*a*b* [20] color space (cf. DIN 5033, ISO 7724/1, JIS Z8722). Concomitantly, the degree of blood microcirculation, in the different test areas, was measured with a laser-Doppler procedure using a multichannel device from Perimed KB, Sweden. An optimal penetration depth of 1.5–2 mm was employed. Data was expressed in perfusion numbers [random units (RU)], which are proportional to the number and velocity of erythrocytes.[21][22]

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The difference in redness a*, and differences in blood flow RU, between the treated and the untreated areas was used as a measure of efficacy. Twenty-four hours after irradiation, the differences in a* measured between the three active-containing preparations and the placebo proved to be statistically significant (Fig. 18.22). Differences in blood flow RU determined by the laser Doppler measurements were also statistically significant (Fig. 18.23). The dose-dependence of erythema reduction was well evident between the empty Nanotopes and the 0.05% and the 0.5% P preparations. The effect observed for the 5% preparation was lower than expected for a 10-fold higher concentration. Obviously, this concentration was higher than the saturation capacity of the skin. High concentration of an active reaching skin saturation had also been reported for liposomes.[23] In the present case, the highest Nanotopes concentration in the stratum corneum appears to be above saturation, while the 1/10 dilution of Nanotopes (5% P) came close to the saturation threshold for D-panthenol-loaded Nanotopes. The testing showed that all D-panthenol formulations were superior to the placebo control. The efficacy of the 1/100 dilution of D-panthenol-loaded Nanotopes (effectively 0.05% P) proved comparable to that of 5% D-panthenol applied as a conventional ointment. This result clearly points to the value of using an active like D-panthenol in a Nanotopes form because superior efficacy is achievable at a far lower dose and lower cost. The superior efficacy of Dpanthenol-loaded Nanotopes is attributed to the small size of the carrier (i.e., Nanotopes particles). This is consistent with the well-known concept that the smaller the particles of the delivery system, the more easily the active will be transported into deeper layers of the stratum corneum. Of course, small particle size is not the only parameter in this regard and effective transport is also dependent on the carrier being sufficiently lipophilic to penetrate the oil-loving surface of the stratum corneum. This data set also illustrates the different reaction kinetics of the Nanotopes-encapsulated Dpanthenol and of the steroid (i.e., the hydrocortisone ointment) used as an experimental control. The hydrocortisone reduced the erythema-increased microcirculation markedly stronger than redness. It was

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Figure 18.22 Colorimetric assessment of the reduction in redness by D-panthenol (P) loaded Nanotopes™ in UV-induced erythema.

Figure 18.23 Assessment via laser Doppler measurements of the reduction in blood flow by D-panthenol (P) loaded Nanotopes™ in UV-induced erythema.

found that six hours after irradiation, the reduction in redness obtained by means of the steroid was comparable only to that observed by 0.05% P Nanotopes. Over time the beneficial effect of the steroid increased. Reduction of redness was obtained comparable to that observed by the 5% and 0.5% D-Panthenol systems after 24 hours and 48 hours (Figs. 18.22 and 18.23). By contrast, the steroid decreased microcirculation in the UV-irradiated site as effectively as the 5% P and 0.5% P Nanotopes

systems. This rapid reduction of blood flow goes along with the well-known bleaching effect of the skin typically obtained by corticoids and explainable by vasodilatation. The present study clearly demonstrates a doseand time-dependent anti-inflammatory effect of aqueous solutions of D-panthenol-loaded Nanotopes. In comparison with the efficiency of the commercial preparation, Nanotopes demonstrated a superior activity six hours after UV-irradiation.

BASCHONG, ET AL.: NANOTOPES™: A NOVEL ULTRA-SMALL CARRIER SYSTEM FOR COSMETIC ACTIVES 18.3.5

In Vivo Performance of Formulated Nanotopes™

In spite of any “scientific” test data, the ultimate test of the value of any formulation is to demonstrate its efficiency in a consumer-perceivable manner, when integrated into a cosmetic formulation and applied in vivo to human volunteers. To evaluate the effectiveness of the Nanotopes-based systems, we used Nanotopes, containing 2% (w/w) vitamin E acetate (TINODERM® E). 5% of these vitamin E acetate-containing Nanotopes were integrated into a cosmetic day cream. The antioxidant activity of the vitamin E acetate was then measured via the inhibition of UV-A-induced squalene peroxidation. For comparison, a placebo day cream was employed as a control. 2 mg/cm2 of both the antioxidant day cream and the placebo were applied for seven days. A twice-a-day regimen was employed on confined areas of the backs of ten volunteers. One untreated test field was employed as a negative control. A second area was treated with free vitamin E in ethanol (0.2%) immediately before irradiation and served as a positive control. The subject’s backs were then irradiated with UV-A light (10 joule/cm²). Subsequently, the skin lipids from the test areas were extracted by treatment with 4 ml ethanol for two minutes. The amount of squalene

381

(SQ) was thereafter determined by conventional HPLC and the amount of squalene-hydroperoxide (SQOOH) was measured via HPLC and post column chemiluminescence detection. The amount of SQOOH was measured in picomoles hydrogen peroxide per µg squalene. As seen in Fig. 18.24, Nanotopes-encapsulated vitamin E acetate inhibited the formation of UV-Ainduced squalenperoxides. As foreseeable, this beneficial phenomenon was dose dependent with better results being obtained at higher levels of Nanotopesencapsulated vitamin E acetate. The formulation containing 10% TINODERM E, or 0.2% free vitamin E acetate, showed an activity slightly superior to that of the 0.2% free vitamin E in ethanolic solution used as positive control. Accordingly, the cream containing a lower concentration of TINODERM E (5%) proved less active than the 10% TINODERM E sample. The effects of the 1% TINODERM E containing preparation were equivalent and, as expected from the 10% TINODERM E sample. These tests clearly showed that the 10% TINODERM E containing day cream performed significantly better than that of the 1% containing TINODERM E preparation and the placebo ( p < 0.05).

Figure 18.24 Sebum peroxidation via squalenoxidation. UV-A induced oxidation of squalen (10 volont.). Effect of vitamin E acetate in Nanotopes™ (TINODERM® E).

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18.4 Conclusions Using sophisticated testing procedures, Nanotopes-encapsulated cosmetic actives have been shown to be superior carriers when compared to conventional liposomes or to surfactant-solubilized actives.[4] The superiority of Nanotopes versus the other carrier systems tested held true in both formulations, carrier-compatible and carrier non-compatible.[17] The improved performance of Nanotopes over liposomes is attributed to their smaller size, as well as the significantly improved resistance to breakdown in the presence of surfactants. It is recognized, of course, that the evidence for improved performance of Nanotopes is indirect evidence that has been delineated from the improved biological activity observed with Nanotopes by contrast with the other systems tested. The experimental evidence points to validation of the hypothesis that delivery of actives by carrier systems provide higher active delivery efficacy. Nanotopes contain much smaller phospholipid-associated particles than liposomes. They have a much higher ratio between the concentrations of the membrane phospholipids to enclosed active than liposomes. By contrast with liposomes, which have much larger particles and total concentration of membrane-constituting molecules make up only a small fraction of the total particulate. Obviously, the Nanotopes are far more effective and efficient at delivering their actives into the skin. The much smaller particles of the Nanotopes, combined with the phospholipids and lecithin in the membrane, provide a surface that is more easily absorbable on the skin. Lecithin itself has known penetration-enhancing properties. This combination of size and membrane composition can act far more efficiently than a liposome in the microenvironment

constituted by a penetrating particle and thereby improve the penetration of the transported active accordingly. Smaller active-carrier particles are believed to penetrate far more easily through the intercorneocyte pores of the stratum corneum to reach the lipid bilayers. Actually, phospholipid-based active-carrier particles such as Nanotopes or liposomes are likely to dissolve in the lipid bilayer where they concomitantly release their active content. Nanotopes also resist disruption larger in view of their higher resistance to disruption by surfactants. Thus, if they last longer, the outer membrane will remain more lipophilic, larger and therefore be able to penetrate better in the barrier lipids. As a result, Nanotopes will dissolve in deeper layers of the lipid barrier and deliver the active closer to the epidermis, the zone of cosmetic interest. Ideally, the improved performance of Nanotopes over liposomes will have to be documented by microscopic or other experimental techniques that will clearly show the distribution of the penetrating particles within the stratum corneum and in the underlying epidermis. To date, such a direct documentation of active-carrier performance has not been conducted for Nanotopes or liposomes. In spite of this lack of direct evidence, it is clear that the smaller size and higher molecular ratio of phospholipid to active contribute significantly to the superior performance of Nanotopes over liposomes. Further, the smaller particle size of the Nanotopes enables enhanced penetration into the intercorneocyte pores and requires less deformation-energy during particle penetration. Last, but not least, since Nanotopes resist backup from surfactant attack better than liposomes, they can penetrate to deeper regions of the lipid membrane barrier simply because they last longer than liposomes do under similar conditions.

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383

18.5 Formulations Formulation 18.1: Nanotopes™ from Stability Tests: o/w Emulsion with TINODERM® A

Phase A

Ingredient Aqua

Weight % 69.75

Glycerol

3.00

Glyceryl stearate/ PEG-100 stearate

5.00

Glyceryl stearate

0.50

Caprylic/capric triglyceride

4.00

C12-15 alkyl benzoate

3.00

Cetearyl isononoate

3.00

Squalane

2.50

C

Sodium acrylates copolymer, paraffinium liquidum, and PPG-1 trideceth-6 (SALCARE® SC91)

1.00

D

Cyclomethicone

3.00

E

Diazolidinyl urea and iodopropynyl butylcarbamate

0.15

F

Aqua, retinyl palmitate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® A)

5.00

Citric acid

0.10

B

Procedure: 1. Heat Phases A and B separately up to 75°C. 2. Add Phase B to Phase A under stirring and homogenizing. 3. Add Phase C after emulsification at 65°C under stirring and add Phase D. 4. At 50°C add Phase E. 5. Cool down to room temperature and add Phase F under moderate stirring. 6. Adjust pH value to 5.7–6.7 with citric acid solution.

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Formulation 18.2: Nanotopes™ from Stability Tests: w/o Emulsion with TINODERM® A

Phase

A

B

Ingredient

Weight %

Decyl oleate

4.00

Cetyl dimethicone copolyol

2.00

Cetearyl isononnoate

2.00

Triglycerin-4-isostearate

1.00

Beeswax

0.50

Hydrogenated castor oil

0.50

Micro-crystalline wax

1.40

Mineral oil

2.00

Isohexadecane

5.00

Glycerol

3.00

Hydrogenated lecithin

0.45

Aqua

69.15

Sodium chloride

0.35

C

Cyclomethicone

3.50

D

Diazolidinyl urea and Iodopropynyl butylcarbamate

0.15

E

Aqua, retinyl palmitate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® A)

5.00

Procedure: 1. Add Phase B into Phase A at 80°C, homogenize a short time (<10 seconds at 10,000 rpm). 2. Under 65°C add Phase C. 3. At 50°C, add Phase D, let cool down. 4. At room temperature, add Phase E.

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Formulation 18.3: Nanotopes™ from Stability Tests: Gel-Fluid with TINODERM® A

Phase

Ingredient Aqua

Weight % 90.47

Glycerol

3.00

Diazolidinyl urea and iodopropynyl butyl-carbamate

0.15

Xanthan gum

1.00

B

PEG-40 hydrogenated castor oil

0.35

C

Aqua, retinyl palmitate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® A)

5.00

D

Sodium hydroxide

0.03

A

Procedure: 1. Pour the ingredients of Phase A together and mix well. 2. Add Phase B into Phase A. Then add Phase C into Phase A/B. 3. If necessary, adjust pH-value (Phase D).

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Formulation 18.4: Nanotopes™ Compatible with Carrier Performance: o/w Emulsion with TINODERM® E

Phase A

Ingredient Aqua

Weight % 69.00

Glycerol

3.00

PEG-100 stearate

5.00

Glyceryl stearate

0.50

Caprylic/capric triglyceride

4.00

C12-15 alkyl benzoate

3.00

Cetaryl isononoate

3.00

Squalane

2.50

C

Sodium acrylates copolymer, paraffinium liquidum, and PPG-1 Trideceth-6 (SALCARE® SC91)

1.00

D

Cyclomethicone

3.00

Phenoxyethanol, and methyl-, butyl-, ethyl-, propyl-, and isopropylenparaben

0.50

Isopropylparaben, and methyldibromo glutaronitrile

0.10

B

E F

Fragrance

G

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

Citric acid

0.02

Procedure: 1. Heat Phase A and B separately up to 75°C. 2. Add Phase B to Phase A under moderate stirring and homogenizing. 3. Add Phase C after emulsification at 65°C under moderate stirring and add Phase D. 4. At 40°C add Phase E and F. 5. Cool to 35°C and add Phase G under moderate stirring. 6. Adjust pH value to 5.7-6.7 with citric acid solution.

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387

Formulation 18.5: Nanotopes™ Compatible with Carrier Performance: w/o Emulsion with TINODERM® E

Phase

A

B

C

D

Ingredient

Weight %

Decyl oleate

4.00

Cetyl dimethicone copolyol

2.00

Cetearyl isononanoate

2.00

Triglycerin-4-isostearate

1.00

Beeswax

0.50

Hydrogenated castor oil

0.50

Microcrystalline wax

1.40

Paraffin oil

2.00

Isohexadecane

5.00

Glycerol

3.00

Hydrogenated lecithin

0.45

Aqua

68.70

Sodium chloride

0.35

Cyclomethicone

3.50

Diazolidinyl urea, methylparaben, propylparaben, and propylene glycol

0.55

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

Fragrance

0.05

Procedure: 1. Add Phase B into Phase A at 80°C, homogenize short time (<10 seconds). 2. Under 65°C add the Phase C, let cool down. 3. Under 30°C, final homogenize 10,000 rpm/15 seconds. 4. At room temperature, add Phase D.

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Formulation 18.6: Nanotopes™ Compatible with Carrier Performance: Gel-Fluid with TINODERM® E

Phase

Ingredient Aqua

Weight % 90.47

Glycerol

3.00

Phenoxyethanol and methyldibromo glutaronitrile

0.15

Xanthan gum

1.00

B

PEG-40 hydrogenated castor oil

0.35

C

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

D

Sodium hydroxide

0.03

A

Procedure: 1. Pour the ingredients of Phase A together and mix well. 2. Add Phase B into Phase A. 3. Add Phase C into Phase A/B. 4. If necessary, adjust pH-value (Phase D).

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389

Formulation 18.7: Nanotopes™ Interfering with Carrier Performance: o/w Emulsion with TINODERM® E

Phase

A

B

Ingredient Dimethicone copolyol and caprylic/capric triglyceride

3.00

C12-15 alkyl benzoate

3.00

Cetearyl isononanoate

4.00

Squalane

3.50

Caprylic/capric triglyceride

5.00

Cetyl alcohol

1.50

Glycerol

3.00

Xanthan gum

0.30

Polysorbate 80

0.15

Aqua C D

E F

Weight %

66.18

Cyclomethicone

3.00

Diazolidinyl urea, methylparaben, propylparaben, propylene glycol

0.70

Sodium acrylates copolymer, paraffinium liquidum, and PPG-1 trideceth-6 (SALCARE® SC91)

1.50

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

Fragrance

0.05

Citric acid 30%

0.12

Procedure: 1.

Add the Phase A into Phase B at 75°C, with medium stirring.

2.

Add Phase C after dispersion, using a rotor/stator mixer.

3.

Add Phase D, just after the mixing.

4.

At room temperature, add Phase E.

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Formulation 18.8: Nanotopes™ Interfering with Carrier Performance: w/o Emulsion with TINODERM® E

Phase

Ingredient Aqua

A

Weight % 65.25

Glycerol

3.00

Sodium chloride

1.00

PEG-30 dipolyhydroxystearate

3.00

Caprylic/capric triglyceride

4.00

C12-C15 alkyl benzoate

4.00

Cetearyl isononanoate

4.00

Squalane

2.00

Microcrystalline wax

2.00

Tristearin and acetylate glycol stearate

1.00

Cyclomethicone

5.00

Phenoxyethanol, and methyl-, butyl-, ethyl-, propyl-, and isopropylenparaben

0.50

Isopropylparaben, and methyldibromo glutaronitrile

0.10

E

Fragrance

0.15

F

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

B

C D

Procedures: 1.

Heat Phases A and B separately up to 80°C.

2.

Add Phase A to Phase B under moderate stirring and homogenizing.

3.

At 65°C add Phase C under moderate stirring one after the other.

4.

At 40°C add Phases D and E.

5.

At 35°C add Phase F under stirring.

6.

Cool down to 28°C under moderate stirring.

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391

Formulation 18.9: Nanotopes™ Interfering with Carrier Performance: Gel-Fluid with TINODERM® E

Phase A

Ingredient Aqua

Weight % 86.10

Phenoxyethanol and methyldibromo glutaronitrile

0.20

Butylene glycol

3.00

Fragrance

0.10

PEG-40 hydrogenated castor oil

0.30

D

Acrylates copolymer (SALCARE® SC81)

4.00

E

Sodium hydroxide (10%)

1.30

F

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

5.00

B

C

Procedure: 1. Mix ingredients of Phase B and add to the water (Phase A). 2. Premix Phase C and add to Phase A/B. 3. Add Phase D and neutralize the mixture with Phase E. 4. Add Phase F under stirring.

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Formulation 18.10: Nanotopes™ from Squalen Oxidation: w/o Emulsion with TINODERM® E

Phase

A

Ingredient

Weight %

Aqua (F1)

70.55

Aqua (F2)

66.55

Aqua (F3)

61.55

Glycerol

3.00

Steareth-10 allyl ether/acrylates copolymer (SALCARE® SC80)

2.00

Cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate

5.00

Caprylic/capric triglyceride

6.00

C12-15 alkyl benzoate

3.00

Cetearyl isononanoate

3.00

Squalane

2.00

C

Cyclopentasiloxane

3.00

D

Sodium hydroxide

1.30

E

Diazolidinyl urea and iodopropynyl butylcarbamate

0.15

F1

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

1.00

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM®)

5.00

Aqua, tocopheryl acetate, polysorbate 80, caprylic/capric triglyceride, and lecithin (TINODERM® E)

10.00

B

or F2 or F3

Procedure: 1. Heat Phase A and Phase B separately to 75°C. 2. Add Phase B to Phase A under moderate stirring and afterwards homogenize 30 seconds at 11,000 rpm. 3. At 65°C add Phase C and Phase D under moderate stirring one after the other. 4. At 50°C add Phase E. 5. Below 35°C add Phase F1 (F2 or F3 resp.) under stirring. 6. Cool to 28°C under moderate stirring. 7. If necessary, adjust pH value to 6.30–6.60 with sodium hydroxide solution 10%.

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393

Acknowledgment We thank David Mettler for editorial help.

References 1. De Polo, K. F., A Short Textbook of Cosmetology, Augsburg/Germany (1998)

J., Aickin, M., Peng, Y. M., Loescher, L., and Gensler, H., Nutr. Cancer, 26:193 (1996)

2. Weder, H. G., and Weder, M., Patent: EP0852941 (1998); Weder, H. G., and van Hoogevest, P., Patent: EP0733372 (1998); Weder, H. G., and Isele, U., Patent: EP0711557 (1996)

12. Mayer, P., and Pittermann, W., Cosmetics & Toiletries, 108:99 (1993)

3. Herzog, B., Sommer, K., Baschong, W., and Roeding, J., SOeFW J., 124:614 (1998) 4. Baschong, W., Artmann, C., Hueglin, D., and Roeding, J., J. Cosmet. Sci., 52:155 (2001) 5. Berne, B. J., and Pecora, R., Dynamic Light Scattering, Dover Publications (2000) 6. Nagarajan, R., Molecular Theory for Mixed Micelles, Langmuir, 1:331–341 (1985) 7. de la Maza, A., and Parra, J. L., Colloids and Surfaces A: Physicochemical and Engineering Aspects, 70:189 (1993) 8. Ribosa, I., et al., Intl. J. Cosmetic Sci., 14:131 (1992) 9. Hiemenz, P. C., Principles of Colloid and Surface Chemistry, 2nd Ed., Marcel Dekker, New York (1986) 10. Rieger, M., Cosmetics & Toiletries, 108:43 (1993) 11. Alberts, D. S., Goldmann, R., Xu, M. J., Dorr, R. T., Quinn, J., Welch, K., Guillen-Rodriguez,

13. Rangarajan, M., and Zatz, J., J. Cosmet. Sci., 50:249 (1999) 14. Landmann, L., Anat. Embryol., 178:1 (1988) 15. Tojo, K., and Lee, A. R. C., J. Soc. Cosm. Chem., 38:333 (1987) 16. Trevithick, J. R., and Mitton, K. P., Biochem Mol. Biol. Intl., 31:869 (1993) 17. Baschong, W., and Lueder, M., SOeFW J., 128:10 (2002) 18. Artmann, C. W., Fundam. Appl. Toxicol., 28:1 (1996) 19. Baschong, W., Hueglin, D., and Roeding, J., SOeFW J., 125 (Apr. 1999) 20. Takiwaki, H., et al., Skin Pharmakol., 7:217 (1994) 21. Fagrell, B., et al., Abstract: San Diego Symp. On Noninvasive Diagnostic Techniques in Vascular Diseases, San Diego, CA (1982) 22. Messmer, K., and Münch, K., med. Wschr., 125:17 (1983) 23. Röding, J., and Artmann, C., Liposome dermatics, (H. C. Braun-Falco, H. J. Korting, and H. J. Maibach, eds.), Springer (1992)

19 Practical Application of Fractal Geometry for Ultra-High Surface Area Personal Care Delivery Systems Michel S. Lefebvre Steripak Pty Ltd. Sydney, New South Wales, Australia

19.1 Fractal Geometry, Fractal Polymers, and the Cosmetic Industry ......................................................................................... 396 19.1.1 Why are Fractal Polymers Important for the Cosmetic Industry? ........................................................... 396 19.1.2 The “Eureka!” Moment ...................................................... 396 19.2 From Cantor Dust to Sierpinski-Menger Sponge: The Fractal World ......................................................................... 397 19.2.1 Applying the Fractal Concept to Personal Care Systems .. 398 19.3 Fractal Geometry: Statistics and Chemistry ................................ 399 19.4 Fractal Poly-Epsilon Caprolactam (FPEC) .................................. 401 19.4.1 Description and Properties ............................................... 401 19.4.2 Cosmetic Applications ...................................................... 403 19.5 Commercially Available Grades ................................................... 403 19.5.1 Nomenclature Used .......................................................... 403 19.5.2 Examples of Fractal Polymer Grades Available ............... 404 19.6 Conclusion .................................................................................... 404 19.7 Formulations ................................................................................. 405 References .......................................................................................... 405

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 395–406 © 2005 William Andrew, Inc.

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19.1 Fractal Geometry, Fractal Polymers, and the Cosmetic Industry

were not strictly self-similar at various scales, which is a fundamental property of any fractal structure (they look the same at various levels of magnification).

Some may argue that scientific development in the 20th century has been marked by three major milestones: the theory of relativity, the development of quantum physics, and the emergence of chaos science. These developments were made possible only through progress in mathematics. Fractal geometry is for the chaos theory what Lorenz transformations and tensors are for relativity.[1] This chapter describes the application of fractal geometry, a mathematical technique, for the development of a possible breakthrough in the next generation of personal care delivery systems. The technology has allowed the development and commercial availability of ultrahigh surface area polymeric states and powder, which can be added to formulated products to produce significantly improved depth of active delivery.

Steripak recently synthesized true fractal polymers, with self-similarity (constant Hausdorff dimension) and with generation numbers above the de Gennes limit.[8] These true fractal polymers have a growing number of important industrial applications ranging from the modification of physical properties of plastic alloys to water purification. Among the wide range of emerging applications are novel delivery systems for the cosmetic/cosmeceutical industry.

The concept of fractal geometry was created by Professor Benoit Mandelbrot as a continuation of the controversial ideas of Cantor, the work of Hausdorff, Van Koch, Julia, and later Godel.[2] The concept represents a complete departure from the formalism of the Bourbaki Mathematical School headed by Mandelbrot’s uncle, Szolem,[3] who virtually dictated mathematical developments from the end of World War II through to the 1960s. Fractal geometry[4][5] has already deeply influenced our world in areas outside polymer chemistry. The use of fractal compression for satellite transmission, television programs, telephone, voice and data communication, and advanced movie special effects is now mainstream technology. Beyond these applications, fractal geometry is also used in fields as diverse as modeling the repartition of bubbles in French champagne to the improvement of solid ionic interfaces in microelectronics.[6] The application of fractal geometry to polymer chemistry was first attempted through the development of hyper-branched polymers, called molecular trees (dendrimers), and star polymers. These molecules were limited to a fixed number of synthesized steps (the de Gennes limit). [7] However, they were not true fractal polymers since they

19.1.1

Why are Fractal Polymers Important for the Cosmetic Industry?

Fractal geometry is not only a tool that enables observation of how Mother Nature creates interfaces of mathematical beauty, but it is also a means to build polymeric structures that have a near-infinite specific surface area. These structures also have a near-zero apparent density and surfaces that are infinitely pleated over themselves without smooth areas. As such, we can say that they are a molecular brush shape. On such surfaces, useful personal care active ingredients can be spread in near-monomolecular layers! As a consequence of their division at the nano scale, products immobilized or adsorbed at the surface of the fractal polymer will exhibit an ultrahigh reactivity. This reactivity[6] is combined with the capability to provide an easy and uniform transfer to the skin. Fractal polymers represent the ultimate nanotechnology delivery system and are an opening to the next generation of products requiring deeper penetration into the skin and significantly improved active delivery.

19.1.2

The “Eureka!” Moment

In the early eighties, an article in The Economist had a very crude description of Benoit Mandelbrot’s work. This work hinted at the possibility of interfaces of infinite specific area existing in

LEFEBVRE: FRACTAL GEOMETRY FOR ULTRAHIGH SURFACE AREA PERSONAL CARE DELIVERY SYSTEMS spaces not at one, two, or three dimensions (one of the few certain images you retain from high school of how our world is built), but of dimensions expressed by numbers ranging from decimal to logarithmic in size. In this world you need an infinite quantity of ink to draw a fractal curve. Furthermore, in this world you don’t need any ink to represent a fractal dust made, nevertheless, of an infinite number of particles. At the time I read Mandelbrot’s pivotal article, I was working in the membrane field and the idea of a membrane of “infinite” surface area was too exciting to be passed by, despite the advice received from an “expert” chemist (noted academic and head of school) that fractal geometry was practically useless by itself, let alone to practically apply to the “infinite” surface area membranes. I invited a few friends to join me in the middle of the Pacific on a remote island for a week to discuss this subject. To facilitate this meeting, we had a plane for the scientists and another for the cook, the food, and the wine. After much conversation, our conclusion was that, yes, it was possible to imagine a fractal membrane. From that moment of conception it took a year to reduce it to practice. It was the first practical application of fractal geometry to interfacial chemistry.[9] The prototype worked very well. We discovered that one square meter of fractal membrane was eight times more effective than one square meter of a classical membrane. It also turned out, however, to be about ten times more expensive. It is difficult to dream and make money at the same time. In 1990, I had the privilege, through the Lefebvre Scientific Foundation, to cosponsor with IBM the first International Chaos Conference in Australia.[10] As luck would have it, I also had the pleasure to share these weeks with Benoit Mandelbrot. This collaboration caused a revival of my firm conviction that it was not only possible but also economically feasible to apply fractal geometry to chemistry. Not knowing that it would take ten years to achieve our goals, we started the work with enthusiasm.

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19.2 From Cantor Dust to Sierpinski-Menger Sponge: The Fractal World In his book The Fractal Geometry of Nature,[2] Professor Benoit Mandelbrot explains how simple the concept of fractal is. If you try to measure the coastline of Australia (in fact it chooses England as an example) the results will be very different if you use a one-meter walking stick, a kilometer gauge on a map, or a one hundred kilometer gauge on a globe. A beetle following the coastline takes a much longer path than if you or I walked the same route. For the bird flying above us the path is even shorter. It is the fractal nature of the coastline, more and more divided as you observe it closer and closer, that creates the paradox of having a fixed object with a variable perimeter. In the past, some mathematical “monsters” have been known to exist. Historically, Cantor, a brilliant mathematician whose sanity was questioned by some of his colleagues, described the following: • Step 1: Take a segment of length “1” (for example, one meter), cut it in three equal parts and remove the central part. • Step 2: For the two segments left, apply the same method (this method is called a “generator”) and cut each of them into three and remove the central part. • Step 3: Do it again, and again, and again…. The result of this procedure is that you obtain a dust. The cumulative length of the remaining dust particles depends on the number of steps. In Step 1, the cumulative length is two thirds. After Step 2, it is two thirds of two thirds of one. After n steps, the cumulative length is two thirds multiplied by itself n times. As n increases, the value decreases. When n becomes infinite, the dust still exists but it now has an infinite number of particles with a cumulative length of zero. This is a curious way to exist and not to exist at the same time. How can we solve this apparent contradiction? Everything is the consequence of the way we see our world. We understand well that segments,

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or lines, are objects with one dimension and that squares are objects with two dimensions. In the same way, a cube is, without doubt, an object with three dimensions. But how do we perceive that? Suppose that I am alone in the universe without any entity outside myself, and, being lonely, I try to solve some fundamental philosophical questions like: “I know that I am because I think, (as another philosopher in another universe has said), but in what dimension do I exist?” Eureka! The answer is simple. I will cut a piece of myself using any gauge and use this piece to make my own measurement. I will then cut this piece using half the gauge and measure myself again. If the second measurement is double that of the first, I will know that I exist in one dimension. If the second measurement is four times the first, I will know that I exist in two dimensions. If the result is eight I know that my world is in three dimensions. In other words, when you divide the scale by a factor of two, the measure of a segment is multiplied by two, the measure of a square is multiplied by four and the measure of a cube is multiplied by “two to the power of three = 8.” We know that a cube exists in a space with three dimensions because it is the power we need to apply to “2” to obtain the result “8.” Mandelbrot expresses this concept by the very fundamental equation: Eq. (19.1)

Nη d = (λ 0)d

where d is the (fractal) dimension, η is the gauge of measure you use, and N is the count you obtain when you use this gauge. When you switch from λ0, to η as a gauge “ruler,” your result is multiplied by N; knowing N permits you to calculate d. For example, for a cube, if N = 8 when η is one half of λ0 then d is equal to 3. So, let’s now try to apply this equation to the Cantor dust. Each time we take a ruler one third in length of the previous one, the length of the Cantor dust is reduced by one third and N = 2 when η is one third of λ0. Resolving the Mandelbrot equation for N = 2 and η = 1/3, we obtain d. Eq. (19.2)

d = log3 2 ≅ 0.63

The “universe” of the Cantor dust does not exist at one dimension or two dimensions; it is at less than one dimension. We see that the universe of the Cantor dust is too small to fill anything within one dimension. Thus, we now know the cumulative length of the segment is zero; the paradox is solved. We also know now why, in our high school universes, this dust seems so strange. Let us now imagine building our own Cantor dust. It will not be along a line, but rather on a plane surface, starting with a square. We cut our gauge in three and obtain nine elementary squares. We then remove the center square and apply the same treatment for each remaining square. Therefore, we obtain the following series:

etc., etc...

After a very large (infinite) number of steps we obtain our fractal structure. We can immediately see that each step reduces the surface area by one ninth. In other words, the remaining surface area of the n th square is (8/9)n. When n is infinitely big, the remaining surface becomes infinitely small. As a consequence, we see that for each step, the perimeter (i.e., the length of the boundary between the square and the outside) increases. We have now obtained a geometric entity with a zero surface but with an infinite perimeter! Applying the same Mandelbrot equation, we can say that its fractal dimension is d = log3 8, something between one and two. Our geometric entity is too big to be written on a line but nonexistent enough to not need any ink to be written on a piece of paper.

19.2.1

Applying the Fractal Concept to Personal Care Systems

The world of chemistry and cosmetics as we know it is in three dimensions.

LEFEBVRE: FRACTAL GEOMETRY FOR ULTRAHIGH SURFACE AREA PERSONAL CARE DELIVERY SYSTEMS In a three-dimensional world, we can develop the corresponding fractal, starting with a cube, by dividing each edge of our cube in three equal parts, we form 27 elementary cubes and, in removing seven of these cubes (one at the center of each face plus one at the center of the cube), we form a hollowed cube weighing 20/27th of the original. We then apply the same method (generator) for each remaining cube to obtain Stage 2. We again apply the same method to each of the smaller remaining cubes of Stage 2 to obtain Stage 3 and so on ad infinitum. The sponge we obtain (called a SierpinskiMenger sponge) has zero weight but infinite surface area. This is because, as before, we have increased the surface area at each step but we have decreased the weight by a constant factor. When the gauge is reduced from 1 to 1/3, the number of cubes left is N = 20. If we then apply the Mandelbrot equation again, with N = 20 and η = 1/3, we obtain: Eq. (19.3)

d = log3 20 ≅ 2.73

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from substances like polypeptides, the very molecular blocks of, for example, your skin (collagen) or your hair (keratin). Let’s see how we can build one.

19.3 Fractal Geometry: Statistics and Chemistry To make any chemical construction you need building blocks. Macromolecules are linear (or evolve from linearity by side reticulations). It is difficult to envisage making a structure at 2.73 dimension from building blocks of 1 dimension. Or is it? Another way to build fractal curves is called the generalized Van Koch Method.[4] This method is not very different from the one used by Cantor because you still start with a segment cut in three parts but you do not remove the center part. On the contrary, you add to the center part more than you have removed. Let’s take this example: 5JAF

The fractal dimension of the sponge created in this way is between 2 and 3. What a wonderful object a Sierpinski-Menger sponge is. It looks as if it is made of voids (square cavities) limited by walls containing within themselves their own smaller square cavities. These walls are peppered with smaller square holes, and this as far as you can see. If you make one of these sponges from wood it would float on water. If you made one from steel it would sink, but still weigh nothing. If you use this sponge to collect a liquid, because the active surface area is infinite, the liquid will arrange itself in a monomolecular layer up to the stage where all voids greater than the molecular volume are covered. Imagine how active substances adsorbed or transiently immobilized (for example, attached by hydrogen bonding) on such a sponge will become. They will be in a neo-colloidal state. They will be infinitely divided, on a stable support, but offering the maximum availability caused by the tremendously large surface of exchange they offer. Imagine how useful such a sponge will be for the personal care industry, especially if it is made

5JAF

5JAF!

Step 1 is the same “1” meter segment. In Step 2, we have removed the center third and completed the construction by adding three (one-third) segments. In Step 3, we have transformed each small segment by applying the generator to obtain the same effect. We can continue in this manner step by step until we obtain a fractal curve of dimension log3 5 ≅ 1.48. Unfortunately, we cannot make linear molecules arrange themselves according to Step 3. It is impossible for atoms to piggy-back each other, as necessary, at the double points of the curve, where the curve touches itself. But the same fractal dimension can be achieved using the following approach:

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5JAF

5JAF

5JAF!

From a fractal geometry point of view, you can represent the fractal curve deformed in any way you like and it will keep its fractal dimension (unless you try to make knots). This is very convenient because it means that you can use plane formulas to represent your fractal molecules. Mother Nature will organize the molecules in another way but the fractal dimension will be conserved. Now, let’s use some chemical blocks and consider the beauty of this macromolecule:

The end fractal curve of Step 3 looks more compatible with chemical constructions. You can generalize the same method by permitting some lateral reticulation. For example, consider the following: 5JAF

5JAF

5JAF!

In this progression, the generator is represented by Step 2. The fractal obtained still has the same dimension, log3 5 ≅ 1.48, meaning that the fractal will cover the same amount of space but with a very different building system. You can also see that the fractal dimension is purely a topologic notion. The same fractal dimension will be obtained by: 5JAF

5JAF

5JAF!

In this plane representation, we can envision each little segment to be a monomeric unit (for example, a peptide), each monomeric unit being linked to the next one by a CO–NH bond with the reticulation either by covalent or hydrogen bonding. We know how to build such molecules. We need only to manufacture a soup containing: • 1 × 27 units oligomer • 3 × 9 units oligomer • 9 × 3 units oligomer • 27 × 1 unit monomer and be sure that we immobilize the biggest one first and the smallest one last. Any chemist will tell you that the world doesn’t work that way, that the only thing you will obtain after polymerization of such a soup is a big hard gel, with nothing in common with the sponge you hoped to obtain.

LEFEBVRE: FRACTAL GEOMETRY FOR ULTRAHIGH SURFACE AREA PERSONAL CARE DELIVERY SYSTEMS But let us have another look at our objective. To make a Sierpinski-Menger sponge, we need a geometric progression of the number of voids. In fact, you can immediately notice that you have three times more smaller holes for each generation and that you can establish a bi-univocal relationship between each hole and each oligomer of the above plane representation. In a step-by-step construction, you will first either need to immobilize the longer elements to create a grid and then fill the grid with smaller elements (called a top-to-bottom construction), or you can establish self-assembling molecules to build the structure around the smaller hole by first relying on the self-assembling property of the generator molecule to construct the larger structures step by step (this is called a bottom-to-top construction). To achieve our goals, the starting material must be a molecular soup containing a preponderance of smaller oligomers compared to bigger ones. In fact, we need a geometric progression with a common ratio of 3, as previously observed above. In other words, our theoretical fractal chemical structure of dimension 1.48 must be used to build a space of dimension 2.73 (the sponge’s space) without gelling. This means there must be no crossover or crowding of, for example, covalent or hydrogen bonds before the geometric shape is established. It also means that the interface of the reaction must be fractal (this is a property of fractal space intersections).[20] Fortunately, some chemists know how to produce a reaction interface that is fractal in nature. In interfacial reactions, when the interface is in the form of a bubble, gelation becomes impossible. If the interface is itself fractal, the fractal dimension of the molecular generator combines with the fractal dimension of the interface to determine the fractal dimension of the end product. (The fractal dimension of the interface is beyond the scope of this chapter but it can be determined using the principles of generalized algebra within nonextensive statistics described in Ref. 20.). It is possible to make a mixture of oligomers of different molecular weights by combining different types of synthesis, or by stopping the polymerization at different stages. However, this approach is gen-

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erally very cumbersome. Another approach[8] is to start with a crystalline form of a polymer at a very high degree of polymerization, and to slowly de-polymerize it, in order to obtain the statistically correct mix having the same fractal repartition. The singlechain statistics that govern this approach are described in Ref. 21. By having the crystalline polymer dissolved in a solvent containing a de-polymerization agent that reacts slowly, it is possible to make a mixture of oligomers of different molecular lengths. By using an interfacial phase inversion process incorporating a foaming agent, it is possible to directly produce the fractal polymer. Examples of useful solvents and the interfacial re-agents used for the various polymers are given in Ref. 8. Fractal polymers can be made from various monomeric systems. However, for personal care industry applications we have initially limited ourselves to polypeptides, in view of their excellent biocompatibility. In the next part of this chapter, some practical examples based on Fractal poly-epsilon caprolactam (FPEC) are described.

19.4 Fractal Poly-Epsilon Caprolactam (FPEC) 19.4.1

Description and Properties

Fractal poly-epsilon caprolactam (FPEC) is made from caprolactam and is, therefore, the fractal equivalent of polyamide 6, the linear polymer made from caprolactam. FPEC has a specific surface area (measured by isotherm helium desorption) typically greater than 400 m2/g and for some grades, the value reaches more than an extraordinarily high level of 200,000 m2/g (measured at the electron cloud interface). Under the microscope, FPEC is seen to be finely divided at all scales. It has an alveolar structure similar to the Sierpinski-Menger sponge. Each microcavity is limited by walls containing nanocavities. This self-replicating structure looks the same under

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS a wide range of magnifications. (See Figs. 19.1, 19.2, and 19.3) These pictures clearly show the fractal nature of the polymers from a scale of a few microns down to the nanometer range. The polymers are made of micron size cavities limited by walls containing smaller cavities. The walls of these cavities contain, again, smaller cavities and this arrangement repeats itself down to the size of a few nanometers. In this particular case, the increase in size of the boundary, between dark grey and light grey when the resolution increases, permits the determination of the fractal dimension using the Mandelbrot equation.

Figure 19.1 Steroscan picture of a microcavity within FPEC.

Further analysis of microphotographs (Fig. 19.4) show that the proportion occupied by the cavities can be different from the one-ninth ratio observed in the fractal sponge model used because the structure is influenced by the microscopic aspect ratio of the polymer chains. (We used a mathematical model where the chains are represented by straight, onedimensional lines).

Figure 19.2 At further magnification, smaller cavities are revealed within the microcavities.

↓

Figure 19.3 Picture of the same alveola at nanometer scale showing nanocavities.

Figure 19.4 FPEC microstructures.

LEFEBVRE: FRACTAL GEOMETRY FOR ULTRAHIGH SURFACE AREA PERSONAL CARE DELIVERY SYSTEMS As a delivery system, the various sizes of microcavities can be tailored to accommodate the size of components to be immobilized and/or adsorbed or delivered. One particularly interesting example is the immobilization of nanocrystals to “oblige” the substance to maintain its division. In Fig. 19.5, we see a clear example of crystal immobilization (in this case NaCl). This “foundation” crystal can be used as a support for silver crystals immobilized by the Catadyn Reaction, one of the recipes used to produce a fractal polymer additive for antiseptic creams.

19.4.2 Cosmetic Applications Nicole Ardoin and Didier Astruc have provided an excellent review of possible applications of molecular trees to pharmaceutical products,[13] where to some extent only performance, not price, matters. For the cosmetic industry, the relatively low cost of FPEC permits its use as an economically efficient delivery system. Due to its structure, FPEC can be used as a delivery system in the same general way microsponges and ultrafine powders, for example, are used. Furthermore, new applications can be specifically designed taking into account the fractal nature of the polymer. The addition of a small quantity of fractal polymers permits us to change the geometry of the interface between the product and the skin. We call it

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the “molecular broom” effect. Fractal molecules act like bristles of various lengths and rigidity. You know how difficult it is to clean a floor with a broom without bristles; you move only the large rocks but the dust is left behind. When the broom has too many very fine bristles the dust is collected but the rocks are left behind. But for a fractal broom having a fractal repartition of bristles of various rigidities, and various lengths, it is easy to collect the dust and the rocks at the same time. FPEC addition is particularly useful when a cleaning agent has to be used at the lowest possible concentration for a given effect. Studies by the University of Western Sydney show that the addition of FPEC, in quantities as small as 0.0125 %, to cleaning agents or solutions permits the reduction of the cleaning time by half.[12] In soaps and shampoo, the addition of FPEC permits the reduction of the cleaning agent fraction and the ability to accordingly increase other fractions. For example, the moisturizing agent content can be increased significantly without losing efficiency. The change of the geometry at the interface between the product and the skin facilitates an increase in the penetration rate of agents carried via the fractal polymer into the skin. With a small addition of fractal polymer, penetration time is often halved. FPEC is both hydrophilic and lipophilic. It can be used to carry and deliver agents both in water phase (i.e., water-soluble antioxidants like vitamin C) or in oil phase (i.e., vitamin D). The dual affinity for oil and water permits the use of FPEC as a stabilizing agent for emulsions of oil-in-water or water-in-oil.

19.5 Commercially Available Grades 19.5.1

Nomenclature Used

All fractal polymers manufactured by Steripak are covered by US Patent No. 6,001,889.[8] Please refer to the text of this patent for reference.

Figure 19.5 NaCl crystal embedded in FPEC.

The FPEC used in cosmetic/cosmeceutical applications are manufactured from highly crystalline poly (epsilon caprolactam) at a degree of polymer-

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ization greater than 120. They conform to the following FDA requirements (facilitating registration for some cosmeceutical applications): specific gravity, 1.15 ± 0.015, melting point, 392°F–446°F. The micelles of the crystalline pre-polymer are partially, or completely, unfolded before the formation of the fractal structure. The codification of the product is as follows (example only): FPEC - HD - 3 - (MA - T15)

19.5.2

Examples of Fractal Polymer Grades Available

FPEC HD3, HD7, and HD10. These solid forms of FPEC look like snowflakes (HD3), like finely divided flat flakes (HD7), or a powder (HD10) used to change the interface between the product and the skin and to deliver oil fractions in hydrophilic products or water-based fractions in water-based emulsions. The product is ready to be used as a support of the active molecules to be delivered and performs like a nanosponge.

The first two letters (either HD or LD) refer to the type of pre-polymer used, and define the density. The high-density polymers have greater resistance while the low-density polymers have shorter maximum length chains. Low-density polymers allow a smoother feel to the end product.

FPEC HD40 (MB – Ag10). This is a broadspectrum antiseptic additive used at low concentration as a bacterio-static agent or at higher concentration for topical antiseptic creams.

The third digit may vary from 2 to 100 (the classical values being: 3, 5, 7, 10, 40, 100). This number expresses the level of unfolding of the micelle before the synthesis in fractal form. A low value (i.e., 3 or 5) means that the micelle is only partially unfolded and the resulting fractal polymer will still contain a crystalline fraction. Such a polymer will be a solid with greater strength and relatively higher active surface area due to the rigidity of the structure.

FPEC LD10 (MB – Cu10). This is a delivery system for anti-aging preparation.

When the value of the digits after the HD or LD nomenclature is high (40 to 100), the fractal polymer is totally amorphous, liquid, with a lower active surface area (but still well in excess of 500 m2/g). The next two letters of the codification method express the type of linkage between the immobilized molecule and the fractal polymer. The third letter is a code for the molecule to be delivered and the last two digits represent the concentration. MA is a code meaning the molecule is stereospecifically attached to the fractal polymer (for example, by hydrogen bonding). In the present example, T is for the bactericidal agent, triclosan, and MA means that the molecule of triclosan is attached at the OH end and that the chlorine shell is fully exposed. MB is the code used when the molecule to be delivered is not stereo-specifically attached, but adsorbed. The last two digits represent the relative concentration (w/w) of the molecule to be delivered as expressed in parts per thousand of the caprolactam fraction.

FPEC HD7 (MA – T15). This is a specific antiseptic for association with other organo-chloride molecules in topical creams for skin disorder treatment.

Soap base: Sodium palmitate/sodium kernelate, glycerin 2%, honey solution 0.5%, (FPEC HD40 0.8%, lavender oil 1.5%). Formulation No. 3 (moisturizing cream): In this example macadamia oil is delivered through the fractal polymer by premixing these two ingredients together before complete formulation. The choice of a silver based FPEC permits bacterio-static properties for long shelf life. Ingredients: Purified water, vegetable glycerin, stearic acid, propylene glycol, cetyl alcohol, triethanolamine, then mixed with 3% of the emulsion of macadamia oil containing 5% FPEC HD40 (MB – Ag10).

19.6 Conclusion The application of fractal geometry to organic chemistry permits the manufacturing of fractal sponges having an ultrahigh surface area. These fractal molecular sponges have great affinity for both water-based and oil-based active ingredients. These ingredients remain so finely divided

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at their surface that their activity is significantly improved.

7. Frechet, J., Cornell University In Science (Aug. 25, 1995)

The fractal nature of the interface between the molecular sponge and the skin permits a more efficient delivery.

8. Lefebvre, M. S., US Patent No. 6,001,889, Polymer with Fractal Structure, (Dec. 1999); Australian Patent PN 5203 (Sep. 4, 1995) 9. Lefebvre. M. S., Fractal Membranes Technology, International Technology Symposium, Sydney, (Oct. 28, 1985)

19.7 Formulations These examples have been chosen only to illustrate the particular properties of FPEC as a delivery system in products where the effect is particularly noticeable. Formulation No. 1 (Soap): In this exfoliant soap we obtain delivery of macadamia oil as a moisturizer to the skin through the fractal polymer. The macadamia oil and the fractal polymer are separately mixed before addition as the last component on the hopper of the milling line. Soap base: Sodium palmate, sodium cocoate (may contain sodium kernelate), glycerin 1.5%, titanium oxide 0.2%, (FPEC HD3 1%, macadamia oil 0.5%).

10. Chaos in Australia, The University of New South Wales, 4–9 Feb; Chaos and Order, Australian National University 1–3 Feb; Ninth National Congress of the Australian Institute of Physics (Jan. 29–Feb. 2, 1990) University of Western Australia 11. Bioactive Polymeric Systems: An Overview, Plenum Press, New York (1985) 12. Nguyen, M. H., and Rai, R. P. D., Improvement of Membrane Cleaning Efficiency by Fractal Polymer in Food Processing, PO1/14, 10th World Congress of Food Science and Technology, Sydney (Oct. 3–8, 1999) 13. Ardoin, N., and Astruc, D., Molecular Trees: From Syntheses Towards Applications, Bull. Soc. Chim. Fr., 132:875–909, Elsevier, Paris (1995)

Formulation No. 2 (Soap): In this “beauty bar” we obtain delivery of the fragrance through the fractal polymer with a premixing of the oil and the FPEC.

14. De Gennes, P. G., and Hervet, H., J. Phys. Lett., 44:L-351 (1983)

References

16. Ottaviani, M. F., Cossu, E., Turro, N. J., and Tomalia, D. A., J. Am. Chem. Soc., 117:4387 (1995)

1. Gleick, J., Chaos, Penguin Books (1987) 2. Mandelbrot, B., The Fractal Geometry of Nature, Freeman, New York (1977) 3. Halmos, P. R., Nicholas Bourbaki, Scientific American, 196 (1957) 4. Mandelbrot, B, Les Objets Fractals, Flammarion, Paris (1975) 5. Sander, L. M., Fractal Growth Processes In Nature, Vol. 332 (Aug. 28, 1986) 6. Le Mehaute, A., Crepy, G., Introduction to Transfer & Motion In Fractal Media, Solid State Ionics, 9&10:17–30 (1983)

15. Tomalia, D. A., Naylor, A. N., and Goddard, W. A. III, Angew Chem., 102:119 (1990)

17. Bigger, J. W., and Griffiths, L. L., Brit. Med. Journal, ii/883 (1932) 18. Miranda, L. P, and Alewood, P. F., Proc. Nat. Acd. Sci., 96(4):1181–1186 (1999) 19. Turro, N. J., Barton, J. K., and Tomalia, D. A., Acc. Chem. Rec., 24:332 (1991) 20. Nivanen, L., Le Mehaute, A., Wang, Q. A., Reports of Mathematical Physics No. 3, Vol. 52 (2003) 21. Aksimentiev, A., and Holyst, R.,, Progress of Polymer Science, 24:1045–1093 (1999)

Part VII Emulsions Optimizing Skin Delivery of Active Ingredients in Emulsions: From Theory to Practice

EMULSIONS

Preparation of Stable, Double Emulsions as Delivery Vehicles for Consumer Care Products

The Delivery Systems' Delivery System

20 Optimizing Skin Delivery of Active Ingredients From Emulsions From Theory To Practice Johann W. Wiechers Uniqema Gouda, The Netherlands

20.1 Introduction ................................................................................... 410 20.2 The Principles of Skin Delivery ..................................................... 411 20.3 Measurement of Skin Penetration ................................................ 412 20.3.1 In-vitro Methods ................................................................. 412 20.3.2 In-vivo Methods ................................................................. 413 20.3.3 Animal Skin Versus Human Skin ...................................... 413 20.3.4 The Need for New Nondestructive Methods ..................... 414 20.4 Formulation Mapping .................................................................... 414 20.4.1 Selecting the Right Model Penetrants ............................... 414 20.4.2 Test Formulations ............................................................. 415 20.4.3 Skin Preparation ............................................................... 415 20.4.4 Diffusion Cells ................................................................... 416 20.4.5 Application of Formulations............................................... 416 20.4.6 Determination of Skin Penetration and Skin Distribution .. 416 20.4.7 Results ............................................................................. 416 20.5 The Importance of Ingredient Selection in Formulations for Dermal and Transdermal Delivery ................................................ 424 20.5.1 Theoretical Considerations ............................................... 424 20.5.2 The Relative Polarity Index (RPI) ...................................... 425 20.5.3 An Example of Using the RPI Concept ............................. 429 20.5.4 The Influence of the Emulsifier ......................................... 430 20.6 Conclusions .................................................................................. 431 20.7 Formulations ................................................................................. 433 Acknowledgments ................................................................................... 434 References .......................................................................................... 434 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 409–436 © 2005 William Andrew, Inc.

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20.1 Introduction In a book about Personal Care Delivery Systems, the first question that needs to be addressed is what “delivery” actually is. Delivery, in general, is defined as the process to insure that the right chemical entity (the active ingredient) reaches the right site (the site of action) at the right concentration (above the minimal effective concentration, but below a possible toxic concentration) for the right period of time (long enough to allow the chemical to do its work). All four R’s (right chemical, right site, right concentration, and right period of time) need to be met for the chemical to manifest its intrinsic activity. In the case of cosmetics, the general definition of delivery needs to be slightly adapted to accommodate the fact that the skin is the usual port of entry of chemicals into the body and therefore the target site is typically within the skin. One of the difficulties that one faces with topical delivery (i.e., delivery to any layer of the skin that is reached before the bloodstream) is the difficulty of measuring the concentration at the site of action. Most techniques quantify the amount of penetrating molecules in the skin as a whole but do not further specify delivery within the various skin

layers, the stratum corneum, viable epidermis, and dermis. None of these are executed as a function of time. In this chapter, the principles underpinning skin delivery as well as common ways of measuring skin penetration are first discussed. Thereafter, skin delivery as a function of the polarity of the penetrating molecule is described followed by the effect of formulation type. Finally, guidelines for the formulation of skin-delivery optimized vehicles are discussed. Before we start our journey through this chapter, let us first follow a penetrating molecule on its journey through skin; it will help us to become acquainted with the terminology of skin physiology. From the outside in, the skin comprises of three layers, the epidermis, the dermis, and the hypodermis. The epidermis is made up of five layers, starting with the stratum corneum (or horny layer) at the top, followed by the glossy layer, the granular layer, the spinous layer, and the basal layer (see Fig. 20.1). In the past, the stratum corneum was considered to be dead, so the other four layers are often referred to as the “viable” epidermis. Despite the fact that the cells in the stratum corneum no longer have cell nuclei, it is nowadays generally recognized

Stratum corneum Pore of sweat gland

Glossy layer Granular layer Spinous layer

Melanocyte

Basal layer

Collagen fiber

Nerve Figure 20.1 Schematic representation of human epidermis identifying the various layers that an active ingredient has to penetrate before reaching the systemic circulation in the dermal tissue. Collagen and nerves are located in the dermis and are not part of the epidermis. (Reprinted with permission from Courage and Khazaka, Cologne, Germany.)

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS that there is still considerable biochemical activity within them, but this has not changed the definition of the viable epidermis. The major difference between the stratum corneum and the viable epidermis relevant in the context of skin delivery is the polarity of these two layers. While the stratum corneum is predominantly lipophilic in nature, the viable epidermis is predominantly hydrophilic. The consequences of these few physiological observations are enormous for our penetrating active ingredient. It is incorporated in the formulation in which it needs to diffuse to the boundary that is in contact with the skin. The first potential problem that our active material encounters is that the viscosity of the formulation may be too high for the chemical to reach even the skin surface. Once this hurdle is cleared, the active will need to partition into the top layer of the skin, also known as the stratum corneum. This predominantly lipophilic layer of only fifteen micrometers thickness constitutes the main barrier for the diffusion of most chemicals. How much active ingredient will partition into the stratum corneum will depend on its solubility in the stratum corneum and its formulation, respectively. It is essential to realize that the term partitioning always describes an equilibrium over two layers of different polarities, whereas diffusion characterizes a transport process within a layer of a single polarity. Our active ingredient first partitions from the formulation into the stratum corneum in which it subsequently diffuses to the deeper end of this layer. Here it partitions into, and then diffuses through, the much more polar glossy, granular, spinous, and basal layers. These can be grouped together as they have basically the same polarity and our penetrating molecule therefore encounters no additional partition barriers. When it has reached the bottom of the granular layer, it moves without too much difficulty into the next layer, the dermis, where it may meet nerve endings and blood vessels for the first time. Once it is taken up in the bloodstream, our active ingredient reaches the heart and, after that, the rest of the body. Once delivery to the dermis has taken place, the active ingredient is therefore considered to be delivered systemically. The times, if they ever existed, that cosmetic ingredients did not penetrate the skin are definitely over. As we will see below, skin delivery depends on the physicochemical characteristics of the pen-

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etrant and, to a lesser extent, on the formulation in which it is incorporated. Skin delivery does not depend on the claim that is being made on the label.

20.2 The Principles of Skin Delivery One of the main functions of the stratum corneum is to act as a diffusion barrier for chemicals entering the skin.[1] Considering the physical thickness of the stratum corneum, a multiple cell layer of only fifteen micrometers, this barrier does a remarkable job in protecting us. The barrier function of the stratum corneum is regulated by the composition, quantities, and packing of individual skin lipids.[2] The orthorhombic packing of these lipids results in an effective barrier having a low permeability. Fick’s law of diffusion defines the flux, J, of chemicals passing through the stratum corneum as:

(Eq. 20.1)

J = k p ⋅ ∆C =

K ⋅D ⋅ ∆C L

In Eq. 20.1, kp is the permeability coefficient, ∆C the concentration gradient over the stratum corneum, K is the octanol/water partition coefficient, D the diffusivity, and L is the length of the diffusion pathway of the penetrating molecule. In order to increase the flux of actives through the stratum corneum, the concentration gradient needs to be as high as possible. Thus, a high concentration of chemical is required in the top layers of the stratum corneum and a low concentration is required at the deeper layers. In order to produce a high concentration in the topmost layers, the solubility of the penetrating molecule in those top layers needs to be high. To fulfill the requirement for a low concentration in the deeper layers of the stratum corneum, the active must have a high solubility in the viable epidermis. Because the stratum corneum and the viable epidermis are contradictory in polarity (the stratum corneum is predominantly lipophilic in nature, and the viable epidermis is hydrophilic), both requirements cannot be met at the same time. It is via a series of such contradictions that the stratum corneum acts as such an excellent barrier to skin penetration.

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The counterbalance phenomenon described above would appear to suggest that not a single chemical can penetrate the skin. However, this is— fortunately for us—not true. Chemicals that have a modest solubility in both lipids and water can, indeed, penetrate the skin. Their permeability, kp, is generally characterized and determined by both their diffusivity and octanol/water partition coefficient. Potts and Guy expressed the molecular basis for skin permeability in a formula that describes the relationship between the molecular characteristics of a penetrating molecule and its physicochemical characteristics:[3] (Eq. 20.2) log k p (cm/s) = − 6.3 + 0.71log K oct/water − 0.0061 ⋅ MW

At about the same time that Eq. 20.2 was proposed, Barratt derived a similar formula covering a wider range of polarities of skin penetrants:[4] (Eq. 20.3) log k p (cm/h) = − 2.355 + 0.820 ⋅ log K oct/water − 0.00933 ⋅ MW − 0.00387 ⋅ mpt

in which mpt is the melting point of the penetrating chemical. From both formulae, it can be seen that the octanol/water partition coefficient, log Koct/water, is more important in determining skin permeability than the molecular weight, MW, or the molecular volume, MV. The more lipophilic a chemical is, the faster it will permeate through the stratum corneum, whereas the bigger it is, the slower it will penetrate. In order to assess the influence of formulation type on skin delivery of chemicals, we performed a large series of experiments in which the skin delivery of four different penetrants were evaluated. These penetrants spanned a large range of polarity. They were all delivered from five different formulation types: an aqueous gel, an o/w-emulsion, a w/o-emulsion, an o/w-microemulsion, and a neat oil.

20.3 Measurement of Skin Penetration The permeability of chemicals into and through skin can be measured in various ways, and to understand what will follow, some basic principles of measuring skin absorption are first described. These range from in-vitro and in-vivo methods to the differences between animal and human skin regarding skin penetration. Some thoughts for the requirements of new techniques for the assessment of dermal delivery are discussed at the end of this section.

20.3.1 In-vitro Methods Most skin penetration work is done in in-vitro setups. These use either the static Franz diffusion cell[5] or the Bronaugh flow-through cell.[6] In both of these techniques, a piece of skin is placed in the skin penetration cell and a receptor fluid is placed underneath the skin in contact with the tissue. Either all the receptor fluid is collected continuously (Bronaugh flow-through cells) or samples thereof are taken periodically (Franz diffusion cells). Bronaugh flow-through cells have a much smaller receptor compartment, so the time delay between the moment that an active ingredient reaches the receptor compartment and when it is being sampled is as short as possible (see Fig. 20.2). It has been shown experimentally that the volume of the receptor compartment needs to be replaced at least roughly seven times per hour for concentration buildup in this compartment not to create a problem.[7] As receptor fluid flow-rates are typically 1 ml/hr, the volume of the receptor compartment should therefore be 143 µl or smaller (1 ml/hr ÷ 7 replacements/hr). Increasing the flow, or inserting small glass beads or magnetic stirrers, may help to insure that a sufficient replacement factor (i.e., flow rate ÷ receptor compartment volume) is achieved. In Franz diffusion cells, where the liquid in the receptor compartment is not replaced, the receptor volumes are deliberately large in order to avoid the buildup of a significant concentration of the active ingredient in the receptor compartment. This buildup would undesirably reduce transdermal skin penetration because it reduces the concentration

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS gradient over the skin and creates an artifact that distorts the test results. The consequences of such buildup is reduction in skin penetration. It is often asked whether the use of Franz or Bronaugh diffusion cells makes any difference at all. Having worked with both of them, I do not really favor one above the other. However, analytical capabilities available for determination of active ingredient levels may constitute a good argument for selecting the Bronaugh cell over the Franz cell. Receptor fluid samples from the latter cell type tend to have lower levels of active ingredient because of the larger receptor compartment and, if the sensitivity of the analytical method is too low, the use of Bronaugh cells may be recommended. Moreover, because the Bronaugh flow-through cell system is used in combination with a fraction collector, samples can be collected throughout the night. More recent models of the Franz diffusion cell system, however, also allow for automatic sampling.

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One of the mistakes often made in in-vitro skin penetration studies is to express the results as a percentage of the dose applied. This is misleading because skin penetration increases with the concentration of the active ingredient in the formulation until a certain concentration is reached. Thereafter, skin penetration remains constant even if higher levels are employed. Above this “critical” level, the percentage penetration decreases whereas the “absolute” penetration remains constant. Therefore, transdermal flux results should always be expressed as µg/cm2·hr or µg/cm2 and dermal delivery results expressed as µg/cm2. If the exact volume is known, dermal delivery may also be expressed as a concentration in µg/cm3.

20.3.2

In-vivo Methods

In in-vivo skin absorption studies, an active ingredient is applied onto the skin of volunteers and the extent of skin penetration is assessed by determining the active ingredient in various biosamples. Under very strict conditions, the use of 14C- or 3Hlabelled tracer molecules is allowed. These tracers facilitate the analysis of penetrated and non-penetrated material. Skin penetration is the sum of the amounts of active ingredient retrieved in tape strips (levels in the superficial layers of the stratum corneum), urine, feces, sweat, and expired air. The applied dose and the non-absorbed dose should also be determined as this allows the calculation of the socalled total recovery (the sum of all the samples relative to the applied dose).[8] Such values should ideally be between 95% and 102% of the applied dose in order to be seen as reliable. The main problems of in-vivo studies are the high cost and the low concentrations of active ingredients that must be measured. This difficulty is a result of the large volumes that are excreted. Of course, the results have far more relevance than those of in-vitro studies.

20.3.3 Animal Skin Versus Human Skin

Figure 20.2 Schematic picture of a flow-through cell used for in-vitro skin penetration studies.

It is foreseeable that for best reliability, results obtained on human skin will be of more relevance than those obtained on animal skin. In cosmetics,

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most products are applied on healthy skin but care should be taken to use parts of the human body on which the product will ultimately be applied. This is important because skin permeability varies with body site. Examples of the more permeable sites are the scrotum and the ear lobe.[9] The face is a part of the human body to which cosmetic products are frequently applied but it should be realized that skin permeability even varies within the face. Distante, et al., recently described this indirectly when she reported the site-variance of transepidermal water loss (TEWL) values on the face.[10] If there is no other choice than to use animal skin, the use of pigskin is strongly recommended. Of all species, the structure and characteristics of pigskin are most similar to that of human skin. Historically, skin penetration experiments have predominantly used rat or rabbit skin. When using such data, it should be realized that rodent skin is about a factor of four more permeable than human skin. This, however, may change considerably as a function of the chemical being tested.[11]

proved, it could be used as a screening method for cosmetic formulations in-vivo, on the relevant application sites, and under realistic conditions. This enhanced technique would greatly help in the development of new, truly active cosmetic products and assessment of their efficacy.

20.4 Formulation Mapping 20.4.1

Selecting the Right Model Penetrants

In order to assess the influence of formulation type on skin delivery, it is essential to conduct such testing as a function of the polarity of the penetrant since the characteristics of the penetrant are very important in determining overall penetration (see Eqs. 20.2 and 20.3). Ideal physicochemical characteristics of chemicals for skin penetration are: • Good solubility in both water and lipids • Low molecular weight and volume

20.3.4 The Need for New Nondestructive Methods The use of in-vitro cells allows a determination of transdermal delivery in a nondestructive way and this can, therefore, be monitored continuously with time. Determining dermal delivery per se is not more difficult but, unfortunately, it is a destructive method. After all, the skin needs to be extracted or dissolved in order to allow determination of the amount of active ingredient within the dermal layers. In order to study this more extensively as a function of formulation, time, and concentration, new innovative techniques to assess dermal delivery need to be developed that are nondestructive. If such tests could be performed in-vivo, this would approach the holy grail of skin-penetration testing. Whereas the previously proposed methods of confocal fluorescence spectroscopy[12] and cutaneous microdialysis[13][14] were, in fact, still somewhat invasive, the recently described confocal Raman microspectroscopy technique[15] may truly be a significant step in the right direction towards the design of new skin delivery systems that allow continuous quantification of dermal delivery. Once the resolution of this technique has been im-

• Low melting point (i.e., below the temperature of the skin, 32°C) • Little or no binding or accumulation in the stratum corneum The following chemicals were selected as model penetrants. These cover a wide range of polarity. Ideally all materials tested have the same molecular weight and are non-ionizable. These include 5-fluorouracil (5-FU), hydrocortisone (HC), testosterone (Test), and ketoconazole (KC). Details of their physicochemical parameters can be found in Table 20.1. Calculated (MacLogP2.0, BioByte) values of the octanol/water partition coefficients (log Koct/water) are also shown and indicate the increasing lipophilicity of the compounds. The quoted literature values for permeability coefficients of the individual materials are taken from recent publications. The pattern in the measured permeability coefficients (all from saturated aqueous solutions) is a clear reflection of the physicochemical properties of the compounds. No literature value for the permeability coefficient of ketoconazole was found. Permeability coefficients were therefore also calculated using the Potts-Guy equation given in Eq. 20.2.[3]

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Table 20.1. Physicochemical Parameters of Four Model Skin Penetrants Covering a Large Polarity Range

Category

Penetrant

Log Koct/water

Molecular Weight

kp (expt) (cm/hr)

kp (calc) (cm/hr)

Hydrophilic

5-Fluorouracil

-0.97

130.1

9.6 × 10-5 [16]

5.9 × 10-5

Medium Polarity

Hydrocortisone

0.54

362.5

2.3 × 10-4 [17]

2.7 × 10-5

Lipophilic

Testosterone

3.22

288.4

2.2 × 10-3 [17]

6.1 × 10-3

Very Lipophilic

Ketoconazole

4.34

532

-

1.2 × 10-3

The observed discrepancy between the calculated and literature kp values for hydrocortisone deserves some attention. There is considerable confusion in the literature concerning the experimental value of kp for hydrocortisone. It has been reported as 1.2 × 10-4, 2.3 × 10-4, and 3.0 × 10-6 cm/hr.[17][18] In this respect, and together with the lack of experimental data for ketoconazole, the predicted values may give a clearer indication of the amount that each chemical will permeate skin. From these predictions, testosterone appears to be the most rapid penetrant, while hydrocortisone appears to be the least rapid. The data shown in Table 20.1 demonstrate that the selected model compounds are suitable in both their breadth of physicochemical properties and their intrinsic permeabilities for the purpose of this study.

20.4.2

Test Formulations

Five formulations (all at 1.0% w/w) were prepared for each penetrant: an aqueous gel, a w/oemulsion, an o/w-emulsion, a microemulsion, and an oil-based formulation. Each formulation type was prepared in the same way for all penetrants with the exception of ketoconazole which required the addition of an antioxidant (sodium sulphite or di-α-tocopherol) in order to prevent otherwise rapid discoloration. All batch sizes were 10.0 gram and contained 1 mCi. The Curie (Ci) is the SI unit of radioactive decay; the quantity of any radioactive nuclide which undergoes 3.7 × 1010 disintegrations per second (or Bq, Becquerel). Radiolabelled (3H) penetrants were purchased from NEN (New England Nuclear, Boston, MA, USA) (5-[6-3H] fluorouracil; [1,2,6,7-3H(N)]-hydrocortisone and [1,2,6,7-3H(N)]testosterone) or custom synthesized by Amersham

Pharmacia Biotech (Little Chalfont, Buckinghamshire, England, UK; [3H]-ketoconazole). The specific activity of the penetrating molecules was 12.5, 84, 96.5, and 4.0 Ci/mmol for 5-fluorouracil, hydrocortisone, testosterone, and ketoconazole, respectively. The radiochemical purity was greater than 97% for all radiochemicals. The radiolabel content and uniformity of dispersion of the penetrants in the formulations was determined by sampling the formulations three times (from the top, middle, and bottom of the container), solubilizing the samples, and liquid scintillation counting. The target radioactivity content was 0.1 µCi/mg of formulation and varied from 0.092 to 0.1271 µCi/mg (mean: 0.106 µCi/mg; median: 0.105 µCi/mg). The content uniformity (expressed in terms of the coefficient of variation in the mean of the three samples) was good, ranging from 0.60% to 4.01% (mean: 1.26%; median: 0.98%).

20.4.3

Skin Preparation

Full-thickness human female skin (breast or abdominal), obtained from frozen sections taken during cosmetic surgery and stored at –20°C, was thawed for processing. Following removal of the subcutaneous fat by blunt dissection, individual portions of skin were immersed in water at 60°C for 45 seconds. The skin was then pinned, dermal side down, on a corkboard. and the epidermis (comprising stratum corneum and viable epidermis) was gently removed from the underlying dermis. The latter was discarded and the epidermal membrane floated onto the surface of water and taken up onto aluminum foil. The membranes were then thoroughly dried and stored at –20°C until used.

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On the day of use, the epidermal membranes were floated onto water from the aluminum foil, taken up onto filter paper supports and trimmed to size. The membranes were then mounted onto diffusion cells. Three different individual donors were used for each penetrant.

cm2 for each formulation. The formulations were applied under non-occlusive conditions. The time of application was recorded and that represented time zero for the run.

20.4.6 20.4.4 Diffusion Cells The skin samples were mounted as a barrier between the halves of horizontal Franz diffusion cells with the stratum corneum facing the donor chamber. The cells were designed such that the area available for diffusion was about 1.0 cm2, the exact area being measured for each diffusion cell. The diffusion cells were immersed in a constant temperature water bath such that the receptor chambers were maintained at 37.0°C ± 0.5°C throughout the experiment. This insured that the skin surface temperature was maintained at 32°C ± 1°C. The receptor chamber contents were continuously agitated by small PTFE-coated magnetic followers driven by submersible magnetic stirrers. The receptor chambers of the diffusion cells were filled with a known volume of either pH 7.4 phosphate-buffered saline (for 5-fluorouracil and hydrocortisone) or 25% ethanol in pH 7.4 phosphatebuffered saline (for testosterone and ketoconazole). These were then capped and allowed to equilibrate to the correct temperature. Twenty-five percent ethanol in pH 7.4 phosphate-buffered saline receptor phase has been shown to not affect the permeability of human skin and to be a good solubilizing agent for lipophilic compounds.[19] On average, fourteen cells were used per formulation for the determination of the penetration; exact numbers ranged from twelve to eighteen.

20.4.5

Determination of Skin Penetration and Skin Distribution

Following application of the formulations, 200 µl samples were taken (using a digital pipette) from each receptor chamber at 2, 4, 8, 24, and 48 hours, and the liquid was then replaced with fresh receptor medium. The level of radioactivity was assessed in each sample by liquid scintillation counting. After removal of the 48-hour receptor phase sample, the surface of the skin in each cell was wiped with a cotton bud in order to remove any remaining formulation. The material was then extracted from the cotton bud and the level of radioactivity assessed. The donor chambers of the diffusion cells were thereafter rinsed with fresh receptor fluid (using eight 0.5ml aliquots), the first five aliquots for each cell being combined and a sample from each assessed for radioactivity content. The remaining three washes for each cells were added separately to scintillation fluid and the level of radioactivity assessed by liquid scintillation counting in order to assess the efficiency of the washing procedure. The diffusion cells were then dismantled and the donor chambers rinsed with one milliliter of industrial methylated spirit, and samples were counted by liquid scintillation counting. Each skin sample was then attached, stratum corneum side up, to a thin section of plastic card and adhered using cyanoacrylate glue. The stratum corneum was then tapestripped ten times using D-squame. Each tape strip was solubilized and the level of radioactivity determined by liquid scintillation counting. This technique allowed a full-mass balance for each experiment.

Application of Formulations

A glass rod was weighed and tared on an electronic balance sensitive to 0.01 mg. A small amount of formulation was placed on the end of the glass rod and the weight of formulation noted. The formulation was then spread evenly over the stratum corneum surface. The rod was then reweighed to indicate the exact amount of formulation applied to the skin surface. The target application was 2 mg/

20.4.7 Results The results obtained from this study can be analyzed in two different ways. The first approach provides information as a function of the penetrating molecule while the second provides information as a function of formulation. First, transdermal delivery

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS is examined in these two different ways. Thereafter, the same approach is carried out and described for dermal delivery. Of these, only transdermal delivery as a function of the polarity of the penetrating molecule is reasonably well understood, as demonstrated by the formulae of Potts-Guy[3] and Barratt.[4]

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applied represented “infinite” dosing. The transdermal penetration of testosterone was observed to be significantly higher than that of the other three chemicals: testosterone >> 5-fluorouracil > hydrocortisone > ketoconazole. Formulations were subsequently ranked for their transdermal penetration; testosterone being first, 5-fluorouracil being second, hydrocortisone being third and, finally, ketoconazole being fourth. If the difference between two formulations was not statistically significant at the p = 0.05 level, these two formulations received the same ranking, with their exact number depending upon how close they were to the next formulation. In other words, if, in the example shown in Fig. 20.3, the skin penetration of 5-fluorouracil and hydrocortisone had been the same, they would have been ranked on a shared third place as they are both much closer to the ketoconazole formulation ranked fourth than the testosterone formulation ranked first. The result of this analysis is listed in Table 20.2.

Transdermal delivery as a function of the polarity of the penetrant. As an example, Fig. 20.3 illustrates the cumulative transdermal delivery as a function of time of a series of different chemicals from a w/o emulsion. As seen from Fig. 20.3, steady-state diffusion was reached for all penetrants and none of the skin penetration profiles showed signs of depletion. This result suggests that the quantities of formulations

In Table 20.2, it can be easily observed that irrespective of formulation, testosterone is always the best penetrating molecule. This is an important finding since it shows that the physicochemical characteristics of a penetrating molecule are more important in determining skin penetration than the formulation in which it is incorporated. Based on the formulae developed by Potts and Guy[3] and Barratt,[4] this should also be the case as listed under “predicted” values. It should be noted that these predictions assume delivery from saturated systems at a thermodynamic activity of 1, whereas this was not the case for 5-fluorouracil from the aqueous gel and

Figure 20.3 Transdermal penetration (expressed as percentage of applied dose) of four chemicals with different polarities from w/o formulations.

Table 20.2. Transdermal Penetration* of Chemicals with Different Polarities (Ranked by Penetrant)

Penetrant Formulation

Hydrophilic (5-fluorouracil)

Medium Polarity (hydrocortisone)

Lipophilic (testosterone)

Very lipophilic (ketoconazole)

Gel

3

3

1

4

w/o

2

3

1

4

o/w

3

4

1

2

Microemulsion

2

3

1

4

Oil

2

3

1

3

Predicted

3

4

1

2

* The molecule with the highest penetration has been given the score of 1, whereas that with the lowest penetration received the score of 4.

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for testosterone and ketoconazole from the oils. Especially ketoconazole in the oil formulation had a much lower thermodynamic activity, which might explain the small discrepancy between predicted and experimentally obtained values. These reflections certainly indicate that transdermal penetration of molecules is generally well understood and can be predicted by theory.

By contrast to the results obtained in Table 20.2, the situation is less clear here. Microemulsions are observed to often deliver more of the active ingredient than the other formulation types. This phenomenon can be explained by the high amounts of surfactant used to stabilize these emulsions. Surfactants can influence the diffusivity of penetrating molecules by acting as skin penetration enhancers.[9][20] However, there is evidence in the literature that surfactant-like enhancers seem to perform less well for highly lipophilic molecules like ketoconazole.[20][21]

Transdermal delivery as a function of formulation. The same data that was used for composing Table 20.2 was this time grouped per penetrating molecule, thereby allowing differences between formulations to be studied. Results are shown in Fig. 20.4 and Table 20.3 in a format similar to the previous analysis.

It is also interesting to note that w/o emulsions and o/w emulsions on average perform equally well. This is in contrast to what is generally assumed, namely that the presence of penetrating molecules in the outer phase of the emulsion enhances penetration. The only difference between the w/o and o/w emulsions studied can be found for ketoconazole, where the presence of the highly lipophilic molecule in the internal phase of the emulsion seems to enhance penetration. It can therefore be concluded that there is no evidence for this assumption in this dataset. As with the predicted values discussed above, the results are not always in complete agreement with what skin penetration theory would predict. For example, the thermodynamic activity of ketoconazole in the oil formulation is the lowest of all, whereas ketoconazole penetration from the oil and o/w formulations was, unexpectedly based on theory, the highest.

Figure 20.4 Transdermal penetration of 5-fluorouracil (expressed as percentage of applied dose) from five different types of formulation.

A final observation from this dataset is that the gels delivered active ingredients consistently at the

Table 20.3. Transdermal Penetration* of Chemicals with Different Polarities (Ranked by Formulation)

Penetrant Formulation

Hydrophilic (5-fluorouracil)

Medium Polarity (hydrocortisone)

Lipophilic (testosterone)

Very Lipophilic (ketoconazole)

Gel

5

3

5

5

w/o

3

3

2

4

o/w

3

3

3

1

Microemulsion

1

1

1

3

Oil

2

1

4

1

* The molecule with the highest penetration has been given the score of 1, whereas that with the lowest penetration received the score of 4.

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS lowest levels. This is of interest since many topical products have been formulated as gels. This seems logical as the intention of topical products is to deliver the active ingredient topically (i.e., into any layer of the skin prior to the bloodstream) and transdermal delivery (representing systemic delivery) is therefore beyond the site of action as discussed in the “Introduction” (Sec. 20.1). Dermal delivery as a function of the polarity of the penetrant. Skin penetration experiments were conducted for a total of forty-eight hours, after which the skin was thoroughly washed and subsequently tape-stripped ten times. All samples, including the remainder of the skin, were analyzed for their radioactivity content. Dermal delivery has been defined as the amounts retrieved in strips 2–10 and the remainder of the skin. The first strip is typically considered to contain residual surface material and was therefore not included in the dermal delivery. As before, for the transdermal delivery, dermal delivery was studied as a function of the polarity of the penetrant. As an example, the percentages delivered dermally from oil formulations are displayed in Fig. 20.5, whereas Table 20.4 provides the ranking of dermal delivery data when all data of all formulations are combined. Although the polarity of the four penetrants is not expressed by their octanol/water partition coefficients in Fig. 20.5, the emergence of a hyperbolic shape for the dermal delivery of these penetrants from an oil formulation can be recognized. This trend seems to be consistent when all data is included. The data given in Table 20.4 suggest that penetrants with a more extreme polarity are retained in the skin more than chemicals with an average polarity. Interestingly, exactly the opposite is true for transdermal penetration; namely, penetrants with an intermediate polarity will penetrate better than penetrants with a more extreme polarity (see Fig. 20.6).

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stratum corneum than 5-fluorouracil, hydrocortisone, and testosterone. There is an almost linear decrease in stratum corneum concentration of ketoconazole whereas the profile for 5-fluorouracil is almost flat. Differences in water stratum corneum profiles have recently been linked to the location of the barrier.[23] If this hypothesis can be extended to molecules other than water, a gradual decline indicates that there would be a continuous barrier in the stratum corneum for ketoconazole, manifesting itself predominantly in the diffusion coefficient. For 5-fluorouracil, however, there would be a sudden barrier in the form of a sudden change in polarity. This would prevent the chemical from penetrating initially but, thereafter would suggest the presence of only a minimal barrier for diffusion through the stratum corneum. Dermal delivery as a function of formulation. The same data discussed above is now grouped per penetrant and yields a rather complex situation. Figure 20.8 illustrates the skin distribution profiles of all ketoconazole-containing formulations showing the gradual decline discussed above. No clear relationships were observed between the amount of ketoconazole in the stratum corneum and, for instance, the amount of oil in the formulation. When comparing all data of the same penetrant from all formulations as, for instance, for hydrocortisone, in Fig. 20.9, it is interesting to note that the general profiles are more or less the same (i.e., high, medium, or low amounts in strip 1 matched with high, medium, or low amounts in strips 2–10 and high, medium, or low amounts in the remainder of the skin) but to a far lesser extent in the transdermal receptor fraction.

This suggests that dermal and transdermal delivery are inversely correlated. Whether this is really the case is discussed later in this chapter in the subsection entitled “Predicting dermal delivery: Are transdermal and dermal delivery inversely correlated?” Figure 20.7 illustrates the stratum corneum profiles from the various molecules that were obtained from tape strips 2–10 for microemulsions. The microemulsions delivered more ketoconazole into the

Figure 20.5 Dermal penetration of four chemicals with different polarities (expressed as percentage of applied dose) from an oil formulation.

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Table 20.4. Transdermal Penetration* of Chemicals with Different Polarities (Ranked by Penetrant)

Penetrant Formulation

Hydrophilic 5-fluorouracil

Medium Polarity (hydrocortisone)

Lipophilic (testosterone)

Very lipophilic (ketoconazole)

Gel

1

3

4

2

w/o

1

2

4

3

o/w

2

4

1

2

Microemulsion

2

4

3

1

Oil

1

3

4

2

* The molecule with the highest penetration has been given the score of 1, whereas that with the lowest penetration received the score of 4.

Figure 20.6 Transdermal and dermal penetration as a function of polarity of the penetrating molecule (expressed by its octanol/water partition coefficient).

Figure 20.7 Stratum corneum distribution of penetrants in tape strips 2–10 after delivery from microemulsions.

Figure 20.8 Stratum corneum distribution of penetrants in tape strips 2–10 after delivery from five different formulation types.

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are formulated as gels. This suggests that gels are not the best formulation types for such preparations. Predicting dermal delivery: Are transdermal and dermal delivery inversely correlated? As suggested in Fig. 20.6, there may be an inverse relationship between transdermal and dermal delivery. If this were true, a simple conversion of Eqs. 20.2 and 20.3 might suffice to predict dermal delivery based on physicochemical properties. Principal component analysis (PCA) is a very suitable technique to identify the existence of linear relationships in complex datasets. Although initially difficult to understand for those not familiar with this statistical techFigure 20.9 Distribution of hydrocortisone between tape strips, nique, it is gradually being accepted remaining skin (skin), and the receptor phase. in cosmetic science where it is particularly useful in the area of sensory science.[23][24] All experimental and physicoWhen dermal delivery, expressed as the amount chemical data (transdermal delivery, dermal deof penetrant retrieved in strips 2–10 and the remainlivery, formulation type, molecular weight, and poder of the skin, was plotted as a function of the larity of the penetrant) were pooled and subjected amount of oil in the formulation (a substitute for the to this analysis. The latter two parameters were in“polarity” of the formulation), a rather confused piccluded since Eqs 20.2 and 20.3 already indicated ture emerges which illustrates the complexity of these are very important factors in determining transdermal delivery of chemicals from formulations (see dermal delivery. Fig. 20.10). This complexity is also illustrated in Table 20.5 where no clear relationships between the polarity of a penetrant and dermal delivery from a given formulation can be observed. Despite this confusion, some interesting observations can be made. First, while transdermal delivery from the microemulsions was consistently high, its dermal delivery was variable. Second, while o/w and w/o emulsions performed roughly equally well for transdermal delivery (see Table 20.3), in dermal delivery they were opposite in nature, clearly favoring the presence of the penetrating molecule in the internal oil or water phase. Finally, gels performed average (i.e., the scores were mainly 3) but consistently. Figure 20.10 Dermal delivery of 5-fluorouracil as a function of the This is of interest since many nonsteroiamount of oil contained in various formulations, a substitute for dal anti-inflammatory drugs (NSAID’s) the polarity of the various formulations.

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Table 20.5. Transdermal Penetration* of Chemicals with Different Polarities (Ranked by Formulation)

Penetrant Formulation

Hydrophilic (5-fluorouracil)

Medium Polarity (hydrocortisone)

Lipophilic (testosterone)

Very Lipophilic (ketoconazole)

Gel

3

2

3

3

w/o

2

1

5

5

o/w

5

5

1

3

Microemulsion

4

4

2

1

Oil

1

3

3

1

* The molecule with the highest penetration has been given the score of 1, whereas that with the lowest penetration received the score of 4.

The output of the PCA analysis is shown in a loading plot in Fig. 20.11 and two score plots in Fig. 20.12. In short, in PCA plots, the position of a loading, or a score, is very important. If two vectors (for the sake of argument: molecular weight and log P) are positioned closely together, they are strongly positively correlated (i.e., if the molecular weight increases, then the log P also increases). If they are mirrored in the origin, then the two are strongly nega-

tively correlated (i.e., if the molecular weight increases, the log P decreases). If the two vectors are positioned under a 90° angle, there is no correlation at all between the two vectors. Figure 20.11 illustrates that log P and MW, the log octanol/water partition coefficient and molecular weight, respectively, are strongly positively correlated. However, it is also seen that transdermal delivery decreases with increasing molecular weight

Figure 20.11 PCA loading plot of the parameters used. Delivery data were log transformed; “log(48h)” stands for transdermal and “log(dermal)” for dermal delivery.

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Figure 20.12 PCA score plot of the delivery data. Top: Scores identified by their chemical structure. Note that they are all groups per chemical. Bottom: Scores identified by the formulation type.

and penetrant solubility in octanol. It must be stressed that the latter inverse relationship is very weak, and certainly is not as apparent as the strong relationships described by Eqs. 20.2 and 20.3. This anomaly may be due to the small size of the dataset (only 4 polarities). The fact that the vectors representing dermal and transdermal penetration are roughly under a 90° angle indicates that dermal and transder-

mal delivery are not correlated at all, and therefore not inversely correlated as suggested by Fig. 20.6. This is in line with the few indirect remarks that could be found in the literature about such a possible correlation. Kumar found no apparent relationship between skin permeability and skin retention in her penetration studies.[26] These two parameters represent transdermal and dermal penetration, respectively.

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The information that can be obtained from Fig. 20.12 is very revealing. Taking all information together, the physicochemical characteristics of the penetrant are more important in determining delivery (that is both transdermal and dermal) than the formulation type in which it is formulated. This can be concluded from the fact that all delivery scores can be grouped by the chemical (Fig. 20.12, top), but not by the formulation (Fig. 20.12, bottom). This means that formulations cannot help to improve the penetration of a molecule that does not have the right physicochemical characteristics to penetrate the skin anyway. In such situations, other means of enhancing skin penetration, such as iontophoresis, skin penetration enhancers, ultrasound, etc., may prove to be useful. The rest of this book deals with other cosmetic delivery systems such as encapsulating technologies. The reader should remember that, unless these systems will affect the skin barrier in one way or another, for example, via iontophoresis, skin penetration enhancers, ultrasound, etc., such delivery systems may assist in insuring the deposition of cosmetic ingredients on the skin but not enhance the skin delivery of many active ingredients into the skin. After all, one of the four R’s in the definition of skin delivery is to reach the right site of action in the skin, and not to retard its ability to penetrate from the skin surface before it can even reach its site of action. The approach outlined in this section offers guidance in the selection of the formulation type once the cosmetic active ingredient and, therefore, its physicochemical characteristics are fixed. Depending upon the site of delivery, dermal or transdermal, Table 20.5 or 20.3 can be used as a guide to select the appropriate type of formulation.

mulations described above in Sec. 20.4, “Formulation Mapping,” were aimed to be of constant thermodynamic activity. However, while they all contained different ingredients among the various formulation types, they were designed to be similar within a given formulation type. In daily practice, the cosmetic formulator cannot change the chemistry of the active molecule that needs to penetrate to a specific site within the skin. However, the formulation type can be selected based on the polarity of the active ingredient and the desired site of action for the active ingredient. Such selections may be made via use of Table 20.3 for transdermal delivery and Table 20.5 for dermal delivery. Once all of this has been done, the next question is “how does one select the right ingredients to formulate an emulsion with optimized delivery?” This section offers a systematic approach to selecting the right emollients which can greatly influence the overall quantity of active ingredient that penetrates the skin.

20.5.1

Theoretical Considerations

Equation 20.1 states that the flux of material into the skin increases when increasing the concentration gradient over the skin. In order to have the greatest possible concentration gradient, the active ingredient should be present at saturation level in the formulation and immediately be removed at the deeper end of the stratum corneum. However, at the same time, the K in Eq. 20.1 can be rewritten as: (Eq. 20.4)

K sc/formulation =

20.5 The Importance of Ingredient Selection in Formulations for Dermal and Transdermal Delivery Given the fact that the physicochemical characteristics of the penetrant determine its skin delivery to a far greater extent than the formulation type, one can ask “how can ingredient selection in the formulation still influence the dermal and transdermal delivery of the cosmetic active ingredient?” All for-

C penetrant in stratum corneum C penetrant in formulation

and this K also needs to be as large as possible. To achieve this, the solubility of the penetrating molecule in the stratum corneum needs to be as high as possible and the solubility in the formulation needs to be as low as possible. If we are dealing with multiphase systems like emulsions as the delivery systems, the solubility in the phase in which the active ingredient is solubilized should be taken as the solubility in the formulation and not the overall concentration. Therefore, for optimal skin delivery the solu-

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS bility of the active ingredient needs to be as high as possible (to create a large concentration gradient, ∆C) and as small as possible (to create a large K). How can one solve this dilemma? The formulation determines the following parameters: • The total amount dissolved in the formulation that is available for skin penetration; the higher this amount, the more will penetrate until a saturation concentration is reached in the skin, therefore a high absolute solubility in the formulation is required. • The polarity of the formulation relative to that of the stratum corneum; if a penetrant dissolves better in the stratum corneum than in the formulation, then the partition of the active ingredient will favor the stratum corneum, therefore a low (relative to that in the stratum corneum) solubility in the formulation is required. Both requirements cannot be fully met at the same time, but the problem can still be solved involving the novel concept of a relative polarity index (RPI).[27] In this systematic approach, it is essential to consider the stratum corneum as yet another solvent with its own polarity. It appears that the stratum corneum behaves very similarly to, but in a somewhat more polar fashion, than butanol with respect to its solubilizing ability for penetrants.[28] The experimentally determined log Koctanol/water of 1butanol is 0.88.[29] For the purpose of this chapter, the polarity of the stratum corneum, as expressed by its octanol/water partition coefficient, is set at 100.8 (i.e., 6.3).

20.5.2 The Relative Polarity Index (RPI) The relative polarity index is a way to compare the polarity of an active ingredient with both that of the skin, and that of the oil phase of a cosmetic formulation predominantly consisting of emollients. It may be visualized as a vertical line with a high polarity at the top and a high lipophilicity at the bottom. The polarity is expressed as the log10 of the octanol/ water coefficient. In order to use the concept of the relative polarity index, three numbers (on log10 scale) are required:

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• The polarity of the stratum corneum, here set at 0.8 (but in reality this value will change with the hydration state of the stratum corneum that is determined, in part, by the external relative humidity[30] • The polarity of the penetrating molecule • The polarity of the formulation For multiphase (i.e., multipolarity) systems like emulsions, this is the phase in which the active ingredient is dissolved. For example, in an o/w emulsion where a lipophilic active ingredient is dissolved in the oil phase, it is the polarity of the homogeneous mixture of the lipophilic active ingredient and internal oil. For the same lipophilic active in a w/o emulsion, it is the polarity of the homogeneous mixture of the lipophilic active ingredient and external oil. For water-soluble active ingredients, it is the polarity of the homogeneous mixture of the hydrophilic active ingredient and the aqueous phase, regardless whether it is internal (w/o emulsion) or external (o/w emulsion). The polarities of these three entities can be placed on the RPI vertical representation line by simply marking their position on the vertical line. Imagine the example of an active ingredient with a log Koct/water equal to that of the stratum corneum (0.8) in a formulation with the same polarity. In this case, the solubility of the penetrant in the stratum corneum and its solubility in the formulation would be the same. After equilibrium is reached, the concentration of active ingredient in the two “phases” (formulation and stratum corneum) would be the same, although the absolute amount in both layers will depend on their respective volumes. Based on the physicochemical characteristics of the system, there would be no drive for the active ingredient to leave the formulation and enter the skin, apart from the fact that the stratum corneum does not initially contain any penetrant. The resulting penetration can therefore be described as a dilution effect. Such a situation is very unlikely because, in reality, almost all active ingredients have polarities that differ from that of the stratum corneum. Following this analysis, two situations need to be discussed separately. In the first case, the active ingredient is more polar than the stratum corneum and, in the second case, the active ingredient is more lipophilic than the stratum corneum.

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Penetrants more polar than the stratum corneum. In order to illustrate the use of the RPI with a penetrant that is more polar than the stratum corneum, it is assumed that the active ingredient is the skin whitener arbutin with a calculated log Koctanol/water of 0.01. In the first step, the polarity difference between the stratum corneum and the penetrant—the so-called penetrant polarity gap (PPG)—is calculated by subtracting the polarity of the penetrant from that of the stratum corneum; in this case, 0.8–0.01 = 0.79 using Eq. 20.5. The penetrant polarity gap (PPG) of arbutin is 0.79. This is illustrated in the vertical representation of the RPI in Fig. 20.13. (Eq. 20.5) penetrant polarity gap (PPG) = polarity penetrant − polarity stratum corneum

In the second step, the polarity of the formulation is calculated by means of Eqs. 20.6 and 20.7. This informs us that a higher concentration of arbutin will be achieved in the stratum corneum than in the formulation if the formulation has a polarity of either above 0.8 (greater than 0.01 + 0.79 according to Eq. 20.6) or below –0.78 (smaller than 0.01 – 0.79, according to Eq. 20.7).

(Eq. 20.6)

polarity of formulation > polarity of penetrant + penetrant polarity gap (PPG)

(Eq. 20.7)

polarity of formulation < polarity of penetrant − penetrant polarity gap (PPG) Having established the boundaries of the polarity of the formulation by means of Eqs. 20.6 and 20.7, in the third step one will need to make a final choice on the polarity of the formulation. As always in skin penetration, there are two opposing effects. The driving force for diffusion is determined by polarity gaps between that of penetrant and stratum corneum (the penetrant polarity gap) on the one hand and penetrant and formulation on the other. When using formulations with polarities beyond those determined by Eqs. 20.6 and 20.7, the solubility of arbutin in the stratum corneum exceeds that of arbutin in the formulation, thereby creating a driving force for partitioning itself into the stratum corneum. The more extreme the difference in polarity between the formulation phase containing the active ingredient and the active ingredient itself, the greater the driving force for partitioning of the active ingredient out of this phase into the stratum corneum. This is illustrated on the left side in Fig. 20.14 by the width of the funnel-shaped blocks that widen as the difference in polarity between formulation phase and active ingredient increases.

Figure 20.13 Visualization of the polarity gap between an active ingredient more polar than the stratum corneum (in this case arbutin) and the stratum corneum using the relative polarity index.

However, if the difference in polarity between the formulation phase containing the active ingredient and the active ingredient itself is increased too much, the active ingredient will no longer dissolve in the formulation phase. This is illustrated by the width of the funnel-shaped blocks on the right side in Fig. 20.14. They narrow down when the solubility of the arbutin in the formulation phase is reduced.

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situation, it is assumed that the active ingredient is octadecenedioic acid (referred to hereafter as dioic acid), a much more lipophilic skin whitener[31] with a theoretical log Koctanol/water of 5.84 and an experimentally determined log Koctanol/water of 5.74 ± 0.29. For simplicity, the value of 5.8 has been used in the calculations. Again using Eq. 20.5, the penetrant polarity gap (i.e., the polarity difference between the stratum corneum and the active ingredient) needs to be calculated first; it is 5 (5.8 − 0.8). See Fig. 20.15. In the next step of our protocol to achieve efficacious formulations, the polarity of the formulation must be calculated. This can again be done using Eqs. 20.6 and 20.7. The polarity of the phase of the formulation in which the active ingredient is dissolved should be more than 5 away from that of the active ingredient itself, i.e., either above 10.8 (5.8 + 5; Eq. 20.6) or below 0.8 (5.8 − 5; Eq. 20.7). For formulations that are less lipophilic than the stratum corneum, the dioic acid is more soluble in the stratum corneum than in the formulation and would therefore ‘prefer’ to be located in the stratum corneum rather than in the formulation. If this is so, it creates a driving force for partitioning of the dioic acid into the stratum corneum. As before, the more extreme the difference in polarity between the formulation and the active ingredient, the greater the driving force

Figure 20.14 Example of the calculation of the polarity of a formulation for penetrants more polar than the stratum corneum. Arbutin is used as an example.

In the case of arbutin, a formulation with a polarity of 4 has a greater driving force for partitioning arbutin into the stratum corneum than a formulation with a polarity of 1 because 3.99 (the absolute polarity difference between formulation phase and active ingredient; 4 – 0.01) is greater than 0.99 (1 – 0.01). Likewise, a formulation with a polarity of –3 has a greater driving force for partitioning arbutin into the stratum corneum than a formulation with a polarity of –1 because 3.01 (|–3 - 0.01|) is greater than 1.01 (|–1 – 0.01|). Only the absolute difference counts. Please remember that the RPI is expressed as the log10 octanol/water partition coefficient, and hydrophilic formulation phases can therefore be characterized by negative values. Practically, of course, it is much more difficult to dissolve arbutin into an aqueous solvent with a polarity of -3 than into a formulation phase with a polarity of -1. Similarly, arbutin will dissolve with greater difficulty in a lipophilic solvent with a polarity of 4 than in a formulation phase with a polarity of 1. Penetrants more lipophilic than the stratum corneum. A much more common situation is one in which the active penetrants are more lipophilic than the stratum corneum. As an example of this

Figure 20.15 Visualization of the polarity gap between an active ingredient more lipophilic than the stratum corneum (in this case, dioic acid) and the stratum corneum using the relative polarity index.

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for partition into the stratum corneum. This is illustrated on the left side in Fig. 20.16. At the same time, the solubility of the penetrant in the formulation will reduce if the polarity difference between formulation and active ingredient is enlarged. This is illustrated on the right side in Fig. 20.16. In the case of dioic acid, a formulation with a polarity of 10 has a greater driving force for partitioning dioic acid into the stratum corneum than a formulation with a polarity of 7 because 4.2 (10 – 5.8) is greater than 1.2 (7 – 5.8). Likewise, a formulation with a polarity of –3 has a greater driving force for partitioning dioic acid into the stratum corneum than a formulation with a polarity of –1 because 8.8 (|–3 – 5.8|) is greater than 6.8 (|–1 – 5.8|). Again, only the absolute difference counts. Practically, of course, it is much more difficult to dissolve dioic acid in an aqueous solvent with a polarity of –3 than –1 or a lipophilic solvent with a polarity of 10 than 7. Using the relative polarity index in practice. From the theory discussed above, it can be concluded that the polarity of the formulation needs to be as far away as possible from the polarity of the active ingredient in order to increase the force that drives the active ingredient into the skin. At the same time, however, the polarity of the formulation needs to be as close as possible to that of the active ingredient to insure the high concentrations that enable sufficient material penetration. In view of these two opposing requirements, which cannot be met at

the same time, it is necessary to describe how to practically find the optimum polarity of the formulation from the point of view of skin delivery. Optimizing the solubility by selecting the primary emollient or solvent. After having calculated the penetrant polarity gap using Eq. 20.5 and hence the acceptable polarity ranges of the formulation via Eqs. 20.6 and 20.7, the formulator should have an idea as to whether the phase containing the active ingredient will be hydrophilic or lipophilic in nature. In other words, will the formulation be at the top or at the bottom of the RPI as indicated by the arrows in Figs. 20.14 and 20.16? It is important to note that if a lipophilic penetrant is dosed in an o/w emulsion and dissolved in the internal oil phase, the phase containing the penetrant is lipophilic in nature whereas the external phase of the formulation may be hydrophilic in nature. In all these considerations, it is the polarity of the phase in which the active ingredient is dissolved that is discussed, regardless whether this is the internal or the external phase. As a first step, an emollient (for lipophilic active ingredients) or a water-miscible solvent (for hydrophilic active ingredients) in which the active ingredient dissolves well should be identified. This primary emollient, or solvent, is chosen in the direction of the required RPI. In other words, chose an emollient with a polarity not too far away from that of the active ingredient, for instance 7 or 8 in case of dioic acid if the polarity of the final formulation will be lipophilic or 4 or 5, if the final formulation will be hydrophilic. Table 20.6 provides RPI values of some typical emollients and hydrophilic solvents that span a wide range and can be used to select a suitable solvent or emollient.

Figure 20.16 Example of the calculation of the polarity of a formulation for penetrants more lipophilic than the stratum corneum. Octadecenedioic acid is used as an example.

Optimizing the driving force by selecting the secondary emollient or solvent. Once a suitable primary emollient or solvent has been selected, the driving force for penetration of the active ingredient into skin needs to be increased by reducing its solubility in that solvent. Incorporating another formulation component, a secondary emollient or solvent, in which the active ingredient is far less soluble but still miscible with the originally

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Table 20.6. Relative Polarity Index Values (Calculated Octanol/Water Partition Coefficients) for Some Hydrophilic Solvents and Lipophilic Emollients Typically Used in Cosmetic Formulations

INCI name Glycerin Dipropyleneglycol

-1.76 -1.17 / -1.23

Propylene glycol

-0.92

Ethanol

-0.32

Triethylhexanoin

2.70

Glyceryl isostearate

4.76

Isopropyl myristate

5.41

Propylene glycol isostearate

6.08

Isopropyl isostearate

7.40

Ethylhexyl palmitate

9.12

Ethylhexyl isostearate

10.05

Vegetable squalane

14.93

Triisostearin

18.60

Trimethylolpropane triisostearate

20.27

Pentaerythrityl tetraisostearate

25.34

Isostearyl isostearate

26.98

chosen solvent or emollient, allows this to be done. When adding increasing amounts of the secondary emollient, or solvent, the solubility of the active ingredient is gradually reduced. As a consequence, the total amount of active ingredient dissolved in the formulation phase, relative to what could be dissolved, increases. The secondary emollient or solvent is added until about 90% of the maximum solubilityis reached, and that will be the composition of the formulation phase containing the active ingredient.

20.5.3

Calculated log P value

An Example of Using the RPI Concept

An example of this concept is the formulation of dioic acid for which formulations with a polarity of more than 10.8 and less than 0.8 would be acceptable as identified by Eqs. 20.6 and 20.7. Propy-

lene glycol isostearate with an RPI of 6.08 was chosen as the solvent for this particular penetrant and the solubility assessed to be 17% w/w. This solubility was too high to guarantee a good driving force for diffusion; therefore, increasing amounts of triethylhexanoin with an RPI of 2.70 were added to reduce the solubility to just above 2% in the total formulation (10% in the oil phase as the oil phase was 20% of the total formulation). In this way, a formulation was created with the composition as outlined in Formulation 20.1 (Sec. 20.7). Another formulation was made without taking the RPI concept into account, only considering the physical stability of the emulsion system. Its composition is given in Formulation 20.2. Skin delivery experiments with delivery-optimized and stability-optimized formulations. The skin delivery of dioic acid from Formulations 20.1 and 20.2 was tested. For the delivery-optimized

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formulation, full-thickness pigskin dermatomed to 400 µm was used in-vitro in a Franz-diffusion cell dosed at a rate of 10 µl/cm2. Cells were left in place for twenty-four hours after which the formulation was removed and the skin was tape-stripped twenty-one times. The strips, remainder of skin, and receptor fluid samples were analyzed in order to assess skin penetration. For the physical stability-optimized formulation, full-thickness pigskin (500 µm) was used in-vitro in a Bronaugh flow-through diffusion cell dosed at a rate of 66 µl/cm2. Cells were left in place for twenty hours after which the formulation was removed, the skin was tape-stripped five times and strips, remainder of skin, and receptor fluid were analyzed in order to assess skin penetration. Results of these experiments are given in Fig. 20.17.

values as a fundamental tool for selecting emollients to enhance skin delivery of active ingredients. The differences in skin penetration methodologies between the two experiments were only minor. The delivery-optimized formulation had a sixfold lower dosing rate than the stability-optimized formulation (favoring the skin penetration from the stability-optimized formulation). Both sets of testing were performed under infinite dosing conditions. Dermal delivery after twenty-two hours may be considered constant after steady-state transdermal fluxes have been achieved (data not shown). In other words, the observed difference in skin penetration from Formulations 20.1 and 20.2 is believed to be due to differences in formulation design rather than to differences in skin penetration methodology.

As can be seen from Fig. 20.17, the total delivery (i.e., the sum of the amounts recovered in the tapes, the skin, and transdermally delivered receptor fluids) is far greater from the delivery-optimized formulation than the physical stability-optimized formulation. (Please note that the delivery-optimized formulation was also physically stable.) These results therefore illustrate the validity of the use of RPI

Because dioic acid needs to be delivered to the melanocytes where it reduces the formation of the tyrosinase enzyme,[32] the enzyme involved in skin color formation, the delivery to the skin layer should be as high as possible. As a result of the use of the RPI concept, skin delivery was increased 3.5-fold, from 4.30 to 14.0 µg/cm2, without an increase in the concentration of the active ingredient in the formulation! Concentrations of above 2% dioic acid, in the stability-optimized formulation, were previously tested for skin delivery[33] and demonstrated that a fourfold increase in dioic acid concentration in the formulation (from 2% to 8%) only resulted in a twofold increase of skin delivery (from 4.3 to 8.0 µg/cm2). Based on this and similar experiences, in order to maximize skin delivery of an active, it may be advisable to modify a standard formulation by selecting emollients according to the RPI concept rather than to change the active ingredient or its concentration.

20.5.4 The Influence of the Emulsifier Figure 20.17 Skin delivery of dioic acid of a stability-optimized formulation and a delivery-optimized formulation according to the relative polarity index principles (for composition details, see Formulations 20.1 and 20.2, respectively). Note that the latter delivers significantly more dioic acid to the skin.

As we have seen, the tested formulations differed only in terms of their emollients. This difference showed that the choice of emollient greatly influences the total quantity of active ingredient ab-

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS sorbed into the skin. Besides the choice of emollient, the effect of emulsifier choice on skin delivery of active ingredients is also of interest. In order to investigate this variable, other formulations containing dioic acid were prepared using the RPI concept (i.e., using the same combination of propylene glycol isostearate and triethylhexanoin). The composition of such a formulation can be found in Formulation 20.3. The only difference in Formulation 20.3 from the formulation described in Formulation 20.1 is the emulsifier system. Skin delivery results are depicted in Fig. 20.18. These show that while the total amount of active ingredient delivered is high in both cases (due to the choice of emollients via the RPI concept), a completely different skin distribution pattern is obtained. Because this has been observed several times using different emulsifiers (both o/w and w/o emulsifiers), it is suggested that the emulsifier influences the distribution of the active ingredient in the skin. We believe that this difference is due to the influence of the emulsifier system on the skin lipid membrane structure. Emulsifier systems that create liquid crystalline formulations affect the liquid crystallinity of skin’s lipid bilayers to a larger extent than emulsifiers that do not create liquid crystalline formulations. The lateral packing of skin lipids is either orthorhombic, hexagonal, or liquid, and they all

431

coexist at the same time. The orthorhombic packing is rigid and therefore characterized by a low permeability; the hexagonal packing is somewhat less rigid as the distances between the individual lipid molecules are larger than in the orthorhombic phase. As a consequence, this packing is more permeable. In the liquid packing, this distance is further enlarged and is therefore even more permeable. When emulsifiers interact with the lipid crystallinity of skin lipids, they cause a transformation from the rigid to more permeable packings. This results in a higher permeability of penetrating molecules (i.e., faster transport). Because distribution profiles like Fig. 20.18 are nothing more than a snapshot in time, differences in skin penetration rates will result in different distribution profiles even when the same amount is going into the skin. This, as we saw above, is caused by the choice of the emollients and they were the same in both formulations. Penetration from the liquid crystallinity inducing sorbitan stearate (and) sucrose cocoate emulsifier system (left-hand side in Fig. 20.18) was more rapid, hence more transdermal and less dermal penetration is seen. The steareth21/steareth-2 system (right-hand side in Fig 20.18) does not induce liquid crystals in the formulation, therefore penetration from such systems is slower, hence less transdermal and more dermal penetration is seen.

20.6 Conclusions

Figure 20.18. Skin penetration results of two almost identical formulations, only differing in their emulsifier system.

With the current legislation in the US and European Community requiring experimental evidence for any claimed cosmetic activity (such as moisturizing, enhancing skin elasticity, or anti-aging), it is essential that the active ingredient is formulated in such a way that these effects are indeed delivered. In this chapter, skin delivery of active ingredients from emulsions—probably the most common type of topical delivery system—has been discussed. One thing has become very clear from all the experimental work conducted: the physicochemical characteristics of the penetrating active ingredient are the primary independent variables that determine the rate of skin delivery, but it is the

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composition of the formulation that determines the extent of the delivery. This means that active ingredients that do not meet the requirements of skin delivery (an octanol/water partition coefficient of 0 to 5, ideally 1–2; a molecular weight below 1500, ideally below 500; and ideally non-ionized species at skin pH) simply will not penetrate the stratum corneum very well. In view of this, one might be better off changing the active ingredient to something more favorable, if that is possible. This chapter focused on the delivery of molecules that can penetrate the skin without any penetration enhancement from emulsions. Systems that enhance skin penetration or offer other additional benefits such as increased stability or a prolonged release are discussed in other sections of this book, in particular, Parts 3–6. As discussed in the “Formulation Mapping” section (Sec. 20.4), the formulation type has some, but only moderate, influence on skin delivery of active ingredients. Microemulsions seem to deliver significantly higher amounts of active ingredients transdermally; a result probably due to the high level of surfactant required to make them. Certainly interesting is the observation that, in contrast to a common but unsubstantiated belief, both transdermal and dermal delivery of active ingredients were found to be higher when the penetrant is incorporated in the internal phase of either an o/w or w/o emulsion. Once the active ingredient and the formulation type have been chosen, one has to create the delivery system that will actually deliver the molecule. This chapter offers a novel approach optimizing the solubility requirements of the active ingredient in the

formulation and the skin, based on skin penetration theory. This applied concept, called the relative polarity index (RPI), allows the formulator to select the polarity of the phase in which the active ingredient is incorporated based on the properties of the active ingredient and the stratum corneum. In order to achieve maximal delivery, the polarity of the active ingredient and the stratum corneum need to be taken into account. It was shown that a two-step process could improve skin delivery of active ingredients. The first step involves selecting a primary emollient with a polarity close to that of the active ingredient in which it will have—per definition—a high solubility. The second step is to reduce this solubility of the active ingredient in the primary emollient via the addition of a secondary emollient with a different polarity (and therefore—per definition— lower solubility for the active ingredient). This approach was experimentally shown to produce a 3.5-fold increase in skin penetration without increasing the amount of active ingredient in the formulation. Further research revealed that the choice of emulsifier is also important: not to increase the amount of absorption of active ingredient into the skin but, surprisingly, to determine the distribution profile of the active ingredient within the skin. Whereas the reasons for the choice of the emollient are clearly understood from a theoretical point of view, the rationale for selecting the right emulsifier remains unclear at present and further research will be necessary to elucidate the exact influence of emulsifier structure on the skin delivery of active ingredients.

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20.7 Formulations Formulation 20.1: Composition (in w/w%) of a Dioic Acid-Containing O/W Formulation Designed According to the Relative Polarity Index Principles

Ingredient Propylene glycol isostearate

Weight % 15.0

Triethylhexanoin

3.0

Octadecenedioic acid

2.0

Steareth-21

5.0

Steareth-2

1.0

Glycerin

4.0

Xanthan gum

0.2

Phenoxyethanol (and) Methylparaben (and) Propylparaben (and) 2-bromo-2-nitropropane-1,3-diol

0.7

Aqua

ad 100

Formulation 20.2: Composition (in w/w%) of a Dioic Acid-Containing Formulation Designed Solely Based on Physicochemical Stability

Ingredient Caprylic/capric triglyceride

Weight % 10.0

Glyceryl stearate SE

3.0

Steareth-21

5.0

Steareth-2

1.0

Cetyl alcohol

2.0

Octadecenedioic acid

2.0

Glycerin

3.0

Benzoic acid

0.2

2-Amino-2-methyl-1-propanol, to pH 5.5

qs

Aqua

ad 100.0

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Formulation 20.3: Composition (in w/w%) of Another Dioic Acid-Containing O/W Formulation Designed According to the Relative Polarity Index Principles Using a Different Emulsifier System

Ingredient

Weight %

Propylene glycol isostearate

15.0

Triethylhexanoin

3.0

Octadecenedioic acid

2.0

Sorbitan stearate (and) sucrose cocoate

5.5

Glycerin

4.0

Xanthan gum

0.2

Phenoxyethanol (and) methylparaben (and) propylparaben (and) 2-bromo-2-nitropropane-1,3-diol

0.7

Aqua

Acknowledgments The author would like to thank several colleagues who have been extremely helpful in collecting or interpreting the data used in this chapter:

ad 100

References 1. Schaefer, H., and Redelmeier, T.E., Skin Barrier, Principlese of Percutaneous Absorption, Karger, Basel, 1996.

• Dr. Adam Watkinson, and other staff at AneX (Cardiff, Wales, UK) for performing the skin penetration experiments described in Sec. 20.4, “Formulation Mapping.”

2. Bouwstra, J.A., Pilgram, G., Gooris, G.S., Koerten, H., and Ponec, M., New aspects of the skin barrier organization, Skin Pharmacol. Appl. Skin Physiol., 14 (2001) 52-62.

• Dr. Ronald Andréa (AcfC, Nieuwegein, The Netherlands) for the multivariate statistical analysis of these data.

3. Potts, R.O., and Guy, R.H., Predicting skin permeability, Pharm. Res., 9 (1992) 663-669.

• Dr. Jon Heylings and other staff at Syngenta Central Toxicology Laboratory (Macclesfield, UK) for performing the skin penetration experiments described in Secs. 20.5.3 and 20.5.4 detailing the RPI concept. • My colleagues Drs. Caroline Kelly, Chris Dederen, Trevor Blease, and Jane Mockford for their continuous support.

4. Barratt, M.D., Quantitative structure-activity relationships for skin permeability, Toxicol. In Vitro, 9 (1995) 27-37. 5. Franz, T.J., Percutaneous absorption. On the relevance of in vitro data, J. Invest. Dermatol., 54 (1975) 399-404. 6. Bronaugh, R.L., and Stewart, R.F., Methods for Percutaneous absorption studies. IV. The flow-through diffusion cell, J. Pharm. Sci., 74 (1985) 64-67. 7. Wiechers, J.W., unpublished data.

WIECHERS: OPTIMIZING SKIN DELIVERY OF ACTIVE INGREDIENTS FROM EMULSIONS 8. Bucks, D.A.W, McMaster, J.R., Maibach, H.I., and Guy, R.H., Bioavailability of topically administered steroids: A ‘mass balance’ technique, J. Invest. Dermatol., 91 (1988) 29-33. 9. Wiechers, J.W., The barrier function of the skin in relation to percutaneous absorption of drugs, Pharm. Wkbl. Sci. Ed., 11 (1989) 185-198. 10. Distante, F., Rigano, L., D’Agostino, R., Bonfigli, A., and Berardesca, E., Intra- and inter-individual differences in sensitive skin, Cosmet. & Toilet., 117 (2002) (7) 39-46. 11. Barry, B.W., Dermatological Formulations – Percutaneous Absorption, Marcel Dekker, New York, 1983. 12. Cullander, C., and Guy, R.H., Visualising the pathways of iontophoretic current flow in real time with laser-scanning confocal microscopy and the vibrating probe electrode, in: Scott, R.C., Guy, R.H., Hadgraft, J., and Boddé, H.E. (Eds.), Prediction of Percutaneous Penetration, volume 2, IBC Technical Services Ltd, London (1991) 229-237. 13. Anderson, C., Cutaneous microdialysis, in: Brain, K.R., and Walters, K.A. (Eds.), Prediction of Percutaneous Penetration, volume 6a, STS Publishing, Cardiff (1998) 16. 14. Benfeldt, E., In-vivo microdialysis for the investigation of drug levels in the dermis and the effect of barrier perturbation on cutaneous drug penetration, Ph.D. thesis, University of Copenhagen, Faculty of Health Sciences, 1999, Acta Dermato-Venereologica, Supplement 206, ISSN 0365-8341. 15. Caspers, P.J., Lucassen, G.W., Carter, E.A., Bruining, H.A., and Puppels, G.J., In vivo confocal Raman microspectroscopy of the skin: Noninvasive determination of molecular concentration profiles, J. Invest. Dermatol., 116 (2001) 434-442. 16. Williams A.C., Cornwell, P.A., and Barry, B.W., On the non-Gaussian distribution of human skin permeabilities, Int. J. Pharm., 86 (1992) 69-77. 17. Johnson, M.E., Blankschtein, D., and Langer, R., Permeation of steroids through human skin, J. Pharm. Sci., 84 (1995) 1144-1146.

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18. Flynn, G.L., Physicochemical determinants of skin absorption, in: Gerrity, T.R., and Henry, C.J. (Eds.), Principles of route to route extrapolation for risk assessment, Elsevier, New York, 1990, pp. 93-127. 19. Bronaugh, R.L., Stewart, R.F., Congdon, E.L., and Giles, A.L., Methods for in-vitro percutaneous absorption studies III. Hydrophobic compounds, J. Pharm. Sci., 73 (1984) 12551257. 20. Ruddy, S.B., Surfactants, in: Smith, E.W., and Maibach, H.I. (Eds.), Percutaneous Penetration Enhancers, CRC Press, Boca Raton, FL, USA, 1995, Chapter 8.1, pp. 245-258. 21. Walters, K.A., Walker, M., and Olejnik, O., Non-ionic surfactant effects on hairless mouse skin permeability characteristics, J. Pharm. Pharmacol., 40 (1988) 525-529. 22. Sarpotdar, P.P., and Zatz, J.L., Evaluation of penetration enhancement of lidocaine by nonionic surfactants through hairless mouse skin in-vitro, J. Pharm. Sci., 75 (1986) 176-181. 23. Wiechers, J.W., and Bouwstra, J.A., Identification of another barrier in human skin: the water barrier, Proceedings of the Annual Scientific Meeting of the Society of Cosmetic Chemists, December 2002, New York, NY, USA. 24. Wiechers, J.W., and Wortel, V.A.L., Making sense of sensory data, Cosmetics & Toiletries, 115 (3) (2000) 37-45. 25. Wiechers, J.W., and Wortel, V.A.L., Bridging the language gap between cosmetic formulators and consumers, Cosmetics & Toiletries, 115 (5) (2000) 33-41. 26. Kumar, S., Malick, A.W., Meltzer, N.M., Mouskountakis, J.D., and Behl, C.R., Studies of in-vitro skin permeation and retention of a leukotriene antagonist from topical vehicles with a hairless guinea pig model, J. Pharm. Sci., 81 (1997) 631-634. 27. Wiechers, J.W., Formulating for Efficacy, Proceedings of the 2003 IFSCC Conference, Seoul, Korea, 2003. 28. Scheuplein, R.J., and Blank, I.H., Mechanism of percutaneous absorption. IV. Penetration of non-electrolytes (alcohols) from aqueous so-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS lutions and from pure liquids, J. Invest. Dermatol., 60 (1973) 286 – 296.

derived ingredient to even Asian skin tone, SÖFW, 128 (September 2002) 2-8.

29. Hansch, C., and Leo, A., Substituent Constants for Correlation Analysis in Chemistry and Biology, J. Wiley & Sons, New York, 1979.

32. Wiechers, J.W., Melanosomes, melanocytes and dioic acid, Proceedings of the 37th Annual Conference of the Australian Society of Cosmetic Chemists, “Cosmetics on a New Horizon”, 13-16 March 2003, Hamilton Island, Queensland, Australia.

30. Bouwstra, J.A., De Graaff, A., Gooris, G.S., Nijsse, J., Wiechers, J.W., and Van Aelst, A.C., Water distribution and related morphology in human stratum corneum at different hydration levels, J. Invest. Dermatol., 120 (2003) 750-758. 31. Wiechers, J.W., Groenhof, F.J., Wortel, V.A.L., Hindle, N.A. and Miller, R.M., Efficacy studies using octadecenedioic acid, a new nature-

33. Wiechers, J.W., Groenhof, F.J., Wortel, V.A.L., Miller, R.M., Hindle, N.A., and DrewittBarlow, A., Octadecenedioic Acid for a more even skin tone, Cosmetics & Toiletries, 117 (July 2002) 55-68.

21 The Delivery Systems’ Delivery System James M. Wilmott*, Duncan Aust*, Barbara E. Brockway*, and Vitthal Kulkarni* The Collaborative Group Stony Brook, New York

21.1

Introduction .................................................................................. 438 21.1.1 History of Cosmetics ........................................................ 438 21.1.2 Contemporary Cosmetics ................................................ 438 21.1.3 The Future ....................................................................... 438 21.2 Current Vehicles for Delivery Systems ......................................... 439 21.3 Issues with Emulsions.................................................................. 442 21.3.1 The “Eureka!” Moment ...................................................... 446 21.4 Surfactant-free Lamellar Phase (Lα) Dispersions: An Alternative to the Conventional Emulsification Process ................................. 446 21.5 Defining a Semiquantitative Aesthetic Scale ................................ 450 21.6 Formulating with Lα Dispersions – System 3™ ........................... 452 21.7 System 3™ Advantages ............................................................... 452 21.8 Conclusion .................................................................................... 454 21.9 Formulations ................................................................................. 455 References .......................................................................................... 472

* This work was originally conducted at The Collaborative Group (now owned by Engelhard Corp.). Authors’ present addresses: James M. Wilmott, Chanel Inc., Piscataway, New Jersey Duncan Aust, DPT Research & Development, San Antonio, Texas Barbara E. Brockway, Optima Chemical, London, England Vitthal Kulkarni, DPT Laboratories, Ltd., San Antonio, Texas Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 437–472 © 2005 William Andrew, Inc.

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21.1 Introduction 21.1.1 History of Cosmetics Formulating cosmetic and personal care products is an ancient art. These products originally contained ground minerals in an oil or grease. They were initially used by men to exaggerate their features during battle, to conduct tribal ceremonies, and to differentiate different tribes or clans. The use of cosmetics by women began in ancient Egypt. Color products accentuated facial features, plant and animal essences provided a scent to the hair and body, and greases and oils were used to treat the skin. Skin care did not really change over the years and typically involved the application of natural oils or glycerin and rosewater preparations. The first widely used cosmetic dates back to 200 AD when the Greek physician, Galen, published a formula that contained only rose water, beeswax, and olive oil.[1] This formula remained essentially unchanged until the late 1800s when borax was added to the basic formula to form a simple cold cream preparation. The principal cleansing agent at the time was a lyebased soap made by mixing potash or lye with animal or vegetable-based fats. The art of soap making became more refined throughout the second millennium. The era of modern cosmetics emerged in the 1940s with the widespread use of synthetic surfaceactive agents. These materials, commonly called surfactants, modified the surface tension of the oil and water phases and enabled the formulator to mix them together to form a composition that was stable for at least the commercial shelf life of the product. These preparations were called emulsions and the surface-active materials used to form them were called emulsifiers. Personal care products continued to evolve throughout the latter part of the 20th Century. Manufacturers improved aesthetic sensations through the use of new, more refined natural oils and synthetic emollients. Product form became more diverse. Traditionally skin care products were used to treat dryness by plasticizing and softening the hard, rough, tight, scaly manifestations of damaged skin.

21.1.2 Contemporary Cosmetics In the late 1960s and early 1970s functional skin treatment products emerged. Product performance expanded beyond the amelioration of superficial dryness, and their benefits evolved to a higher therapeutic level. The boundary between cosmetics and dermatological products began to blur. Cosmetic problems such as aging, uneven skin pigmentation, slack skin, cellulite, sensitive skin, oily skin, and dryness were identified and agents were sourced or developed to address these conditions. These skin disorders were often associated with conditions such as sunburn, acne, and the need for topical analgesia, etc. Cosmetics turned more to medicine for its resources, and dermatology became a source for agents that could provide either a marketing or performance advantage. As the number and potency of functional materials increased, there arose a need to control the delivery of these agents in order to mitigate potential irritation, target their transfer to the desired location in the skin, or protect environmentally unstable materials for a commercially viable period of time. Again, the personal care market borrowed from the latest advances in medical research. Table 21.1 is a summary of some of the major delivery systems currently being used in the personal care market place, the types of active they carry, and their primary benefit.

21.1.3

The Future

The trend toward even greater performance in personal care products will continue as we move further into the 21st Century. New, more potent therapeutic agents are being sourced from the fields of biotechnology, pharmaceuticals, and botanicals. Materials such as enzymes, growth factors, antioxidants, cytokines, DNA, genetic promoters, and other sophisticated materials are already being evaluated in the research facilities of leading manufacturers and suppliers. These agents, though more effective than previously used actives, are often sensitive to environmental conditions such as oxygen, heat, and light. Thus, there will be a need for equally sophisticated delivery systems that will protect these sensitive actives from their formulation and environmen-

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439

Table 21.1. Delivery Systems Most Commonly Used in Personal Care

Classification

Description

Diameter

Liposomes

Phospholipid-based unilamellar or multilamellar bilayer vesicles.

100–500 nm

Hydrophilic and hydrophobic actives

Nanodispersions

Phospholipid-based micellular dispersion.

100–500 nm

Hydrophobic actives

Vesicles

Surfactant-based vesicles or micelles

100–500 nm

Typically hydrophobic actives

Polymeric

Crosslinked acrylate or allyl methacrylate polymer

10–500 microns

Typically hydrophobic actives

Microencapsulates

Aldehyde crosslinked protein

100–5000 microns

Typically hydrophobic actives

Encapsulates

Crosslinked guar, alginate, or other carbohydrate polymer

5–500 microns

Typically hydrophobic actives

Entrapment/Clathrate

Clathrate of cyclodextrin

N/A

Hydrophobic actives

Linked

Active ingredient is covalently or ionically linked to polymeric support

N/A

Hydrophilic and hydrophobic actives

tal surroundings. In fact, the cover article of a recent edition of Chemical and Engineering News describes a series of new delivery approaches that have shown early promise in enhancing therapeutic efficacy.[2] While drug delivery systems have received much attention because of their potential, what is often overlooked is the vehicle into which these delivery systems are incorporated. The remainder of this chapter focuses on the proper selection of the vehicle into which the delivery systems are added in order to insure their performance is not compromised. This chapter also explores a new approach to vehicle development that is completely compatible with most, if not all, delivery systems. This new approach is actually a delivery system for delivery systems. The technology employed is more hospitable to the active materials contained within the delivery sys-

Materials Carried

tem. As a result, it offers virtually unlimited aesthetic and form modification capabilities that will enable the user to truly enjoy the experience of applying the product. This new formulating approach is called System 3™. The approach is derived from the very processing technology that was developed to prepare vesicular and liposomal delivery systems.

21.2 Current Vehicles for Delivery Systems The delivery systems most commonly used in cosmetic and personal care products almost universally owe their genesis to the treatment of medical disorders. Tremendous resources are allocated annually in the pursuit of new therapeutic agents. These

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

agents are generally administered orally, injected intramuscularly, or injected intravenously with the hope they will eventually migrate to the site where they are needed to treat the disorder. Unfortunately, the lack of specificity of these therapeutic agents often results in unwanted side effects. As a result of this lack of specificity, researchers have initiated the relatively new science of delivery systems technology. The new science is concerned with the development of methods for incorporating the active ingredient into a suitable microvessel or “delivery system,” or chemically attaching the active to a support in order to make a prodrug. The latter approach provides a more stable, chemical modification of the physiologically active ingredient. Either the biochemistry of the skin or the external environment slowly breaks down such modified actives in order to regenerate the active agent. The intention of both of these approaches is the same. They seek to protect the active from a hostile environment, to target the delivery of that active to the site of the disorder, and to control the active’s release properties in order to provide a localized and sustained therapeutic benefit. In almost all cases, the “vehicle” into which the delivery systems are added is water or saline solution. The aesthetic properties of the vehicle are not of consequence in these systems since the therapeutic effect is all that is desired. However, this situation changes abruptly when one uses a delivery system in a product designed for topical administration. Most dermatological products have very limited aesthetic considerations. Typically, the active agent is simply solubilized or dispersed in a standard ointment, salve, or aqueous gel. Standard vehicles, considered pharmaceutically acceptable by the United States or British Pharmacopoeias, are usually selected since the addition of a new active will necessitate a new drug application (NDA) and extensive clinical testing. As a result, many over-the-counter (OTC) drug and dermatological Rx products are aesthetically unexciting. The use of delivery systems in cosmetic and personal care products has an entirely different set of aesthetic requirements. In general, the sensory experience associated with the application of a cosmetic is often the principal reason why a customer might purchase the product. Typical cosmetic vehicles are aqueous-based, anhydrous, or a combination thereof.

Hydrous or aqueous vehicles are principally composed of water that has been thickened to achieve a desired rheological profile. This is usually accomplished by means of the incorporation of a synthetic or natural polymer. Polymers that are most frequently used in the preparation of aqueous-based cosmetic compositions are listed in Table 21.2. These materials impart the desired rheological properties to the product and are designed to take the form of a serum, viscous fluid, or gel. The advantage of these vehicles is they are generally compatible with the delivery system containing the active ingredient. However, the aesthetic properties of such vehicles are very limited and materials that are added to improve the tactile, olfactory, and visible features of the product can be detrimental to the delivery system. Anhydrous vehicles, by definition, contain no water. They have different tactile and rheological properties from aqueous-based systems. Such vehicles take the form of a spray; a very low viscosity fluid or serum; a gel; or a solid, waxed-based stick. These materials are typically composed of hydrocarbons, hydrocarbon esters, natural oils, silicones, or waxes. They have limited aesthetic properties and tend to leave the skin feeling greasy or oily. Such materials are not compatible with many of the current delivery systems. This is particularly true for the vesicular, polymeric, and clathrate systems shown in Table 21.1. The hydrophobic bilayer or micellar character of common vesicular delivery systems tend to simply fuse or dissolve in the hydrophobic character of the anhydrous vehicle. This phenomenon destroys the structure and function of the delivery system and is, therefore, undesirable. Clearly, the preferred cosmetic and personal care vehicle for topical application contains both aqueous and anhydrous phases. Such products have virtually unlimited aesthetic properties and can be applied in many forms such as serums, lotions, and creams. However, these components are generally incompatible with one another unless an agent is added that more significantly reduces the interfacial tension between the oil and the water phases. This phenomenon allows the formation of a two-phase system in which one of the phases (e.g., the oil) is suspended in the other (e.g., the water). Such ingredients are called surface active agents (surfactants). A special subcategory of surfactants is called an

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441

Table 21.2. Rheological Modifiers

Type

A. Carbohydrate

Thickening Agent 1. Algin

19. Gellan gum

2. Calcium alginate

20. Guar gum

3. Propylene glycol alginate

21. Hydroxypropyl quar

4. Carrageenan

22. Guar hydroxypropyltrimonium chloride

5. Calcium carrageenan

23. Hyaluronic acid

6. Sodium carrageenan

24. Dextran

7. Agar

25. Dextrin

8. Cellulose gum

26. Locust bean gum

9. Carboxymethyl hydroxyethylcellulose

27. Mannan

10. Hydroxyethylcellulose

28. C1-5 aklylgalactomannan

11. Hydroxypropylcellulose

29. Starch

12. Hydroxypropylmethylcellulose 30. Hydroxyethyl starch phosphate 13. Methylcellulose

31. Hydroxyethyl distarch phosphate

14. Ethylcellulose

32. Pectin

15. Chitosan

33. Sclerotium gum

16. Hydroxypropyl chitosan

34. Gum tragacanth

17. Carboxymethyl chitosan

35. Xanthan gum

18. Chitin

B. Polymeric

1. Carbomer

12. Acrylate/acrylamide copolymer

2. Sodium carbomer

13. Acrylate copolymer

3. Acrylate/C10-C30 alkyl acrylate crosspolymer

14. Acrylate/hydroxyester acrylate copolymer

4. Acrylic acid/acrylonitrogen copolymers

15. Acrylate/octylarylamide copolymer

5. Ammonium acrylate/ acrylonitrogen copolymer

16. Acrylate/PVP copolymer

6. Glyceryl polymethacrylate

17. AMP/acrylate copolymer

7. Polyacrylic acid

18. Ethyl ester of PVA/MA copolymer

8. PVM/MA decadiene crosspolymer

19. Isopropyl ester of PVP/MA copolymer

9. Sodium acrylate/vinyl isodecanoate crosspolyer

21. PVP

10. Ethylene acrylic acid copolymer

22. Sodium polyacrylate

11. Ethylene/VA copolymer (cont’d.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 21.2. (Cont’d.)

Type

C. Inorganic

Thickening Agent

1. Bentonite

6. Sodium maganesium silicate

2. Quaternium-18 bentonite

7. Lithium magnesium silicate

3. Hectorite

8. Silica

4. Quaternium-18 hectorite

9. Hydrophobic silica

5. Magnesium aluminum silicate

D. Protein/Peptide

1. Albumin

5. Milk protein

2. Gelatin

6. Wheat protein

3. Keratin

7. Soy protein

4. Fish protein

8. Silk protein

emulsifier. These materials not only lower the interfacial tension at the oil/water interface but, with the input of shearing energy, they enable the formation of droplets of one phase within the other. Such emulsifiers have a wide range of surface-active properties. When carefully selected, they can stabilize the incorporation of oil into a water phase or water into an oil phase. The resulting product is called an emulsion. In many cases, such emulsions are prepared by heating the oil and water phases to a temperature of 70°C or greater before combining the two phases. The purpose of heating the phases is to insure that all waxes used are melted, and that the two phases have a low enough viscosity so the two phases can mix freely. The oil and water phases are typically mixed together until they achieve a homogeneous appearance. Thereafter, they are slowly cooled to insure the formation of appropriately smallsized droplets. It is essential that the droplets be very small in order to insure the stability of the emulsion since, in these cases, Brownian motion will retard sedimentation. Such emulsions typically have a homogeneous, opaque, white appearance. They provide a smooth, pleasant feel upon application to the skin, hair, or other epithelial surfaces. In fact, the fields of surfactant chemistry and emulsion science have become a major disciplinary area that a competent cosmetic chemist must master in order to be a successful formulator. The proper use of surfactants to form all of the various types of useful emulsions can become a totally engaging, lifelong pursuit. The vehicle formed by the combination of an aqueous phase with an anhydrous phase is the primary focus of the remainder of this chapter.

21.3 Issues with Emulsions The introduction of surfactants to the cosmetic industry has provided a “double-edged sword” for formulators. Although the many different types of surfactants have yielded a vast array of cosmetics with very desirable aesthetic properties, they have also generated undesirable issues associated with their use. To the formulator, the development of emulsion-based products is replete with problems. Such development is a time consuming process. Further, these issues are generally limiting towards the goal of achieving desirable aesthetic properties. These issues can produce thermodynamically unstable, nonreproducible, and difficult-to-scale emulsions in the manufacturing process. It is easy to understand, therefore, why the time to develop a traditional emulsifier-based product is so lengthy. Seldom does a formulating company’s marketing department or Business Development function request exactly the same formulation. Generally, new marketing concepts will necessitate a change in composition from prior art. This change can cause a cascade of undesirable events. Different aesthetic properties are also frequently requested by Marketing in order to generate new products with new claims. When changes to either the aqueous phase or oil phase are made, the emulsifier blend, which was effective in previous systems, generally must be altered. This may result in a change in one or more aesthetic, performance, or safety properties. Immediate stability of the composition is often compromised as a result and, worse, such instability

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM is not usually identified until the second or third month of accelerated stability testing. This behavior may indicate a potential problem with the long-term shelf life of the product, and it is insidious since it requires either rebalancing of the emulsifier ratios or a change in the emulsifiers selected. To be effective in today’s demanding market place, the formulator cannot wait until a potential problem arises in order to address it. Generally, a sequential approach to problem resolution will result in an extended time to develop a product. This will result in a delay in the projected launch date that can cost the organization millions of dollars in anticipated revenues. As a consequence, the formulator is best served by trying to anticipate potential issues. Multiple batches, having several ingredient variations, are typically prepared in order to address any unexpected contingencies. This process is filled with unnecessary redundancy and is generally unacceptable in commercial practice. Compounding the above mentioned issue is the effect that processing can have on the outcome of a batch. Emulsion stability is dependent on a variety of parameters such as the zeta potential, particle size, crystal formation, and water binding activity of the ingredients employed to achieve the desired rheological properties of the product. These parameters are dependent on the temperature to which the oil and water phases are heated, the rate of heating, the method and rate of mixing of the phases when combined at elevated temperatures, and the rate of cooling. Most emulsions require heating to insure that all higher melting point materials, such as waxes and butters, are completely melted, dissolved, or dispersed in the appropriate phase. Some emulsions can be made without heating but these systems preclude the use of higher melting point materials that can add richness to the aesthetics of the final product. Further, if the rate of mixing is high, there is a chance that air can be entrapped in the emulsion. This phenomenon causes an undesirable decrease in the specific gravity of the product and an increase in product viscosity. Any variability in processing can lead to a range of undesirable rheological and textural properties. This issue can occur even if the formulation is not modified! The term “product by process” is well known in the patent art and describes this phenomenon.

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Often, if two or more formulators prepare the same product, the resulting compositions may vary considerably. This surprising variation can occur even though each person utilized the same lots of raw ingredients. The unsettling phenomenon occurs because it may be very difficult to exactly reproduce all of the processing parameters used to make an emulsion. If any of the processing variables is modified unexpectedly the particle size variations may occur or the crystalline properties of the emulsion can be compromised. Table 21.3 is a chart containing the results from an experiment to determine the effect of processing on the final properties of a 5% petrolatum-containing cream. All preparations contained the same lots of ingredients. The data demonstrate that the viscosity and specific gravity can vary dramatically depending upon the processing parameters employed to make the batch. Since there is so much uncertainty at the “bench” level in the laboratory, there is often concern that a typical 500 g to 2000 g lab preparation will not translate directly to a manufacturing environment. This concern is often well founded. Compounding this scale-up problem is the fact that equipment used in the laboratory generally does not correlate with that used in the plant. There is usually a need for an intermediate phase during scale-up that facilitates this transition. Some equipment is engineered to mimic plant conditions but at a fraction of the size. Even so, scale-up issues abound. To deal with the vagaries of scale-up, the product may be subjected to a wide range of processing variations in order to optimize the conditions of manufacture. Products made at each level of scale-up are typically subjected to accelerated stability testing in order to insure the integrity of the product for its anticipated shelf life. When one adds the processing variability and the need for scale-up to the uncertainty of the selection of the emulsifier system, it is almost a wonder that any product ever makes it to the market on time. As a consequence, most formulators tend to stay with the tried and true approaches of the past. A significant alteration to these systems, or the development of an entirely new system is often laced with unknown issues that can severely jeopardize the launch of a new product. Beyond the problems already cited, there are other problems with current emulsifier-based products as well. Some surfactants are not compatible

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Table 21.3. Petrolatum Cream (5%) – Standard Emulsion Test Results

Sample

Specific Gravity

Initial Viscosity (cP)

Viscosity (cP) 24 hr @ 25°C

Viscosity (cP) 24 hr @ 50°C

1. Optimum manufacturing procedure

0.912

99,970

140,580

26,560

2. Overheated phases

0.937

85,910

93,720

29,690

3. Forced cooling

0.952

93,720

109,340

29,700

4. Ambient cooling

0.941

51,550

96,840

131,200

5. Paddle mixing

0.959

62,480

85,910

78,100

6. Rapid homogenization

0.803

112,460

124,960

20,620

7. Underheated phases

0.931

51,550

96,840

20,600

Note: Viscosity measurements were taken with a Brookfield LVT model viscometer. with many of the new ingredients that formulators would like to use. This limits the types of materials and delivery systems that can be used in such products. For example, surfactants destroy liposomes and denature proteins and genes. This situation makes it virtually impossible for cosmetic chemists to take advantage of the new biochemical tools that are proving to be so useful in medical and food applications. Figure 21.1 demonstrates the complete incompatibility of vesicular delivery systems in a standard emulsion vehicle. In this study, phosphatidyl cholinebased liposomes were incorporated into a traditional emulsion prepared using triethanolamine (TEA) stearate and nonionic emulsifiers. The emulsion was then stored at 25°C, and the liposome integrity was monitored by the release of a fluorescent dye from the liposome. What can be readily observed is the rapid deterioration of the liposome in the conventional emulsion vehicle. As seen in Fig. 21.1, the noticeably rapid release of fluorescence in the emulsionbased vehicles demonstrates the well-known and widely publicized fragility of liposomes in the presence of surface-active agents. Similar

undesirable results can be obtained with nanodispersions and vesicular systems as well. Further, it is fairly well established that absorption, entrapment and clathrate delivery systems are also compromised in a surfactant-based system. While the polymeric or cyclodextrin-based structure of such delivery systems is not destroyed, the low surface tension of the aqueous phase promotes a partitioning of the hydrophobic active from the entrapping lattice. As a consequence, the performance agent (i.e., active) is now vulnerable to the environment. In this case, the value of the delivery system for providing control of the amount of active released is irreversibly compromised. This is particularly distressing given the fragility of the new biological and

Figure 21.1 Liposome stability in a conventional emulsion.

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botanical therapeutic agents that are showing so much promise in medical and personal care applications.

to air at high temperature can cause oxidation and lead to both rancidity and an undesirable color change.

As is well known to any first year biochemistry student, oligopeptides, proteins, and nucleic acid polymers are denatured in the presence of surfactants and heat. These are two conditions closely associated with the processing and production of emulsions. Many critically important biochemicals, such as vitamins and organic mercaptans, are susceptible to oxygen, heat, and light. Therefore, if the protection afforded by the encapsulating system is destroyed, then the therapeutic value of the active ingredient is lost.

The complexity of the manufacturing procedure for personal care emulsions, and its dependence on many processing variables, leads to frequent quality issues. This is especially true with respect to the products final textural and rheological properties. If any factors such as the heating, cooling or mixing rates are not carefully duplicated, the material prepared may have different properties than the preceding batches of the same product! As a result, the stability of the emulsion may vary from batch to batch.

Further, many materials with unique aesthetic properties cannot be emulsified easily, if at all. Useful molecular weight silicones, silicone and hydrocarbon-based gels, and fluorinated compounds are all very difficult to incorporate into a stable emulsion system.

Often, the difference of a single parameter is significant enough to cause the product to be outside the established optimum specifications. Inevitably, batches have to be either discarded or reworked. The lack of reproducibility is especially problematic when the product contains a physiologically active agent. Lack of reproducibility, due to manufacturing variations, can affect product performance and decrease consumer satisfaction. It also results in products having undesirable aesthetic properties that the user may perceive as a lack of quality. This will ultimately lead to consumer dissatisfaction, or reduced compliance in product use.

Traditional emulsion systems also create difficulties in manufacturing. The need for heating and cooling systems, specialized high and low-shear mixing, and assorted additional processing devices makes the manufacture of emulsion systems very capital intensive. Further, the equipment specifications and energy requirements will vary from country to country. This situation will cause a modification in the processing variables thereby making it almost impossible to have a truly “global” manufacturing protocol. The energy needed to process such products can be significant and undoubtedly will add to the final cost of the finished unit. This is especially true in Europe and Asia where the price of energy is very expensive. Similarly, there is a long duration of time required to prepare a batch. It can take from 5 to 24 hours, or more, to complete the processing of emulsions depending on the batch size and number of sub-phases required. These concerns minimize manufacturing cacacity, add to the cost, and reduce the gross margin of the final product. The need for high temperature water or steam to heat the phases of the batch can cause damage to heat-sensitive actives such as retinoids and proteins. Prolonged heating of certain materials can accelerate the reaction of the active agent with other components in the emulsion, or with air, if the material is oxygen sensitive. For example, the exposure of unsaturated hydrocarbons, such as vegetable oils,

The presence of a significant amount of surfactant in an emulsion can strip the lipid barrier of the skin. It can also disrupt the lipid bilayer of epithelial cell membranes, thereby leaving the tissue vulnerable. The surfactants themselves may evoke an irritation. Furthermore, the resulting damaged skin barrier then can permit the passage of other materials that can cause irritation, or increase skin sensitivity. Figure 21.2 illustrates the migration of auxiliary emulsion components into the skin. These components include the preservative, chelating agent, fragrance, buffers, and actives. Migration of these components is sufficient to allow penetration deeply enough into the lower layers of the skin and evoke an irritation reaction. The literature is replete with clinical evidence of the damaging consequences that can occur with the use, or overuse, of such surfactants. Effendy and Maibach state that “many surfactants elicit irritant reactions when applied to the skin, partially due to their relative ability to solubilize lipid membranes.”[3] Barany, Lindberg, and Loden

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21.4 Surfactant-free Lamellar Phase (Lα) Dispersions: An Alternative to the Conventional Emulsification Process The current formulation paradigm has considerable vagaries. It is filled with difficulties in manufacturing and a potenFigure 21.2 Penetration of emulsion content into the skin. tially negative impact on the end user in view of compromised performance and irritation. It is, therefore, easy to understand the need claim that “the majority of adverse skin reactions to and desirability of finding an alternative approach to personal care products are presumed to be caused [4] the manufacture and formulation of conventional by substances like surfactants.” In view of their emulsion systems. Ideally, the resulting formulation surface-active nature, surfactants and emulsifiers would have the same, or improved aesthetic propercan alter membrane fluidity, disorganize lipid structies, and would be prepared without the use of traditure, denature both proteins and nucleic acids, distional surfactants and emulsifiers. But where can rupt barrier function, and release inflammatory mesuch a system be found? What means can be emdiators. The results of these actions on the skin can ployed that will allow two immiscible substances to lead to a variety of undesirable conditions; these inmix? The answer to these questions appears to lie clude redness, dryness, scaliness, swelling, and tightmore in the realm of physics than chemistry. Anness. Other conditions that can occur include itchother approach does, indeed, exist. It has been found ing, fissuring, stinging, roughness, and even clinical [5]–[11] that familiar hydrophobic materials (i.e., oils, waxes, conditions such as contact dermatitis. silicones, etc.) can be formed into stable aqueous dispersions via the application of an extraordinary high pressure, high shear process that utilizes unique 21.3.1 The “Eureka!” Moment blends of alkylated phosphatidyl choline (PC). •~ Emulsifier

• Fragrance

n Chelating agent

Interesting things happen when one uses physical methods instead of chemical methods to combine water and oil phases. Stable, surfactant-free dispersions emerge as a new possibility. It all began one day when the simple act of adding a dispersion of a sunscreen to water, thickened with a carrageenan biopolymer, opened a door that gave a glimpse into the future. My team at Collaborative Laboratories and I recognized the virtually unlimited potential of mixing various dispersions together. Having spent over twenty-eight years in developing or managing the creation of countless cosmetic and personal care products, I realized the new approach could resolve almost all of the issues that existed with the preparation of conventional emulsion systems. Further, the technology could be readily transferred to topical drug delivery, nutritional products, veterinary medicine, and even household and industrial applications.

Molecules of phosphatidyl choline and certain other phospholipids will spontaneously form assemblies with one another in water at extremely low concentrations. These assemblies are typically bilayers with the polar head group of the molecule interacting with the external and internal aqueous phases. Concurrently, the nonpolar, aliphatic portion of several molecules interacts with one another or with a non-polar fluid to form the bilayer. Phosphatidyl choline (PC) can form up to eleven different stereochemical assemblies in water depending on the alkyl groups present, the phase transition temperature of the molecule, the concentration of phosphatidyl choline present, the temperature at the time of formation, and the shearing energy applied during formation. Some of these assemblies are more thermodynamically stable than others.

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM Typically, assemblies formed above the temperature at which the molecule changes the structural character of the phospholipid (i.e., transition temperature) are more stable because of the lower entropy present. However, assemblies often transition to a less stable assembly as the system is cooled. Blends of phospholipids generally form more stable assemblies probably due to the synergistic packing of the phospholipids. Ideally, if one could introduce energy without the use of heat, then it would be possible to form more stable assemblies. One type of more stable assembly is known as the lamellar phase (Lα). A solution to the above stated problem is the introduction of high energy input at low temperatures. This can be achieved by exposing phospholipids to extremely high shear rates under extreme pressure. Such shear is achieved by having the fluid physically diverted into two channels that impinge upon one another in a chamber at velocities that can approach 500 m/sec. Further, the shearing action resulting from this geometry takes place under extremely high pressures ranging from 10,000 to almost 50,000 psi. Upon exiting the chamber, the fluid expands as it returns to atmospheric pressure, and this causes an ultra-efficient break-up of the hydrophobic material. Under the right combination of shear and pressure, enough energy can be imparted to allow almost instantaneous formation of extremely small droplets of the hydrophobic fluid which are stabilized by the concomitant formation of Lα phospholipid assemblies. Since the formation process is almost instantaneous, the amount of time that the process media needs to be exposed to high shear rates and extremely high pressures can be very short indeed! This time duration is so short, in fact, that the phospholipid assemblies formed do not have time to disassemble before they are no longer exposed to the shear and pressure conditions used to form them. Remarkably, by employing this procedure, lipophilic materials can be successfully incorporated into an otherwise all water-based product. The most important state in which the phospholipid assembly can exist for generating stable oil-inwater dispersions is the fluid lamellar or Lα phase, also known as the liquid crystalline phase. The liquid crystal phase exists as a transition between the solid and liquid states. The existence of this phase is only possible above the gel-to-liquid crystalline transition temperature (i.e., required energy level) of the

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phospholipid or mixture of phospholipids used. The gel-to-liquid crystalline transition temperature is defined by that amount of work input needed to change the structural character of the native phosphatidyl choline molecule that exists as a less stable Lβ phase (also known as a gel phase) to a more stable Lα phase. The Lα phase has two phospholipid assemblies that can form. The first type is the usual unilamellar or multilamellar phospholipid bilayer. This bilayer has large regions of water between the bilayers. Figure 21.3 is an illustration of a unilamellar liposome containing an encapsulated aqueous phase.

Figure 21.3 Liposome bilayer.

The second type of assembly that can form is the result of a conversion that occurs in the presence of relatively large amounts of hydrophobic materials and water. Here, the phospholipids rest at the surface of the hydrophobe droplet. The lipophilic tails of the phospholipids extend into the hydrophobe while the more polar heads of the phospholipids interact with the surrounding water to produce a micelle-like structure. Unlike many emulsions prepared by conventional means, the amount of hydrophobe that can be accommodated into a stable, water miscible dispersion can be greater than fifty percent by weight. Different hydrophobes vary in their ability to be incorporated into the stable Lα phase configuration. Generally, non-polar hydrophobes can be incorporated much more easily than more polar ones. Higher purity hydrophobes will usually be capable of incorporation at higher levels than those of lower purity. Most silicone derivatives can be incorporated at very high levels. Figure 21.4 is an illustration of a

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particle containing a high level of an oil whose surface is stabilized by the presence of phospholipid molecules.

Figure 21.4 Micelle-like phospholipid assembly of an oil.

the distribution of particle sizes for the micelles is extremely narrow. While a small amount of phospholipid is required for the formation of Lα dispersions, the resulting product can clearly be considered to be surfactant-free. The phospholipid molecules contained in the Lα dispersions have the tendency to self assemble into micelles even in the absence of a hydrophobe. This happens even when the concentration of phospholipid is extremely small (less than 10-10 millimolar). As a result of this behavior, the phospholipids produce essentially no irritation when applied to the skin. Further, they do not promote skin barrier damage, but rather promote its repair since phospholipids constitute a critical component of the cellular membrane. Oil dispersions made by the high pressure/high shear process, using these phospholipids, have a surface tension that is essentially the same as water. Figure 21.5 illustrates a comparison of the surface tension of pure water (73 dynes/cm), an Lα dispersion (71 dynes/cm), and a conventional oil-in-water emulsion (25 dynes). Figure 21.6 depicts the contact angle of a droplet of water on skin treated with an Lα dispersion (61°), a cationic emulsion (37°), an anionic emulsion (13°), and a conventional nonionic emulsion (15°). These data suggest that Lα dispersions are truly different than surfactant-based emulsions and, in fact, may be considered surfactant-free.

The critical aspect of the production of stable Lα-phase dispersions is processing at low temperatures and using high-energy input. The process used must exceed the energy level requirements needed for the transition from the gel phase to the liquid crystalline phase without actually heating the system to the transition temperature. The Lα-phase assembly must be formed in a fraction of a second, One of the most interesting aspects of the Lαand the conditions that allowed the assembly to form phase dispersions made by the high shear/high presmust then be removed immediately after the assemsure process is the viscosity of the final dispersion. bly formation is complete. The result of this process is a stable dispersion of highly concentrated hydrophobes that can, thereafter, be freely dispersed in water or water-based products. Typically the particle size of the micellar structures created during the process will be from 100 to 500 nanometers in diameter. This size is about 1/ 10 to 1/50 the size of particles produced by standard emulsification techniques. Further, the use of the high pressure, high shear processing described Figure 21.5 Surface tension of Lα dispersions and a conventional emulsion. above, is so efficient that

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM

Lα Dispersion (θ = 60.9°)

Cationic Emulsion (θ = 37.1°)

Anionic Emulsion (θ = 13.0°)

Non-ionic Emulsion (θ = 14.8°)

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Figure 21.6 Contact angle measurements of water on treated skin.

Typically, any stable emulsion containing 25% or higher concentration of petrolatum will have a Brookfield LVT viscosity measuring over 100,000 centipoise. By contrast, a high-shear, high-pressure processed dispersion of 25% petrolatum in water will have a much lower apparent viscosity in the range of less than about four hundred centipoise as recorded by a Brookfield LVT viscometer. As a result of this low viscosity, such dispersions can be readily sprayed by means of a finger-actuated pump sprayer. This astonishing difference is entirely due to the type of dispersions produced by the high shear, high pressure process. A formula containing 50% petrolatum, processed by the described high shear, high pressure process, is a stable, elegant lotion with an apparent Brookfield viscosity of approximately 4,000 centipoise. The exact same formula, made by conventional homogenization, has an initial viscosity of 360,000 centipoise, is extremely inelegant and is not stable at room temperature for more than seven days. Further, the high pressure, high-shear process imparts a negative charge or zeta potential on the

surface of the micelle that repels them from neighboring micelles. Therefore, the hydrophobic micelles are free to move past one another, thereby creating a low-viscosity, fluid environment. High molecular weight polydimethylsiloxanes, having a viscosity of 60,000 centipoise and higher, have an excellent skin feel when incorporated into a topically applied product, but their rubbery texture and chemical composition make them very difficult to successfully emulsify into a cosmetic or pharmaceutical composition. A 30% Lα-phase dispersion of such a high molecular weight dimethicone is a low viscosity liquid that is completely water dispersible! Lα dispersions can sometimes provide a method to incorporate ingredients that do not lend themselves to processing by any conventional emulsification system. For example, it is possible to make stable 30%–50% Lα-phase dispersions of fluorinated materials such as polytetrafluoroethylene and perfluoropolymethylisopropyl ether. These dispersions

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can be further diluted in water, even though neither of these two materials is considered to be easily emulsifiable by conventional means. Lα dispersions can be made with virtually any hydrophobic material by carefully controlling the selection of phospholipids and the processing conditions during manufacture. One interesting property of these dispersions is they can alter the aesthetic properties of virtually all materials. This feature results in the opportunity to create new sensations with familiar materials. Conventional materials such as petrolatum, lanolin, waxes, and natural oils are given a new “life” and purpose. Since the micelles of each hydrophobic material are made the same way, they are all independent of any surfactant, and, because they have approximately the same particle size and negative surface charge, there is no tendency for the micelles to coalesce. High pressure, high shear manufactured dispersions of various low polarity lipophilic agents (lipophiles) mix together readily, without issue. The practice of balancing the hydrophilic and lipophilic emulsifiers (HLB), depending on the composition of the lipophilic phase, that is used so commonly in the preparation of standard emulsion systems is now made obsolete by Lα systems. Thus, a virtually infinite array of lipophilic dispersions can be mixed, in any proportions, without creating any instability in the final blend.

21.5 Defining a Semiquantitative Aesthetic Scale A series of Lα dispersions can be prepared that have a range of aesthetic properties ranging from “very light,” with no residual feel to “very emollient” with a noticeable and prolonged residual feel. This range of properties permits the generation of a spectrum of tactile sensations that can be combined to create virtually any aesthetic experience. An arbitrary aesthetic scale from 1 to 1,000 can be established in order to describe the aesthetic properties of a given dispersion. Those having a light, rapidly absorbing property would be on the low end of the scale. Dispersions having a more unctuous, long-lasting effect, would be designated with a value at the higher end of the scale. Other lipophilic dispersions could then be assigned intermediate values depend-

ing on the degree of tactile properties they demonstrate. For example, a low viscosity, hydrogenated polyisobutene dispersion is assigned the number 100 for its light tactile impression and fleeting after-feel. By contrast, a cetearyl alcohol dispersion is assigned a value of 900 because of its pronounced emolliency and noticeable, prolonged waxy after-feel. Similarly, cylcomethicone, phenyl trimethicone, a higher viscosity hydrogenated polyisobutene, petrolatum, gelled silicone, and gelled hydrogenated polyisobutene have been assigned numbers of 200, 300, 400, 500, 600, and 700, respectively. Recently, dispersions of grape seed oil, cotton seed oil, olive oil, mineral oil, and cocoa butter have been developed. These have been assigned numbers of 250, 450, 650, 750, and 850, respectively. Mixing these dispersions creates a virtually limitless range of tactile properties. Statistically speaking, the mixing of the simple fifteen aesthetic-modifying dispersions described above, can produce fifteen factorial combinations (1.307 × 1012) when the concentration of each active modifier is constant! Table 21.4 is a chart that illustrates the effect of various aesthetic-modifying dispersions on the properties of a final product. When the concentrations are varied, almost limitless numbers of combinations of aesthetic behavior are possible. This effect is analogous to that obtained in the color field, where the blending of three primary colors (red, blue, and yellow) can create virtually any shade of color that exists simply by varying the ratio of each of these primary colors. History shows that, with these three agents, artists have been able to produce countless great masterpieces that possess myriad shades of colors. Lα dispersions of lipophilic performance materials (i.e., actives) can also be readily prepared. These materials provide the finished product with its functionality. Sunscreen agents such as ethylhexyl methoxycinnamate, octacrylene, and homosalate can be incorporated into stable Lα dispersions at levels from 30 to 50 wt%. Similarly, retinoids, vitamin E (α-tocopherol), α-bisabolol, polydimethylsiloxane, essential fatty acids, and petrolatum can be made into stable dispersions in order to provide the finished product with a range of useful properties: these include anti-aging, antioxidant, anti-inflammatory, moisturization, and skin protectant features. Such

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM dispersions are completely compatible with the Lα dispersions used to modify the aesthetic properties. Since all of the dispersions discussed thus far are made essentially devoid of traditional surfactant, they offer a powerful new degree of flexibility since they are compatible with the sophisticated delivery systems being created for pharmaceutical and

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personal care applications (Table 21.1). Liposomes, nanospheres, encapsulates, and many other types of delivery systems maintain their integrity when mixed with Lα dispersions. By contrast, emulsifiers and other surfactants rapidly disrupt such systems, which makes them valueless in the formulated product.

Table 21.4. Properties of Aesthetic Modifying Dispersions

Aesthetic Modifier*

Initial Feel

Absorbency/ Playtime

Residual

AM 100

Very light

Short

Low, smooth

AM 200

Very light

Short

AM 300

Light

Medium

AM 400

Light but with richer texture

Medium

Comments Increases opacity of final product. Oil-free.

Helps to reduce any tackiness in Emollient with finished product. Imparts a matte smooth after-feel finish. Light, silky after-feel

Helps to minimize tackiness in finished product. Provides "dry" emolliency to the end-feel.

Emollient with slight tackiness

Use in products for normal-oily skin. Consider using AM 200 or AM 300 to eliminate any tack. Increases opacity of final product.

Slightly unctuous Tackiness can be reduced with rub in with rich, AM 200 or AM 300. Provides slightly tacky good residual feel. after-feel

AM 500

Rich

Medium

AM 600

Elegant texture

Short

AM 700

Rich

Long

Unctuous, slighty Excellent waterproofing agent for tacky emollient sunscreens. after-feel

Long

Unctuous, waxy after-feel

Tackiness can be reduced with AM 200 or AM 300. Increases viscosity.

Waxy

Increases opacity of final product. Adds body with elegant waxy after-feel. Reduces tackiness.

AM 800

AM 900

Rich, heavy

Very rich

Very long

Emollient, silky after-feel

Good moisture barrier. Ideal for sunscreens and waterproofing. Reduces tack and drag.

* Asthetic modifiers are oil-in-water dispersions manufactured by Collaborative Laboratories.

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21.6 Formulating with Lα Dispersions – System 3™ The Lα dispersions are freely miscible with water and can be infinitely diluted if desired. The dilution process simply reduces their viscosity. However, if the water is first thickened with a natural or synthetic rheological-modifying agent, then the addition of the Lα dispersions creates a product that looks and feels like traditional emulsion systems. Examples of such rheological modifying agents include: carbohydrate polymers such as xanthan gum or acrylate-based polymers like Carbomer. Depending on the amount of the thickening agent or agents used, the final form of the formulated product can be designed to be a thick cream, a soft cream, a lotion, a serum, or even a low-viscosity fluid. Virtually every aqueous thickening agent is compatible with the Lα dispersions. However, materials such as xanthan gum, methacrylate polymers or copolymers, starches, and silicates that introduce thixotropy (i.e., viscosity decreases with time at constant shear rate), permit the formulation of elegant finished goods. If the final system is to be acidic, or contain significant amounts of acids such as alpha-hydroxy acids, then the use of xanthan gum, sclerotium gum, hydroxethyl cellulose, magnesium aluminum silicate, carrageenan, and modified starches is recommended for use with Lα dispersions. Other potentially useful polymeric thickening materials can be found in Table 21.2. These thickened water phases should contain little, preferably no, surfactant. The presence of surfactant can perturb the stability of the surfactantfree dispersions, or the delivery systems selected for the desired active ingredients. Water soluble performance ingredients such as glycerin, vitamin C, or herbal extracts can be added directly to the thickened aqueous phase. Products can be made that are indistinguishable from standard emulsion systems. More importantly, formulations with unique aesthetic and performance properties can be prepared that enhance the enjoyment of the customer during use. The preparation of surfactant-free formulas requires three components: a thickened water phase, a selection of L α dispersions to produce the desired aesthetic properties (i.e., System 3™), and an active, or performance material. The active can be present by itself, or incorporated into a delivery system. This combination of materials provides the

final product with its functionality. They may be combined concurrently, or sequentially. Since the particle size of the lipophilic dispersions are already preestablished by the high pressure, high shear processing, they can be simply mixed into the thickened water phase with gentle agitation at room temperature. The rheological properties demonstrated are primarily due to the presence of the thickening agents employed. They are completely independent of the complex processing conditions required to make conventional emulsions. No heat or extraordinary processing conditions are required. More remarkably, these systems are far more stable than their emulsifier-based counterparts. The hydrated thickening agent(s) provide a matrix into which the Lα aesthetic and performance dispersions are embedded. As long as the thickening agent retains its integrity at various temperatures, then the product will maintain its stability. Thus, unlike ordinary emulsions, these dispersions have the potential to be thermodynamically stable indefinitely!

21.7 System 3™ Advantages Surfactant-free formulating has many advantages. The time development, from concept to the market place, is dramatically reduced. There is no longer a need for the preparation of multiple, redundant formulations. Laboratory efficiency can be increased dramatically. Typically, surfactant-free formulations can be prepared in 10–15 minutes. This allows a formulator to prepare 30 or more prototypes daily. This acceleration in speed of formulation variation is amenable to the effective use of statistically designed experiments. The aesthetic and rheological properties of the product can be evaluated immediately. There is no need to wait overnight to determine the properties of the product, as is often the case with standard emulsions. Greater flexibility and rapid formulation changes are possible. Since the products are devoid of traditional surfactants, they are less irritating to the skin. A much wider range of aesthetic product types can be made. The compounding of surfactant-free formulations is a cold process that readily scales to manufacturing conditions. The need for multiple pilot batches to optimize the processing conditions is virtually eliminated.

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM Surfactant-free formulations have distinct advantages in manufacturing as well. They are significantly less expensive to produce. The process conditions are uncomplicated. Labor, overhead, and processing time can be reduced from 50% to 75%. This improvement in production efficiency results in plant capacity increases without any additional capital investment. If capital equipment is needed, it will generate savings of about 70%–80% as compared to processing equipment needed for the manufacture of conventional emulsions. Since no heating and cooling is required, energy savings can be greater than 90%. There are fewer materials to compound, and no sub-phases are required. Quality is dramatically improved since it is much easier to insure batch-tobatch reproducibility. There is little waste, and virtually no “rework” of a batch is required. Kettle dwell time is greatly reduced, and the product can be transferred directly to the filling line once ingredient additions are completed. In fact, continuous processing is possible. Finally, the ease of manufacturing enables the product made with Lα dispersions to be made exactly the same in any location in the world. Perhaps most importantly, the consumer benefits from the use of surfactant-free formulations. The Lα-based systems are potentially more efficacious and less irritating. Therefore, they will have much greater consumer appeal. The integrity of liposomes and other delivery systems is maintained since the Lα-based systems are essentially surfactant free. This permits the optimal penetration of the desired physiologically active ingredients, while retarding the penetration of unwanted materials. Further, liposomes are completely compatible with the System 3 vehicle. Figure 21.7 shows the long-term stability of the liposome when stored at elevated temperatures in a System 3 base. System 3 formulations have other interesting properties that enable them to serve as the ideal vehicle for various delivery systems. This capability is the basis for calling Sytem 3 formulations, “The delivery systems’ delivery system.” As stated previously, since no surfactant is present, the System 3 vehicle has a surface tension essentially the same as water (see Fig.

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21.5). When applied to a surface like hair or skin, the lipid barrier of the substrate is not compromised. Penetration of the active is then controlled by the nature of the delivery system and not by the properties of the vehicle. This is extremely important because it allows the formulator to fully describe any beneficial or negative effects solely based on the properties of the contained active, without any confounding effect of the vehicle. The use of System 3 typically provides lower penetration of the vehicle components into the skin and, consequently, irritation potential is reduced as compared to standard emulsion. Because of the low penetration, the uniformity of the resulting layer of product on the skin allows for an even distribution of the active and/or the delivery system at the skin surface. This property is readily confirmed when 20.0% of a nanodispersion containing 37.5% ethylhexyl methoxycinnamate and 10.0% butylmethoxydibenzoylmethane is added to a System 3 vehicle so that the concentration in the final product is 7.5% and 2%, respectively. (See Formulation 21.1 at the end of the chapter.) The sun protection factor (SPF) performance of this formula is compared with a conventional surfactant-based emulsion containing the same level of sunscreen in Fig. 21.5. It can be seen that there is essentially a doubling of the SPF value when the System 3 vehicle is employed. Another added advantage observed is that the System 3 formula is essentially waterproof, whereas the conventional emulsion vehicle is not. In fact, the conventional emulsion vehicle would require the addition of supplemental waterproofing agents to achieve this effect.

Figure 21.7 Compatibility of liposomes in a System 3TM base.

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The System 3 method is appropriate for virtually any personal care or pharmaceutical application. However, it should be the method of choice with products designed for children, or for anyone with compromised, or sensitive skin. New, unique aesthetic properties can be imparted to the formulated product, thereby creating more elegant systems, and heightening the enjoyment of using the preparation. Since the quality of the product can be maintained so tightly, the consumer will experience the same benefits from purchase to purchase. Brand loyalty will increase with greater compliance to the usage directions.

21.8 Conclusion Surfactant-free formulating offers many advantages versus the conventional method of making emulsifier-based cosmetic, personal care, and drug

products. The compatibility of such Lα-based systems with delivery systems and with the emerging therapeutic agents makes System 3 an ideal formulating vehicle. The novel technical approach provided by System 3 opens the door for a whole new range of possibility for today’s cosmetic chemist. This approach offers a distinction in kind, rather than degree. Its power is so great that it requires cosmetic chemists to enter an unfamiliar realm and think with a completely new mindset. Formulators must be willing to let go of their old “tried and true” ways of thinking about formulating. They must be willing to accept ideas contradictory to well-learned and deeply ingrained principles. If the formulating chemist is truly open to new approaches for creating unique and highly efficacious products, then the use of surfactant-free formulating will provide him (or her) with a powerful new tool that will assist in the development of the next generation of superior personal care and pharmaceutical products.

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21.9 Formulations The Lα dispersions that constitute the System 3 formulating method described in this chpater can be mixed to create topical compositions that possess an almost infinite level of aesthetic diversity. They are generally compatible with the actives and delivery systems being used in today’s cosmetic, OTC,

and pharmaceutical preparations. These properties offer the consumer a wide range of tactitle and visual experiences as well as enhanced performance benefits. Some examples of products that can be made with these dispersions can be found the folowing formulations.

Formulation 21.1: Suncare: SPF 15 Lotion

Phase

Ingredient Moisturizing base

Function

Weight %

Viscosity control

35.25

Deionized water

A

16.75

Advanced moisture complex

Moisturization

1.00

Aesthetic Modifier - 200

Emollient

9.50

Aesthetic Modifier - 300

Emollient

4.50

Aesthetic Modifier - 400

Emollient

11.50

Solarease II

Sunscreen

20.00

Germazide MPB

Preservative

0.50

Liposomes C and E

Antioxidant

1.00 Total

100.00

Mixing Procedure 1. Weigh the moisturizing base into a vessel large enough for the entire batch. 2. With propeller and sweep agitation, add deionized water and mix until a smooth, uniform lotion results. 3. With continued mixing, sequentially add the remaining ingredients ensuring the product is smooth and uniform before adding the next ingredient. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.2: Suncare: SPF 50 Plus Cream – Mixed Chemical and Physical Sunscreens

Phase A

B

Ingredient

Function

Weight %

Cationic/acid stable base

Viscosity control

18.30

Germazide MPB

Preservative

TioSperse Ultra TN

Sunscreen

25.00

Solarease OMC/B3

Sunscreen

25.00

SanSurf OC/OS

Sunscreen

25.00

Eusolex HMS

Sunscreen

5.00

Liposomes C and E

Antioxidant

1.00

0.70

Total:

100.00

Mixing Procedure 1. Weigh cationic/acid stable base into a vessel large enough for the entire batch. 2. Add Germazide MPB with propeller and/or sweep agitation. 3. Sequentially add ingredients in Phase B to the main batch. 4. Mix entire batch until it is smooth and uniform. Use homogenizer to increase smoothness and gloss. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.3: Suncare: SPF 50 Plus Cream – Chemical Sunscreen

Phase A

B

Ingredient Lotion base

Function

Weight %

Viscosity control

Deionized water

37.00 11.30

Germazide MPB

Preservative

0.70

Aesthetic Modifier - 100

Emollient

5.00

Aesthetic Modifier - 200

Emollient

5.00

Solarease Plus

Sunscreen

30.00

Uvinul N-539-SG (Octocrylene)

Sunscreen

10.00

Liposomes C and E

Antioxidant

1.00 Total

100.00

Mixing Procedure 1. Weigh lotion base into a vessel large enough for the entire batch. 2. Slowly add deionized water to main batch and mix with propeller and/or sweep agitation until system is smooth. 3. Sequentially add ingredients in Phase B and mix until smooth. 4. Mix entire batch until completely uniform. Use a homogenizer to achieve a smooth, glossy appearance. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.4: Suncare: Self-Tanning Lotion with Sunscreen Liposomes

Phase

Ingredient

Function

Weight %

Deionized water

72.03

Germazide MPB

Preservative

1.50

Keltrol CG-RD (Xanthan gum)

Thickening agent

0.18

Magnesium aluminum silicate (veegum ultra)

Thickening agent

1.40

Sodium carboxmethylcellulose (CMC 7MF)

Thickening agent

0.56

Unisene 99K (Glycerin, 99%)

Humectant

3.00

Aesthetic Modifier - 300

Emollient

8.00

Sunscreen liposomes

UV absorber

5.00

C

Unitone DH (dihydroxyacetone, 60% aqueous)

Self-tanning agent

8.33

D

Unicept CA (citric acid, 20% aqueous)

pH adjustment

Q.S.

A

B

Total

100.00

Mixing Procedure 1. Weigh deionized water into a vessel large enough for the entire batch. Mix sufficiently to form a vortex. Add Germazide MPB. 2. Sprinkle in the remainder of Phase A and mix until a smooth, uniform fluid results. 3. Sequentially add the ingredients in Phase B and mix until smooth. 4. Add Phase C and mix until smooth. 5. Add a sufficient amount of Phase D to adjust pH to between 5 and 6. 6. Mix entire batch until smooth and uniform. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.5: Suncare: After-Sun Lotion

Phase

A

Ingredient

Function

Lotion base

Viscosity control

Advanced moisture complex

Humectant

Weight % 35.00 5.00

Deionized water

B

C

20.40

Germaben II

Preservative

0.50

Aesthetic Modifier – 500

Emollient

10.00

Aesthetic Modifier – 600

Emollient

10.00

Aesthetic Modifier – 700

Emollient

10.00

Aesthetic Modifier – 750

Emollient

5.00

SanSurf bisabolol

Anti-irritant

2.00

Activera liposomes

Soothing agent

1.00

Ultrasomes

Repair UV damage

0.50

Photosomes

Repair UV damage

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Add lotion base to a vessel large enough to contain the entire batch. Mix with propeller and sweep-blade agitation. 2. Slowly add the deionized water and mix batch until it is smooth. 3. Add the advanced moisture complex and mix batch until smooth. 4. Sequentially add the ingredients in Phase B, mixing each until uniform before adding the next ingredient. 5. Add fragrance (if desired) and mix batch until smooth and uniform. Use a homogenizer to assist in this process, if necessary. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.6: Moisturizer: Moisturizing Lotion with Moisturizing Liposomes

Phase

Ingredient

Function

Deionized water

A

B

C

Weight % 55.74

Germazide MPB

Preservative

1.50

Keltrol CG-RD (Xanthan gum)

Thickening agent

0.18

Magnesium aluminum silicate (veegum ultra)

Thickening agent

1.00

Sodium carboxmethylcellulose (CMC 7MF)

Thickening agent

0.25

Unisene 99K (Glycerin, 99%)

Humectant

3.00

Aesthetic Modifier AM – 300

Emollient

33.33

Moisturizing liposomes

Humectant

5.00

Fragrance

q.s. Total

100

Mixing Procedure 1. Weigh deionized water into a vessel large enough for the entire batch. Mix sufficiently to form a vortex. Add Germazide MPB. 2. Sprinkle in the remainder of Phase A and mix until a smooth, uniform fluid results. 3. Sequentially add the ingredients in Phase B and mix until smooth. 4. Add Phase C and mix until smooth. 5. Mix entire batch until smooth and uniform. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards

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Formulation 21.7: Moisturizer: Moisturizing Cream for Oil Skin

Phase

Ingredient Lotion base

A

B

C

Function

Weight %

Viscosity control

38.00

Deionized water

14.90

Aesthetic Modifier - 900

Emollient

8.50

Advanced moisture complex

Humectant

5.00

Germaben II

Preservative

0.50

Unilene BG (butylene glycol)

Moisturizing agent, viscosity control

4.00

SeaMollient

Moisturizing agent, viscosity control

1.50

Aesthetic Modifier - 100

Emollient

8.50

Aesthetic Modifier - 200

Emollient

8.50

Aesthetic Modifier - 300

Emollient

8.50

Humectant liposomes

Moisturizing agent

1.00

Moisturizing liposomes

Moisturizing agent

1.00

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh lotion base in a vessel large enough for the entire batch. 2. Slowly add the deionized water to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the advanced moisture complex and mix the batch until smooth. 4. Add the Aesthetic Modifier - 900 to the batch and mix until it is uniformly dispersed throughout. 5. Sequentially add the ingredients in Phase B to the main batch and mix until smooth and uniform. 6. Add fragrance and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.8: Moisturizer: Moisturizing Cream for Normal Skin

Phase

Ingredient Lotion Base

A

B

C

Function

Weight %

Viscosity control

40.00

Deionized water

22.40

Advanced moisture complex

Humectant

5.00

Germaben II

Preservative

0.50

Aesthetic Modifier - 400

Emollient

8.50

Aesthetic Modifier - 500

Emollient

8.50

Aesthetic Modifier - 600

Emollient

8.50

Humectant liposomes

Moisturizing agent

1.00

Moisturizing liposomes

Moisturizing agent

1.00

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh lotion base in a vessel large enough for the entire batch. 2. Slowly add the deionized water to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the advanced moisture complex and mix the batch until smooth. 4. Sequentially add the ingredients in Phase B to the main batch and mix until smooth and uniform. 5. Add fragrance and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.9: Moisturizer: Moisturizing Cream for Dry Skin

Phase

A

B

C

Ingredient

Function

Weight %

Moisturizing base

Viscosity control

49.40

Advanced moisture complex

Humectant

5.00

Aesthetic Modifier - 900

Emollient

19.00

Germaben II

Preservative

0.50

Unilene BG (butylene glycol)

Moisturizing agent, viscosity control

5.00

SeaMollient

Moisturizing agent, viscosity control

2.00

Aesthetic Modifier - 400

Emollient

8.50

Aesthetic Modifier - 600

Emollient

8.50

Humectant liposomes

Moisturizing agent

1.00

Moisturizing liposomes

Moisturizing agent

1.00

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh moisturizing base into a vessel large enough for the entire batch. 2. Slowly add the advanced moisture complex to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the Aesthetic Modifier - 900 and mix the batch until it is uniformly dispersed throughout. 4. Sequentially add the ingredients in Phase B to the main batch and mix until smooth and uniform. 5. Add fragrance and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.10: Moisturizer: Moisturizing Lotion

Phase

A

Ingredient

Function

Weight %

Lotion base

Viscosity control

35.00

Advanced moisture complex

Humectant

5.00

Deionized water

B

C

27.40

Germaben II

Preservative

0.50

Aesthetic Modifier - 400

Emollient

10.00

Aesthetic Modifier - 500

Emollient

10.00

Aesthetic Modifier - 600

Emollient

10.00

Humectant liposomes

Moisturizing agent

1.00

Moisturizing liposomes

Moisturizing agent

1.00

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh moisturizing base into a vessel large enough for the entire batch. 2. Slowly add the advanced moisture complex to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the Aesthetic Modifier - 900 and mix the batch until it is uniformly dispersed throughout. 4. Sequentially add the ingredients in Phase B to the main batch and mix until smooth and uniform. 5. Add fragrance and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.11: Anti-aging: Anti-aging Cream

Phase

A

B

C

Ingredient

Function

Weight %

Moisturizing base

Viscosity control

45.00

Advanced moisture complex

Humectant

4.00

Deionized water

24.40

Aesthetic Modifier - 900

Emollient

8.00

Germaben II

Preservative

0.50

Unilene BG (butylene glycol)

Moisturizer/viscosity control

5.00

Aesthetic Modifier – 600

Emollient

5.00

Aesthetic Modifier - 700

Emollient

5.00

MatrixyL

Collagen stimulation

0.50

AHA Liposomes

Desquamation

1.00

Actizyme E3M-M

Desquamation

0.50

Rovisome ACE

Antioxidant

0.50

Liposome centella

Collagen stimulation

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Add moisturizing base to a vessel large enough to contain the entire batch. Mix with propeller and sweep-blade agitation. 2. Slowly add the deionized water and mix until the batch is completely smooth. 3. Add the advanced moisture complex and mix batch until smooth. 4. Add Aesthetic Modifier - 900 and mix until the batch is completely uniform. 5. Sequentially add the remaining ingredients in Phase B, mixing each until uniform before adding the next ingredient. 6. Add fragrance (if desired) and mix batch until smooth and uniform. Use a homogenizer to assist in this process if necessary. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.12: Anti-aging: Serum

Phase

Ingredient

Function

Weight %

Deionized water A

B

C

71.05

Universene NA2 (disodium EDTA)

Chelating agent

0.05

Germazide MPB

Preservative

1.00

Keltrol CGRT

Viscosity control

0.60

Unicolic G7 (glycolic acid)

Desquamation

1.50

Unichem LACA (lactic acid, 88%)

Desquamation

5.00

Unichem SOHY25 (sodium hydroxide, 25%)

pH Adjustment

3.10

Aesthetic Modifier - 500

Emollient

10.00

Aesthetic Modifier - 600

Emollient

5.00

MatrixyL

Collagen stimulation

0.10

AHA Liposomes

Desquamation

1.00

Actizyme E3M-M

Desquamation

0.50

Rovisome ACE

Antioxidant

0.50

Liposome centella

Collagen stimulation

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Add deionized water to a vessel large enough to contain the entire batch. Mix with propeller agitation. 2. Sequentially add EDTA and Germazide MPB mixing each until dissolved before adding the next ingredient. 3. Slowly sprinkle Keltrol CGRT into the batch and mix until smooth and uniform. 4. Sequentially add the remaining ingredients in Phase B mixing until the batch is uniform before the addition of the next ingredient. 5. Add fragrance, if desired, and mix until a smooth, uniform fluid results. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.13: Anti-acne: Lotion with Salicylic Acid in Cyclodextrin

Phase

Ingredient

Function

Weight %

Deionized water A

B

68.00

Universene NA2 (disodium EDTA)

Chelating agent

0.05

Germazide MPB

Preservative

1.00

Keltrol CGRT

Viscosity control

0.60

Unicolic G7 (gycolic acid, 99%)

Exfoliant

1.00

Unichem LACA (lactic acid, 88%)

Exfoliant

0.60

Unichem SOHY 25 (sodium hydroxide, 25%)

pH adjustment

1.75

SanSurf Bisabolol

Anti-inflammatory

2.00

Aesthetic Modifier - 200

Emollient

5.00

Salidex

Active (salicylic acid) in cyclodextrin Total

20.00 100.00

Mixing Procedure 1. Weigh the deionized water into a vessel large enough for the entire batch. Begin mixing with propeller agitation. 2. Sequentially add the Disodium EDTA and Germazide MPB. 3. Increase the propeller speed to make a vortex and slowly sprinkle in the Keltrol CGRT and mix until smooth and uniform. 4. Sequentially add the remaining ingredients, mixing each until uniform. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

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Formulation 21.14: Lightening: Serum

Phase

Ingredient

Function

Weight %

Deionized water A

B

C

79.65

Universene NA2 (disodium EDTA)

Chelating agent

0.05

Germazide MPB

Preservative

1.00

Keltrol CGRT

Viscosity control

0.60

Unicolic G7 (glycolic acid)

Desquamation

1.00

Unichem LACA (lactic acid, 88%)

Desquamation

0.60

Unichem SOHY25 (sodium hydroxide, 25%)

pH adjustment

2.00

Unojic A (kojic acid)

Tyrosinase inhibitor

1.00

Vitagen

Pigment inhibitor

0.50

Aesthetic Modifier - 600

Emollient

Rovisome C

Pigment inhibitor

0.50

Melarrest L

Pigment inhibitor

3.00

Actizyme E3M-M

Desquamation

0.50

10.00

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Add deionized water to a vessel large enough to contain the entire batch. Mix with propeller agitation. 2. Sequentially add EDTA and Germazide MPB mixing each until dissolved before adding the next ingredient. 3. Slowly sprinkle Keltrol CGRT into the batch and mix until a uniform, smooth fluid results. 4. Sequentially add the remaining ingredients in Phase B mixing until the batch is uniform before the addition of the next ingredient. 5. Add fragrance, if desired, and mix until a smooth, uniform fluid results. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM

469

Formulation 21.15: Anti-oxidant: Cream

Phase

A

Ingredient

Function

Lotion base

Viscosity control

Advanced moisture complex

Humectant

Weight % 40.00 5.00

Deionized water

B

C

22.80

Germaben II

Preservative

0.50

Aesthetic Modifier - 400

Emollient

10.00

Aesthetic Modifier - 500

Emollient

10.00

Aesthetic Modifier - 600

Emollient

10.00

Scavenol

Antioxidant blend

0.50

Actiquench GTP 20

Antioxidant

0.50

Oxyzomes

Antioxidant

0.50

Coenzyme Q10 Liposomes

Antioxidant

0.10

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh lotion base in a vessel large enough for the entire batch. 2. Slowly add the deionized water to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the advanced moisture complex and mix the batch until smooth. 4. Sequentially add the ingredients in Phase B to the main batch and mix until smooth and uniform. 5. Add fragrance, if desired, and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

470

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 21.16: Body Care: Anti-cellulite Lotion

Phase

A

Ingredient

Function

Lotion base

Viscosity control

Advanced moisture complex

Humectant

Weight % 35.00 5.00

Deionized water

B

C

41.90

Chlorelline

Skin revitalizing agent

0.50

Germaben II

Preservative

0.50

Aesthetic Modifier – 100

Emollient

5.00

Aesthetic Modifier – 200

Emollient

5.00

Aesthetic Modifier - 300

Emollient

5.00

Firming liposomes

Firming agent

1.00

Vexel

Slimming agent

0.50

Phytotal SL

Slimming agent

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Add lotion base to a vessel large enough to contain the entire batch. Mix with propeller and sweep-blade agitation. 2. Slowly add the deionized water and mix until the batch is completely smooth. 3. Add the advanced moisture complex and mix batch until smooth. 4. Add Chlorelline and mix until uniform. 5. Sequentially add the remaining ingredients in Phase B, mixing each until uniform before adding the next ingredient. 6. Add fragrance (if desired) and mix batch until smooth and uniform. Use a homogenizer to assist in this process, if necessary. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

WILMOTT, AUST, BROCKWAY, KULKARNI: THE DELIVERY SYSTEMS’ DELIVERY SYSTEM

471

Formulation 21.17: Body Care: Hand and Body Lotion

Phase

A

B

C

Ingredient

Function

Wt. %

Lotion base

Viscosity control

35.00

Advanced moisture complex

Humectant

5.00

Deionized water

28.40

Aesthetic Modifier - 900

Emollient

1.00

Germaben II

Preservative

0.50

Aesthetic Modifier - 500

Emollient

10.00

Aesthetic Modifier - 600

Emollient

10.00

Aesthetic Modifier - 700

Emollient

9.00

Humectant liposomes

Moisturizing agent

0.50

Unisene 99K (glycerin)

Humectant

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh Lotion base in a vessel large enough for the entire batch. 2. Slowly add the deionized water to the batch with propeller and/or sweep agitation. Mix until smooth and uniform. 3. Add the Advanced moisture complex and mix the batch until smooth. 4. Add the Aesthetic Modifier – 900 and mix until the batch is completely smooth and uniform. 5. Sequentially add the ingredients in Phase B to the main batch mixing each until the batch is smooth and uniform before adding the next ingredient. 6. Add fragrance if desired and mix until uniform. Use a homogenizer if desired to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

472

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 21.18: Hair Care: Styling Cream

Phase

A

Ingredient

Function

Lotion base

Viscosity control

Advanced moisture complex

Humectant

Weight % 50.00 1.50

Deionized water

B

C

31.40

Germaben II

Preservative

0.50

Aesthetic Modifier - 300

Emollient

PVP/VA W735

Hair fixative

6.00

Humectant liposomes

Moisturizing agent

0.50

Fragrance

0.10 Total

100.00

Mixing Procedure 1. Weigh lotion base in a vessel large enough for the entire batch. 2. Slowly add the deionized water to the batch with propeller and/or sweep agitation. Mix until completely smooth and uniform. 3. Add the advanced moisture complex and mix the batch until smooth. 4. Sequentially add the ingredients in Phase B to the main batch mixing each until the batch is smooth and uniform before adding the next ingredient. 5. Add fragrance, if desired, and mix until uniform. Use a homogenizer, if desired, to make the final product smooth and glossy. This formula is offered for informational purposes to represent a particular product concept. There is no expressed or implied warrantee regarding its use in commerce. The authors are not responsible and should be held harmless for any regulatory, legal, performance or safety liabilities that that may result from its use. Each individual or company is encouraged to conduct the appropriate due diligence to insure the formula meets internal corporate standards.

References

6. Rieger, M., Cosmetics and Toiletries, 110(4) (1995)

1. Jass, H. E., The Chemistry and Manufacture of Cosmetics, 2nd Ed., (M. G. DeNavare, ed.), p. 237, Continental Press, Orlando (1975)

7. Kawasaki, Y., Quan, D., Sakamoto, K., and Maibach, H. I., 18th International IFSCC Congress, pp. 37–50 (1994)

2. Henry, C. M., Chemical and Engineering News, 80(34) (2002)

8. Casterton, P. L., Potts, L. F., and Klein, B. D., Toxicology In Vitro, 8(4) (1994)

3. Effendy, I., and Maibach, H. I., Contact Dermatitis, 33(4) (1995)

9. Bielfeldt, S., Parfuem Kosmet, 71(5) (1990)

4. Barany, E., Lindberg, M., and Loden, M., Contact Dermatitis, 40(2) (1999)

10. Walters, K. A., Methods for Predicting the Effect of Surfactants on Skin, Seminar at In Cosmetics, Birmingham, UK (1990)

5. Rhein, L. D., J. Society of Cosmetic Chemists, 48(5) (1997)

11. Zeidler, U., J. Society of Cosmetic Chemists, Japan, 20(1) (1986)

22 Preparation of Stable Multiple Emulsions as Delivery Vehicles for Consumer Care Products Study of the Factors Affecting the Stability of the System (w1/o/w2) Mouhcine Kanouni* and Henri L. Rosano The City College of the University of New York Department of Chemistry New York, New York

22.1 Introduction/Objectives ................................................................. 474 22.1.1 Uses and Application/Objectives ..................................... 474 22.1.2 Multiple Emulsion Stability ................................................ 475 22.1.3 Other Factors Affecting Stability of Multiple Emulsions ... 475 22.2 Materials/Methods ......................................................................... 475 22.2.1 Materials ........................................................................... 475 22.2.2 Methods............................................................................ 476 22.2.3 Mechanical Equipment ..................................................... 476 22.2.4 Evaluation Techniques ..................................................... 476 22.3 Experiments ................................................................................. 479 22.3.1 Surface Isotherms ........................................................... 479 22.3.2 Particle Size Determination ............................................. 480 22.3.3 Pendant Drop Method to Measure Dynamic Interfacial Tension ............................................................................. 480 22.4 Results and Discussion ............................................................... 480 22.4.1 Monolayer Experiments—Study of the Primary Interface .... 481 22.4.2 Investigation of Polyglycerol Ester of Ricinoleic Acid ....... 484

* Present address: Faculty Natural Science Dept., Hostos Community College, Bronx, New York Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 473–498 © 2005 William Andrew, Inc.

474

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 22.4.3 Interactions Between the Low- and High-HLB Emulsifiers at the o/w2 Interface ...................................... 485 22.4.4 Determination of the Minimum Amount of Primary Surfactant to be Used in the Preparation of the w1/o Emulsion ....................................................... 487 22.4.5 Determination of the Optimum Amount of Solute Necessary to Stabilize the Primary w1/o Emulsion and the w1/o/w2 Multiple Emulsion .................................. 488 22.4.6 Selection Criteria for the Water Soluble Polymeric Thickener ......................................................................... 489 22.4.7 Influence of the Concentration of the Betaine/Sodium Lauryl Ether Sulfate Mixture on the Rheological Properties of Xanthan Gum and the Resulting w1/o/w2 Stability ...... 489 22.4.8 Droplet Breakup in Double Emulsion Systems ................ 493 22.5 Measurement of the Dynamic Interfacial Tension Oil/Water Using the Pendant Drop Tensiometer Method. ............................. 493 22.5.1 The Pendant Drop Technique .......................................... 493 22.5.2 Equilibrium Adsorption Measurement and Discussion .... 494 22.6 Conclusion .................................................................................... 494 References ......................................................................................... 496

22.1 Introduction/Objectives

cream formulations to yield a more agreeable aqueous feel than the typically oily texture.

22.1.1 Uses and Application/ Objectives

On the work reported in this chapter, the first objective targeted was to be able to formulate a stable double emulsion w1/o/w2 with a concentration of 15% surfactant in the outside aqueous phase w2. By contrast with all previous formulations described in the literature, which contain, at most, 2% to 4% of surfactant in w2,[5] this was an ambitious venture. The target of 15% was chosen to meet surfactant levels of some cosmetic industrial standard for good foaming. The second objective of this work was to formulate a multiple emulsion using soybean oil as the oil phase, as most cosmetic formulators are now trying to avoid the use of mineral oil in their products. In most of the previous studies[1]–[3] reviewed, paraffin or mineral oil had been used. In the rare instances when soybean oil was employed, difficulty had arisen in stabilizing the multiple emulsions with edible compounds.[8] It is believed that the difficulty in obtaining a stable double emulsion with soybean oil was due to its higher solubility in water than mineral oil.

Currently, multiple emulsions are infrequently used. However, their potential applications are numerous and the studies of these systems are now an active field of research.[1]–[5] This is especially true in such product areas as drug-delivery systems, cosmetics, and foods. Water/oil/water (w1/o/w2) emulsions allow the encapsulation of active molecules in the internal aqueous phase. This capability allows the masking of tastes and/or smells, and protections against oxidation, light, or enzymatic degradation. It also provides controlled liberation of the active ingredients, with the trigger being dilution, shearing, or agitation. Examples of research on multiple emulsions containing insulin in the internal aqueous phase have been tested orally on diabetic rats.[6] In cosmetic or food-chemistry applications, multiple emulsions have the potential to allow mayonnaise, sauces, or hand-

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES 22.1.2

Multiple Emulsion Stability

Previous studies on the stabilization of multiple emulsions. The stability and formation of multiple emulsions has been intensively studied recently.[7]–[9] From a theoretical and practical point of view, it was determined that balancing the osmotic pressure with the Laplace pressure[10] was an effective technique to avoid Ostwald ripening.[11] In addition, the physical-chemical properties of the surfactants at the o/w2 interface and the interaction of the high-HLB (hydrophile-lipophile balance) surfactants dissolved in the aqueous phase were found to play a major role in the stability of the emulsions. Thus, Rosano, et al.,[10] and Ficheux, et al.,[12] have found that increasing the concentration of a surfactant, such as sodium dodecyl sulfate (SDS), in w2 destabilizes the multiple emulsions. This chapter is a continuation of the prior investigation of the optimal preparation and stability of w1/o/w2 emulsions.[13] In previously published work, both theoretical and experimental approaches were developed which investigated and defined the stability of w1/o/w2 multiple emulsions. The theoretical approach emphasized the role of Ostwald ripening in countering stability in w/o emulsions. This research investigated the addition of an oil-insoluble solute (NaCl) to the inner water phase of the multiple emulsion system as one means to prevent the undesirable “ripening” mechanism. This theoretical approach assumed complete stability of the w1/o/w2 interfacial films and no diffusion of salt from w1 to w2. The oil-insoluble solute (NaCl) was shown to stabilize both the first w1/o emulsion and the inner water droplets at the o/w2 interface. Experimentally, and confirming the theoretical predictions, the presence of an electrolyte in w1 was also shown to be necessary for stability to the multiple emulsion. In summary, three possible factors seemed significant in their potential ability to influence the stability of w1/o/w2. These were: • Laplace and osmotic effects between the water droplets in the w1/o emulsion and the two aqueous phases, w1 and w2. • Interactions between the low- and high-HLB emulsifiers at the o/w2 interface. • The influence of polymeric thickener-hydrophilic emulsifiers interaction in the outer water phase (w2).

475

Based on these theoretical considerations, the experimental approach to preparing stable w1/o/w2 emulsions emphasized the choice of surfactants and polymeric thickeners as well as the influencing of an optimal concentration of solute to be added to w1. The research undertaken sought to clarify certain aspects of the interactions cited above (between low- and high-HLB emulsifiers and between polymeric thickeners and hydrophilic emulsifiers) that have not been previously explained in the literature. Another objective of this study was to analyze the role of the properties of the interfacial film formed by the low-HLB surfactant. This work investigated the primary interface w1/o and studied the properties of selected surfactant monolayers including cetyl dimethicone copolyol, the polyglycerol ester of ricinoleic acid, and PEG-polyhydroxystearate copolymers.

22.1.3 Other Factors Affecting Stability of Multiple Emulsions It is well known but might still be necessary to emphasize that multiple emulsion stability can be enhanced by: • Decreasing the droplet size of the internal phase. • Obtaining an optimum ratio of water to oil in w1/o and oil to water in o/w2. • Increasing the low shear viscosity of the emulsion.

22.2 Materials/Methods 22.2.1

Materials

The oil phase selected was light mineral oil (LP) (Fischer Scientific, Fair Lawn, NJ), hexadecane (Sigma, Saint Louis, MO), or octyl palmitate (Goldschmidt Chemical Corp., Hopewell, VA) and soybean oil (Bestfoods North America). The lipophilic emulsifiers intensively studied and used for the preparation of the w1/o emulsions were:

476

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

• Abil EM 90®, a cetyl dimethicone copolyol (Goldschmidt Chemical Corp., Hopewell, VA) with a molecular weight of 14,000.[15]–[17] • Arlacel P135®, a PEG-30 dipolyhydroxystearate,[18] block copolymer with a molecular weight of 5000 (ICI Surfactants, Wilmington, DE). • Polyglycerol ester of ricinoleic, Grinstead PGR90® (Danisco Ingr., Inc., New Century, Kansas). See Fig. 22.1 for the structure of the above surfactants. The hydrophilic emulsifier employed was selected from sodium lauryl ether sulfate (SLES) ethoxylated (Steol CS-330 ®, Stepan Company, Northfield, IL 60093; 28.5% active), sodium dodecyl sulfate (SDS) (Aldrich Chemical Company, Milwaukee, WI). Cocamidopropylbetaine (betaine) was also used (Tego Betaine F®, Goldschmidt Chemical Corp., Hopewell, VA; 30% active, 5% NaCl). The polymeric thickeners employed were xanthan gum (XG) and guar gum (GG) (Colony Industries Inc., Holtsville, NY), Carbopol® 941 (CP) (BF Goodrich, Cleveland, OH), and hydroxyethylcellulose (HEC) (Aqualon Division, Hercules Inc., Wilmington, DE).

pseudo-plastic water-soluble polymeric thickener as a stabilizer for the external water phase was selected. Guided by results from earlier work, emulsions were prepared by the following multistep method: a w/o emulsion was obtained by emulsifying an aqueous phase in an oil phase containing a low-HLB emulsifier (Table 22.2), using an UltraTurrax mixer at 9500 rpm for 10 minutes. Next the w 1/o emulsion was added drop-by-drop into the aqueous phase (w2) containing a high-HLB emulsifier and the thickener (Tables 22.2 and 22.3). The second step is accomplished by means of reduced mechanical work using a 600 rpm mechanical stirrer, for five minutes, during the addition of the w1/o emulsion to the outer water phase w2 . Finally, a 1000 rpm mechanical stirrer was employed 10 minutes to complete the preparation of the multiple emulsion.

22.2.3

The dispersions of water-in-oil or oil-in-water were made either with an Ultra-Turrax mixer (model Antrieb T25, Janke and Kunkel, Staufen, Germany) or with a conventional mechanical stirrer.

22.2.4 22.2.2

Methods

Using techniques and materials similar to those described earlier,[10] we prepared w1/o/w2 emulsions and investigated their stability visually and through video-microscopy. (Table 22.1, 22.2, and 22.3 show the standard formulations, modified by the results of the current study.) First, the surface monolayer properties of Abil EM 90 were experimentally studied, to enable the theoretical calculation of the minimum amount needed to prepare w1 and to clarify the experimental high-HLB/low-HLB surfactants interactions. After calculating the minimum amount of Abil EM 90 needed to prepare a stable w1/o emulsion, the optimum amount of salt required to stabilize both the initial w1/o emulsion, the final w1/o/w2 system was experimentally studied. Then the appropriate

Mechanical Equipment

Evaluation Techniques

Microscopic and visual observations. Samples of all emulsions prepared were stored at room temperature for visual observation (i.e., checking for physical separation of the emulsion into two phases). The microscopic structure was tracked by video-microscopy (Axiovert 135 inverted microscope, Carl Zeiss Inc., Germany). During microscopic examination, the samples were prepared with caution in order to prevent deformation of the droplets or breakdown of the multiple emulsions, due to the stress produced by the cover slide. Rheological measurements. The rheological analyses were performed at different shear rate at room temperature using a synchro-electric model LVT Brookfield viscometer, spindle number 2.

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

477

(a)

(b)

(c)

Figure 22.1 Structure of the surfactants that allow the preparation of a stable w1/o/w2 emulsion over a one-month period at room temperature: (a) schematic structure of A-B-A block copolymer (Arlacel P135), (b) cethyl dimethicone copolyol (Abil EM 90®), and (c) polyglycerol esters of ricinoleic acid (PGR).

478

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 22.1. Preparation of Several w1/o Emulsions with Different Low-HLB Surfactant in w1

Composition % (w/w) H2O

w1

59.6

NaCl

0.40

Soy bean oil

Oil

36.0

Low-HLB surfactant

4.0

Table 22.2. Standard Formulation for w1/o/w2 Using Tween 60 as High-HLB Surfactant

Composition % (w/w)

w1

Oil

H2O

58.5

NaCl

0.4

Acetic acid

pH = 4

Soybean oil

36

Low-HLB surfactant

4.0

37.5 g of w1/o

in w2

H2O

w2

61.25

High-HLB surfactant

0.525

NaCl

0.5

Acetic acid

pH = 4

Xanthan gum

0.6

Table 22.3. Standard Formulation for w1/o/w2 When Using Sodium Lauryl Ether Sulfate and Betaine as High-HLB Surfactant

Composition % (w/w) w1

Oil

H2O

18.78

NaCl

0.72

Light mineral oil Low HLB surfactant H2O

0.48 19.6

®

w2

10.02

Tego Betaine F ®

50-X (14.7-Y Betaine)

Steol CS-330

X (Y sodium lauryl ether sulfate)

Xanthan gum

0.4

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

479

22.3 Experiments

22.3.1

The force-area (∆A) and surface potential-area (∆V/∆A) characteristics of the low-HLB surfactants at the water-air interface have been extensively investigated in this chapter. The experimental apparatus for measuring surface pressures and potentials is shown in Fig. 22.2. All experiments were conducted within a Faraday box.

Surface pressures. Surface pressures were determined from the surface tension measurements, which were made by suspending a sandblasted platinum blade from a transducer-amplifier (Model 311A, The Sanborn Co., Waltham , Mass.). The transducer output was recorded continuously on a Mocon recorder (type DB/40, Kipp & Zonon, Holland).

The surfactant solution in n-hexane was deposited onto the aqueous surface with an Alga micrometer syringe (Burroughs Wellcome and Co., Tuckahoe, NY).

Surface potentials. Surface potentials were measured with an air-ionizing electrode[19] (a radium226 source, U.S. Radium Corp., Morristown, NJ), placed 1 to 2 mm above the surface of the liquid substrate, and connected to a precision potentiometer (Model 2730, Honeywell, Denver Division), a high-input resistance electrometer (Model 610B, Keithley Instruments Inc., Cleveland, Ohio) and a trough electrode (Ag/ AgCl or calomel) dipped into the bulk of the aqueous substrate. The radioactive

The substrate and film were retained in a fused silica trough (31.2 × 13.6 × 2.5 cm) of 1.5-liter capacity. Dusting calcinated talcum powder onto the surface and removing it, with the aid of a hollow glass tip connected to an aspirator, cleaned the surface.

Surface Isotherms

Figure 22.2 Experimental apparatus for measuring surface pressure and surface potential. (1) Transduceramplifier. (2) Fused silica trough. (3) Moving Teflon® barrier. (4) Farraday box. (5) Support for Pt blade. (6) Mechanical drive. (7) Potentiometer. (8) Alga micrometer syringe. (9) Speed control for mechanical drive.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

electrode was connected to the input terminal of the electrometer with Amphenol low-noise graphitized shielded cable and connectors. The emf of the cell, composed of the radioactive electrode, trough electrode, potentiometer, and electrometer, all connected in series, was measured immediately after cleaning the surface of the aqueous substrate (Vo), and compared with the emf after spreading a film on the surface (V). The difference between the two emf’s (V – Vo) is the surface potential. The potentiometer opposed a convenient fraction of the cell emf, and the electrometer output was recorded continuously. An automatic barrier drive, with variable speed control, permitted determination of an optimum compression rate and reproducible ∆A and ∆V – A isotherms. The continuous reduction of the surface area results in a measured surface pressure for stable films. These are considerably above their equilibrium spreading pressures (ESP), but still below their monolayer stability limit (MSL), which is defined[20] as the maximum pressure attainable in the film without collapse occurring.

22.3.2 Particle Size Determination Particle size analysis of the formulation of water/oil emulsions was performed using a Brookhaven Instrument BI 90 Plus (light scattering). In this analysis, the diluent (soybean oil) was filtered with a 0.1 micrometer PTFE syringe filter before adding the concentrate. The soybean oil that was supplied appeared to be free of debris, but upon filtration, the oil was visibly cleaner and crystal clear. Approximately 10 ml of the soybean oil was then filtered into a 20 ml scintillation vial. One drop of the w1/o emulsion was placed in the plain oil and agitated manually using a mini-vortex. The diluted sample was agitated until color uniformity and homogenous turbidity was reached. About 3.5 ml of the diluted solution was then decanted into a square plastic sampling cuvette, and placed in the B90 Plus particle size analyzer. The particle size analysis of each sample consisted of five three-minute runs for a total run time of fifteen minutes.

22.3.3

Pendant Drop Method to Measure Dynamic Interfacial Tension

The Rennan, et al.,[21] experimental arrangement was employed to measure the equilibrium and dynamic tensions using the static pendant drop and following Lin, et al.[22] With this technique, white light generated from a tungsten bulb is collimated and then reduced in intensity by a series of pinholes, lenses, and filters. The collimated beam is thereafter passed through a transparent quartz cell (2.5 × 4 × 4 cm) which is thermostated (23°C ± 0.5°C). A drop of oil is formed at the tip of an inverted stainless steel, flat-tipped capillary using a microsyringe. The growth of the drop is stopped when the diameter of the droplet reaches 2 to 3 mm. Formation time for the drop does not require more than a second with this method. Parallel light, passing over the drop, creates a silhouette of the pendant drop that is then imaged onto a CDD array video camera (Sony XC-77) using an objective lens. A PC-operated Scion LG-3 frame board, using N.I.H. software, digitizes and saves as many as thirty images per second to RAM. A timer (FOR.A, Japan) records the time directly onto the video frames, allowing the captured frames to be sequenced accurately. Distances on the video images are calibrated using a tungsten sphere of known diameter (1.5876 mm). Laplace equations are used to describe the bubble shape and are numerically integrated. Their mathematical solutions are then fitted to the edge profile of the digitized image by adjusting the surface tension.[23] The surface tension of pure water using this technique is determined to be 72.3 mN/m (i.e., dynes/cm) at 23°C ± 0.5°C.

22.4 Results and Discussion Among the different classes of primary surfactants (low HLB) tested (Table 22.4), three (Fig. 22.1) were found that allowed preparation of a stable w1/o/w2 emulsion over several months at room temperature: • Cetyl dimethicone copolyol (Abil EM 90) • A-B-A block copolymer (Arlacel P135) • Polyglycerol ester of ricinoleic acid (Grinstead PGR 90)

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

481

Table 22.4. The Different Classes of Primary Surfactant (Low HLB) Tested for Their Ability to Produce a Stable w/o Emulsion

Surfactant

HLB

Mono and diglyceride: (BFP 75)

Stability of emulsion 1 month @ room temperature Not Stable

Hexaglyceryl tetraoleate (Poly 6-4-0)

5

Not Stable

Decaglyceryl decaoleate (Poly 10-10-0)

3

Not Stable

Polyglycerol esters of ricinoleic acid (PGR® 90)

2

Stable

Polyglycerol esters of fatty acids (PGE)

3

Not Stable

Decaglyceryl x-oleate (ADM Caprol ET)

Not Stable

Fluid lecithin from mixed phospholipid (Actiflo®)

2

®

Cethyl dimethicone copolyol (Abil EM 90 )

Stable

®

Sorbitan monosterate (Span 60 ) ®

Not Stable

Not Stable

Sorbitan tristerate (Span 65 )

4.7

Not Stable

Sorbitan monooleate (Crillet NF®)

2.1

Not Stable

A-B-A block copolymer (Arlacel P135®)

We investigated the primary w1/o interface and studied the properties of the monolayer of cetyl dimethicone copolyol; the polyglycerol ester of ricinoleic acid; and PEG-polyhydroxystearate copolymers.

22.4.1

Monolayer Experiments— Study of the Primary Interface

A Langmuir trough was used to measure surface pressure versus surface area. Figures 22.3 and 22.4 represent the compression-decompression isotherms surface pressure of the cetyl dimethicone copolyol and the polyglycerol ester of ricinoleic, respectively, dissolved in n-hexane and spread on a 1% NaCl pre-foamed solution (to insure that no extraneous surface-active substances were present, we used the foam fraction technique to clear out the impurities). The two resulting monolayers exhibited similar properties: surface pressure as high as 35 mN/m, and perfectly reversible compression-decompression isotherms were observed for both surfaces.

Stable

The latter property supports the hypothesis that when these basically insoluble surface active substances are adsorbed at the oil/water interface, they can be subjected to mechanical constraints without structural damage. As seen in Fig. 22.5 alone, an inflection point in the compression of the polyglycerol ester of ricinoleic acid (PGR 90), situated at around 300 Å2/molecule, is revealed by a maximum in the apparent elasticity (Fig. 22.6). This inflection point seems to indicate a maximal condensation of the two-dimensional phase and provides the limiting area occupied by a comprehension of the molecules. Present at higher surface coverage (higher compression pressures), a pseudo-plateau is noticeable in the curve. This suggests the appearance of a three-dimensional phase involving the expulsion of the polyglycerol ester of ricinoleic acid. When sufficient pressure has been applied to the surface to push monolayer materials upwards and outwards into the air above the compressed liquid surface, a decrease of the surface potential was noticed (see Fig. 22.5).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 22.3 Compression-decompression isotherm of a film of cetyl dimethicone copolyol spread over a 1% NaCl solution.

Figure 22.4 Compression-decompression isotherm of a film of polyglycerol ester of ricinoleic acid spread over a 0.1% KCl solution.

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

483

Figure 22.5 Surface pressure and surface potential of a film of polyglycerol ester of ricinoleic acid spread over a 0.1% KCl solution.

π (mN/m)

Elasticity (m/N) at Mid-range surface

420

2.05

A (mid-range): 380

340

5.8

Elasticity: 56.1

300

6.80

A (mid-range): 250

200

9.1

Elasticity: 174

Segment Å2/molecule

lier work, Rosano, et al., concluded that the increased film elasticity was quite important for achieving stability of a microemulsion. Consequently, in our study, the high values obtained for film elasticity provide the interfacial film with strong resiliency during stresses. As a result, such films do not break, and allow for a stable emulsion.

In Figs. 22.5 and 22.7, which represent the surface potential of polyglycerol ester of ricinoleic and PEG-polyhydroxystearate copolyElasticity: 123 6 35.0 mer, respectively, it is noteworthy to report the initial high surface potential (about 320 mV). Figure 22.6 Elasticity of a film of polyglycerol ester of This indicates the strong orientation of the surricinoleic acid at some critical surface area. factant molecules at the interface even before the compression of the film. This result is consistent with those obtained by Habif, et al.,[25] and In Fig. 22.6, the elasticity at the 3 different segthus described that the hydroxyl group on the ments of the isotherms of the polyglycerol ester of polyglycerol ester of ricinoleic molecule, is directed ricinoleic was determined. Surface film elasticity into the water phase. Consequently, this leads to a increases when the pseudo-plateau is reached and, high surface potential. Let’s assume that the expulthereafter, decreases upon further compression. sion of the polyglycerol ester of ricinoleic, involving These changes in surface elasticity are also reflected mostly the hydroxyl group in the molecule, occurred in the surface potential isotherm (Fig. 22.5). It is toward the aqueous subphase, because of the high important to note, from Fig. 22.6, the extremely high affinity of this functionality for water. If this asvalues found for the elasticity (56.1, 174, 123 m/N) sumption is correct, then it explains the increased as compared to the elasticity values (6.2, 15.0, 24.3 potential of polyglycerol ester of ricinoleic at the m/N) found by Rosano, et al.,[24] for a dipalmitoyl same compression area observed in Fig. 22.5. This phosphatidylcholine (DPPC) film. Based on this ear-

40

23.0

A (mid-range): 23

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 22.7 Surface potential of a film of PEG- polyhydroxystearate copolymer spread over a 0.1% KCl solution.

process of the displacement of the hydroxyl group may be initiated before reaching the plateau and, more precisely, after a close-packed film is formed (increase of ∆A-surface area and ∆V-surface potential). Later, during compression of the film, the observed decrease of the surface potential correlates with the increased surface pressure. This further suggests the expulsion of the hydroxyl function to the opposite of the water subphase (repulsion of the hydroxyl function).

22.4.2 Investigation of Polyglycerol Ester of Ricinoleic Acid In the search to better identify and understand the surface properties observed for the polyglycerol ester of ricinoleic acid, according to the description and properties of the product received from the manufacturer, the polyglycerol moiety is composed of not less than 75% of di-, tri-, and tetraglycerols and contains no more than 10% of polyglycerols equal to or higher than heptaglycerol. Using this information, the molecular weight of the various esters possible for this compound was calculated. Further, the manufacturer lists the iodine value of polyglycerol ester of ricinoleic acid, which represents the num-

ber of grams of iodine absorbed per 100 g of a substance, to be 72–103. Assuming I2 (254 grams per one double bond), we calculated the molecular weight and iodine value of the various esters, and these are shown in Tables 22.5, 22.6, and 22.7. As seen in Tables 22.5, 22.6, and 22.7, the polyglycerol is highly esterified (at least 4 acids per glycerol, and probably naming 5). The excess in the iodine value suggests a mixture of triglycerol and tetraglycerol oligomers, which is very common in the oligomerization process of glycerol. Assuming a molecular weight of 1400, the area per molecule in the monolayer of polyglycerol ester of ricinoleic acid spread on water has been calculated from Fig. 22.4 and reported in Fig. 22.5. The linear triglycerol has the following formula:

2C

CH CH2 O CH2 CH OHOH OH

CH2

H2 O CH2 CH C OH OH

Assuming 1.5 Å between C–C, the molecule has a length of 15 Å. Ricinoleic acid (18 carbon-cis) has a linear length of around 27 Å, consequently, the maximum surface area occupied by the polyglycerol ester would be about 810 Å2 per molecule. The surface isotherm (Fig. 22.5) shows that the

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

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Table 22.5. Molecular Weight and Iodine Value for Diglycerol Oligomer

Ester MW Diglycerol (166 g/mol)

MW (g/mol)

Iodine Value

1 acid + diglycerol

438.5

49

2 acids + diglycerol

715

71

3 acids + diglycerol

992.5

76

4 acids + diglycerol

1273

79

Table 22.6. Molecular Weight and Iodine Value for Triglycerol Oligomer

Ester MW Triglycerol (240 g/mol)

Mw (g/mol)

Iodine Value

1 acid + triglycerol

520

48

2 acids + triglycerol

801

63

3 acids + triglycerol

1081

70

4 acids + triglycerol

1362

74

5 acids+ triglycerol

1642

77

Table 22.7. Molecular Weight and Iodine Value for Tetraglycerol Oligomer

Ester MW Tetraglycerol: 314

Iodine Value

1 acid + tetraglycerol

613.5

41.4

2 acids + tetraglycerol

875.3

56.52

3 acids + tetraglycerol

1361.8

74.5

4 acids + tetraglycerol

1467

86.5

5 acids + tetraglycerol

1751.5

surface pressure starts to increase below 400 Å, which once again suggests that although the molecules are still flat at the interface, at least two of them must mesh as the molecular repulsion process begins.

22.4.3

Mw (g/mol)

Interactions Between the Lowand High-HLB Emulsifiers at the o/w2 Interface

In Fig. 22.3, a film of the surfactant Abil EM 90 produced a stable and reproducible compression surface isotherm at 22°C. Due to the great flexibility of the silicone backbone, in this silicone copolyol compound, the cetyl dimethicone copolyol chains are capable of being compressed without any breakdown

of the film. This is verified since the we did not reach the collapse pressure during our experiments. The compression isotherm (Fig. 22.8) of a duplex film[26] of Abil EM 90/hexadecane does not show any interaction between the two layers of the film. In Fig. 22.9, curve A, after a film of Abil is spread and then compressed at 3 mN/m, 3 mg of betaine is injected under the film. After 30 minutes, 3 mg of sodium lauryl ether sulfate is then injected under the film as well. Throughout the experiment, the surface pressure is recorded as a function of time, showing a marked increase with each injection. The sodium lauryl ether sulfate is observed to penetrate into the film of betaine adsorbed into the cetyl dimethicone copolyol film. This indicates clearly that sodium lauryl ether sulfate is more surface active

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 22.8 Compression isotherm of a duplex film cetyl dimethicone copolyol/hexadecane, spread over a 1% NaCl solution.

Figure 22.9 Evolution of the surface tension as a function of time after injection of 3 mg sodium lauryl ether sulfate and/or betaine under a cetyl dimethicone film compressed at 3 mN/m. Curve A: injection of betaine followed by injection of sodium lauryl ether sulfate. Curve B: injection of sodium lauryl ether sulfate followed by injection of betaine.

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

487

than betaine and displaced both betaine and the lowHLB surfactant from the surface. The displacement of Abil EM 90 takes place as the surface pressure goes above the collapse pressure of Abil EM 90. Bruno, et al.,[35] have investigated the same phenomena and reached the same conclusion with sodium dodecyl sulfate displacing Abil Em90 using neutron reflectivity measurements.

w1/o interface is saturated can now be calculated. In emulsion preparation, as shown by Rosano,[27] if enough mechanical work is provided to the system, it can usually be assumed that all the surfactant molecules will be adsorbed at the w1/o interface as long as the concentration of surfactant is sufficiently great to fill up surface area created during the mechanical agitation.

In a parallel experiment in Fig. 22.9, curve B, the sodium lauryl ether sulfate is injected into the film of Abil Em90 first, and betaine is injected 25 minutes later. With this procedure, the increase of the surface pressure is even sharper than seen when betaine was injected first. However, here the betaine injection produces no change in surface pressure. This proves once again that betaine cannot displace sodium lauryl ether sulfate from the surface. Calculating the slope, at the beginning of the film penetration, revealed that sodium lauryl ether sulfate penetrated into the Cetyl dimethicone film 2.7 times faster than betaine. The absence of a second increase in slope indicates that betaine does not penetrate into an Abil-sodium lauryl ether sulfate mixed monolayer.

Theoretically, if V is the volume of the dispersed phase (w1), and a the number of water droplets with an average radius, r, then:

Since sodium lauryl ether sulfate was observed to penetrate more rapidly than betaine, under the same conditions, it is obvious that the role played by the amount of mechanical work applied to the system during the multiple emulsion formulation is crucial. The results obtained with the mixed films Abil/ sodium lauryl ether sulfate and Abil/betaine suggest an explanation for the different behaviors observed in multiple emulsions prepared with betaine as compared with hydrophilic surfactant versus those prepared with sodium lauryl ether sulfate. This phenomenon could explain the decrease in size of the w1/o droplets when increasing the sodium lauryl ether sulfate concentration in the outer aqueous phase.[10][12]

Eq. (22.1)

The total interfacial area, A, produced by the formation of these w1/o droplets will be equal to: Eq. (22.2)

Determination of the Minimum Amount of Primary Surfactant to be Used in the Preparation of the w1/o Emulsion

Based on the work described, the minimum amount of lipophilic polymeric surfactant needed to prepare the w1/o emulsion in such a way that the

A = a × 4π × r 2

Therefore, the ratio of both Eq. (22.1) and (22.2) leads to the relationship:

Eq. (22.3)

A=

3V r

If we assume the adsorption of one monolayer of surfactant at the w1/o interface, replacing A of Eq. (22.3) by n × σ where n is the total number of molecules of surfactant and σ the molecular area occupied by a molecule of surfactant, then:

Eq. (22.4)

r=

3V n ×σ

σ=

3V n×r

therefore:

Eq. (22.5)

22.4.4

4 V = a × π × r3 3

By substituting the data obtained for a formulation of w1/o emulsion, made of 1.5 g of polyglycerol ester of ricinoleic acid, 38.5 g of soybean oil, and 58.5 ml of water and an average diameter measured of the w1 droplet of 269.8 nm (Table 22.8), we can calculate the experimental area occupied

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

(σ) by a molecule of polyglycerol ester of ricinoleic acid.

Eq. (22.6) σ =

3 × 58.5 1.5 269.8 × 6.02 × 1023 × × 10−7 1400 2

σ = 201.7 Å2 From Fig. 22.5, this area σ corresponds to a surface pressure of 9 mN/m and a surface potential of 355 millivolts. As a result of this analysis, we are led to the conclusion that the molecule lies flat at the w1/o interface probably due to the presence of the –OH group on the ricinoleic chains. Thus, it is the positioning of this hydroxyl functionality that is responsible for the high surface potential observed in Fig. 22.5. Furthermore, as seen in Fig. 22.3, the polymeric surfactant starts to be compressed at an area of 0.5m2/mg. Therefore, using Eq. (22.3), we can calculate that, for a volume of dispersed phase of 20.00 ml, 0.48 g of polymeric surfactant (Abil EM 90) will correspond to a diameter of the w1/o droplets of about 0.5 µm.

22.4.5

Determination of the Optimum Amount of Solute Necessary to Stabilize the Primary w1/o Emulsion and the w1/o/w2 Multiple Emulsion

It is necessary to add an oil-insoluble solute to the water phase in order to stabilize a w1/o emulsion.[14] The optimum amount was determined experimentally according to the following: Various formulations of w1/o emulsions, prepared with hexadecane as the oil phase, and with different concentrations of salt (NaCl) in the inner water phase were prepared. The lipophilic emulsifier chosen for this work was Abil EM 90 at a concentration of 4.6% (w/w). The results showed that above a concentration of 0.3 g/L of NaCl in w1, stabilization of the w1/o occurs. In the multiple emulsion formulation, we used 0.72% (w/w) of NaCl was used to osmotically balance the NaCl in the w2 phase brought by the betaine. In practice, a chloride electrode was used to determine the NaCl concentration in w1 and w2 as a function of time.

Table 22.8. Particle Size Determination Using Light-Scattering Method for a Formulation of w1/o Emulsion Made of 1.5 Grams of Polyglycerol Ester of Ricinoleic Acid, 38.5 Grams of Soybean Oil, and 58.5 Milliliters of Water

Run

Effective Diameter (nm)

Half Width (nm)

Polydispersity

1

348.0

99.0

0.159

2

380.0

159.1

0.321

3

240.2

83.7

0.121

4

302.3

157.9

0.273

5

340.4

187.7

0.304

282.3

137.5

0.236

18.4

19.7

0.040

269.8

126.1

0.218

Mean Standard error Combined

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES 22.4.6 Selection Criteria for the Water Soluble Polymeric Thickener All multiple emulsions, w1/o/w2, prepared without a thickener in the external w2 water phase, separate over time.[28] Consequently, we investigated the selection criteria for a polymeric thickener that would prevent phase separation when added to the formulations, but would not interact destructively with other ingredients. Several water-soluble polymers were evaluated for their rheological properties. As indicated by Fig. 22.10, which shows a plot of the log of the solution viscosity in water versus the log of shear stress, xanthan gum and Carbopol® are seen to exhibit the appropriate pseudo-plastic properties. Most likely, these pseudo-plastic properties cause the emulsion droplets to remain suspended in the continuous medium and thus sedimentation/creaming of the emulsions is avoided. In view of the presence of NaCl in w1/o/w2 formulations, the effect of NaCl on these polymer solutions were also investigated. Observing that in the presence of 1.5% (w/w) NaCl in water, Carbopol thickener lost its pseudo-plastic properties and xanthan gum retained them. Consequently, xanthan gum was selected as the optimal watersoluble polymer.

22.4.7

489

Influence of the Concentration of the Betaine/Sodium Lauryl Ether Sulfate Mixture on the Rheological Properties of Xanthan Gum and the Resulting w1/o/w2 Stability

Figure 22.11 shows a plot of log viscosity versus log of shear stress for stable multiple emulsions, and Table 22.9 graphed in Fig. 22.12 represents the effect of SLES/betaine ratio on the viscosity of surfactant solutions containing xanthan gum. In the presence of surfactants, Betaine and sodium lauryl ether sulfate were found to maintain the pseudo-plastic properties of xanthan gum, if the proportion of betaine to sodium lauryl ether sulfate was at least 66% (w/w). Above 66 % (w/w) of betaine, the extrapolated viscosity at zero shear rate stress is 30 Pa·sec which is high enough to provide long-range stability to the system since it behaves as a solid at low shear rate, (i.e., has an apparent yield stress). This is illustrated in Table 22.10, where the % separation of various multiple emulsions is shown after both 45 and 220 days.

Figure 22.10 Viscosity as a function of shear stress for various polymers [xanthan gum (XG), hydroxyethylcellulose (HEC), guar gum (GG), Carbopol 941 (CP)]. Solutions prepared in water.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 22.11 Viscosity as a function of shear stress for the stable formulations containing betaine and sodium lauryl ether sulfate.

Table 22.9. Effect of SLES/Betaine Ratio on the Viscosity of Surfactant Solutions Containing Xanthan Gum

Betaine (g) 5.18

Steol (g)

% Betaine (w/w)

Viscosity A (mPa/s)

Viscosity B (mPa/s)

20

20.6

25

30

10.6

21.5

33.0

640

180

12.8

19.3

39.9

1760

1150

14.27

17.83

44.4

7600

6200

15.4

16.69

48.0

13600

10000

16.41

15.69

51.1

4000

4160

18.2

13.9

56.7

4000

2450

20.7

11.6

76.4

1200

800

25.7

6.4

100

100

Viscosity A: speed rate 1.5 rpm. Viscosity B: speed rate 12 rpm.

80

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491

Figure 22.12 Effect of SLES/betaine ratio on the viscosity of surfactant solutions containing xanthan gum.

Table 22.10. Effect of Xanthan Gum Addition on Physical Stability of Multiple Emulsion Composition

% Betaine (w/w) (betaine/sodium lauryl ether sulfate mixture)

% Separation after 220 days @ RT + xanthan gum

% Separation after 45 days @ RT - xanthan

0

43.7

62.4

14

45.0

62.0

30

50.0

52.0

49

56.7

64.0

61

0.0

66

0.0

73

0.0

63.0

100

0.0

61.7

Figures 22.13 and 22.14 show the structure of a multiple emulsion after 1 and 220 days. No difference was noticed in size or aspect of the inner water droplets, proving that the osmotic and Laplace pressure are well balanced. Table 22.11 gives the formulation of a 220 days w1/o/w2 stable emulsion in which light mineral oil is replaced by octyl palmitate and the surfactant mixture is betaine/SDS. In Table 22.12, replacing Steol

by SDS again yields a multiple emulsion that demonstrates stability for at least 220 days. Table 22.13 reports the effect of different anionic surfactant on physical stability of multiple emulsion in the presence of xanthan gum. The outcome conclusions and explanations of those results are explained through surfactant interactions and viscosity change for each formulation.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 22.13 Picture taken after 1 day for the standard formulation with 32.3% (w/w) of Tego® Betaine F and 17.7% of Steol® CS 330. Magnification x350, no dilution, room temperature.

Figure 22.14 Picture taken after 220 days for the standard formulation with 32.3% (w/w) of Tego® Betaine F and 17.7% of Steol® CS 330. Magnification x 350, no dilution, room temperature.

Table 22.11. Stable Multiple Emulsion Formulation with Octyl Palmitate

Table 22.12. Stable Formulations Betaine/SDS

Composition % (w/w) w1 Oil

H2O

18.78

NaCl

0.72

Octyl palmitate

Oil

0.48

H2O w2

w1

10.02

Abil EM 90

Composition % (w/w) H2O

18.78

18.78

NaCl

0.72

0.72

10.02

10.02

0.48

0.48

Light mineral oil Abil EM 90 H2O

54.9

54.8

54.9

Betaine

8.6

10.9

Betaine

9.7

SDS

3.5

SDS

6.2

3.9

Xanthan gum

0.4

Xanthan gum

0.4

0.4

w2

Table 22.13. Effect of Different Anionic Surfactant on Physical Stability of Multiple Emulsion in the Presence of Xanthan Gum

Betaine (g)

STEOL (g)

SDS (g)

% Betaine (mol/mol)

% Betaine (w/w)

% Separation after 1 day

% Separation after 30 days

5.43

1.95

70.0

73.53

0

0

4.32

3.1

54.0

58.2

0

0

7.24

7.44

44.5

49.3

4.6

22.7

7.24

7.44

54.0

49.3

7

48.5

9.7

5.0

70.0

66.0

0

0

Molecular mass of SDS = 288.4 g/mol

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES 22.4.8

Droplet Breakup in Double Emulsion Systems

The mechanisms by which various types of liquid agitation can provide the energy necessary for breakup of disperse phases have been extensively reviewed by Stroeve and Varanasi,[29] Grossiord and Seiller,[30] and Lucassen-Reynders.[31] Essentially, the deformation and breakup of a droplet occurs when the stress exerted on the droplet by the flow is high enough to overcome the (o/w) interfacial cohesion due to the Laplace pressure:

∆P =

Eq. (22.7)

2δ r

For a laminar flow, the ratio of these opposing stresses is known as the capillary number (Ca), and is defined by the following equation:[31]–[33]

Eq. (22.8)

Ca =

ηc ⋅ γ ⋅ R σ

ηc = viscosity of the continuous phase R = radius of the droplet to be broken up σ = interfacial tension γ = rate of shear In order for the droplet to break into fragments, it is necessary for it to elongate sufficiently. This implies that the hydrodynamic shear rate has to exceed the opposing cohesion constraint due to capillary forces. Rumscheidt and Mason[34] have discussed the division of droplets. They found, experimentally, that droplets break up into two or more segments when the capillary number (Ca) exceeds a critical value, Cacr. Experimentally, Cacr is found to depend on the type of flow and on the viscosity ratio of the two liquids. The critical value of Cacr, according to Grossiord and Seiller,[30] must be around 1 unit. When discussing the formation of single or multiple emulsions, the role and behavior of the surfactant at the interface is significant. When an w1/o interfacial area increases rapidly, the interfacial tension rises and conditions favor droplet recoalescence. In regards to interfacial viscosity, the role is difficult

493

to measure, and is generally ignored. Thus, when discussing single emulsion formation, only one type of droplet fragmentation is visually considered: either w/o or o/w. By contrast, with single emulsion formation, multiple emulsions have two types of droplet fragmentation that must be considered: 1. The fragmentation of the w1/o droplets in w2. 2. The fragmentation of the w1 droplets in o. Thus, the analysis of the droplet break up in double emulsion systems is quite complicated. We have attempted to explain a certain number of experimental results listed in Table 22.14 that shows a series of observations on multiple emulsions using the basic formulation. Experimentally, viscosity of the w2 phase is necessary to emulsify w1/o in w2, as can be seen in experiments 3, 5, and 8 in Table 22.14. Even when w2 is sufficiently viscous, sodium lauryl ether sulfate and sodium dodecyl sulfate are seen to be emulsifiers that are too efficient. This is due, most probably, to their penetration at the o1/w interface, and the transient decrease of the interfacial tension. Betaine, being more of an oil dispersant, does not seem to affect the w1/o emulsion. Finally, in order to obtain long-term stability of the multiple emulsion, the external water system (w2) has to be pseudoplastic and this is achieved by the use of xanthan gum, as described previously (Sec. 22.4.6).

22.5 Measurement of the Dynamic Interfacial Tension Oil/Water Using the Pendant Drop Tensiometer Method 22.5.1

The Pendant Drop Technique

To measure the dynamic interfacial tension, the pendant drop technique was used as described in Sec. 22.3.3. The technique employs a drop of oil, nhexadecane, that is formed from a needle tip into the aqueous surfactant solution. The drop shape thereafter determines the surface tension of the drop.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 22.14. Observation from a Series of Experiments Based on the Same Basic Formulation and Mechanical Stirring

Experiment

Formulation

1

Betaine alone

Large droplets-double emulsion separation

2

Sodium lauryl ether sulfate alone

Medium/large droplets-double emulsion separation

3

Betaine + xanthan gum

Medium droplets-no separation

4

Sodium lauryl ether sulfate + xanthan gum

Low viscosity/double emulsion separation

5

SDS + Carbopol

High viscosity/single emulsion

6

Betaine + Carbopol

Large droplets/double emulsion separation

7

Betaine + sodium lauryl ether sulfate

Form initial gel-single emulsion

8

#3 then sodium lauryl ether sulfate Double emulsion/no separation

With a clean interface adsorption, oil/water, the droplet is impulsively formed in the aqueous solution and the reduction in interfacial tension is measured as the surfactant adsorbs at the interface. Aqueous solutions are prepared using water from a Milli-Q® water purification system. This technique allows understanding of the difference in behavior observed between sodium lauryl ether sulfate and betaine, when it is employed as a secondary surfactant in the outer aqueous phase w2.

22.5.2

Qualitative Observations

Equilibrium Adsorption Measurement and Discussion

With this technique, the dynamic interfacial tensions were measured between an oil phase of nhexadecane (with and without the presence of Abil EM 90). The water phase contained sodium lauryl ether sulfate and betaine (concentration: 10-4 M) and a 50/50 mixture of both surfactants. Figure 22.15 shows the dynamic surface tension relaxation for adsorption into a clean interface for three aqueous solutions (betaine, sodium lauryl ether sulfate, and mixture). The time, t = 0, in these relaxations represents the point at which the hexadecane droplet growth is terminated.

From Fig. 22.15, one can explain the difference in behavior observed when betaine and sodium lauryl ether sulfate are used as the surfactant in w2. With betaine, we observe a higher droplet size of w1/o/w2 than with sodium lauryl ether sulfate. Figure 22.15 shows that the interfacial tension drops more rapidly, and to a lower interface tension with sodium lauryl ether sulfate (9.0 mN) than with betaine (18.0 mN). Due to a lower interfacial tension between the oil phase and the water phase, when sodium lauryl ether sulfate is used rather than betaine, smaller droplets of w1/o/w2 are expected and will eventually result in a single emulsion (o/w).

22.6

Conclusion

New protocols enabling preparation of selected w1/o/w2 multiple emulsions have been achieved and presented in this chapter (U.S. patent 6,235,298). One type uses soybean oil with edible ingredients, while the other containing 15% (w/w) of surfactants in the external phase. Previously, both theoretical and experimental approaches to the stability of such w1/o/w2 multiple emulsions have been conducted, though incompletely. The theoretical approach

KANOUNI, ROSANO: PREPARATION OF STABLE MULTIPLE EMULSIONS AS DELIVERY VEHICLES

495

Figure 22.15 Surface tension relaxation function of time in clean interface (hexadecane/water) adsorption.

emphasized focuses on the role of Ostwald ripening in countering stability in w/o emulsions. The addition of an oil-insoluble solute to the inner water phase of the system is also described in order to produce an osmotic pressure opposed to the Laplace pressure and thereby increase w1/o/w2 stability. The previous studies assumed complete stability of the w1/o/w2 adsorbed interfacial films. However, studies demonstrate that after several low-HLB surfactants were tested, only three were found to produce stable w1/o emulsions. These were: • Cethyl dimethicone copolyol (Abil EM 90 ICI). • A-B-A block copolymer (Arlacel P135 Rhodia). • Polyglycerol ester of ricinoleic acid (Grinstead PGR 90 - Danisco). The results obtained from our monolayer studies show that certain conditions need to be attained in order to produce the required stable interfacial films, w1/o and o/w2. The following was found: • The film formed by the low-HLB surfactant at the w1/o interface should be reversibly expandable and compressible, and irreversibly adsorbed in order to set the stage for formation of stable w1/o/w2 multiple emulsions.

• The long term stability of the multiple emulsion requires achieving a balance between the Laplace and the osmotic pressure (between w1 droplets in oil). Our theoretical approach, and experimental results seem to explain how a small quantity of salt in the water-in-oil droplets is able to achieve this necessary balance, by opposing osmotic forces with an equal Laplace pressure. Video microscopic observations of the multiple emulsions versus time make it possible to determine the optimal salt concentration necessary to balance osmotic pressure between the two water phases. • The presence of a pseudo-plastic thickener is necessary in the outside water phase in order to reach a viscosity ratio (preferentially around 1) of both phases (w1/o and w2). This allows dispersion of the viscous primary emulsion into the w2 aqueous phase. Further, the pseudo-plastic rheological properties of the thickener essentially precede a yield stress behavior at low shear rate and thereby prevent phase separation. • Interactions between selected low- and highHLB emulsifiers at the o/w2 interface should not destabilize the films if multiple emulsion stability is to be achieved

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Some of the main applications of multiple emulsions described in this chapter would depend on the active compounds solubility and if they are incorporated into the inner-water phase w1 or the oil phase. Some of the active compounds that are water-soluble can be designed to remain on the skin or hair after application as opposed to being rinsed from the skin or the hair. It is also possible to have water-soluble active compounds that are designed to be rinsed from the skin or the hair after the compounds perform their intended functions. Examples of consumer care applications include, but are not limited to, hair and skin conditioners, hair and skin cleansers, hair fixatives, hair growth promoters, hair dyes, deodorants, antibacterial compounds, topical anesthetics, sunscreen, and other cosmetic effectives compounds. To better present the advantages of multiple emulsions, let’s consider the case of a water-soluble hair conditioner containing quaternary ammonium compounds. Quaternary ammonium compounds are excellent hair conditioners, but have an incompatibility with anionic surfactants such as sodium dodecyl sulfate and anionic dyes. Therefore, quaternary compounds are generally not used in shampoo conditioners or anionic dye-based formulations. By incorporating the quaternary compounds in the inner aqueous phase w1, it is now possible, for instance, to formulate an efficient shampoo-conditioner.

8. Yoo, Y., and Lim. S., Polilino, 21(3):490–498 (1997) 9. Kover, T., Csoka, I., and Eros, I., Hung. Pharmazie, 52(2):166–167 (1997) 10. Rosano, H. L., Gandolfo, F., and Hidrot, J. P., Colloid Surf. A., 138:109–121 (1998) 11. Aronson, M. P., and Petko, M. F., J. Colloids Interface Sci., 159:134 (1993) 12. Ficheux, M. F., Bonakdar, L., Leal-Calderon, F., Bibette, J., Langmuir, 14:2702–2706 (1998) 13. Ute, B., Granum-Verlag, 268:46–59 (1996) 14. Rosano, H. L., Gandolfo, F., and Hidrot, J. P., Colloid Surf. A., 138:109 (1998) 15. Magdassi, S., Frenkel, M., and Garti, N., J. Dispersion Sci. and Technol., 5:49 (1984) 16. Garti, N., Colloids Surf. A., 123:233 (1997) 17. Hameyer, P., and Jenni, K. R., 18th International I.F.S.C.C.-Congress, Venice, Italy (Oct. 3–6, 1994) 18. ICI publication, 42-8E/3966.2Ed.S.DH (Apr. 1997) 19. Garti, N., Colloids Surf. A., 123:233 (1997) 20. Garti, N., Colloids Surf. A., 123(4)(5) (1997) 21. Rennan, P., Green, J., Maldarelli, C., J. Colloids Interface Sci., 205:1213–1230 (1998) 22. Lin, S. Y , McKeigue, K., Maldarelli, C., AIChe, 36:1785 (1990)

References 1. Grossiord, J. L., Seiller, M., and Puisieux, F., Rheol. Acta., pp. 32, 168–180 (1993) 2. Cole, M. L., and Whateley, T. L., J. Controlled Release, 49(1):51–58 (1997) 3. Lee, C. H., Tsai, J. S., and Huang, J. J., Shipin Kexue, 24(3):269 (1997) 4. Nakhare, S., and Vyas, S. P., J. Microenscapsulation, 12(4):409 (1995) 5. Ohkouchi, H., and Nakano, M., Drug Delivery Systems, 9(1):31 (1994) 6. Silva Cunha, A., Grossiord, J. L., Puisseux, F., and Seiller, M., J. Microencapsulation, 14(3):311–319 (1997) 7. Chen, C., Tu, Y., and Chang, H., J. Agric. Food Chem., 47:407–410 (1999)

23. Kwok, D. Y, Cheung, L. K., Park, C. B., Neumann, A. W., Polymer Engineering Sci., 38:757–764 (1998) 24. Rosano, H. L., Habif, S., and Oleksiak, C., Surfactant in Solution, 11:431–456 (1991) 25. Habif, S., Normand, P. E., Oleksiak, C. B., and Rosano, H. L., Biotechnol. Prog., 8:454– 457 (1992) 26. Rosano, H. L., Habif, S., and Oleksiak, C., Cavallo, J. L., and Pelura, T. J., Surfactants in Solution, 11:125 (1991) 27. Rosano, H. L., J. Soc. Cosmet. Chem., 25:609–619 (1974) 28. Pal, R., Encyclopedia of Emulsion Technol., 4:112-118 (1996) 29. Stroeve, P., and Varanasi, P. P., J. Colloid Interface Sci., 99(2):360-373 (1984)

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30. Grossiord, J. L., and Seiller, M., Les Cahiers de Rhéologie, Vol. 15 (1997)

36. Kyziztos, W. L. P., Langmuir, 16:7612–7617 (2000)

31. Lucassen-Reynders, E. H., Encyclopedia of Emulsion Technol., 4:63 (1996)

37. Kabalnov, A. S., and Shchukin, E. D., Colloid and Interface Sci., 38:69–97 (1992)

32. Grace, H. P., Chem. Eng. Sci., 48:277 (1982)

38. Princen, H. M., and Mason, S. G., Colloid Sci., 20:353–375 (1965)

33. de Bruijin, R. A., Chem. Eng. Sci., 48:2877 (1993) 34. Rumscheidt, F. D., and Mason, S. G., J. Colloid Sci., 16:238 (1961) 35. Buno, J., Lee, L. T., and Cabane, B., Langmuir, 15(22):7585–7590 (1999)

39. Lemlich, P., Ind. Eng. Chem. Fundam., 17(2):89–93 (1978) 40. Walstra, P., Encyclopedia of Emulsion Technol., 4:1–62 (1996) 41. Monsalve, A., and Schechter, R. S., Colloid and Interface Sci., 97(2):327 (1984)

Part VIII Foams

Coascervate Foam Delivery Systems

FOAMS

Hydrophilic Active-Filled Polyurethane Delivery Systems: "Soft Cell Approach to Personal Care"

23 Coacervate Foam Delivery Systems Manuel Gamez-Garcia* Amerchol Technical Center Edison, New Jersey

23.1 23.2 23.3 23.4

Introduction ................................................................................... 501 Coacervate Foams ....................................................................... 502 Analysis Methodology ................................................................... 502 Results ......................................................................................... 503 23.4.1 Formation of Coacervates ................................................ 503 23.4.2 Properties of Coacervate Foams ..................................... 504 23.4.3 Application of Coacervate Foams ..................................... 507 23.5 Conclusions .................................................................................. 510 References .......................................................................................... 511

23.1 Introduction Foams with singular characteristics not present in common foams have been observed to form when anionic detergent systems are mixed with polycations. These types of foams are referred to in this chapter as coacervate foams. They are typical of detergent compositions undergoing coacervation, or phase separation, by the Lochhead-Goddard effect.[1] The foams are produced by the simultaneous action of shear and dilution during a washing/rinsing process. The three main features of these coacervate foams are: 1. The lamellar “crust” generated by these foams has the same composition as the high viscosity gel coacervate produced during shampoo dilution.

2. The lamellar “core”[3] of the foam has an interstitial phase composed of the same liquid forming the conjugate coacervate co-phase. 3. These coacervate foams contain insoluble actives that are either adsolubilized in polycation/surfactant/ water complexes forming the lamellar “crust,” or flocculated and dispersed by granular coacervates in the lamellar “core” of the foam. These features of the coacervate foams can be used to deliver insoluble actives onto substrate surfaces, in particular to keratinic substrates. This useful property appears to result from the transfer foam coacervate to substrate of a polycation/surfactant/water complex that produces a thin film coating which acts as a gel network immobilizing insoluble actives.

*Present address: Firmenich, Plainsboro, New Jersey Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 501–512 © 2005 William Andrew, Inc.

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23.2 Coacervate Foams There are a few studies in the cosmetic scientific literature on the interaction of foams with keratinic substrates during washing. This is surprising in light of the fact that cleansing and conditioning of hair and skin take place mostly when detergent systems are in the foam phase.[2] Foams consist of agglomerated air bubbles produced by aqueous surfactant solutions in which the air compartments are separated by thin liquid films. The three main layers constituting these thin films are the two outer layers composed of a palisade of surfactant molecules forming the walls or crust[3] of the foam lamella, and a “core” at the center of the lamella containing an aqueous surfactant solution. The structure of these types of lamellar films is critical to foam properties and stability. The foam lamella structure has already been shown to depend on parameters such as surface tension, double-layer repulsion, Laplace pressure, Plateau suction pressure, and Marangoni effects.[4] Furthermore, it has been found that when foaming solutions contain polymers, foam properties, and stability are also dependent on the foam’s film visco-elasticity.[4][5] Indeed, various scientists have already found that the formation of surface-active polycation/surfactant complexes in surfactant solutions dramatically affects film rheology and foam stability.[6][7] Since the formation of coacervates containing polycation/surfactant/water complexes is typical of shampoos undergoing dilution (Lochhead-Goddard effect), it can be anticipated that the stability and properties of shampoo foams are also affected by coacervation. The importance of this phenomenon has not yet been well appreciated in the cosmetic industry even though it is commonplace to find shampoos designed to undergo coacervation during the foaming stage.[8] Previous work has already shown that when coacervates are produced from shampoos by shear and dilution, the coacervates tend to partition and adsorb preferentially into the crust of the foam lamella. During this process, the liquid co-phase tends to remain in the lamellar core.[2][9] It is in this sense that the term “coacervate foam” is applied here, (i.e., the term is used to refer to foams which have a lamella “crust” composed of a high viscosity gel coacervate and a lamellar “core” composed of a

low viscosity co-phase). This chapter will show that the partitioning of coacervates in foams leads to the formation of foam structures that have transient thin film coating properties that assist in the delivery of insoluble actives. Coacervates have been reported to act as vehicles to separate insoluble actives by solubilization.[10] Coacervates are also known to be able to flocculate insoluble actives by the sequential process of coacervate nucleation, growth, and droplet bridging.[1] The co-phase of the coacervate, on the other hand, has been found to have a composition typical of a concentrated detergent solution, (i.e., lean in polycation chains and rich in surfactant molecules).[10] Yet another characteristic of gel coacervates is that they are composed of polycation/surfactant/water complexes whose electrostatic charge is predominantly positive (the coacervate phase). This phase is in thermodynamic equilibrium with a negatively charged solution of surfactants (the cophase).[11] Since coacervate foams contain both phases arranged in a lamellar fashion, it will ultimately be shown in this chapter that active delivery with these foams is intimately related to the cleansing action of the detergent solution.

23.3 Analysis Methodology Analysis of foam structure from model shampoos was carried out by optical microscopy. Foams were produced using a commercial blender, and foam volume was measured using a graduated cylinder. Quantification of coacervate gel particles in foams was carried out by optical microscopy. Separation of complex coacervates was carried out by centrifugation. The level of polycation content in coacervates was measured using the following procedure: Gel coacervates, either from dry foams or from solutions, were first dialyzed in a cellulosic membrane with a 60,000 MW cutoff to extract the surfactants. The amount of polycation was then determined by gravimetry. The cationic polymers used in this study were various low and high molecular weight polycations (polyquaternium-10) with different levels of cationic substitution (CS). The polymers, manufactured by Amerchol, were as follows: one low molecular weight polycation, JR-125, two medium molecular weight (MMW) polycations, JR-400 and LR-400, with a high and low level of cationic substi-

GAMEZ-GARCIA: COACERVATE FOAM DELIVERY SYSTEMS tution (CS), respectively, MW << than 600 k; two high molecular weight (HMW) polycations, JR-30M and LR-30M, with a high and low level of CS, MW << 1.2 million. The hair used in these experiments was Brown European from IHI Valhala, New York. Silicone oil was used as the insoluble active and the surface substrate was hair. Analysis of silicone deposition on hair was carried out by x-ray fluorescence using the method of Gruber, et al.[12] Levels of silicone deposition were also confirmed by using solvent extraction and analysis of silicone by atomic absorption spectrophotometry. The following surfactants in different combinations were used to formulate various shampoos as required, namely: sodium lauryl ether sulfate, 2 moles (SLES-2); ammonium lauryl sulfate (ALS); cocamido propyl betaine (CAPB); disodium cocoampho diacetate (DCADA); and ethyene glycol distearate (EGDS).

23.4 Results 23.4.1

Formation of Coacervates

In the past, it has been shown that shampoos can undergo phase separation with coacervate formation when they are diluted with water.[1][9] For instance, both a high-viscosity gel coacervate and a low-viscosity liquid “co-phase” have been reported to form after shampoo dilution. In a real hair washing process, however, shampoos are not only diluted during the application step, but they are also sheared

503 simultaneously, thereby producing abundant foam. The evolution of coacervates during “shear-foaming” has already been studied in the past. These studies have shown that the gel coacervate particles appearing in the hazy shampoo solution, partition between the core and the crust of the foam lamella.[9] During this partitioning phenomenon, a fraction of the granular gel coacervates rearrange and adsorb at the air/water interface forming the walls or crust of the foam lamella. The remaining portion of the granular gel coacervates remain dispersed in the interstitial liquid of the foam, (i.e., in the lamellar core). In the present work, the partitioning of coacervates in foams was studied by using model shampoos. For instance, Fig. 23.1 illustrates the process of coacervate partitioning from foams produced by a model shampoo (15% SLES-2, 0.5% JR-30M, 3% CAPB) when diluted in a 1 to 5 ratio with water. Figure 23.1 shows that when the shampoo is undiluted, its appearance is clear and transparent. However, after dilution with water, the shampoo turns hazy. Figure 23.2 displays a microscopic image of the granular gel coacervates responsible for the observed haziness. Experiments show that centrifugation of the hazy solution leads to separation of the dispersed granular coacervates into a thick, homogeneous gel layer at the bottom of the centrifugation tube, while the second is a liquid co-phase at the top of the tube (see Fig. 23.1). Mixing and stirring these two phases was observed to re-disperse the gel particles and resulted in the production of abundant foam. Figure 23.1 also shows that when the foam was poured into a separatory funnel and allowed to

Figure 23.1 Schematic representation of coacervate partitioning in foam. Model shampoo (15% SLES-2, 0.5% JR-30M, 3.0% CAPB).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS a coacervate foam that was allowed to dry for a period of six hours. Figure 23.3a also shows that, after this long drying period, most of the coacervate bubbles were still intact. This phenomena indicates that the mechanical stability of the polycation/surfactant/water complexes forming the lamellar crust is very high. In order to better visualize the adsorption of these complexes at the lamella crust, Fig. 23.3b shows a schematic diagram of the differences between a normal and a coacervate foam.

23.4.2

Figure 23.2 Microscopic image of coacervate particles produced upon dilution of model shampoo of composition 15% SLES-2, 0.5% JR-30M, 3.0% CAPB.

stand and drain for about five minutes, the aging process led to two main components; these included a dry foam at the top of the funnel, and a drained liquid at its bottom. Analysis of the dry foam and drained liquid described above confirmed that the dry foam was essentially composed of the gel coacervate material separated by centrifugation while the drained liquid had the same composition as the liquid co-phase. The gel character of the lamellar crust in a coacervate foam can also be appreciated in Fig. 23.3a. This figure shows a foam shell formed after drainage of

Properties of Coacervate Foams

Shampoo dilution and partitioning of coacervates in foams. Following the application of shear-foaming, the rearrangement, and adsorption of granular gel coacervates at the lamella crust is not always complete. The degree of coacervate partitioning was observed to be dependent on the following parameters: foam dilution, polycation molecular weight, surfactant platform, and shear rate. The fraction of granular coacervate particles that did not adsorb at the lamella crust was invariably seen dispersed in the thin lamellar core. For instance, Fig. 23.4 shows the fraction count of gel particles which were not adsorbed at the lamella crust as a function of foam. This study was carried out on foams made with various polycations having different molecular weights.

Figure 23.3 (a) Microscopic image of dry coacervate shell after foam drainage of a model shampoo (15% SLES-2, 0.5% JR-30M, 3.0% CAPB), and (b) schematic representation of Gibbs channels in normal and coacervate foams.

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505

Figure 23.4 Count fraction of gel coacervate particles in foam core vs parts of water added to dilute a model shampoo (15% SLES-2, 0.5% polycation, and 3.0% CAPB).

Medium molecular weight polycations (MMW) caused gel particle count in the lamellar core to decrease gradually with dilution until a minimum threshold value was reached. Once the minimum had been reached, the fraction of gel particles increased again. High molecular weight polycations (HMW), on the other hand, resulted in a low gel particle fraction count. This difference between medium and high molecular weight polycations indicates that the tendency of polycation/surfactant/water complexes to adsorb at the lamella crust is higher with HMW polycations than with the MMW ones. It was also noted that the stability of the film formed by polycation/surfactant/water complexes changes with dilution. Shear and partitioning of coacervates in foams. The parameter that most strongly affected coacervate partitioning was foam shear rate. For instance, Fig. 23.5 shows that if a shampoo solution is stirred at low rpm, only a few foam bubbles form and most of the granular coacervates remain unchanged and dispersed in the liquid co-phase. However, as the rpm of the stirrer in the foaming vessel is increased, the foam volume also increases and the amount of free granular coacervate particles in the solution decreases.

When certain critical shear rate (CS) values are reached, total partitioning of coacervates in the foam crust occurs. At these critical shear rate values, no free coacervate particles are perceived in the lamellar liquid. It is interesting to note that microscopic observations of foams produced at critical shear revealed that, as the bubbles start to break, there is an immediate appearance of broken pieces of lamellar crust. The lamellar pieces appeared, then either adsorbed at the top of a bubble, or dispersed in the lamellar liquid (see Figs. 23.6a and 23.6b). When the shear rate was increased beyond the critical value, foam volume began to decrease and a higher level of broken lamellar pieces appeared in the lamellar liquid.

The experiments described above clearly indicate that shear rate has a critical impact on rearranging the granular coacervates and incorporating them into the outer lamllar crust, thereby forming lamellar coacervates. Furthermore, the results suggest that there is a quantitative relationship among foam stability, shear rate, and the rheological properties of the coacervates. For example, the foams appear to reach maximum stability with shear at SC. After this point is reached, the rheological properties of the polycation/surfactant/water complexes appear to reach a brittle stage, and can no longer sustain the extension required to increase foam volume without breaking. Observations similar to these have already been made by other scientists.[13] Results of our experiments also indicate that the ratio between lamellar and granular coacervates in foams depends on the shear rate employed to generate the foam. In the past, it has been shown that granular coacervates have the ability to flocculate silicone or mineral oil droplets by forming agglomerations of oil droplets and coacervates (oil floccoacervates).[9] When solutions containing these oil floc-coacervates were stirred and turned into foams, two main types of floc-coacervates were formed in the foam (see Figs. 23.7a and 23.7b). These were

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either granular or lamellar floc-coacervates. Both types of coacervates appeared to entrap insoluble actives either by flocculation or by adsolubilization. Figure 23.7b shows a foam with a lamellar floccoacervate containing cetyl alcohol adsorbed at the lamella surface. Various scientists have already re-

ported the adsolubilization of fatty materials by layers of surfactants.[14]-[16] The lamellar floc/coacervates were found in some instances to be birefringent under polarized light, indicating liquid crystal formation. These structures were found to adsorb onto the crust of the foam lamella.

Figure 23.5 Fraction count of gel coacervate particles in foam core and foam volume in (cc) vs shear rate given in rpm of a model shampoo (15% SLES-2, 0.5% JR-30M, 3.0% CAPB).

a

b

Figure 23.6 (a) Microscopic image (X80) of pieces of broken lamella dispersed in foam core, and (b) adsorbed onto the surface of a foam bubble. Model shampoo: 15% SLES-2, 0.5% LR-30M, 3.0% CAPB.

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Figure 23.7 (a) Microscopic image (X80) of granular floc-coacervates on foam, and (b) lamellar floc-coacervates forming lamellar crust.

23.4.3

Application of Coacervate Foams

Delivery of insoluble actives with coacervate foams. The deposition of silicone to hair from shampoos by using polymers has already been reported in the literature. Enhanced silicone delivery to hair with polycations does not occur simply by the formation of silicone-polycation floc-coacervates; there is one more required condition for silicone delivery to happen.[12] After the silicone-polycation flocs form in the shampoo, they need to be brought into contact with the hair surface and also need to be subjected to the action of shear against the surface. Incidentally, this is precisely what happens during the foaming process, and hence the need to understand the interaction of foams containing floc-coacervates with surface substrates. First, let’s analyze the ability of foams to deliver silicone via silicone-polymer-floc formation. As mentioned in Sec. 23.4.2, shear foaming induces the formation of two types of polymer-insoluble floc structures that can be easily observed under the microscope namely, the formation of granular floc-coacervates and floc-coacervates with lamellar structures (see Fig 23.8). For a particular shampoo composition, the formation level of these structures was found

to be dependent on polycation molecular weight. Silicone delivery efficiency, in turn, was found to be dependent on type of floc-coacervate structure and, therefore, on polycation molecular weight. Figure 23.9 shows variations in silicone deposition on hair washed with foams containing different polycations, leading to different mixtures of granular and lamellar coacervates. In Fig. 23.9, it is shown that the HMW polycation polymer JR-30M induces levels of silicone deposition higher than the shampoo control and also higher than those shampoos containing other polycations. The type of foam structure formed by polymer JR30M consisted of a mixture of both granular and lamellar floc-coacervates with a predominantly high level of lamellar coacervates. In contrast, the MMW polycation JR-400 produced lesser levels of silicone deposition on hair than those observed with the JR30M polycation. Polymer JR-400 leads to the formation of foams with a few granular floc-coacervates and a high level of unflocculated silicone droplets. High levels of silicone deposition correspond, thus, to the formation of mixed floc-coacervates structures with a predominant lamellar structure composition. In contrast, low levels of silicone deposition correlate well with foam structures containing mostly non-flocculated silicone droplets.

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Figure 23.8 Micrographs (X80) showing structural changes of floc-coacervates when sheared from solution into foams after shear at 600 rpm. Model shampoo: 15% SLES-2, 0.5% JR-30M, 3% CAPB, 0.5% NaCl plus various insolubles. (a) Broken flocs, (b) milled flocs, and (c) lamellar flocs.

Figure 23.9 Levels of silicone deposition from a detergent formulation containing polycations of different molecular weight and different degrees of cationic substitution.

GAMEZ-GARCIA: COACERVATE FOAM DELIVERY SYSTEMS The possible explanation for these observations is as follows. Flocculation of dispersed material in the presence of shear is known in the literature as ortho-kinetic flocculation. The term is used to refer to flocculation assisted by shear.[17] Shear of shampoo dilutions in the form of foams is a necessary condition to attain high substantivities with shampoos containing polycations.[12] Thus, shear of the shampoo during washing produces a thin foam film of polycation/surfactant/water complexes that coats the hair surface. Once this film is formed on the substrate, it promotes flocculation of silicone droplets during shear. In contrast, when low molecular weight polycations are used, coacervates are not formed in the shampoo solution; this hinders the ability of the silicone droplets to flocculate on the hair surface. Thus, the role of shear and foam production during shampooing is crucial to insoluble active delivery because it rearranges coacervates into the foam crust, mills the silicone droplets, and promotes their flocculation onto the hair surface.

in solution. In Figs. 23.10a and 23.10c, it can be seen that the size of silicone droplets has been reduced substantially in diameter after shear (from ~15 µm to ~0.1 µm) indicating that droplets and coacervates have been milled by the action of shear. The silicone droplets are still, however, flocculated onto the thin coacervate gel layer, indicating that during shear they are immobilized by ortho-kinetic flocculation. The stability of the film was not affected after it lost about 90% of its water content, and the silicone droplets remained spherical in shape even after ten hours of drying at ambient conditions. Upon touching with the fingers, the floc-coacervate film was seen to have a slippery feel. Similar films have been observed to form on the hair surface, although its clear detection by optical microscopy is not straightforward due to the high levels of surface heterogeneity. These observations indicate that the deposition of insoluble actives from foams onto substrate surfaces occurs as the lamellar coacervates adsorb and flocculate milled droplets of silicone as they are sheared against the surface.

Examples of silicon droplet milling by shear in the presence of coacervates can be seen in Figs. 23.10 (a, b, and, c). These pictures show the progressive changes in droplet size as silicone droplets forming floc-coacervates with the polymer are sheared onto a glass slide. Shear was produced by gently applying circular motion with a finger on the glass slide containing the silicone floc-coacervates

a

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Deposition and cleansing with coacervate foams. The role of surfactants during washing is to reduce the work of adhesion of soil, then solubilize, emulsify, and disperse the soil once it is detached from the substrate. In this manner, once the soil particles have been dispersed they can be removed by

b

c

Figure 23.10 Micrographs (X120) of silicone flocculated droplets on coacervates (a) before shear on a glass slide, and (b) and (c) after 5 and 10 seconds of gentle shear with the fingers, respectively. Model shampoo: 15% SLES-2, 0.5% JR-30M, 3% CAPB, 0.5% NaCl, 1.0% dimethicone.

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the flow of water. If the soil particles are not well dispersed they will redeposit again.[15] This implies that nondispersible particles will tend to deposit onto the substrate. Incidentally, the phenomenon of coacervation in shampoos allows the formation of nondispersible coacervate gel particles in a soluble co-phase. Because of their poor dispersability, the coacervate particles flocculate and settle rapidly.[1] Since coacervation is a thermodynamic phenomenon, the composition of the coacervate gel phase does not change during shear foaming. This means that the nondispersability of coacervates and floc-coacervates persists all along the washing process. Thus, high levels of polycation and insoluble deposition are expected to occur from the crust of a coacervate foam during the washing process.[2]

hair tresses that have been pre-oiled with capric/ caprylic triglycerides is almost negligible when washed with the dry foam alone. In contrast, when the hair tress was washed with the drained liquid, the level of oil removal was high. Levels of oil removal from hair washed with the whole foam were invariably lower than those removed by the drained liquid alone. These observations indicate that coacervate foams have a dual character, (i.e., their crust acts as the vehicle for deposition while their core acts as the detergent system).

Quantification of polycation and silicone deposition onto hair from the crust or dry foam showed, indeed, that the levels of deposition are quite substantial (see Fig. 23.11). In contrast, the deposition of these actives from the drained liquid was seen to be nil. In these experiments, the hair was washed, either with the dry foam alone, or with the drained liquid. Figure 23.11 also displays the different cleansing abilities of each foam component. The graphs in this figure show that the level of oil removal from

The partitioning of polyquaternium-10 coacervates in foams during shampoo shear and dilution, produces foams with multifunctional performance properties. The coacervates foams were shown capable of delivering polycations and silicone to the hair surface. These properties appeared to result from the transfer foam-to-substrate of polycation/ surfactant/water complexes which adsorb onto the substrate during shear foaming.

23.5 Conclusions

Figure 23.11 Levels of polycation and silicone deposition from dried foam and drained liquid. Also, levels of capric/caprylic triglycerides oil removal by the dry foam and drained liquid.

GAMEZ-GARCIA: COACERVATE FOAM DELIVERY SYSTEMS

References 1. Goddard, E. D., Polymer/Surfactant Interactions in Applied Systems, in: Principles of Polymer Science and Technology in Cosmetics and Personal Care (E. D. Goddard and J. V. Gruber, eds.), p. 184, Marcel Dekker, New York (1989); see also Gamez-Garcia, M., “The Deposition of Insoluble Actives from Anionic Detergent Systems,” to be published. 2. Gamez-Garcia, M., Polycation Substantivity to Hair, IFSCC, 4:99–107 (2001) 3. Isenberg, C., ed., The Science of Soap Films and Soap Bubbles, Dover Publications, New York (1992) 4. Rosen, M. J., Foaming and Anti-Foaming By Aqueous Solutions of Surfactants, in: Surfactants and Interfacial Phenomena, (M. J. Rosen, ed.) pp. 276–303, John Wiley & Sons, New York (1988) 5. Bikerman, J. J., Mechanical Properties of Foams, in Foams (J. J. Bikerman, ed.), Ch. 7, p. 184, Springer Verlag, New York (1973) 6. Narmsinhan, G., On Static Drainage of Protein Stabilized Foams, in: Foods, Polymers, Gels, and Colloids, Proc. of Intl. Symp. (E. Dickinson, ed.), Food and Chemistry Group of The Royal Society of Chemistry, Norwich, (Mar 28–30, 1990) 7. Graham, D. E., and Phillips, M. C., The Conformation of Proteins at the Air-Water Interface and Their Role in Stabilizing Foams, in: Foams, (R. J. Akers, ed.), Proceedings of a Symposium organized by the Society of Chemical Industry, Colloid and Surface Chemistry Group, Brunel University (Sep 8–10, 1975) 8. Schrader, E. M., Coffindaffer, T. W., and Caldwell, B. H., Conditioning Shampoo Composition, U.S. Patent 6,004,544 (1999) 9. Gamez-Garcia, M., Foams: Colloidal Phases with Cleansing and Delivery Properties, XXIIth IFSCC International Congress, Edinburgh, England (2002)

511 10. Gullickson, N. D., Scamehorn, J. F., and Harwell, J. H., Liquid-Coacervate Extraction, in: Surfactant-Based Separation Process (J. F. Scamehorn and J. H. Harwell, eds.), Surfactant Science Series, Marcel Dekker, Inc., New York (1989) 11. Dubin, P. L., and Davis, D., Stoichiometry and Coacervation of Complexes Formed Between Polyelectrolytes and Mixed Micelles, Colloids and Surfaces, 13:113-124 (1985) 12. Gruber, J. V., Lamoureaux, B. R., Joshi, N., and Moral, L., The use of X-Ray Fluorescent Spectroscopy to Study the Influences of Cationic Polymers on Silicone Oil Deposition from Shampoo, J. Cosm. Sci., 52:131–136 (Mar/ Apr, 2001) 13. Prins, A., Dynamic Surface Properties and Foaming Behavior of Aqueous Surfactant Solutions, in: Foams, Proceedings of a Symposium organized by the Society of Chemical Industry, Colloid and Surface Chemistry Group, Brunel University (Sep 8–10, 1975) 14. Harwell, J. H., and O’Rear, E. A., Adsorbed Surfactant Bilayers as Two Dimensinal Solvents: Admicellar-Enhanced Chromatography, in: Surfactant-Based Separation Process, ( J. F. Scamehorn and J. H. Harwell, eds.), Surfactant Science Series, Marcel Dekker, Inc. New York (1989) 15. Lisssant, K. J., Detergency: Theory and Test Methods, (K. J. Lissant, ed.) Surfactant Science Series, Marcel Dekker Inc, New York (1980) 16. Garrett, P. R., The Mode of Action of Antifoams, in: Defoaming, Theory and Industrial Applications (P. R. Garrett, ed.), p. 1, Surfactant Science Series, Vol. 45, Marcel Dekker, New York (1993) 17. Sonntag, H., Coagulation Kinetics, in: Coagulation and Flocculation; Theory and Applications, (B. Dobias, ed), Ch. III, Surfactant Science, Marcel Dekker, New York (1993)

24 Soft Cell Approach to Personal Care Hydrophilic Active-Filled Polyurethane Delivery Systems

James A. Smith and Betty Jagoda Murphy ReGenesis LLC Montclair, New Jersey 24.1 Forming Reactive Substrates Containing Actives ........................ 514 24.2 “Eureka!”—Formulation Plus Applicator In-Situ ............................ 514 24.3 Exploring Hydrophilic Polyurethane Technology ........................... 514 24.3.1 The Formulator as Chemical Artist ................................... 515 24.3.2 Limitations ......................................................................... 516 24.3.3 Understanding Hydrophilic Polyurethane Stability ............. 516 24.4 Hydrophilic Polyurethane Shaped or Molded Foams ..................... 517 24.4.1 Types and Functional Characteristics for Skin Care Products ........................................................................... 517 24.4.2 Marketing Benefits Versus Traditional Skin Care Products519 24.4.3 Types and Functional Characteristics for Hair Care Products ........................................................................... 519 24.4.4 Marketing Benefits Versus Traditional Hair Care Products 521 24.5 Hydrophilic Polyurethane Foam Film Coatings ............................ 521 24.5.1 Types and Functional Characteristics for Skin and Hair Care........................................................................... 521 24.5.2 Marketing Benefits of Foam Film Coatings ....................... 523 24.6 Hydrophilic Polyurethane Foam Laminates (Cast Foam) ............ 523 24.6.1 Marketing Benefits - Foam Laminates .............................. 523 24.7 Manufacturing Techniques and Methods ...................................... 524 24.7.1 Molding Foams ................................................................. 524 24.7.2 Casting Foams ................................................................. 524 24.7.3 Coating Foam Films ......................................................... 525 24.8 Summary ...................................................................................... 525 24.9 Formulations ................................................................................. 526 24.9.1 Patents ............................................................................. 532

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 513–532 © 2005 William Andrew, Inc.

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24.1 Forming Reactive Substrates Containing Actives The development of disposable substrate-based delivery products for personal care such as premoistened towelettes, dry water-activated cleansing wipes, etc., has traditionally been an involved two-step process. First, the formulator must develop a stable formulation. Then he or she must select an appropriate substrate into which the solution, lotion, gel, or ointment can be impregnated or coated. In some instances, the substrate-based delivery vehicle may be selected because of an unusual or desirable characteristic such as texture, feel, look, or performance on the skin. Manufacturers of these disposable substrate materials have made considerable advances in the last few years. New fiber compositions and manufacturing processes have resulted in new and superior nonwoven and paper materials, making them more efficient application vehicles, consumer acceptable, and cost efficient. Although these recent advances provide a wide variety of functional properties, the formulator’s “holy grail” has always been to develop a product where the formulation and applicator is produced at the same time. Almost all personal care wipe products share one disadvantage: they are relatively thin materials that can only hold and dispense a limited amount of liquid, just a few grams, of product. Moreover, they can only absorb and retain limited amounts of liquids and solids. Another disadvantage, particularly for paper wipes developed for cleaning hands following eating in restaurants, is that they can be both rough and nonabsorbent.

24.2 “Eureka!”—Formulation Plus Applicator In-Situ To address the deficiencies cited above, ReGenesis has developed a series of novel systems based on hydrophilic polyurethane prepolymers. Utilizing this technology, formulators can combine, in an “in situ” reaction, a wide variety of aqueous personal care formulations with urethane prepolymers. Under appropriate mixing conditions, the combina-

tion of the aqueous phase and the hydrophilic polyurethane prepolymer generates a material that, when cured, results in a unique flexible foam, the “holy grail,” both the formulation and delivery system in one! The aqueous phase portion of these flexible foam formulations provides considerable opportunities for creative chemists because it can be composed of a broad selection of active ingredients. These active ingredients can be in the form of dispersions, solutions, and emulsions, including those with high levels of solvents, as well as moisturizing ingredients, surfactants, solids, fragrances, and polymers. The resulting flexible foams are capable of dispensing active ingredients while, at the same time, absorbing all manner of soil from skin and hair. These foams can be molded, cast into sheet stock, or coated onto other carrier materials, as desired. The result of such processing is the creation of a finished product consisting of an active formulation that is contained within, and is an integral part of, the applicator itself. This technology is capable of providing a wide range of new skin and hair care products. While the process described above is beautifully simplistic, these hydrophilic polyurethane systems require a great deal of understanding and R&D experience before the promise of unique, effective, and cost efficient products can be realized.

24.3 Exploring Hydrophilic Polyurethane Technology Before we delve into developing products with hydrophilic polyurethane prepolymers, it will be useful to describe certain basics of conventional polyurethane plastics and highlight the differences between conventional and hydrophilic polyurethanes. Conventional polyurethane plastics are generally found in three forms: elastomers, films, and hydrophobic foams, rigid and both rigid and flexible. These polymers contain carbamate units, –NHCOO–, which are typically referred to as urethane groups in the polymer backbone. The plastics are usually obtained by the reaction of a diisocyanate with a “macroglycol,” commonly known as a polyol. The polyol may be used by itself, or in combination with

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a short-chain glycol extender (butane diol) and is combined under controlled conditions with a tin catalyst and a small amount of water (3% to 5%). Very few additives can be included in the formation of these types of plastics making them essentially 100% polyurethane. Conventional urethanes classically require specialized high-pressure, high-throughput, mixing production lines. Although they are utilized over a broad spectrum of applications, the most common applications are molded parts, furniture, and airline industry cushions.

The foaming mechanism characterized above follows these steps:

By comparison, hydrophilic polyurethanes are quite different from conventional urethanes because they are based on easy-to-handle liquid prepolymers. These prepolymers are made from aromatic polyisocynates such as toluene diisocyanate (TDI) or diphenylmethane diisocyanate (MDI), or aliphatic polyisocynates like isophorone diisocyanate (IPDI) or hexamethylene diisocyanate (HDI). These prepolymers will react with any protic compound such as ones containing (1) hydroxyl groups (e.g., water, alcohols, polyols, phenols); (2) amino groups —both primary and secondary; and (3) carboxylic acid groups, and can form foams, films, or elastomers.

The chemist developing personal care delivery systems based on hydrophilic polyurethane prepolymers needs to consider the following facts while formulating:

A finished hydrophilic polyurethane foam product usually consists of an aqueous phase containing water plus at least one personal care active ingredient reacted with a selected prepolymer. Usually the aqueous phase represents 60%–80% of a finished foam product, while the prepolymer makes up 20%–40%. When these phases are mixed under controlled conditions, the resulting reaction produces carbon dioxide (CO2), causing the formation of a foamed structure.[1] (See Fig. 24.1.)

RNCO + H2O → RNHCOOH (unstable carbamic acid) RNHCOOH → RNH2 + CO2 (amine formation, gas generation) RNH2 + RNCO → RNC=ONR | | H H (urea chain extension, cross-linking formation)

• Hydrophilic polyurethane prepolymers are water-activated and can result in foams containing 20% to 65% water. • Hydrophilic polyurethane prepolymers are capable of high additive-loading with such ingredients as surfactants, solvents, abrasives, other solid ingredients, fragrances, colorants, moisturizers, etc. • Hydrophilic polyurethane prepolymers can produce foams or films with a wide variety of flexibility and texture. This is a result of generating cell structures ranging from completely closed to fully reticulated (i.e., opened) in varying cell sizes. They can also produce elastomers or gels. • Hydrophilic polyurethane based foam products, by their very nature, have the ability to absorb high levels of water as well as other liquids. Using proper formulation techniques and depending on the envisioned end use, the developer can readily control the wetting ability and absorptivity of the finished foams. • Hydrophilic polyurethane exothermic reactions occur at low temperatures and pressures making them relatively easy to handle.

24.3.1

Figure 24.1 Diagram of polyether polyisocyanate pre-polymer.

The Formulator as Chemical Artist

The formulator working with hydrophilic polyurethane prepolymers to create personal care prod-

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ucts is in an enviable position. However, because the final foam product will be both applicator and dispenser of active ingredients, the aqueous phase formulation(s) must be specifically designed to work with these specialized polymers and generate a usable foam. Individual ingredients in the aqueous phase can definitively impact particular aspects of the cell structure and the resultant foam’s viability. It is, therefore, necessary to carefully select the correct combination of ingredients, not only for the desired type of personal care effect, but for their influence on cell size, foam strength, resilience, ease of dispensing, skin feel, soil absorption, etc. Since the final product is the outcome of a combination of effects, and the formulation’s components influence the all-inone substrate foam formation, working with hydrophilic polyurethanes requires the formulator to have an artistic sensibility and a sensory feel for the envisioned final product.

as chlorine, bromine, and fluorine as well as ingredients that contain high levels of amines have a deleterious effect on the final foam structure. While the negative effects on the foam caused by shortchained alcohols are evidenced during the foaming process or immediately thereafter, the ill effects from halogen or amine-based compounds are often not materialized until the finished foam has aged.

24.3.2

24.3.3 Understanding Hydrophilic Polyurethane Stability

Limitations

Like all chemical systems, hydrophilic polyurethane reactive formulations have both chemical and physical limitations. A major chemical limitation is that in order for the foaming reaction occur, there must be a water-based formulation to combine with the hydrophilic polyurethane prepolymer. Consequently, from a chemical selection standpoint, the formulator must accept that certain ingredients will not work in these systems. For example, strong oxidizing or reducing agents cannot be included in formulas since they will react with, or interfere with, the polymerization step in forming the final foam polymeric substrates. Further, use of high levels of hydrocarbon solvents (in excess of 15%) usually result in poor quality foam structures because they either (a) essentially solubilize the polymer during the reaction stage, or (b) the finished products will exhibit exceptionally weak strength or durability. Alcoholic solvents, especially those that are short chain alcohols, will interfere with the polymerization reaction. These solvents act as a polyol due to their C–OH group and enter into the reaction. This process produces weak links in the polymeric chain. On the other hand, small amounts of alcoholic solvents can sometimes be accommodated, especially if they are part of a more intricate composition of other ingredients. Halogen-based compounds such

From a physical standpoint, the product form itself can be a limiting factor. The aqueous phase ingredients must be selected with care and knowledge as to the potential role they will play in influencing cell size, foam strength, resiliency, thickness, etc. These effects will greatly determine if the final product will be a soft, reticulated foam pad, or a firm molded shape. Conversely, if the product is to be a thin foam film coating, or will be laminated to a fabric as it is being cast, a different set of ingredient criteria will need to be considered.

Understanding the limitations of formulating with hydrophilic polyurethane prepolymers is paramount in establishing stability parameters for a given final product. In general, hydrophilic polyurethane products are light sensitive and have a tendency to darken or discolor upon aging, however certain UV absorbent ingredients can be added to the prepolymer to enhance its light stability. Exposure to heat can have a similar effect. With these factors in mind, accelerated thermal stability testing is a “must do” as soon as a prototype formulation is made. There are differences among the available hydrophilic urethane prepolymers that can also alter product stability. Some types of these prepolymers produce foams with greater strength than others; some have better halogen stability allowing more flexibility in the aqueous phase composition, and still others exhibit better light and thermal stability. Generally speaking, while freeze/thaw cycles seem to have little effect on these kinds of polymers themselves, the aqueous phase component of the final foam can be affected. As one might expect, the aqueous phase formulation contained within these foams or films can impact any of these stability properties and the need to experiment with different ingredients to determine

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE their effect on overall stability is part of the R&D program. Simply put, there is no substitute for the “Edisonian” approach in the development of these urethane foam products. In view of the fact that these hydrophilic polyurethane foams can contain high amounts of water, have a large surface area and considerable air space within the cellular network, the selection of an appropriate preservative system is extremely important to prevent bacterial or fungal growth. Since the finished foamed product is the consequence of an exothermic polymerization reaction, it is necessary to challenge the microbiological properties of the finished product. Many of the commonly available preservatives are acceptable for use in hydrophilic polyurethane products including the parabens, Kathon CG®, Glydant® and Neolone® and combinations thereof. Since certain halogen-containing molecules employed as preservatives, will react with the urethane prepolymer itself, it is possible that certain preservatives could be tied up during the reaction step rendering them ineffective.

24.4 Hydrophilic Polyurethane Shaped or Molded Foams One of the outstanding characteristics of products formulated with hydrophilic polyurethane prepolymers is their ability to be molded, or cut into diverse and functional shapes. They can be “foamed” directly into molds of all manner of designed forms including animal shapes like the proverbial yellow duck for floating in the bath, while at the same time providing sudsy bar-soap type lather or creamy cleanser. Other kinds of personal care foamed products can be obtained by casting a formulation into a round sausage-like mold and allowing the foam to cure. After de-molding, the foamed sausage is vertically die-cut to form very thin circles that resemble drink coasters. Depending on the formulation, the exterior surfaces are usually covered with a thin “skin.” Unless the mold has been specially treated, this skin is not reticulated and the release of the product formula through the skinned surface is greatly impeded. Thus, the desirable use surface for a wipeon product is the “cut” surface because it exposes the preferred reticulated cellular structure (Fig. 24.2).

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With the end use in mind, products may be formulated in such a way that the structure can be controlled to provide (a) large or small cells, (b) reticulated or non-reticulated foam, (c) very flexible or stiff foam, (d) very wet or dry feeling foam, and (e) dense or airy foam.

24.4.1

Types and Functional Characteristics for Skin Care Products

Hydrophilic polyurethane foam products are ideal for skin care applications because they can effectively and uniformly dispense a wide variety of active ingredients. They can be used with or without water. Such materials absorb and retain soils, they can be soft and elegant, and they generally feel luxurious on the skin. Under the proper manufacturing conditions, they can be consistently produced within specifications and readily packaged. Cleansing. One of best functional uses for hydrophilic polyurethane products is skin cleansing. This is so because these hydrophilic polyurethane polymers can accept a broad scope of aqueous detergent systems ranging from simple solutions to multiple combinations of surfactants in an emulsified state. Nonionic, anionic, cationic, and amphoteric types of surfactants can be incorporated into these reactive polymers with relative ease. Even ingredient combinations that may be unstable prior to foaming can be formulated with a high degree of confidence due to the stabilizing effect of the resultant foam. This gives the formulator the ability to develop sophisticated systems that invite the inclusion of ingredients that will leave the skin not only clean, but also conditioned, smooth, and treated (Fig. 24.3).

Figure 24.2 Open-celled hydrophilic foam.

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(See Skin Care Formulation 24.1 at the end of this chapter.) Makeup removal. Exemplifying the innovativeness of this hydrophilic polyurethane technology is the removal of facial makeup from the skin. The product utilizes an aqueous phase consisting of a water-based lotion combined with emollients and pigment dispersants. The aqueous phase is reacted with a hydrophilic polyurethane prepolymer and molded in a tubular configuration. The cured product is then die cut into ready-to-use round, thin, spongy disks. The finished product is a luxuriously soft, moist, reticulated foam that dispenses an effective moisturizing cleanser that efficiently dissolves and removes all types of facial and eye makeup including waterproof mascara (Figs. 24.4 and 24.5). (See Skin Care Formulation 24.3 at the end of this chapter.) Treatments. Many types of skin treatment ingredients can be dispensed from hydrophilic polyurethane foam products. Generally speaking, there will be multiple ingredients involved in any treatment formulation. The formulator can choose from a selection of moisturizing esters, oils, or solvents such as glycols, glycerin derivatives, silicone derivatives, emollient waxes, etc. In the cosmeceutical arena, a diverse range of “anti-aging” and other skin treatment formulations are also possible. Makeup application. The excellent release properties of hydrophilic polyurethane foam systems make them ideal for the uniform application of color cosmetics to the skin. Pigmented formulations such as foundation makeup must be water-based in order to react with the hydrophilic polyurethane prepolymers. Moreover, the key to the uniform release of the pigment colors is the selection of the appropriate prepolymer, or combination of prepolymers, to allow a smooth transfer of the makeup from the foam to the skin. (See Skin Care Formula 24.3 at the end of this chapter.)

Figure 24.3 Ready-to-use facial cleansing cushion.

Dermabrasion. Many skin-care regimens suggest an initial gentle abrasion step for the removal of dead skin before any additional treatments are applied. Hydrophilic polyurethane systems provide a perfect vehicle for this step. Various cosmetically acceptable abrasive materials such as aluminum oxide crystals, feldspar, ground fruit pits, mini-fibers, polyethylene granules, etc., can be added at relatively high levels (40% or more) to the aqueous phase. These can be processed into a finished foam product that will exhibit a special “soft abrasive” action. The final foam presents all of the aggressive properties of the undissolved particles as well as the attractive advantage of the softness of the foam itself. An additional benefit of this system is that the abrasives can be chemically locked into the foam matrix structure thereby eliminating the usual residual grit that conventional abrasive creams leave on the skin or in the wash basin. If a formula does contain levels of abrasive particles in excess of 50%, the foam is not recommended for this purpose since it tends to dry out and resemble sandpaper.

Figure 24.4 One side of the Makeup Remover Cushion gently and effectively removes all types of eye makeup, including waterproof mascara. (See also Fig. 24.5.)

Figure 24.5 The other side of the same Makeup Remover Cushion efficiently removes facial cosmetics and leaves the skin clean, moisturized, and smooth. (See also Fig. 24.4.)

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE 24.4.2 Marketing Benefits Versus Traditional Skin Care Products Skin care products consisting of active ingredients included during the in-situ formation of the dispensing substrate offer numerous and exciting marketing benefits. One key marketing benefit is the visual appeal of the product itself since it is a combination of formulation and applicator, all in one. By contrast, traditional skin care products, no matter how newly discovered the active ingredient, are generally dispensed from the usual bottles or tubes as lotions, gels, or solutions, and applied to the skin by hand or by the means of some implement. Hydrophilic polyurethane products are recognizably different, physically innovative, and ultra convenient, yet more sophisticated in form than earlier technology. For example, pre-moistened wipes that were originally developed as hand or baby wipes, can hold only a limited amount of liquid, depending on the absorptivity of the nonwoven or paper sheet stock. When compared to most of these pre-moistened wipes, the hydrophilic polyurethane foams systems can hold enormous amounts of liquids. At the same time, they can consistently dispense a given formulation over a given time period, in essence, providing “time release” action to a product’s function. These systems can be ready-to-use or be dried during manufacturing for reactivation with water at the time of use. Hydrophilic polyurethane foam products have great absorption capabilities and can retain oily soils removed from the skin (sebum, makeup, dirt, etc.) without releasing and redepositing them elsewhere on the skin. Spongy sheets, molded shapes, granules, pads, and laminates all demonstrate the breadth of the product forms possible.

24.4.3

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brushing the hair or wiping it directly on the tress. The ability to provide time-release characteristics for the actives, and their high absorptive capacity for both water and soils, contribute to advantages of hydrophilic polyurethane foams in the hair care arena. The foams can be formed into suitable thin sheets, wedges, and other shapes for convenient use. Moreover, the wide range of ingredients that can be formulated in situ offers formulators and marketers alike an untapped opportunity to give consumers new ways to manage their hair care routines (Fig. 24.6). Cleansing. As a hair cleansing and refreshing product, hydrophilic polyurethane foam products enable the use of a water/solvent mixture that integrates “leave on” hair shampoo ingredients without the disadvantage of a discernible residue. Such products are formed by reacting a formulated aqueous phase cleansing system with an appropriate hydrophilic polyurethane prepolymer. The “foam” stream is molded into a brick shape, die cut into 3" × 4" × 3/8" sheets, and individually pouched in a barrier film. To use the hair cleansing product, the fully reticulated (open celled) foam sheet is pushed down over the plastic bristles of a styling brush; in effect the foam sheet is impaled by the bristles. The dry hair is then simply brushed clean by repeated and thorough brushing. As the foam sheet comes in contact with and is brushed through the hair, it releases a moist, refreshing, and cleansing system that effectively removes oils, particulate soils, hair spray, and other styling ingredients. The hair is left looking clean, shiny, and bouncy, and smelling fresh. Unlike older versions of waterless hair shampoos that were based on starches, the hydrophilic polyurethane systems are not powdery and leave no dulling residues (Fig. 24.7). (See Hair Care Formulation 24.5 at the end of this chapter.)

Types and Functional Characteristics for Hair Care Products

Just as hydrophilic polyurethane foam products demonstrate clear advantages for skin care products, they similarly offer advantages for the hair care market. Formulated specifically for hair treatment, they can conveniently impart cleansing, conditioning, structuring (styling), and temporary hair color by simply affixing a foamed sheet to a brush and

Figure 24.6 Hydrophilic polyurethane foam Hair Treatment Sheet readily attaches to the brush and is ready to use.

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Figure 24.7 Hair Refreshing Sheet is conveniently brushed through dry hair to quickly refresh and revive hair in-between shampoos.

Conditioning and repair. A product, similar to that described above for hair cleansing, can be formulated to both condition and repair the hair shaft. This is accomplished by brushing a specifically formulated foam sheet through wet or dry hair. It is important to check the release properties of the active ingredients such as the quaternary surfactants in order to select the optimal ones for inclusion in the formulation. As with the hair cleansing sheets, such products can be applied by brushing through the hair. Hair color. Foam delivery products for providing temporary hair color (color cosmetics for the hair) are similarly produced by formulating water-based colored pigment dispersions with hair styling polymers. Such dispersions are reacted with hydrophilic polyurethane prepolymers to achieve a flexible, open-celled foam sheet, which is then die cut and packaged. For “all over” hair color, the color dispensing sheets are impaled on a plastic styling brush and brushed through wet hair. If a streaked coloring effect is desired, the product can be wetted prior to brushing on dry hair and through selected tresses. Permanent hair color formulations that utilize dyes in combination with peroxides are more difficult to incorporate in these systems due to the reactivity of the oxidizing agents. These materials can disrupt the polymerization of hydrophilic polyurethane prepolymers into finished foam (Fig 24.8). (See Hair Care Formulation 24.6 at the end of this chapter.) Styling. One of the unique attributes of hydrophilic polyurethane prepolymers is their ability to be

combined with other polymers such as those in hair styling gels, mousses, and sprays. Mixtures of styling polymers may be solubilized, or dispersed in water, combined with an appropriate hydrophilic polyurethane prepolymer, and then cast onto release paper on a moving conveyor belt. The resultant foam is a reticulated cellular product that can be die cut into suitable sizes for delivering styling polymers to wet hair by brushing or wiping. The styling sheets are conveniently brushed through the hair while it is being styled and blown dry as usual. They may also be brushed through wet hair which is then allowed to “air” dry. The degree of styling/hold properties can be competitive with hair care styling products currently available (Fig. 24.9). (See Hair Care Formulation 24.7 at the end of this chapter.) Ethnic hair care. Hair care products for the ethnic market represent a rather interesting opportunity for a series of hydrophilic urethane foam delivery systems. The curlier, kinkier, and more chemically processed the hair, the greater the need for

Figure 24.8 Water-activated Hair Color Sheet is brushed through just shampooed hair to neatly and uniformly dispense a temporary hair color formulation.

Figure 24.9 Hair Styling Sheet dispenses fixative ingredients as just shampooed hair as it is styled and blown dry.

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE products that eliminate stress on the hair. The consistent use of chemicals to straighten hair tends to damage, dry, and embrittle it. While petrolatum-based products are routinely used to condition and nourish the hair to keep it soft and re-moisturized, they may also leave the scalp and hairline feeling coated and oily, potentially causing acne, which dermatologists often attribute directly to hair pomades. Aside from the freshening, styling, and conditioning sheets mentioned in the preceding sections, the hydrophilic urethane foams can be formed into convenient wedges to dispense cleansing ingredients directly to the scalp, leaving tightly braided “corn rows” undisturbed. A foam sheet that can be either smoothed over or brushed through the hair can deliver a shine and re-moisturizing formulation. To combat “frizz,” a silicone-derived ingredient can be dispensed without laying a heavy coating on the scalp.

24.4.4 Marketing Benefits Versus Traditional Hair Care Products The hair care category is a huge factor in the personal care industry. It is made up of bottles of hair shampoos and conditioners, sprays or tubes of fixatives for styling, and caps, gloves, and assorted dispensers for hair coloring. By capitalizing on the special attributes and characteristics of formulated hydrophilic polyurethane foam delivery products, the opportunity clearly exists to provide a series of novel, but very functional and competitive hair care sheets that dispense active ingredients simply by brushing the hair. Such foam sheets are neat, convenient, portable, and easy to use. The styling and coloring sheets have particular advantages over their currently marketed counterparts because they are dispensed directly to the hair without messy, sticky residues coming in contact with the hands. The cleansing sheet’s ability to keep hair fresh and clean in-between normal shampooing offers tremendous benefits to busy people. This type of product offers the consumer the look and feel of “just shampooed” hair in a couple of minutes, and it can be used anywhere. In certain areas of the world, and when water is limited, such products could have a significant impact.

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24.5 Hydrophilic Polyurethane Foam Film Coatings Both nonwoven and woven textile fabrics are currently being manufactured with conventional polyurethane coatings to enhance particular attributes, (i.e., hand, stiffness, body, or water repellency). Similarly, the unique properties of hydrophilic polyurethane prepolymers can allow them to be readily formulated into functional coatings on nonwoven and other substrates for skin care use. As in other forms described in earlier sections, the aqueous phase portion of the reaction mixture can contain a wide variety of functional materials such as surfactants, moisturizers, abrasives, silicones, polymers, fragrances, topical drugs, etc. Hydrophilic polyurethane foam film coatings for this purpose are applied to nonwovens and other carriers at relatively low temperatures (5°C to 10°C) to prevent the reaction mixture from forming largecelled thick foams. These reaction mixtures are coated with a spreader bar and/or a doctor blade combination so as to spread the mix as evenly and thinly as possible. The coated nonwoven is quickly conveyed through an oven designed to handle fabrics and dry them to precise moisture content. Finally, the processed material is rolled up for subsequent cutting into specific sizes and packaged.

24.5.1

Types and Functional Characteristics for Skin and Hair Care

Hydrophilic polyurethane foam film coated nonwoven formulations can be designed to clean and moisturize the skin in one step. The coated sheet stock can be dried, and cut into the desired sized sheets to be activated with water prior to use for effective skin cleansing. As with other hydrophilic polyurethane products, upon hydration, the active ingredients are released slowly from the film coating. It should be noted that the “active-filled” polyurethane film itself does not dissolve in the presence of water. Instead, the film swells slightly and allows the cleansing/treating ingredients in the film to be released and become available to the skin surface. Such films are actually extremely small-celled “nano”

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foams especially formulated to release materials contained within the cell walls. Combination hydrophilic polymers. The inclusion of other hydrophilic or hydrophobic polymers in the formulation can modify the functional characteristics of the hydrophilic polyurethane prepolymers. Durability, stiffness, flexibility, rubbery-ness, surface feel, encapsulation of solids, retention or release of ingredients from within the foam matrix, etc., are just some of the properties that can be designed into finished products by including selected combinations of various polymers. Polymer solutions, emulsions, or solids such as, acrylics, polyvinyl pyrrolidones, polyvinylidene dichlorides (PVDC), acrylic latex copolymers, etc., can be added to the aqueous phase along with other ingredients prior to being combined with a hydrophilic polyurethane prepolymer. Selection of active ingredients. Virtually any liquid or solid active ingredient can be incorporated in the aqueous phase as an emulsion, dispersion, or solution and reacted with the prepolymer to form a film coating. The exceptions are those mentioned above such as alcohols, oxidizing or reducing agents, and reactive amines. A major factor controlling proper film coating is viscosity. If the aqueous/polymer mix is too viscous it will be difficult to control the amount evenly applied to a nonwoven substrate. Conversely, water-thin viscosity mixes can quickly soak into a porous substrate. Ideally, viscosities of 1500 cps to 7000 cps for an aqueous phase are most suitable. With hydrophilic polyurethane systems, water should really be considered an active ingredient because there is a minimum stoichiometric amount of water necessary to cause a reaction to take place. Therefore, the formulator needs to determine if the coating will be oven-dried and reactivated with water, left slightly moist, or even allowed to carry a large amount of water. For example, if the formulation includes large amounts (35% to 50%) of “water loving” solids such as, aluminum oxide, fumed silica, feldspar, diatomaceous earth, etc., the resultant films will be very dry to the touch. Formulations that contain high levels of moisturizing ingredients such as emollient esters, mineral and silicone oils, fatty acid derivatives, etc., will tend to feel more moist, flexible, and even greasy. Certain formulations could result in films that even ex-

ude these ingredients through the films, even dried films. This is why hydrophilic polyurethane polymer formulating is an artistic science. The envisioned finished product and its usage must remain constantly in focus. Selection of substrate carrier. Film coatings on nonwoven substrates are dependant on the selection of the nonwoven for the final products use. Coated onto a densely woven substrate, the film will more likely attach itself to the surface, especially on thick materials. Understandably, coating onto a wispy, thin, open-weave nonwoven will most likely result in the molten formulation permeating each and every strand. The fibers or fiber blends tend to increase or decrease absorbency of the reactive coating. Hydrophilic fibers generally will absorb more coating per square foot than more hydrophobic types. Factors influencing performance on skin/ hair. Aside from the obvious importance of the coating formulation ingredients themselves, there are other more subtle factors that will influence product performance: controlled release of actives, thickness of film, flexibility, abrasive nature of fillers/substrate, ratio of aqueous phase to polymer, manufacturing process, and temperatures. Of all the factors, the greatest influences are manufacturing oriented: the polymer to aqueous phase ratio, mix head speed/throughput, and the temperature of the respective phases. High ratios of polymer (40% to 90%) to aqueous phase cause the cured film coating to be thicker, tougher, and less likely to release active ingredients quickly, and to hide the benefit of the substrate being coated. Conversely, high levels of aqueous phase (75% to 95%) can render the film frail and more moist than desired, lengthen cure times, make film sticky, and can be readily washed out of substrate. Mix head speed for a given throughput of product (lbs/min) is very important as well. For a specific formulation, at excessively high mixer speeds, the resultant reaction mixture produces a film that can be bubbly, soft, and less durable. At lower-thanrequired mix head speeds, the film is under mixed which is characterized by an uneven coating of smooth and rough areas. This nonuniform product would have areas in the film with and without the desired functional ingredients.

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE Finally, the temperature of the respective phases, aqueous and prepolymer, needs to be carefully controlled. Low temperatures result in the small cell size films that are usually preferred. If a more traditional larger celled foam film coating is desired, then temperatures of either phase or both need to be raised.

24.5.2

Marketing Benefits of Foam Film Coatings

Compared to the emergence of currently marketed skin care products delivered via nonwoven wipes, hydrophilic polyurethane foamed-film coated nonwoven wipes offer the consumer clear advantages. The “nanofilm” coating provides an elegant plush feel to the nonwoven carrier and allows for the inclusion of a wider variety of ingredients. The foamed film also acts as a reservoir for the cleansing or treatment formulation in that it will be dispensed over a longer period of time than traditional wipes, which tend to quickly release their active ingredients as soon as they are in contact with water. While the current spate of facial cleansing cloths can retain a sudsing cleanser for small areas, the foamed-film towelettes can be successfully used as a washcloth for the entire body in a shower or bath without losing the sudsing lather before the shower is over. (See Skin Care Formulation 24.4, Sec. 24.9).

24.6 Hydrophilic Polyurethane Foam Laminates (Cast Foam) Another interesting property of hydrophilic polyurethane foams is their ability to be laminated to nonwovens or paper substrates at the time they are being formed. The “foam stream” can also be delivered from the mix head so that it is sandwiched inbetween a top and bottom layer of coated release paper, a process that reduces the usual formation of a skinned surface. This technique is known as casting foam because the fluid exothermic reaction mixture is cast between a belt moving at a given speed on the bottom surface and rollers on top. The casting technique relies on balancing throughput from the mix head with the time neces-

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sary for the foam to reach the cure stage. As the growing fluid sponge moves down the conveyor, the foam is allowed to rise to a given height, providing a uniform finished thickness (Fig. 24.10). Laminates are made by covering the moving belt with a layer of nonwoven fabric on the surface. The mixture is released from the mix head onto the moving belt and is covered on the top with a second layer of nonwoven material. As the fluid reaction mixture “grows,” it becomes a soft foam held between the fabrics and becomes integrally embedded in the fibers of the top and bottom layers of nonwoven. When the foam is cured, it cannot be detached from the nonwoven. At the end of the conveyor, the cured “foam sandwich” can be split to expose a cut reticulated foam surface on one side. The smooth nonwoven fabric surface makes up the reverse side.

Figure 24.10 Cross section view of hydrophilic polyurethane foam filled with abrasive and detergents laminated to nonwoven substrate.

24.6.1

Marketing Benefits - Foam Laminates

The primary marketing benefit of foam laminate products is that the two different sides of the same product can achieve two different actions. Depending on the product’s use, both the nonwoven side and the cut foam side can be selected for specific activity on the skin. For example, the foam sponge can be formulated with abrasives in a personal care cleansing composition to provide an aggressive or deep cleansing action. The laminated, nonwoven side can then be utilized as a soft, smooth fabric that will allow the cleansing action but restrict abrasivity.

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Conversely, the nonwoven itself may be selected for its open weave, “hairy” style that can act as a stimulating or invigorating scrubber, while the foam sponge side consists of a water-activated, creamy moisturizing lather that is released through the nonwoven matrix.

24.7 Manufacturing Techniques and Methods A major concern in the development of hydrophilic polyurethane products is the manufacturing capabilities. For the most part, they are not usually available in-house, but are more likely found at specialized contract manufacturing facilities. Another alternative is to purchase custom engineered machinery that may be brought in-house or placed at a contract packer. It is one thing to formulate numerous experimental products in the laboratory with bench-top mixing equipment, a balance, plastic cups to mix materials together, and a reliable vented hood; and quite another to produce and package finished personal care products under GMP/FDA conditions. While hydrophilic polyurethane production equipment isn’t very complicated, it does require specific types of equipment for different forms of foam manufacturing. The one element common to all hydrophilic polyurethane manufacturing operations, which is key to producing any desired product, is the meter mix equipment itself. This is the heart of the production equipment that combines the aqueous phase with the polymer phase under controlled conditions to form the finished foam product. Typical meter mix equipment is made up of separate temperature controlled holding tanks containing the aqueous and polymer phases. These respective phases are brought together in a certain ratio via pumping, usually using accurate gear pumps, into a mixing chamber called the “mix head.” The mix head contains baffles and rotating blades to mix both phases in seconds at a given speed. The resultant reaction mix comes out of the mix head in its “cream” state having the appearance of a milkshake and then enters the final production stage of curing either as a molded, cast, or coated product.

24.7.1

Molding Foams

One of the most useful characteristics of these types of hydrophilic polyurethane foam products is the fact that they can be molded into almost any size or shape—sticks, cylinders, balls, rectangles, wedges, or even animals. The liquid reaction mix delivered from the mix head can be poured into various forms/ molds and allowed to expand into solid foam taking the shape of the mold. The mold needs to be vented to allow the carbon dioxide gas produced by the insitu exothermic reaction to escape. The cured molded foam product can be subsequently cut into various finished shapes and packaged. In certain instances, the mold itself can be the finished package. For example, surfactant-containing foam can be molded right into an animal or character shape and sealed in a plastic overwrap for shelf appeal. The foam animal is removed from the mold and used with water for skin cleansing. An example of a molded hydrophilic polyurethane product currently on the market is the Today® Contraceptive Sponge marketed by Allendale Pharmaceuticals, Inc.

24.7.2 Casting Foams The majority of conventional polyurethane foam is produced by a manufacturing technique called casting. Just about all urethane airline cushions, padded furniture, mattresses, etc., are produced by casting foam the height of a railroad car on a moving conveyor trough lined with release paper. The cured foam is then cut into huge blocks and further processed into appropriate shapes for end use. Similarly, but on a much smaller scale, hydrophilic polyurethane foam products can be produced by casting into sheet stock. Usually the maximum width for casting filled personal-care foam products is about 36". Maximum thickness is usually 2" or 3". In this case, the two-phase liquid reaction-mix is allowed to flow from the mix head onto a moving belt lined with release paper, or in the case of laminated cast foam, onto a delivery substrate such as a nonwoven fabric. As the reaction proceeds, foam is produced with the characteristic generation and release of carbon dioxide. Usually these foam products have a controlled height achieved by inserting rollers or plates on top of the growing foam as it moves down the conveyor. Release paper can even be placed on

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE top of the rising foam. As the cured foam reaches the end of the conveyor, the release paper is rolled up exposing the finished moist foam sheet stock, which is ready for packaging or further processing. Alternatively, this sheet stock can be dried in an oven, rolled up, and eventually cut and packaged. Hydrophilic polyurethane cosmetic foam cut into wedges or circles for makeup application is produced this way.

24.7.3 Coating Foam Films Personal care hydrophilic polyurethane formulations can also be coated on different substrates such as, nonwoven fabric, paper, cloth, plastic foam, flexible composites, etc., for the delivery of skin cleansers, moisturizers, acne treatments, and antiwrinkling actives, etc. Additionally, secondary functional activities, such as abrasion, stimulation, absorption, hand, thickness, density, etc., can be achieved by the substrate itself. Producing uniform thin-film coatings is the most difficult manufacturing system to perfect. It requires a fairly sizable conveyor engineered to handle roll goods, equipped with a coating mechanism, oven-drying, and rewind capabilities. This involves efficient timing because of the width of the substrate (which can be six feet or more) and

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the necessity of uniformly spreading the cream state mixture quickly across the web under controlled temperatures. The coating mechanism that is key to dispensing the cream state mixture is called a spreader bar. It is fitted with at least one mix head to pump the reaction mixture through special holes located in the bottom of the spreader bar so it is evenly coated onto the moving substrate. This action is done in such a way that the substrate is in direct contact under the spreader bar. The cream state coating is completely absorbed into the substrate using controlled temperatures at a given speed. The cured, coated substrate can be cut and packaged, or alternatively oven dried prior to packaging.

24.8 Summary Hydrophilic polyurethane prepolymers are the foundation for in-situ delivery systems with all the sophisticated benefits the personal care category demands. For the first time, the formulator can provide a range of formulations within a soft-celled applicator that carries its own treatments for revolutionary skin and hair care.

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24.9 Formulations Formulation 24.1: Skin Care—Cleansing Cushion

Ingredient

Function

Weight %

Emulgade SE

Emulsifier

5.00

Emulgin B2

Emulsifier

1.00

Cetiol OE

Emollient

4.00

Myritol 331

Emollient

3.00

Sepicide HB2

Preservative

1.00

Euxyl K400

Preservative

0.20

Glycerol

Emollient

3.00

Water, distilled

Diluent

47.80

Hypol prepolymer 2002

Foam matrix

35.00 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with water and glycerol heated to 75°C. In a separate vessel, melt “oil phase” Emulgade, Emulgin, Cetiol, and Myritol together to 75°C with agitation. Add oil phase with rapid mixing until emulsion is formed. Continue mixing and begin cooling mixture in water bath to 40°C. When batch reaches 40°C, add Sepicide and Euxyl. Continue stirring and cooling until batch reaches 25°C. Mix aqueous emulsion with prepolymer (Hypol) with high-shear mixing in a ratio of 1.85:1 (aqueous phase to polymer). Polymer temperature should be approximately 85°C and the aqueous phase 30°C. Allow foam to cure for approximately 5 to 10 minutes.

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527

Formulation 24.2: Skin Care—Makeup Remover Cushion

Ingredients

Function

Weight %

Water, distilled

Solvent/diluent

Triethanol Amine

Combines with fatty acid

0.22

Methylparaben

Preservative

0.07

Propylparaben

Preservative

0.07

Ceraphyl 368

Moisturizing solvent

7.29

Cetiol HE

Surfactant/emollient

0.78

Ceraphyl 847

Pigment dispersant

4.86

NeoFat 1855

Fatty acid emulsifier

1.54

Carnation Light Mineral Oil

Soil remover/solvent

13.93

Cerasynt 945

Emulsifier

1.55

Pluronic L-62

Cell size control agent

0.47

Glydant

Preservative

0.11

Foam matrix

31.00

®

Hypol Prepolymer 2002

38.11

Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with the water and begin heating to 75°C. Add TEA and methylparaben to water. A post-addition oil phase made up of 368, 847 and mineral oil is accomplished by taking 35% to 40% of the total amount of each these items in formula and mixing together in separate container. In another vessel heat and mix the remaining items—Ceraphyls, Cetiol, Cerasynt, Neo Fat, mineral oil, and propylparaben—together to 75°C. Add oil phase into water with rapid agitation until emulsion is formed. Cool emulsion slowly to 40°C with continued agitation; then add the Pluronic L-62 and Glydant. Once the emulsion has reached 25°C, add the remaining post-addition oil phase (at 25°C) with agitation. The emulsion at 25°C is reacted with prepolymer at 90°C with rapid agitation in a ratio of 2.22:1 (aqueous phase to polymer). Reaction mixture foam is allowed to cure for 8 to 10 minutes.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 24.3: Skin Care—Makeup Application Cushion

Ingredient

Function

Weight %

Water, distilled

Diluent

39.70

Glycerol monostearate

Emulsifier

5.00

NeoFat 1855

Emulsifier

10.00

Propylene glycol

Solvent

2.00

Aculyn 33

Thickener

0.90

Triethanolamine (TEA)

Emulsifier

1.00

Fragrance

Scent

1.50

Sicovit yellow

Color pigment

5.00

Sicovit red

Color pigment

1.00

Sicovit black

Color pigment

0.50

Phenoxyethanol

Solubilizer

1.00

Methylparaben

Preservative

0.20

Propylparaben

Preservative

0.20

Hypol Prepolymer 2002

Foam matrix

32.00 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with water, TEA, methylparaben, propylene glycol, and Aculyn to 75°C. In a separate vessel, melt “oil phase” monosterate, Neo Fat, color pigments, and propylparaben together to 75°C with agitation. Add oil phase with rapid mixing until emulsion is formed. Continue mixing and begin cooling mixture in water bath to 40°C. When batch reaches 40°C, add phenoxyethanol and fragrance. Continue stirring and cooling until batch reaches 25°C. Mix aqueous emulsion with prepolymer (Hypol) with high-shear mixing in a ratio of 2.12:1 (aqueous phase to polymer). Polymer temperature should be approximately 85°C and the aqueous phase 30°C. Allow foam to cure for approximately 5 to 10 minutes.

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE

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Formulation 24.4: Skin Care—Nanofoam Film Cleansing Sheet

Ingredients

Function

Weight %

Water, distilled

Diluent

32.53

Steol CS-370

Surfactant

10.27

Standapol LF

Surfactant

14.38

Velvatex BA-35

Foam builder

3.84

Schercemol DISD

Moisturizer

0.70

Celite SFSF

Film modifier

7.68

Kathon CG

Preservative

0.10

Methylparaben

Preservative

0.20

Propylparaben

Preservative

0.01

Robertet TZ-37

Fragrance

0.29

Trepol® Prepolymer

Foam matrix

30.00 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with the water and heat to 65°C. With continueous mixing, add items in order: Steol CS-370, Standapol LF and Velvatex BA-35; mix until surfactants are totally dissolved. Begin cooling mixture to 40°C with continued mixing and add: Schercemol DISD, both parabens and Kathon. Continue to maintain rapid mixing and slowly sift in Celite SFSF powder. After the solids are uniformily mixed into the batch, add fragrance. Cool aqueous phase to 20°C and react with prepolymer (at 25°C) with rapid mixing. Then pour reaction mixture on to nonwoven sheet (such as 1.25 ox/yd2 and spread with doctor blade; dry in oven at 50°C–60°C for 3 to 5 minutes.

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Formulation 24.5: Hair Care—Hair Cleansing Sheets

Ingredients

Function

Weight %

Water, distilled

Solvent/diluent

56.73

Velvatex BA-35

Surfactant

0.50

Standapol T

Surfactant

1.14

Standamid LD

Foam booster

0.06

Pluronic L-62

Cell size control agent

0.66

Belmay 1987-8300R

Fragrance

0.79

Glydant

Preservative

0.52

Isopar K

Solvent

5.26

Lamepon PA-TR

Protein

1.01

PVP/VA E635

Styling resin

3.03

Hypol® Prepolymer3000

Foam matrix

30.30 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with the water and heat to 50°C. With mixing, add items in order: Standapol T, Standamid LD, Velvatex BA-35, Lamapon PA-TR, Pluronic L-62, and PVP/VA E-635. Begin cooling mixture in water bath to 40°C. When batch reaches 40°C, add Glydant and Isopar K. When Isopar K is added, the batch becomes an unstable emulsion. Finally, add the fragrance. Maintain stirring and cooling until batch reaches 25°C. Mix aqueous phase with prepolymer (Hypol) with high-shear mixing in a ratio of 2.30:1 (aqueous phase to polymer). Polymer temperature should be approximately 85°C and the aqueous phase 25°C. Allow foam to cure for approximately 3 to 10 minutes.

SMITH AND MURPHY: SOFT CELL APPROACH TO PERSONAL CARE

531

Formulation 24.6: Hair Care—Temporary Hair Color Sheets

Ingredients

Function

Weight %

Water, distilled

Solvent/diluent

Celquat H-100

Hair fixative

0.69

Peptein 2000

Protein

2.30

Glydant

Preservative

0.51

Pluronic P-75

Cell size control agent

0.64

PVP/VA E-635

Styling resin

5.56

Fragrance 143-046

Fragrance

0.21

Sodium chloride

Release agent

0.32

Ganex P-904

Styling polymer

1.21

PVP K-90

Styling polymer

1.95

7054 Cosmetic iron oxide red

Hair color pigment

8.65

®

Hypol Prepolymer 2002

47.16

Foam matrix

30.80 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with water followed by Celquat H-100. Heat mixture to 50°C with rapid mixing until Celquat fully dissolves. Continue mixing and add items in order: PVP K-90, Ganex P-904, PVP/VA E-635, Pluronic P-75, and Peptein 2000. Begin cooling mixture in water bath to 40°C. When batch reaches 40°C, add salt, Glydant and pigment with sufficient mixing (do not whip-in air) and finally the fragrance. Continue stirring and cooling until batch reaches 25°C. Mix aqueous phase with prepolymer (Hypol) with high shear mixing in a ratio of 2.25:1 (aqueous phase to polymer). Polymer temperature should be approximately 85°C and the aqueous phase at 25°C. Allow foam to cure for approximately 3 to 10 minutes.

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Formulation 24.7: Hair Care—Hair Styling Sheets

Ingredients

Function

Weight %

Water, distilled

Moisten hair

53.44

Celquat H-100

Hair fixative

0.80

Peptein 2000

Protein

2.64

Dantogard

Preservative

0.60

Pluronic P-75

Cell size control agent

0.73

Sodium chloride

Resin release agent

0.36

Fragrance 143-046

Fragrance

0.68

PVP/VA E-635

Styling polymer

6.37

PVP K-90

Styling polymer

2.23

Ganex P-904

Styling polymer

1.38

®

Hypol Prepolymer 3000

Foam matrix

30.77 Total

100.00

Procedure Charge a suitable vessel equipped with high-shear mixing equipment with water followed by Celquat H-100. Heat mixture to 50°C with rapid mixing until Celquat fully dissolves. Continue mixing and add items in order: PVP K-90, Ganex P-904, PVP/VA E-635, Pluronic P-75, and Peptein 2000. Begin cooling mixture in water bath to 40°C. When batch reaches 40°C, add salt, Glydant, and pigment with sufficient mixing (do not whip-in air) and finally the fragrance. Continue stirring and cooling until batch reaches 25°C. Mix aqueous phase with prepolymer (Hypol) with high-shear mixing in a ratio of 2.25:1 (aqueous phase to polymer). Polymer temperature should be approximately 85°C and the aqueous phase 25°C. Allow foam to cure for approximately 3 to 10 minutes.

24.9.1 Patents U.S. Patent 4,806,572 U.S. Patent 4,856,541 U.S. Patent 5,002,075 U.S. Patent 5,261,426 Other patents pending

Part IX Structured Systems Non-Aqueous Delivery Systems With Controlled Rheological Behavior

Sugar Based, Structured Surfactant Systems

STRUCTURED SYSTEMS

Cubasomes and Self-Assembled, Bicontinuous, Cubic Liquid Crystalline Phases as Personal Care Delivery Systems

Intelligent Polymers and Self-Organizing Liposome Gel Delivery Systems

Shear Thinning Lamellar Gel Network Emulsions as Delivery Systems

Pro-Lipid® Skin-Mimetic Lamellar Gel Carrier and Delivery Systems

25 Sugar Structured Surfactant Systems (S4TM) Raeda M. Smadi and John Hawkins Huntsman Performance Products Division Surface Sciences Austin, Texas

25.1 Sugar Structured Surfactant Delivery System (S4™) .................. 536 25.2 Conventional Structured Surfactant Systems .............................. 536 25.2.1 Dispersed Lamellar Systems ........................................... 536 25.2.2 Expanded Lamellar Systems ............................................ 536 25.2.3 Spherulitic Lamellar Systems ........................................... 537 25.2.4 Advantages of Conventional Structured Systems ............ 537 25.2.5 Drawbacks of Conventional Structured Systems for Personal Care Use ...................................................... 537 25.3 Sugar Structured Surfactant Delivery System ............................. 538 25.3.1 Structurant ........................................................................ 538 25.3.2 Role of Co-structurant ...................................................... 539 25.3.3 Surfactant Types ............................................................... 539 25.3.4 Suspended Additives ........................................................ 540 25.4 Properties of S4™ ........................................................................ 540 25.4.1 Optical Properties ............................................................. 540 25.4.2 Rheology ........................................................................... 541 25.4.3 Thermal Stability ............................................................... 542 25.4.4 Preservative free ............................................................... 542 25.4.5 Performance ..................................................................... 542 25.5 Applications of the S4™ ............................................................... 542 25.6 Conclusions .................................................................................. 545 25.7 Formulations ................................................................................. 545 References .......................................................................................... 546

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 535–546 © 2005 William Andrew, Inc.

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25.1 Sugar Structured Surfactant Delivery System (S4™) Structured surfactant systems are utilized in a wide variety of applications, and are useful for delivering suspended actives to substrates like skin and hair. A structured surfactant system is a pourable composition comprising water, surfactant, and (usually) a structurant which forms a three-dimensional lyotropic liquid-crystal matrix that is capable of suspending solid particles. The system has a yield stress high enough to suspend solid particles, but low enough to allow the system to flow as a normal liquid.

about seventy weight percent surfactant in water. They usually contain a thick turbid phase with no solid-suspending properties. Three other forms of lamellar phase are currently employed in structured surfactant systems. These are dispersed lamellar, expanded lamellar, and spherulitic lamellar.

25.2.1

Dispersed Lamellar Systems

Dispersed lamellar phases are prepared by salting out blends of surfactant out of solution with electrolytes. They are comprised of bilayers stacked in a three-dimensional “house of cards” type of structure (see Fig. 25.2).

This chapter focuses on a novel structured surfactant system that is comprised of water, surfactant, and a soluble carbohydrate (sugar) as a structurant. This system has benefits over conventional surfactant systems, while maintaining the capability of providing excellent suspending power of solid, liquid, and gaseous particles.

25.2 Conventional Structured Surfactant Systems All structured suspending surfactant systems are based on the presence of a lamellar phase. Most surfactants form such a lamellar phase (shown in Fig. 25.1) when mixed with water in specific proportions. A standard lamellar phase is utilized in the manufacture of systems that contain a high-concentration active substance. These systems are typically

Figure 25.2 Disperse lamellar phase.

The domains of the dispersed lamellar are interspersed with electrolyte-rich aqueous phase. They form a thick, opaque, gel-phase-like system that have solid-suspending properties. These systems have flow characteristics that are superior to standard lamellar phase formulations. In practice, however, they are not widely used because the expanded and spherulitic lamellar phases have much better flow and suspension properties.

25.2.2

Expanded Lamellar Systems

Expanded lamellar phases tend to form when very soluble blends of surfactant are salted out of solution. This occurs in systems containing high concentrations of sodium lauryl ether sulfates (see Fig. 25.3). Figure 25.1 Standard lamellar (Lα) phase.

SMADI AND HAWKINS : SUGAR STRUCTURED SURFACTANT SYSTEMS (S4™)

Figure 25.3 Expanded lamellar phase.

Figure 25.4 Spherulitic lamellar phase.

In Fig. 25.3, the expanded phase combines the lamellar domains of dispersed lamellar with the structure of standard lamellar. The domains lie parallel to each other with a bilayer separation of about eighty angstroms. This separation distance is approximately twice the separation found in standard lamellar systems.

25.2.4

Examples of this expanded lamellar system are thin liquids that are translucent. They have a low yield stress, and are unable to suspend anything larger than very fine particles (e.g., zeolites). Furthermore, the lamellar domains have a tendency to reconfigure themselves at low temperatures (e.g., 4°C), and congregate to form spherical aggregates. Such aggregates are not space-filling, therefore, separation is observed quite often.

25.2.3 Spherulitic Lamellar Systems By far, spherulitic systems comprise the largest proportion of useful suspending systems. They combine low viscosity upon pouring and low application shear rates and have high suspending power. As such, they are extremely robust and can serve to suspend a wide variety of particulates and, consequently, useful active ingredients. They are comprised of well-defined spherical bodies that are referred to as spherulites, in which surfactant bilayers are arranged as concentric shells (see Fig. 25.4). The spherulites in these systems usually have a diameter in the range 0.1 to 15 microns. They are dispersed in the aqueous phase in the manner of a classical emulsion and generate an opaque, creamy appearance.

537

Advantages of Conventional Structured Systems

Conventional structured surfactants are used to deliver suspended actives in several applications. These include builders in laundry detergents, abrasives in hard-surface cleaners, and pesticides in agrochemical preparations. The structured system of choice is usually the spherulitic one. This system provides thin, fluid, solid-suspending compositions over the temperature range of 0°C to +40°C. They are freeze/thaw stable and shear thinning. Manufacture can be carried out with simple blending equipment. Formulations are reproducible and scale-up is easily accomplished from laboratory to manufacturing plant. Intermediate pilot-plant-size trials are generally unnecessary.

25.2.5

Drawbacks of Conventional Structured Systems for Personal Care Use

Existing structured surfactant formulations have several disadvantages that have limited their application, especially in the area of cosmetics and personal care. These include the following: • Unless a substantial amount of electrolyte is present, the choice of surfactant is limited to a fairly small range of relatively insoluble surfactants such as sodium dioctyl sulfosuccinate. For many personal care applications, these are not the surfactants of choice from a performance point of view and, in some cases, they are totally inappropriate.

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• Spherulitic or dispersed lamellar structured surfactants are opaque. This opacity limits the visual effects that can be achieved and may be perceived by market and consumer as being less attractive than a clear system in some applications. • Expanded lamellar systems typically have limited suspending power. They are usually formed over narrow concentrations and/or temperature ranges which makes them difficult to manufacture and use in practice. • Most surfactant systems require preservatives to prevent microbial spoilage. Preservatives are expensive, ecologically undesirable, and may cause sensitivity problems for some users. There is, therefore, a need, especially in personal care applications, for suspending systems that are clear, transparent, and mobile. Such systems could contain high levels of relatively soluble surfactants, and not require the presence of high levels of electrolytes as structurants. A cleaning composition that does not require added preservatives would also be very desirable.

25.3 Sugar Structured Surfactant Delivery System

Figure 25.6 is a SAXS plot that shows the scattering pattern observed from a typical S4 formulation. The position of the peak corresponds to the dspacing (or repeat spacing) of the lamellar bilayer system is seen to be 716 Å. Table 25.1 compares a sugar-induced lamellar phase system with the three types of conventional lamellar suspending phases. Of the four types of systems, only the S4 system is transparent. This is because the spacing between the surfactant bilayers is greater than that of the wavelength of light. The other types of lamellar systems scatter light, thereby giving an opaque creamy appearance. Of all the different system types, the S4 system exhibits the highest yield stress. The yield stress is so high that it can support extremely dense particulates, even lead shot!

25.3.1 Structurant S4 system structurants are soluble carbohydrates such as sucrose, glucose, and fructose. The levels of carbohydrate needed to induce structure (40 weight percent) are sufficiently high to inhibit microbiological growth in the medium by producing an osmotic pressure that is higher than that of the medium, causing dehydration of bacteria. Also, it acts as an effective biodegradable and non-allergenic preservative.

Sugar structured surfactant systems are novel aqueous delivery systems that are comprised of surfactant, carbohydrate, and water. These systems are formed by the interaction of surfactants with watersoluble carbohydrates. The carbohydrates act as a “structurant” by “pushing” the dissolved surfactant out of solution in the form of liquid crystals. Figure 25.5 shows the sugar-induced liquid crystals forming parallel sheets of lamellar phase. The sheets are usually in excess of 500 angstroms (Å) apart; this distance is an order of magnitude greater than those seen in conventional structured systems. Lamellar systems can be identified by their characteristic texture under a polarizing microscope, or by small angle x-ray scattering (SAXS). The scattering angle is inversely proportional to the repeat distance between regular structural features.

Figure 25.5 Sugar-induced lamellar phase.

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539

Figure 25.6 SAXS for S4 formulation.

Table 25.1. Structured Systems Comparison

Dispersed Lamellar

Spherulitic Lamellar

Expanded Lamellar

Sugar Induced Lamellar

D-spacing, A

40

40

80

>200

Appearance

Opaque

Opaque

Opaque

Transparent

Yield, Nm^2

Nil

Ca. 0.4

< 0.4

> 0.4

None

Phosphates and carbonates

Zeolites

0.4 mm Lead

Suspended actives

25.3.2 Role of Co-structurant When sugar alone is insufficient to induce liquid crystal formation, a co-structurant maybe required. Typical co-structurants consist of electrolytes and any water-soluble salt that tends to lower the solubility of a surfactant in water. Examples include sodium carbonate, sodium citrate, or (most commonly) sodium chloride. The amount of additional electrolyte that may be required will depend upon the solubility of the surfactant in the aqueous/salt system. An excess of electrolyte beyond the concentration required to form the structure is generally undesir-

able since it tends to promote spherulitic lamellar phase and, hence, undesirable cloudiness.

25.3.3 Surfactant Types The surfactant employed in an S4 formulation can be selected from all available types including nonionic, anionic, cationic, and amphoteric. Some examples of the surfactants that are commonly used in personal care formulations, which form the S4 phase when “desugared,” include alcohol

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ethoxylates, alkanolamides, alkyl polyglycosides, sorbitan esters, ether sulfates, sarcosinates, and betaines. One or more of the surfactant types can be used in the S4 system to meet the target applications requirements.

25.3.4

Suspended Additives

The S4 can suspend water insoluble solids, liquids, or gaseous particles. Particulate solids include exfoliates (talc, clays, polymer beads, etc.), pearlizers (mica, glycol distearate), glitter, pigments, porous particles (so-called microsponges), and microcapsules containing absorbed active ingredients. As such, they make ideal carriers for certain delivery systems detailed elsewhere in this book. Liquid form suspended actives include emollients such as mineral oils, and conditioning agents such as silicone oil. Figure 25.7 shows examples of suspended additives.

25.4 Properties of S4™ 25.4.1 Optical Properties Transparency. The transparent appearance of an S4 formulation is shown in Fig. 25.8. This property is considered to be one of the key features of this technology and makes it particularly suitable for personal care applications.

Figure 25.7 Suspended particles.

Color-immiscible regions. S4 systems can easily be adapted to provide optically variegated fluid surfactant compositions. Surfactant-based consumer products often depend upon novel appearance and packaging for their consumer appeal. For example, striped toothpaste, marbled soap, and blue speckled detergent powder are successfully promoted based on their characteristic appearance. In the past, it was not possible to produce lasting variegation in a homogenous pourable-liquid formulation. There have been products sold in the market that combine two or more immiscible liquids of different densities and colors which segregate into horizontal bands. However, the visual effects achievable by this method are limited. Products based on this approach have a practical disadvantage because their functional components are not evenly distributed between the different bands. Hence, the product performs inconsistently unless it is vigorously agitated immediately prior to use. By contrast with prior art, S4 formulations may be used to suspend colored granules to produce a speckled effect. An impressive effect that was hitherto unachievable can be obtained as follows. Two or more portions of a thin, structured S4 system containing dispersed colored pigment are mixed in a transparent container in such a way as to produce a variegated appearance. No migration of pigment through the composition is observed in the undisturbed sample, even after prolonged standing (two years). The variegation thus remains stable to a remarkable degree. Furthermore, provided the container is substantially

Figure 25.8 Appearance of S4 (left) and conventional (right) structured surfactant systems.

SMADI AND HAWKINS : SUGAR STRUCTURED SURFACTANT SYSTEMS (S4™) full, even the agitation caused by normal handling during distribution does not significantly affect the variegated appearance of the product. Yet the product is a thin, mobile liquid. (See Fig. 25.9.) The effects obtainable with an S4 can be extremely varied depending upon how the different colored portions of the S4 system are charged to the container. It is possible to obtain horizontal or vertical stripes, whorls, or numerous other decorative effects. Any pattern or optical effect that can be instantaneously obtained by charging visually distinct liquids to a transparent container can be rendered substantially permanent, at least until the product is poured from the container. With suitable filling techniques, it is even possible to produce readable characters so that liquid products may even be marked with trademarks or logos. Any water insoluble pigment used in cosmetics or detergents can be employed. Birefringence. The S4 structure is a liquid crystal dispersion that exhibits optical anisotropy. Anisotropic crystals, or birefringent materials, have distinct crystallographic axes. They interact with light in a manner that is dependent upon the orientation of the crystalline lattice with respect to the incident light. When anisotropic crystals refract light, the resulting rays are polarized and travel at different velocities. One of the rays travels with the same velocity in every direction through the crystal and is termed the ordinary ray. The other ray travels with a velocity that is dependent upon the propagation

Figure 25.9 Colored stripes and swirls.

541

direction within the crystal. This light ray is termed the extraordinary ray. The distance of separation between the ordinary and extraordinary rays increases with increasing crystal thickness. The two independent refractive indices of anisotropic crystals are quantified in terms of their birefringence, which literally means “double refraction” and is a measure of the difference in refractive index. The birefringence phenomenon can be used for a unique and stunning presentation of personal care products. This effect can be achieved by using polarized packaging containers, or polarized labeling to expose the birefringence in the present of direct light (see Fig. 25.10).

25.4.2 Rheology S4 formulations exhibit a non-Newtonian, pseudoplastic behavior with a measurable yield stress. The rheology measurements shown in Fig. 25.11 were performed at ambient temperature (25°C) using a Bohlin rheometer with a cone-andplate geometry. The flow curve of the viscosity versus shear rate indicates shear thinning, which means that viscosity decreases as the shear rate increases. This behavior allows the formulation to flow easily under pouring or application conditions. The flow curve of the shear stress versus shear rate indicates a high yield stress that is determined by the extrapolated Bingham yield value. This high yield value indicates a large capability for suspending water-insoluble particles.

Figure 25.10 Birefringence crystals between polarizers.

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Figure 25.11 Rheological behavior of the S4.

25.4.3

Thermal Stability

S4 formulations are stable over a wide range of temperatures from below zero to more than fifty degrees centigrade. They are also unaffected by freeze-thaw cycling. By contrast, conventional structured systems are freeze-thaw stable but have an upper temperature limit of about forty degrees centigrade.

25.4.4

Preservative free

S4 formulations do not require preservatives in order to prevent microbiological growth. Challenge testing, which is also known as preservative efficacy testing (PET), can determine if a product can withstand contamination. Challenge testing was performed on an S4 body wash formulation containing 40% sucrose are shown in Table 25.2. The results show that the sugar alone has adequately preserved the formulation. These results are explained by the tendency of high sugar content to reduce water activity, and produce an osmotic pressure that causes dehydration of the microbes. The absence of preservatives reduces irritation potential, and removes any incompatibility that may otherwise occur between the preservatives and the other ingredients.

25.4.5

Performance

Salon evaluation. An S4 structured shampoo formulation was prepared and evaluated by a panel

of people using a half-head salon test. The panel was selected to represent the full range of hair types, colors, and lengths. Hair was washed by applying equal amounts of S4 and a standard control shampoo to each side of the head. This treatment was then followed by a trained assessment, and scores were recorded for each of the relevant parameters as shown in Fig. 25.12. Results indicate that the S4 formula performed as well as the control. There were no significant differences between any of the attributes studied. Foam potential. The foam potential of an S4 body wash formulation was evaluated against two commercial brands of body wash. Foam height was measured using 200 ml of 0.1% solution in a Waring blender mixed for 10 seconds at room temperature (RT) then poured into a 500 ml graduated cylinder. The foam test was performed at two levels of water hardness, zero and 150 ppm. Figures 25.13 and 25.14 show that the S4 formulation has an equivalent foam potential to that of the brands, even in hard water.

25.5 Applications of the S4™ An S4 formulation can fulfill all conventional structured system applications when personal care formulations are required to suspend solid particulates. The appealing physical appearance of S4 makes it ideal for cosmetic and personal care applications. Many personal care applications deliver water-insoluble particulate solids. These include ex-

SMADI AND HAWKINS : SUGAR STRUCTURED SURFACTANT SYSTEMS (S4™) foliates, pearlizers, glitter, and pigments. In shampoos, body lotions, shower gels, and hair creams, oils and oil soluble materials such as emollients and conditioners must be suspended. S4 may also be

543

employed in pharmaceutical products and in the food industry for drug and flavor delivery. The S4 actively promotes creativity in the development of novel formulations in personal care.

Table 25.2. Challenge Testing

Organism

CFU per ml detected 48 hrs

7 days

14 days

21 days

28 days

4.13 × 10

6

<10

<10

<10

<10

<10

5.05 × 10

6

<10

<10

<10

<10

<10

Escherichia coli

4.78 × 10

6

<10

<10

<10

<10

<10

In-house Contaminants

5.21 × 106

<10

<10

<10

<10

<10

Aspergillus niger

1.77 × 107

<10

<10

<10

<10

<10

Candida albicans

7

<10

<10

<10

<10

<10

Pseudomonas aeruginosa Staphylococcus aureus

Result adequately preserved.

Figure 25.12 Salon evaluation.

0

2.66 × 10

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 25.13 Foam heights (0.1% solution @ RT, 0 ppm water hardness).

Figure 25.14 Foam heights (0.1% solution @ RT, 150 ppm water hardness).

SMADI AND HAWKINS : SUGAR STRUCTURED SURFACTANT SYSTEMS (S4™)

25.6 Conclusions The S4 technology provides transparent formulations, excellent suspending power, a wide range of viscosity, ease of formulation and manufacture, shear thinning behavior, self-preservation, low freezing point, and a wide thermal stability range (-5°C to +50°C). The technology provides the ability to suspend solid, liquid, and gaseous particles and is particularly suited to personal care applications. Moreover, this system can also provide various impressive visual/ decorative effects that are difficult or impossible to obtain by other methods.

25.7 Formulations There are an infinite variety of formulations available. Each different surfactant/fragrance blend will require its own unique combination of sugar and electrolyte to induce the stacked lamellar structure typical of the S4. The preferred way of preparing these systems is to first select the required surfactant and blend it together with the chosen fragrance and oils.

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A series of samples are prepared at various levels of sucrose (usually around the 40% w/w level). The samples are thereafter deaerated by low G (~ 1500 rpm) centrifugation. Examination of the samples will then reveal whether any structure is present. This can be quite simply carried out by shaking some air into the samples and observing whether or not the bubbles remain suspended. If none of the samples show the structure, then a co-structurant (typically sodium chloride) is required. Samples are then prepared at gradually increasing electrolyte levels until the minimum level of electrolyte required to induce the structure is defined. It is important to keep the electrolyte level to the minimum required since any excess promotes the other forms of structured lamellar (dispersed, expanded, and spherulitic) phases. These latter three types all scatter light and, therefore, give undesirable cloudy samples. A very interesting and useful observation is that if different S4 compositions are mixed together in any proportion, then the result has always been found to be a new, stable, S4 formulation. Some simple examples of S4 formulations are included here: Formulations 25.1–4 are shampoos, Formulation 25.5 is a body wash, and Formulation 25.6 is a liquid hand soap.

Formulations 1–4: Shampoo

Ingredient ®

EMPICOL ESB/70

Formula #1 14.2

®

EMPILAN CDA Sucrose Sodium chloride

Formula #2

40

Formula #3 11.4

14.2

10

2

55

40

50

5

2

2

5

6

Perfume Sodium citrate Water

Formula #4

2 Balance

Balance

Balance

Balance

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Formulation 25.5: S4 Body Wash

Ingredients ®

EMPICOL ESB/70 Sodium lauryl sarcosinate Sucrose

Formula #5 11.4 2.0 39.0

®

EMPIGEN OT

0.3

Sodium chloride

8.0

Ethanol

1.0

Perfume (Quest AF 30211)

1.0

Red microcapsules (Hallcrest HC 2077)

1.0

Water

Balance

Formulation 25.6: S4 Liquid Hand Soap

Ingredients ®

Formula #6

EMPICOL ESB/70

14.3

EMPIGEN® BS/FA

5.0

EMPILAN® KCL/7

0.5

C12-C15 alkyl polyglycoside

2.0

Sucrose

51.0

Sodium Chloride

4.0

Perfume

0.2

Water

Balance

References 1. Lambie, A. J.; Akred, B. J.; Nicholson, W. J.; and Newton, J. E., U.S. Patent 6,200,586, Biocidal and agrochemical suspensions (2001) 2. Hatchman, K., U.S. Patent 6,194,354, Drilling fluid concentrates; U.S. Patent 6,177,396, Aqueous based surfactant compositions (2001)

3. Blezard, M.; Williams, M. J.; Grover, B. W.; Nicholson, W. J., Messenger, E. T., and Hawkins, J., U.S. Patent 5,964,692, Functional fluids and liquid cleaning composition and suspending media (1999) 4. Hawkins J., U.S. patent 5,952,285, Concentrated aqueous surfactant compositions (1999)

26 Shear-Thinning Lamellar Gel Network Emulsions as Delivery Systems Irma Ryklin and Blaine Byers Stepan Company Northfield, Illinois

26.1 26.2 26.3 26.4

Introduction ................................................................................... 548 The “Eureka!” Effect ..................................................................... 548 Preparation of Lamellar Gel Network Emulsions .......................... 549 Molecular Identification.................................................................. 550 26.4.1 Chemistry and Function.................................................... 550 26.4.2 Molecular Modeling of Sodium Stearyl Phthalamate ......... 550 26.4.3 Interfacial Tension (IFT) .................................................... 552 26.5 Identification and Characterization of Lamellar Gel Network Structure ......................................................................... 552 26.5.1 Conductivity Method .......................................................... 552 26.5.2 Rheological Method .......................................................... 554 26.6 Applications .................................................................................. 554 26.6.1 Skin Irritation ..................................................................... 554 26.6.2 Moisturization Effect of RM1 in Creams and Lotions ........ 556 26.6.3 SPF Enhancement in Sunscreen Formulations ............... 559 26.6.4 Formulating Sprayable Products ...................................... 564 26.7 Conclusion .................................................................................... 564 26.8 Formulations ................................................................................. 565 References .......................................................................................... 568 Acknowledgment ..................................................................................... 568

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 547–568 © 2005 William Andrew, Inc.

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26.1 Introduction The majority of current products in the skin and sun care market are formulated emulsions. These products are designed to have the appearance and flow behavior of lotions or creams. As skin care products become more sophisticated with the incorporation of new arrays of active ingredients, their optimal delivery of these active ingredients becomes increasingly important. To this day, such emulsions continue to be the most popular vehicle for delivering functional cosmetic ingredients to the skin. In recent years there has been an increasing interest in “multiple-phase,” oil-in-water emulsions. Such systems should not be confused with “multiple emulsions,” which may be considered ordinary twophase emulsions in which droplets of the dispersed phase contain even smaller-sized droplets that are miscible with the external or continuous phase.[1] “Multiple emulsions” can be a water-in-oil-in-water type where internal and external phases are separated by an oil phase or an oil-in-water-in-oil type, where the two oil phases are separated by a water phase. The modern multiple-phase emulsions are not simple mixtures of oil, water, and emulsifiers, but are more complex systems. [2][3] They are polydispersed systems that contain several surfactant and amphiphilic emulsifiers and not only usual phases of water and oil, but additional phases as well. The additional phases generally form in aqueous media when an emulsifier, in excess of amount required to form a monomolecular layer at the oil-water interface, interacts with a continuous water phase and are called lamellar phases. In lamellar phases, surfactant molecules are arranged in bilayers separated by layers of water (Fig. 26.1). The carbon chains of the bilayers can exist in a number of physical states such as ordered, or gel, and disordered, liquid crystalline. In gel state, the hydrocarbon chains are packed in a hexagonal subcell with rotational motion about the long axes, whereas in the liquid crystalline state, they are disordered and liquid-like. The order-disorder transition, Tc , is the melting point of the carbon chains. When chains melt, the lamellar arrangement of bilayers still persists due to the strong forces linking the polar groups together. The melting and transition occurs at a characteristic temperature, influenced primarily by the hydropho-

Figure 26.1 Schematic diagram of an emulsion droplet stabilized by multilayers of lamellar liquid crystals.

bic part of the surfactant. The liquid crystalline gel transition temperatures of many amphiphile/surfactant combinations are above ambient, so that crystalline phases occur only at the high temperatures during preparation; upon cooling, gel phases form. The presence of additional lamellar phases, either crystalline or gel, responsible for creating a structuring effect in the emulsions is known to be a key to improved stability, desired rheological profile, and improved active delivery properties.[4][5] Selection of the emulsifier system is one of the most important aspects of formulating effective multiple-phase emulsions useful as delivery system vehicles. The emulsifier system is responsible for providing the desired structuring effect and should be carefully selected to maximize the emulsions delivery properties, as well as being nonirritating and safe.

26.2 The “Eureka!” Effect In light of the cosmetic industry’s need for emulsification systems that allow one to produce modern structured cosmetic creams and lotions, it was very exciting for our company when we discovered a technology which utilizes a non-conventional anionic rheology-modifier/emulsion-stabilizer capable of forming lamellar or crystalline structuring in multiple phase emulsions. This key ingredient was sodium stearyl phthalamate (STEPAN-MILD® RM1).

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS The initial discovery of elegant emulsions that exhibited outstanding rub-in and skin feel led us to explore and fully develop what turned out to be a non-conventional emulsifying system. In contrast to conventional emulsifying systems that required different emulsifiers for oils with different “required” hydrophilic-lipophilic balance (HLB) values, our nonconventional system appeared to be independent of HLB! It was equally capable of emulsifying a full range of oils with required HLB ranging from 5 to 12. Surprisingly, and unexpectedly, it was also observed that the concentration of emulsifier system did not have to be varied since it could easily emulsify low-oil volume fraction as well as high-oil volume fraction emulsions. Results of further developmental work and a number of applied experimental techniques allowed us to establish that when our non-conventional emulsifier, sodium stearyl phthalamate, is combined with a low-HLB emulsifier and a polymeric emulsifier, it is capable of producing multiple-phase, oil-in-water emulsions that have a lamellar gel network structure. The formed structure provides a unique combination of benefits. These include a stabilizing mechanism that enhances the product’s stability and an extremely favorable rheological profile that provides unique sensory and performance characteristics to cream and lotion products. Another benefit of the technology is the strong moisturizing effect on the skin. This is attributed to the compatibility of the resulting lamellar gel structure with the natural lamellar structure of the stratum corneum lipids. Further, we also observed a significant SPF enhancement in sunscreen formulations using the technology and, since the emulsifying system is water-insoluble at room temperature, emulsions based on it are inherently mild.

26.3 Preparation of Lamellar Gel Network Emulsions The technology enables the preparation of oilin-water emulsions with a pH level above 6.5. A typical emulsion system is composed of three ingredients with sodium stearyl phthalamate as a key component that functions both as a rheology modifier

549

and as an emulsion stabilizer. The recommended sodium stearyl phthalamate concentration is from 1.0% to 1.5% and is employed in conjunction with a low-HLB emulsifier (such as glyceryl stearate) in a 2:1 ratio. An anionic polymeric emulsifier, such as pemulen (acrylates/C 10-30 alkyl/acrylate crosspolymer), is also included in an approximately 5:1 ratio (sodium stearyl phthalamate to polymeric emulsifier). The emulsification system is highly cost effective because the total amount of all components ranges from 1.7% to 2.5%. Emulsions made with this technology are extremely versatile since it is capable of producing stable emulsions with various oils and active ingredients, over a wide range of HLB values and a broad range of oil concentrations (5% to 45%). A standard method of emulsion preparation includes the following steps: • The polymeric emulsifier is added to the aqueous phase, and neutralized to a pH of 7.0–7.4 prior to the addition of sodium stearyl phthalamate. Addition of the neutralizing agent after combining aqueous and oil phases at high temperature is possible, but not preferred. • Sodium stearyl phthalamate is added to the aqueous phase of the emulsion at 72°C– 75°C, with moderate agitation, and mixed for at least fifteen minutes. This procedure allows the material to dissolve and form a lamellar liquid crystalline phase. • A low-HLB emulsifier is added to the oil, which is kept separately at this point in the process. • The emulsification is then carried out at a temperature of 72°C–75°C by adding the oil phase to the water phase and mixing for at least 25–30 minutes. • pH modifiers, preservatives, and other temperature sensitive substances are added at temperatures below 40°C. • Homogenization at high temperature is not required, but can be applied at a temperature lower than 35°C, if desired. • Equilibrate the emulsion overnight prior to evaluation.

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26.4 Molecular Identification 26.4.1 Chemistry and Function The sodium stearyl phthalamate was prepared according to the procedure described in patent WO 91/01970[6] and is a free-flowing white powder at 98% solids. The chemical structure of STEPANMILD® RM1, the key component of the emulsification technology, is represented in Fig. 26.2. Sodium stearyl phthalamate is insoluble in water at room temperature, but becomes water-soluble at high temperature. As such, it interacts at the oil/ water interface, displaying interfacial tension reduction properties at elevated temperatures.

Figure 26.2 Chemical structure of sodium stearyl phthalamate.

26.4.2

Molecular Modeling of Sodium Stearyl Phthalamate

In order to better understand the unique properties that sodium stearyl phthalamate (STEPANMILD® RM1) exhibited, two molecular modeling studies were conducted. In the first one, the structural features were examined. Semi-empirical molecular modeling, Fig. 26.3, shows two hydrophilic and two hydrophobic areas in the molecule. The anionic carboxylate head group is cross planar to the hydrophobic aromatic ring (torsional angle of 75°) and positioned orthogonal to the amide hydrophile. The amide hydrophile is also cross planar to the aromatic ring with a torsional angle of 40.5°. In addition, the oxygen atom of the amide linkage is pushed away from the ortho carboxylate oxygens, thereby providing hydrophilic character on opposite sides of the hydrophobic groups.

Figure 26.3 Semi-empirical molecular model of sodium stearyl phthalamate.

Because of the 40.5° torsional angle in the amide linkage, the hydrophobic aromatic ring and stearyl chain are locked in an “out-of-plane” configuration and provide two distinctly hydrophobic areas in this molecule. The rigid aromatic hydrophobic area is planar while the aliphatic hydrophobic area is linear in nature. This molecular configuration provides for a widely spread hydrophilic head group consisting of the anionic carboxylate and the amide linkage on opposite sides of two distinctly different hydrophobic areas. Based on the unique molecular features of RM1 identified above, a second molecular modeling study was conducted to examine how RM1 molecules pack together. Three aggregate conformations of RM1 were subjected to standard molecular modeling techniques using HyperChem™ software. For comparative purposes, the sodium salt of stearic acid was also modeled as a control. RM1 and sodium stearate were geometrically optimized using semi-empirical techniques. Five molecules of either RM1 or sodium stearate were placed in an aggregate conformation in a periodic “box.” Geometry optimization was performed using molecular mechanics techniques with MM+ force field calculations (see Fig. 26.4). The relative energy of each of these systems was used for comparison of the stability of the aggregate conformations. The lowest energy configuration for an aggregate of RM1 was determined to be where the carboxylates are on alternating sides of the hydrophobic axis (i.e., by rotation of the molecule about the hydrophobic axis). This results in a very stable configuration shown in Fig. 26.4 with a relative energy of -9.6 kcal/mole. Closer inspection of this model shows tight packing of the aromatic rings suggesting a stable orientation. Additionally, less repulsion

Figure 26.4 Geometry-optimized molecular model of RM1 aggregates.

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS is observed between neighboring molecules of RM1 due to the proximity of the carboxylate hydrophiles. The carboxylate hydrophiles actually pack very well, with the amide oxygen of the neighboring molecule being inserted between them. In contrast, the lowest energy configuration for an aggregated sodium stearate showed the carboxylate head groups of sodium stearate to be packed entirely randomly (see Fig. 26.5). The alkyl chains demonstrate more “randomness” compared with RM1. The calculated energy of this system is in excess of 5.4 kcal/mole, which is significantly greater than the aggregate conformation determined for RM1 (see Fig. 26. 4), even though sodium stearate has fewer atoms than does RM1. When compared to the packing of the traditional soap emulsifier, sodium stearate, the RM1 aggregate configuration has tighter packing, and is more ordered than the sodium stearate in both the hydrophilic and hydrophobic portions of the molecule. Based on the molecular modeling process, we conclude that RM1 is uniquely structured to provide a rigid aggregate at the oil/water interface. A closer look at Fig. 26.4 also suggests the existence of a channel of “hydrophilicity” flowing between the two hydrophobic areas (alkyl chains and aromatic rings) that could entrap water and ionic species, thereby stabilizing a gel network. It is very well known in biology that di-alkyl lipids are the structural element of cell membranes. It is also well known that lipids are an important component of the stratum corneum. On the other hand, polar di-alkyl lipids (such as the lecithins) are natural surfactants with a hydrophobic portion composed

Figure 26.5 Geometry-optimized molecular model of sodium stearate aggregates.

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of two hydrocarbon chains of different lengths. In cells, the components of the cell wall create highly ordered regions which alternate with some disordered regions, and the transition temperature is close to the physiological temperature. In the stratum corneum, the lipids forming the barrier appear to entrap water in a manner similar to a liquid crystalline gel network.[3] From structural considerations, RM1 can be described as a polar di-alkyl compound with two uneven hydrophobic areas (benzene and stearyl). The polar groups separate the two hydrophobic regions by forming an interface that appears to be roughly perpendicular to the two hydrophobic groups. One could assume that when this type of structure is coupled with its unique packing, it can be compared to a natural emulsifier such as lecithin, a Geminitype surfactant, and even a polymeric-type surfactant. Based on our molecular modeling, we conclude that the water appears to be entrapped in emulsions made with RM1 in a manner similar to the way water is entrapped in the cell wall and stratum corneum. The lamellar gel formed by RM1 (see Fig. 26.6) appears to supply more water continuously, because it contains bound water entrapped inside the channels of “hydrophilicity” described above. Consequently, RM1 has a desirable impact on moisturization by providing the presence of additional water molecules. In conclusion, the molecular modeling we conducted suggests that our emulsification technology works through a lamellar gel network, which provides enhanced stability and superior aesthetics to the resulting multiple-phase oil-in-water emulsions. In addition to this lamellar gel network in the water

Figure 26.6 Bilayers with STEPAN-MILD® RM1 aggregates and glyceryl stearate.

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phase, RM1 displays an unexpected behavior during packing that also provides rigidity at the oil/water interface. We can speculate that the unique packing creates hydrophilic channels and tight hydrophobic layers in the water phase. Ionic and other hydrophilic “active” species could be transported through the channels. Hydrophobic components could be incorporated in the tight hydrophobic layers, thus providing a liquid crystalline gel matrix somewhat similar to the stratum corneum and the cell wall.

26.4.3 Interfacial Tension (IFT) Sodium stearyl phthalamate is insoluble in water at room temperature but, at high temperature, it becomes water soluble and interacts at the oil/water interface displaying strong interfacial tension (IFT) reduction properties, which are critical to the emulsification process. In order to demonstrate the IFT properties, two sets of experiments were conducted to measure IFT. All experiments were performed above 70°C (to insure that the RM1 is dissolved in water). The first experiment relied on the Kruss K12 Tensiometer utilizing the du Nouy ring method. Since this method cannot measure the IFT accurately below 2 mN/M (milliNewton/meter), the second experiment utilized a spinning drop tensiometer. This instrument has the capability of measuring very low levels of IFT from <5 mN/M to 10-6 mN/M. As seen in Fig. 26.7, the data of the first experimental evaluation (the du Nouy ring method) indicated that a 0.1% solution of a combination of STEPAN-MILD® RM1 with a low-HLB emulsifier (glyceryl stearate) at a 2:1 ratio reduces the IFT of water/isopropyl palmitate (IPP) from 31 mN/M down to 1 mN/M.

Results of the second method (spinning drop tensiometer) are shown on Fig. 26.8. The graph illustrates the IFT reduction recorded for different concentrations of sodium stearyl phthalamate at the water/IPP interface with 0.5% low-HLB emulsifier, glycerol monooleate (GMO). A ratio of 2:1 RM1:GMO reduces the IFT of water/IPP below 1 mN/M. This is a sufficiently low IFT to produce the desired effect during emulsification. It allows the emulsifying system to effectively emulsify different types of oils. It is interesting to point out that the IFT graph starts at 1.7 mN/M, which corresponds to 0.1% RM1 in water and 0.5% GMO in IPP. This data point correlated well with the du Nouy ring measurement, suggesting that very low levels of the emulsifying system components at an established ratio provide strong, spontaneous emulsification.

26.5 Identification and Characterization of Lamellar Gel Network Structure 26.5.1

Conductivity Method

Conductivity measurements have proven to be a powerful tool for determining structural changes taking place in the aqueous phase of the multiplephase oil-in-water emulsion. The ability of the RM1 emulsification system to create multiple-phase structured emulsions was characterized by means of conductivity measurements using an Orion Conductivity Meter Model 115. According to the process of emulsion preparation (see Sec. 26.3), the oil phase was added to the water phase, and emulsification was carried out for a standard period of 25–30 minutes with a turbine agitator. During the cool down period, an electrode was introduced into the emulsion, and conductivity data was recorded. Results of the conductivity measurements during the cool down period are demonstrated in Fig. 26.9.

Figure 26.7 Interfacial tension reduction at isopropyl palmitate/water interface at 70°C.

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Figure 26.8 Interfacial tension measurements of STEPAN-MILD® RM1 with 0.5% glycerol monooleate in isopropyl palmitate.

Figure 26.9 Conductivity measurements performed during the cooling phase for emulsions prepared with STEPANMILD® RM1, Pemulen TR-1, and STEPAN® GMS.

The graph shown in Fig. 26.9 clearly identifies the structuring process during the cool-down phase of emulsion preparation with the two distinct phases and a phase-transition temperature being identified by means of their differing conductivity. As can be seen from the graph, conductivity is essentially constant at the elevated temperature of about 75°C and through part of the cooling process, indicating no changes in the aqueous phase of the emulsion. However, a sharp decrease in conductivity is observed at around 45°C. This can be associated with the phase transition temperature (Tc) of the emulsifiers, RM1, and GMS. At this temperature, and below it, the lamellar liquid-crystalline phase created by the sodium stearyl phthalamate based emulsifying system

at elevated temperature converts into a lamellar gel network structure.[3] The sharp decrease in conductivity associated with the phase change of RM1 correlates very well with the idea that, when the hydrocarbon chains of the bilayers of surfactant RM1 molecules solidify (become ordered) at the Tc, the water becomes entrapped in the channels of the network, thereby affecting the conductivity process within the emulsion. Emulsions exhibiting such behavior exist in the form of a lamellar gel network phase at room temperature, and are also referred to as multiple-phase emulsions.[3] Again, we point out such multiple-phase emulsions are not to be confused with the term “multiple emul-

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sions,” which have only two phases, but may occur as oil-in-water-in-oil or water-in-oil-in-water.

26.5.2 Rheological Method Rheological behavior of emulsions has become increasingly important for today’s formulators in optimizing the performance and sensory attributes of final products.[7] An emulsifying system can be the key to an emulsion’s rheological behavior. Measurements were performed on a prototype RM1-based emulsion containing 15% isopropyl palmitate as the oil phase. Experiments were carried out on a Weisenberg rheometer with a measuring geometry of coaxial cylinders at 22°C–25°C, using standard techniques. The non-Newtonian (viscoelastic) rheological behavior of an emulsion has been attributed to the structure formed by its ingredients.[4] Formation of lamellar gel network structures in an oil-in-water emulsion based on sodium stearyl phthalamate results in an extremely favorable rheological profile. This profile is illustrated by the graphs presented in Fig. 26.10, a and b. The dramatic decrease in apparent viscosity observed with increasing shear rate, as demonstrated in Fig. 26.10a, suggests strong shear thinning flow characteristics. When the data is presented in shear-stress versus shear-rate format (Fig. 26.10b), the overall character of the emulsion’s flow behavior can be seen to be moderately thixotropic with some yield stress. As shear rate increases, the gel “network” structure of the emulsion breaks down, and the viscosity of the system decreases (upper curve). When the shear force is removed, the initial conditions restore, and the structure rebuilds rapidly (lower curve). Moderate thixotropic character can be seen in a slightly lower viscosity in the downward curve versus the upward curve of the graph. Collapse of the lamellar gel network structure due to shear force applied during application of the emulsion to skin results in low viscosity of the emulsion at the high shear rates typical of application. The low infinite viscosity of the product characterizes how emulsion behaves during spreading. Consequently, emulsions based on RM1 demonstrate ease of application as a result of the low viscosity during application. Thixotropy, generally, gives an indication of the degree to which the emulsion flows

into the skin’s valleys. If structure recovers too quickly, the formulation will remain on the skin’s peaks giving a greasy feel. If recovery is too slow (or if there is no structure, as in Newtonian fluids), the formulation will flow into the skin’s valleys, giving a dry feel. The described shear thinning and moderate thixotropic characteristics of the emulsions based on RM1 demonstrate a very favorable rheological behavior, where both of these properties work together to provide a uniform coverage of the skin’s surface. Emulsions containing sodium stearyl phthalamate, therefore, make an extremely effective delivery system for contained actives and provide an exceptional skin feel during and after application.

26.6 Applications 26.6.1 Skin Irritation Along with extremely desirable functions such as cleansing, foaming, and emulsification, the application of surfactants in personal care products can also cause some adverse reactions upon contact with skin.[8] One example of this is irritation, and as a result, a need for mildness is one of the major requirements for a topical product’s performance. In the case of emulsions, emulsifying systems are well known to play a significant role in the degree of skin irritation of the finished product.[9] The use of emulsifiers in topical formulations is based on their ability to emulsify lipids in water regardless of their origin. Due to this fact, the same emulsifiers used to stabilize the emulsions may, and frequently do, interact with the lipids of the skin and undesirably alter its permeability barrier. The extent of this interaction between emulsifiers and skin lipids depends upon the chemical structure and, consequently, the properties of the emulsifier. Toxicological Studies of RM1. The complete study of the sodium stearyl phthalamate toxicological profile as a raw material was conducted. This included eye and skin irritation, as well as sensitization properties. It was established that RM1 is mild, and does not cause any sensitizing reactions to the skin. Additionally, a study was conducted to compare the mildness characteristics of the final emulsion formulated with sodium stearyl phthalamate-

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(a)

(b) Figure 26.10 (a) Apparent viscosity vs shear rate. The data is indicative of shear-thinning behavior. (b) Shear stress vs shear rate profile for an emulsion (indicative of moderate thixotropy).

based emulsification system. A comparative clinical irritation study of both formulated emulsions was performed by an outside testing laboratory on twentyseven panelists using a cumulative fourteen-day patch test method. The control lotion was based on a conventional anionic system containing TEA/stearate and a polymeric thickener. A similar skin lotion was prepared utilizing the sodium stearyl phthalamate

emulsifying system. Both emulsions contained 15% of isopropyl palmitate. Results of this irritation testing are summarized in Table 26.1. As seen in Table 26.1, the skin lotion based on the sodium stearyl phthalamate system was two categories milder than a similar control composition prepared with the TEA/stearate. The additional mildness provides a significant advantage

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Table 26.1. Cumulative Irritation Test (14 Days, 27 Panelists)

Formulation Tested

Score

Classification

Skin lotion (sodium stearyl phthalamate emulsifying system)

23

Category 1 Mild material – no experimental irritation

Control skin lotion (TEA/stearate/Carbomer)

181

Category 3 Possibly mild in normal use

for formulators working with potentially irritating active ingredients since it enables the formation of a final product with minimal overall irritation. Results of both studies lead to the conclusion that sodium stearyl phthalamate has an excellent safety profile and this behavior is understandable in light of its chemical structure and permeability properties. Due to the fact that RM1 is a relatively large molecule (MW = 440) and is insoluble in water at ambient temperature, it is fair to assume that the material does not disturb the lipid barrier between the skin cells and is, therefore, much milder than conventional emulsifying systems.

26.6.2 Moisturization Effect of RM1 in Creams and Lotions The hydration state of the stratum corneum determines its softness, smoothness, and flexibility. When the rate of water loss from the surface of the skin, promoted by environmental conditions or exposure to solvents or detergent solutions, exceeds the rate of replacement by the body tissue, the stratum corneum of the skin will frequently become rough, chapped, and dry.[10] The function of moisturizing preparations is to increase the water content of this tissue, and a variety of approaches are known. One of the possible ways of providing such moisturizing effects is to create a protective barrier on the skin (occlusive film). Such a film reduces the normal water-loss from the corneum surface to the atmosphere and, therefore, improves its water-holding capacity.[11]

Occlusivity measurements. For practical purposes, the water content of the stratum corneum is measured by an indirect method based on electrical properties of the water.[12] A Nova Dermal Phase Meter, DPM 9003, was employed to evaluate changes in the water-holding barrier properties of stratum corneum as related to the occlusive effect of tested products on the skin. The DPM is an electronic instrument designed to non-invasively measure biophysical characteristics of the skin using an in-vivo capacitance measurement. Capacitance is an electrical (or biophysical) property of skin that provides insight into the level of hydration of the stratum corneum. The stratum corneum has a high electrical resistance by nature, which decreases when moisturized. When the instrument probe is held on the surface of the skin, DPM 9003 produces readouts in DPM units. These units are directly related to the skin’s electrical capacitance, and indicate the amount of water that diffuses through the skin and accumulates under the probe. Lower DPM values indicate improved water-holding barrier properties of the stratum corneum. Lower DPM values may, therefore, be related to the moisturizing, occlusive effect of an applied skin care product. A therapeutic moisturizing cream containing 25% petrolatum and based on a sodium stearyl phthalamate emulsifying system was prepared according to a standard mixing procedure. This cream was compared with neat petrolatum as the positive control, and untreated skin as a negative control. The system was designed to deliver moisturizing occlusive properties.

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS The study was performed on ten people, both male and female, who ranged in age from 20 to 45 years, and had different skin types. Testing was conducted in controlled conditions of 60%–65% relative humidity and 20°C–22°C. Panelists equilibrated to the environmental conditions for at least thirty minutes before the products were applied. The inner surface of the panelist’s forearm was divided into three squares of 2.5 × 2.5 cm. A standard amount of 30 mg of the test product was gently and uniformly spread in each of two squares with one square remaining untreated. One hour following product application, the probe of the instrument was placed on the skin and readings were taken.

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shows that water loss increases with time following application but is highest for untreated skin and is significantly reduced by using the therapeutic moisturizing cream. Petrolatum, our positive control, is known to be one of the best occlusive ingredients that can reduce transepidermal water loss to almost zero when

The composition of the prototype therapeutic moisturizing skin cream used in the study is shown in Table 26.2. Graphs in Fig. 26.11 demonstrate an example of an occlusivity evaluation on one individual, with “normal” skin. The example illustrates the overall character of the moisturizing effect of the tested products on the skin during a 20-minute measuring period. The figure

Figure 26.11 Occlusivity study on individual with normal skin (one hour after application).

Table 26.2. Therapeutic Cream for Dry Skin with 25% White Petrolatum

Phase

Ingredients D.I. water

Water

Oil

Weight % q.s. to 100.0

Pemulen TR-1 (Noveon): acrylates/C10-30 alkyl acrylate crosspolymer

0.2

NaOH: sodium hydroxide

0.08

STEPAN-MILD® RM: sodium stearyl phthalamate

1.0

STEPAN® GMS PURE: glyceryl stearate

0.5

Penreco Ultima (Penreco): white petrolatum

25.0

®

20.0

®

STEPAN CETYL ALCOHOL, NF: cetyl alcohol

1.0

Germaben II (ISP): propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

1.0

STEPAN IPP: isopropylpalmitate

Total oils emulsified

45.0%

pH

7.4-7.6

Appearance

Soft cream

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applied to the skin in a sufficient quantity.[10] Data obtained for petrolatum in our testing confirmed this observation of prior workers. While the electrode was held on the skin covered with petrolatum, all the readings fluctuated slightly around 100 DPM units, indicating that no water diffuses through a layer of petrolatum. On the contrary, when the electrode was placed on untreated skin, moisture was continuously penetrating through unprotected skin and accumulating under the probe. This phenomenon resulted in a constant increase in DPM units. An improvement in skin barrier properties over the untreated skin was obviously demonstrated in the experiment when skin was treated with the therapeutic moisturizing cream containing sodium stearyl phthalamate. In a 20-minute evaluation, water was accumulating under the probe, but to a much lesser extent than it did with the untreated skin. Bars in Fig. 26.12 summarize the results of the panel test on people with different skin types. This study allowed us to determine the statistical significance of the RM1-provided improvement in skin moisturization. Each bar represents an average of readings taken after ten minutes of holding a probe on skin that was treated with a product an hour earlier. Statistical analysis of this study indicates that, with a 95% confidence, the therapeutic moisturizing cream formulated with sodium stearyl phthalamate provided significant improvement in the water-holding barrier properties. As expected, the occlusive effect obtained with neat petrolatum was statistically better than that obtained with the therapeutic moisturizing cream containing 25% petrolatum.

Visual assessment of skin moisturization. The moisturizing effect of the RM1 formulated emulsion was evaluated using a modified “Scotch®-tape” test followed by visual evaluation under a LEICA GZ6 Stereomicroscope. Moisturizing products are used to restore and/ or to maintain a normal function of stratum corneum and prevent appearance of dry skin. The condition of dry skin, which afflicts everyone at some time is either due to environmental conditions, exposure to detergents, or age, and is visually characterized by an appearance of roughness and scaling.[13] The “Scotch®-tape” method is based on evaluating this phenomenon. As a result of the application to and removal of electrical tape from the skin, white dry skin cells adhere to the black tape. The amount of white dry skin cells is inversely proportional to the level of moisturizing effect provided by a product. The same therapeutic cream formulated with sodium stearyl phthalamate and containing 25% petrolatum that was evaluated in the occlusivity study was also tested against neat petrolatum as the positive control and untreated skin as a negative control. The study included four people with dry skin. After one hour following product application, black electrical tape was pressed to each designated square on the skin, held on the spot for ten seconds, and removed. The tapes were further viewed under a stereomicroscope to determine the amount of dry cells removed and, thereby, ending up on the tape surface. The results of the tape test are shown in Fig. 26.13. As clearly seen in Figs. 26.13 a, b, and c, skin treated with petrolatum does not show any scaling and looks perfectly lubricated (Fig. 26.13a). On the contrary, untreated skin has a significant amount of large white flakes of dry skin cells (Fig. 26.13b). When skin was treated with the therapeutic moisturizing cream based on sodium stearyl phthalamate, the amount and size of dry skin cells appear to be significantly smaller, indicating strong moisturization and lubrication of skin (Fig. 26.13c).

Figure 26.12 Occlusivity panel study (one hour after application).

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(a)

(b)

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(c)

Figure 26.13 Moisturizing effect of the products evaluated by the “Scotch® tape” method (X400): (a) neat petrolatum, (b) untreated skin, and (c) therapeutic moisturizing cream.

The results of the tape test show good correlation with the DPM measurements and correlate well with the occlusive effect provided by the same products on the skin. Taken together, these data present a good visual demonstration of the strong moisturizing effect delivered by the emulsion based on RM1, sodium stearyl phthalamate, technology.

26.6.3

SPF Enhancement in Sunscreen Formulations

As identified in the above described studies, the emulsifying system based on RM1 provides a structuring effect in the external phase of the emulsion due to a lamellar gel network formation. As a result, formulated products using RM1 display a unique rheological profile that makes them extremely effective delivery systems for active ingredients employed in the emulsion. This effect is especially pronounced when the active ingredients are sunscreen agents. In-vivo evaluations such as SPF static and waterproof tests, were conducted by an independent laboratory. Good correlation with in-vitro studies was observed. This demonstrated that the RM1 emulsifying system provides a synergistic effect of physical and organic sunscreens. Recently, the use of inorganic sunscreens such as titanium dioxide (TiO2) and zinc oxide (ZnO), in combination with organic filters, as well as the sole UV actives has become popular. The key role of an emulsifier system in developing high efficiency

sun protective compositions is well known and has been indicated by earlier workers in a number of papers.[14][15] Our work demonstrated that multiple-phase, structured oil-in-water emulsions based on the nonconventional, anionic rheology-modifier–emulsionstabilizer, sodium stearyl phathalamate, serve as an exceptional delivery vehicle when formulating highSPF products with TiO2 and ZnO. One of the methods known to the cosmetic industry to increase sun protection factor (SPF) of sunscreen products is to combine inorganic sunscreens (e.g., physical sunscreens such as titanium dioxide or zinc oxide) and organic sunscreens. This approach has a number of advantages: • Physical sunscreens allow reduction of a formulation’s potential for irritation by reducing the amount of organic sunscreens needed and by improving the photostability of chemical actives.[16] • Organic sunscreens enable potential reduction of the undesirable whitening effect associated with physical filters such as TiO2 and ZnO. • A synergistic effect between organic and physical filters is possible that allows the achievement of target SPF numbers with reduced concentration of actives. In addition, such sunscreen formulations are extremely efficient in providing protection over a broad spectrum of UVA and UVB radiation.[16] Some

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disadvantages of this formulating route include the remaining potential for irritation, as well as the occurrence of the whitening effect on the skin, if the sunscreen composition is not formulated properly. Titanium-dioxide/organics combination. Titanium dioxide is recognized as a successful inorganic physical sunscreen due to its inert nature and compatibility with different ingredients in formulations. It has been widely used in combination with organic sunscreens in a variety of sun and skin care commercial products. The contribution of the sodium stearyl phthalamate emulsification system to the TiO2/organics sunscreen formulations has been studied in two sets of compositions. The first was being formulated using a conventional anionic system of TEA/ stearate/Carbomer and the second, which contained similar ingredients at the same active levels, was based on the sodium stearyl phthalamate emulsifying system. As demonstrated in Fig. 26.14, an outstanding SPF enhancement of up to 40% was achieved in a system containing RM1 compared to a conventional emulsion employing the same level of sunscreens. Obtaining desirable waterproofing properties are an important aspect of formulating sun protection creams and lotions. The same prototype formulation based on sodium stearyl phthalamate and containing micronized TiO2 (3.2% active) in combination with 3.5% ethylhexyl-p-methoxycinnamate and 1.5% benzophenone-3 was also tested by the inde-

pendent laboratory for the waterproof SPF. The study was conducted in vivo, on five subjects, on a skin type 1, 2, or 3. According to the procedure of the method, panelists were subjected to four immersions in water for twenty minutes each. The results of this study are shown in Table 26.3.

Table 26.3. RM1 Impact on SPF Waterproofing Formulation

Stepan Formulation

In vivo static SPF

23

SPF waterproof

22

As seen in Table 26.3, there was a strong waterproofing effect using RM1without adding any waterproofing agents. The intrinsic waterproofing effect of STEPAN-MILD® RM1 can be understood to be related with the water insolubility of the RM1 molecule at ambient temperature and, consequently, its desirable inability to re-emulsify oils upon contact with water. Another extremely important aspect of formulating physical sunscreen-containing emulsions using RM1 can be demonstrated by the micrograph in Fig. 26.15. Extensive work with micronized, hydrophobically treated, titanium dioxide (TiO2) suggests that the RM1 emulsification technology generates oil-in-water emulsions with the inorganic sunscreens that are well encapsulated in the oil phase. Figure

Figure 26.14 SPF values represent average of measurements performed in vitro and in vivo.

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emulsifiers such as C 10-30 alkyl acrylate crosspolymers in one formulation. Such systems are widely used in the cosmetic industry to stabilize emulsions,[19] and there is a need to find ways around this problem. A series of experiments were conducted to evaluate the role of sodium stearyl phthalamate in providing compatability of ZnO with a widely-used polymeric emulsifier (acrylates C10-30 alkyl-acrylate crosspolymer).

Figure 26.15 Micrograph of sunscreen emulsion with micronized TiO2 water-resistant SPF 25 (X600).

26.15 demonstrates the micrograph of an RM1-based sunscreen emulsion with micronized TiO2 (3.2% active TiO2 in combination with 3.5% ethylhexyl-pmethoxycinnamate and 1.5% benzophenone-3). An extremely uniform distribution of oil droplets containing encapsulated TiO2 can be noted. Uniform and effective dispersion of TiO2 within the oil phase of the emulsion, as shown in Fig. 26.15, combined with the ability of the RM1 technology to uniformly distribute and deliver these particles to the skin surface, results in a desirable, non-whitening effect. This effect was positively identified by a visual panel evaluation. Zinc-oxide/organics combination. As far as it is currently known, sunscreen formulations comprising combination of zinc oxide and organics are less common.[17] Nevertheless, the increasing demand to provide “broad spectrum protection,” as well as the trend to incorporate UV filters in the daily use skin care and other cosmetic products, continue to stimulate an increasing interest in such combinations. Significant advantages of ZnO as a sunscreen agent include its effectiveness in blocking UVA and UVB radiation, photostability for effective coverage throughout a day, and a long history of safety. However, there are some limitations of using ZnO that are attributed to a very reactive nature of this product and the accompanying problems of formulation stability.[18] In addition, the formulating experience in the industry indicates that it is very difficult to combine zinc oxide and polymeric thickeners/

The prototype formulation shown in Table 26.4 is a result of extensive optimization work, and demonstrates the unique ability of sodium stearyl phthalamate to provide stable and effective emulsions containing both polymeric emulsifier (acrylates C10-30 alkyl-acrylate crosspolymer) and ZnO. The stability of developed compositions was monitored at both ambient and elevated temperatures. Freezethaw testing was conducted as well. Incorporation of ZnO and it’s distribution in the oil and aqueous phases of the emulsion play an important role in achieving desired emulsion stability (both in terms of pH and temperature), as well as SPF values. Extensive microscopy work has been performed to study these phenomena and effects. Visual monitoring of the emulsion’s structure was conducted using an optical microscope (Olympus BH2) at 400X magnification. The formulation shown above in Table 26.4 was observed under the microscope after storage for one month, at ambient, and 45°C. Micrographs (a) and (b) in Fig. 26.16, illustrate the effect of storage at different temperatures on emulsion structure and the potential for phase separation. As the photomicrographs demonstrate, the initial oil droplets small size and uniform distribution are very good, with ZnO clearly incorporated in the oil phase of the emulsion. Storage at elevated temperature for one month caused some insignificant coalescence of oil droplets and resulted in very slight oil droplet enlargement. Overall droplets size and distribution, however, remained very similar to the initial droplet size and distribution of the oil phase within the emulsion. These observations prove good high temperature stability of the formulation and correlate with visual observations of the stability of the sample stored in the oven.

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Table 26.4. RM1 Complete UV Protective Lotion with ZnO and Ethyl-P-Methoxycinnamate (SPF 24.6*)

Phase

Ingredient

Weight %

D.I. water Water

q.s. to 100.0

Pemulen TR-1 (Noveon), acrylates/C10-30 alkyl acrylate crosspolymer

0.2

NaOH, sodium hydroxide

0.07

STEPAN-MILD® RM1, sodium stearyl phthalamate

1.0

®

STEPAN OCTYL ISONONANOATE , ethylhexyl isononanoate

Oil

10.0

Dow Corning 345 fluid (Dow Corning), cyclomethicone

2.0

Parsol MCX (Givaudan-Roure), ethylhexyl-p-methoxycinnamate

6.0

Z-Cote® HP1 (BASF), zinc oxide and dimethicone

3.0

®

0.5

®

STEPAN CETYL ALCOHOL, NF, cetyl alcohol

1.5

STEPAN® STEAROL ALCOHOL 97, stearyl alcohol

1.5

Vitamin E (Roche), tocopheryl acetate

0.05

Germaben II (ISP), propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

1.0

STEPAN GMS PURE, glyceryl stearate

9.0% 8.2–8.5 Lotion

Total Sunscreens pH Appearance *In vivo (6 individuals).

(a)

(b)

Figure 26.16 Micrographs showing the effect of elevated temperature on emulsion structure (X400): (a) 1 month at RT, (b) 1 month at 45°C.

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS The best prototype formulations were tested in vitro and in vivo by outside testing companies in order to confirm the expected, broad-spectrum protection. An in-vivo study was performed using a labsphere ultraviolet transmittance analyzer, in the range of wavelengths covering both UVA and UVB ranges from 290 nm to 450 nm. Final SPF numbers represented an average of four runs for each sample. In-vivo testing was done on six subjects of skin type II. This type of skin represents “sensitive” skin, that always burns easily and tans minimally. Table 26.5 demonstrates the in-vitro and in-vivo SPF values as well as critical wavelengths (CW) for the tested composition (Table 26.4). As seen in Table 26.5, the prototype formulation demonstrates a strong synergistic effect of ZnO and OMC (ethylhexyl-p-methoxycinnamate). This results in a high protection for sunlight in the UVB range, and a sufficient UVA protection as measured by Boots 1–5 star system. Formulating with inorganic sunscreens as the only active. The well-known, strong commercial trend of using physical UV filters as the sole sunscreen active is attributed to concerns by dermatologists about irritation and the allergic potential of organic sunscreens for infants, children, and people with sensitive skin. Inorganic blocking agents such as ultrafine TiO2 and ZnO attenuate UV light via a combination of absorption and scattering. They are also known to provide a broader wavelength range of protection than most chemical sunscreens. In addition, physical sunscreens are biodegradable, chemically inert, and essentially nonirritating. The biggest challenge in formulating with inorganic sunscreens as the only active is the difficulty in achieving high SPF values. This is especially true in oil-in-water emulsions. Further, such formulations with a high concentration of

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physical sunscreens will impart an undesirable whitening effect to the skin. Extensive formulation work has been conducted to develop prototype formulations with TiO2 and combinations of TiO2 and ZnO at different concentrations with up to 12% actives. In addition to standard stability requirements at ambient and elevated temperatures, these compositions were also evaluated for the level of protection provided and aesthetic properties obtained. Some examples of sample formulations are shown in Formulations 26.1 and 26.2 in Sec. 26.8. Results of in-vivo testing on four subjects by an independent laboratory demonstrate a high ratio of SPF units per active percent of physical sunscreens (more than 3), a ratio not easily achieved with conventional emulsifiers where agglomeration of physical sunscreens is more likely to occur. As identified through extensive microscopy studies (see example shown on the micrograph in Fig. 26.15) uniform and effective dispersion of TiO2 within the oil phase of the emulsion, combined with the ability of the RM1 technology to uniformly deliver and distribute the sunscreen particles on the skin, results in a highly desirable, non-whitening effect as previously described. The sodium stearyl phthalamate-based emulsification system has been found to be extremely efficient in formulating high-SPF, broad-spectrum UV protection skin and sun care products. The results of the conducted work described in this chapter demonstrate that the sodium stearyl phthalamate based emulsification system allows formulators to achieve a variety of desirable objectives. These include target performance with reduced level of actives, SPF enhancement for combinations of inorganic and organic sunscreens, minimization of the whitening effect of ZnO and TiO2 on the skin, and shiny emulsions with a pleasant, light skin feel.

Table 26.5. Results of SPF Testing (on Formulation Shown in Table 26.4)

Product

In vivo SPF

Critical wavelength (CW), nm

Mean absorbance ratio

Boots star rating

In vitro SPF

Emulsion with ZnO

24.6

370

0.42

✯✯

23.0

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

It was also discovered that sodium stearyl phthalamate provides the unique possibility of combining ZnO with acrylates/C10-30 alkyl acrylate crosspolymers in sunscreen formulations. This ability is highly attractive since it solves a previously unachievable goal of the industry.

26.6.4 Formulating Sprayable Products Sprayable lotions are gaining more and more popularity in the market place. This is attributed to a number of advantages of spray delivery systems. Some of the conveniences include the ease of application as well as improved product coverage on the skin. However, as cosmetic chemists are well aware, formulation of sprayable products presents a major challenge. The challenge is attributed to the fact that, on one hand, sprayable lotions should have low enough viscosity to be sprayable, while on the other hand, viscosity should be high enough to provide desired shelf life and stability of the finished product. One answer to this challenge is to provide a system with an optimum emulsion rheological profile. Such a profile will require high shear thinning behavior (low viscosity) of the emulsion at high shear rates (spraying) and relatively high viscosity at lower or zero shear rates typical of shelf life stability and pouring. The ability of an emulsion to quickly recover its high viscosity on the skin after application at high shear is critical to prevent dripping from the skin surface. Selection of an appropriate emulsification system is key to providing the desired rheological behavior of the emulsion. The formation of the RM1-based lamellar gel network structure in formulated products, combined with the desirable shear thinning flow characteristics of resulting structured multiple-phase emulsions, were demonstrated earlier in this chapter and have proven to be extremely favorable in formulating sprayable skin lotions. An example of one of such product is presented in Formulation 26.3 in Sec. 26.8. The relatively high initial viscosity of 2,000 cps at low shear rates insures good physical stability of the product (up to one month at 50°C with no separation), and, consequently, an adequate shelf life.

Collapse of the lamellar gel network structure due to high shear force during spraying results in a desirably low emulsion viscosity and good sprayability properties of the product. Rapid recovery of the structure prevents the product from running off the surface of the skin. Rubbing the product on the skin during the application process creates high shear rates again and consequent reduction of the product’s viscosity due to shear thinning properties of the emulsion. This provides ease of application and good spreading of the product on the skin. Moderate thixotropy of the emulsions based on RM1 ensures uniform coverage of the skin surface. As was confirmed in panel testing, sprayable lotions containing sodium stearyl phthalamate demonstrate an exceptional skin feel during and after application.

26.7 Conclusion The emulsification technology presented in this chapter works through liquid gel network formation that provides stability and superior aesthetics in multiple-phase, oil-in-water emulsions. The emulsifying system containing STEPAN-MILD® RM1 improves delivery of cosmetically active ingredients such as sunscreens, silicones, moisturizers, and vitamins; and results in highly efficient products. The RM1 emulsifying system displays a synergistic effect with physical sunscreens in a combination with organic sunscreen agents, as well as imparting waterproofing of finished formulations. RM1 also provides a unique solution to the previously unsolved problem of the desire to combine a polymeric emulsion with a polyvalent element (zinc in zinc oxide). The emulsions based on this technology are extremely mild and are highly efficient in providing a strong occlusive effect on the skin which translates into enhanced skin moisturization and improvement in a “dry skin” condition. The unique combination of attributes described in this chapter make the emulsification technology implementing sodium stearyl phthalamate an ideal candidate for formulating elegant moisturizing products, including creams and lotions for sensitive skin.

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS

565

26.8 Formulations In addition to the sample formulations presented here (Formulations 26.1 through 26.3), see Table 26.2 “Therapeutic Cream for Dry Skin with 25% White

Petrolatum,” and Table 26.4 “RM1 Complete UV Protective Lotion with ZnO and Ethyl-P-Methoxycinnamate.”

Formulation 26.1: Water Restistant UVA/UVB Sunblock for Babies with TIO2 (SPF 26.0*)

Phase

Ingredient D.I. water

Water

q.s. to 100.0

Carbowax PEG 400 (Dow Chemical) PEG-8

4.0

Pemulen TR-1 (Noveon), acrylates/C10-30 alkyl acrylate crosspolymer

0.2

NaOH, sodium hydroxide

0.09

STEPAN-MILD® RM1, sodium stearyl phthalamate

1.0

Finsolv TN (Finetex), C12-15 alkyl benzoate

13.0

®

Oil

Weight %

STEPAN OCTYL PALMITATE, ethylhexyl palmitate

11.0

Dow Corning 345 (Dow Corning), cyclomethicone

3.0

Ganex V-216 (ISP), PVP/hexadecene copolymer

2.0

Eusolex T-2000 (EMD Chemicals) titanium dioxide, alumina, and simethicone

10.0

STEPAN® GMS PURE, glyceryl stearate

0.5

Vitamin E acetate (Roche), di-alpha-tocopheryl acetate

0.1

Germaben II (ISP), propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

1.0

Total Sunscreens PH Viscosity @ 25°C Brookfield RV 6 @ 20 rpm (cps) Appearance * Screening in-vivo testing

8.0 7.0–7.2 Lotion

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Formulation 26.2: Sensitive Skin Complete UV Protective Sunblock with TiO2 and ZnO (SPF 32.3*)

Phase

Ingredient D.I. water

Water

q.s. to 100.0

Carbowax PEG 400 (Dow Chemical) PEG-8

4.0

Pemulen TR-1 (Noveon), acrylates/C10-30 alkyl acrylate crosspolymer

0.2

NaOH, sodium hydroxide

0.09

®

STEPAN-MILD RM1, sodium stearyl phthalamate ®

Oil A

1.0

STEPAN OCTYL PALMITATE, ethylhexyl palmitate

10.0

Z-Cote HPI (BASF), zinc oxide and dimethicone

3.0

STEPAN® GMS PURE, glyceryl stearate

0.5

®

Oil B

Weight %

WECOBEE S, hydrogenated vegetable oil

1.0

Finsolv TN (Finetex), C12-15 alkyl benzoate

15.0

Ganex V-216 (ISP), PVP/hexadecene copolymer

2.0

Eusolex T-2000 (EMD Chemicals), titanium dioxide, alumina, and simethicone

10.0

Germaben II (ISP), propylene glycol, diazolidinyl urea, methylparaben and propylparaben

1.0

Total % Sunscreens

11.0

PH

8.0–8.5

Viscosity @ 25°C RV 6, 20 rpm (cps)

25,000

Appearance * Screening in-vivo testing

Soft cream

RYKLIN AND BYERS: SHEAR-THINNING LAMELLAR GEL NETWORK EMULSIONS AS DELIVERY SYSTEMS Formulation 26.3: Sprayable Lotion with Silicone

Phase

Ingredient D.I. water

Water A

q.s. to 100.0

Propylene glycol

1.0

Pemulen TR-1 (Noveon), acrylates/C10-30 alkyl acrylate crosspolymer

0.2

NaOH, sodium hydroxide

0.08

®

Oil B

C

Weight %

STEPAN-MILD RM1, sodium stearyl phthalamate

1.0

Versene NA (Dow Chemical), disodium EDTA

0.1

STEPAN® GMS PURE, glyceryl stearate

0.5

NEOBEE® M-5 cosmetic, caprylic/capric triglyceride

1.0

®

STEPAN OCTYL ISONONANOATE, ethylhexyl isononanoate

2.0

DC 345 fluid (Dow Corning), cyclomethicone

1.0

Propylene glycol

1.5

Germaben II (ISP), propylene glycol and diazolidinyl urea and methylparaben and propylparaben

1.0

Citric acid Total oils emulsified pH Viscosity @ 25°C Brookfield RV 4 @ 20 rpm cps Appearance

q.s. to pH 7.0–7.5 4.0% 7.0–7.5 2,000 Lotion

567

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References 1. Fox, C., In Introduction to Multiple Emulsions, Cosmetic & Toiletries, 101:101–112 (1986)

10. Middleton, J., Methods of Skin Moisturizing, Cosmetic & Toiletries, 92:34–38 (1977)

2. Friberg, S., and Larsson, K., Liquid Crystals and Emulsions, Advances in Liquid Crystals, (G. M. Brown, ed.), Vol. 2, pp. 173–195, Academic Press, London (1976)

11. Rieger, M., Skin, Water and Moisturization, Cosmetic & Toiletries, 104:41–51 (1989)

3. Eccleston, G., Multiple-phase oil-in-water emulsions, presented at the Annual Meeting of the Society of Cosmetic Chemists, New York, pp. 1–22 (1989)

12. Tagami, H., Quantitative Measurements of Water Concentration of the Stratum Corneum, Acta Dermatovenerologica (Stockh.), pp. 29–33 (1994) 13. Morizot, F., et al., Sensitive Skin, Cosmetic & Toiletries, 113:59–65 (1998)

4. Rena, L., et al., Secondary Structural Rheology of a Model Cream, J. Soc. Cosmetic Chemists, 45:77–84 (1994)

14. Hewitt, J. P., Advances in Physical Sunscreens, Global Cosmetic Industry, p. 29, (2000)

5. Suzuki, et al., Secondary Droplet Emulsion: Contribution of Liquid Crystal Formation to Physico-Chemical Properties and Skin Moisturization Effect of Cosmetic Emulsions, Abstracts, IFSCC in Paris, I:117–137 (1992)

15. Dahms, G. H., Formulating with a Physical Sun Block, Cosmetics and Toiletries, 107:87 (1992)

6. Goze, J., et al., Patent # WO 91/01970, Cyclic Amidocarboxy Surfactants, Synthesis and Use Thereof, (Dec. 1996) 7. Dahms, G., Choosing Emollients and Emulsifiers for Sunscreen Products, Cosmetic & Toiletries, 109:45–52 (1994)

16. Hewitt, J. P., Novel Formulation Strategies for High SPF and Broad Spectrum Sunscreen products, First European UV Sunfilters Conference, Paris (1998) 17. Mitchnik, M., Zinc Oxide, An Old friend to the Rescue, Cosmetic & Toiletries, Vol. 107 (Oct., 1992)

8. Rieger, M., Surfactant Interactions with Skin, Cosmetic & Toiletries, 110:31–50 (1995)

18. Johncock, W., Sunscreen Interactions in Formulations, Cosmetic & Toiletries, Vol. 114 (Sep., 1999)

9. Ghyczy, M., and Vacata, V., Concepts for Topical Formulations Adjusted to the Structure of the Skin, Chinica Oggi, 9:17–20 (1999)

19. Chiarelli, J., et al., Sunscreen Composition, Patent W/O 99/15144 (Apr., 1999)

Acknowledgment A number of Stepan employees contributed to the work described in this chapter, and their help is greatly appreciated. Some of the material included in this chapter was first presented at the Advanced Technology Conference: Europe, 1998, in a paper entitled “Versatile and Efficient Emulsification Technology Based on a Non-Conventional Anionic Rheology Modifier.” Other information was presented at the 2000 Cesio

Conference in a paper entitled, “Use of Non-Conventional Lamellar Gel Network Technology for Producing Elegant Moisturizing Creams and Lotions,” and at the XXI IFSCC International Congress 2000 in a paper entitled, “Formulating Efficient Broad Spectrum UV Protection Oil-in-Water Creams and Lotions with Zinc Oxide.” This material is used with the permission from Cosmetics and Toiletries Magazine, Cesio, and IFSCC.

27 ProLipid® Skin-Mimetic Lamellar Gel Carrier and Delivery Systems Mark E. Rerek International Specialty Products Wayne, New Jersey

27.1 Introduction ..................................................................................... 570 27.1.1 Definition of Lamellar Gel Organization ............................ 570 27.1.2 Lamellar Gels and Skin Lipid Organization ....................... 571 27.1.3 The “Eureka!” Moment ...................................................... 571 27.1.4 Determining ProLipid® Lamellar Gel Structure ................. 571 27.1.5 Product Structuring with ProLipid® Lamellar Gels ........... 572 27.2 Formulating with ProLipid® Lamellar Gels .................................... 573 27.2.1 Selection of ProLipid® Lamellar Gel Systems ................... 573 27.2.2 Preparation of ProLipid® Lamellar Gel Emulsions ............ 573 27.3 Delivery of Functional Materials from ProLipid® Lamellar Gel Formulations .............................................................. 574 27.3.1 Demonstration of Lamellar Gel Structure in ProLipid® Emulsions ......................................................... 574 27.3.2 Long Lasting Moisturization .............................................. 574 27.3.3 Delivery and Substantivity of Sunscreen Agents .............. 575 27.3.4 Delivery and Substantivity of Ascorbic Acid ...................... 576 27.4 Extended Insect Repellency with a ProLipid® 151 Lotion ............. 576 27.5 Extended Fragrance Release with ProLipid® Systems ............... 577 27.6 Conclusions .................................................................................. 577 27.7 Formulations ................................................................................. 578 References .......................................................................................... 586

* Current address: Reheis, Inc., Berkeley Heights, New Jersey Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 569–586 © 2005 William Andrew, Inc.

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27.1 Introduction 27.1.1 Definition of Lamellar Gel Organization Amphipathic molecules containing polar head groups and nonpolar hydrocarbon chains can spontaneously organize into sheet-like (lamellar) bilayers. These bilayers are divided by water channels, depending on the specific nature and balance of their hydrophilic and hydrophobic portions. The bilayers have a repeat unit of two in which the non-polar hydrocarbon chains are oriented towards each other and the polar head groups are oriented toward the water channel (Fig. 27.1). The bilayers stack in a large number of sheets and form a three-dimensional array. Within the general bilayer organization, the hydrocarbon chains can be organized into three phases: crystalline, lamellar gel, and lamellar liquid crystal.[1] The general bilayer organization and crystallographic sub-cells for these three phases are shown in Fig. 27.2. In the crystalline phase, the amphipathic molecules are packed together very tightly through both hydrophilic (hydrogen bonding) and hydrophobic (van der Waals’ forces) stabilization. In this state of compaction, the hydrocarbon chains are arranged in a fully extended, all trans configuration that allows them to form an orthorhombic sub-cell structure. The

Figure 27.1 Schematic representation of an amphiphile lamellar bilayer. The fundamental repeat unit consists of two molecules. These molecules are oriented with their head groups and hydrophobic tails toward each other, either in parallel or perpendicular orientation.

lamellar gel phase, sometimes called the “ordered” state, is similar to the crystalline phase. In this phase, the hydrocarbon chains are also arranged in a fully extended, all trans configuration. However, the lamellar gel phase differs from the crystalline phase in that the molecules are not as tightly packed together. This looser chain packing gives rise to a hexagonal sub-cell structure. Like the crystalline and lamellar gel phases, the lamellar liquid crystal phase has a bilayer molecular arrangement. However, in this phase, the hydrocarbon chains are conformationally disordered and essentially behave as liquids. As a result, this phase does not have a distinct crystallographic sub-cell structure. Another consequence of the liquid behavior of the hydrocarbon chains is that the spacing between bilayers is compacted as compared to the extended chain structures of the crystalline and lamellar gel phases. Each of the three phases (crystalline, lamellar gel, and lamellar liquid crystal) have distinct head group aqueous characteristics. In the crystalline phase, the head groups are directly hydrogen bonded, and often, there is little, or no water present. In the lamellar gel phase, the head groups are hydrogen bonded to each other, and to water as well. In the liquid crystal phase, there are discrete water channels between head groups of each bilayer.

Figure 27.2 Schematic representation of the lamellar crystalline phase, lamellar gel phase, and lamellar liquid crystal phase and their chain packing crystallographic sub-cell organization.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS 27.1.2

Lamellar Gels and Skin Lipid Organization

The lipids of the skin are believed to exist in all three packing phases described above, but most of the packing is believed to be in the lamellar gel phase.[2] It has been shown previously that the skin lipids provide its primary barrier function.[3] Therefore, it is logical to conclude that the barrier properties of the skin lipids arise from their lamellar gel phase organization. It was proposed by Forslind[4] that the lamellar gel lipids of the skin form discrete domains that are separated by liquid crystalline grain boundaries. Forslind called this organization the domain mosaic model of stratum corneum lipids (Fig. 27.3). In this model, the lamellar gel lipids provide the barrier properties while the liquid crystalline lipids provide the semi-permeable (tortuous path) aspect of the barrier as well as its mechanical flexibility and resiliency. More details on the structure of skin are presented elsewhere in this book (see, for example, Ch. 3).

27.1.3

The “Eureka!” Moment

ProLipid® lamellar gel systems. In dry skin, the lipid barrier, resident in the stratum corneum, is often damaged. This results in a detrimental higher rate of water loss and further skin damage. One way to repair the resulting dry skin is to replenish

Figure 27.3 Schematic representation of Forslind’s domain mosaic model of the skin lipid barrier.

571

the lost skin lipids. Looking at Forslind’s Domain Mosaic Model, we had the idea that when using lipid replenishment to restore the compromised skin barrier in dry skin, one needed to restore the lamellar gel barrier. However, we envisioned that it might not be necessary to use the exact chemical composition of the skin lipids for this purpose. Different compositions of lipids could be used, as long as they formed a lamellar gel with the same general physical chemical properties as the native skin lamellar gel. Further, we speculated that a lamellar gel with identical physical properties could incorporate itself into the compromised upper lipid layers by fusing with the skin lipid lamellar gel. Once incorporated, the exogenous lamellar gel would then restore the skin’s barrier function, thereby giving long-lasting moisturization and skin barrier strengthening to dry skin. It was envisioned that the long-lasting moisturization would arise from two properties. First, in the short term, the incorporated lamellar gel would resist removal, thereby keeping the barrier function, which in turn maintains moisture balance. Second, in the long term, once the barrier function was restored, the skin could heal itself from within. With this thought pattern crystallized, we proceeded on the development path which resulted in the creation of ProLipid products.

27.1.4 Determining ProLipid® Lamellar Gel Structure There are several physical techniques that identify and/or give insight into lamellar gel structure. These are transmission electron microscopy (TEM), optical microscopy using cross polarized light, Fourier transform infrared spectroscopy (FTIR), and small angle x-ray scattering. The two most commonly used techniques that provide complimentary information are optical microscopy using crossed polarized light and FTIR spectroscopy. Optical microscopy is a simple, rapid technique for determining the uniformity of droplet size in an emulsion. The addition of two light polarizers at right angles to each other (crossed polarizers) provides insight into molecular organization in the sample. Cross-polarized light is refracted by ordered phases giving rise to patterns characteristic of the specific type of order-

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ing.[5] Thus, for example, lamellar phases produce a characteristic Maltese cross-like structure under cross-polarization (Fig. 27.4) while isotropic phases appear black under cross-polarized light. Fourier transform infrared (FTIR) spectroscopy is a powerful technique that is used to determine chain structure from the sensitivity of several hydrocarbon vibrational modes.[6] Two parameters that are particularly sensitive to chain fluidity are CH2 stretching and CH2 wagging vibrations. The CH2 stretching peak frequencies provide a direct measure of chain conformational order. By measuring the CH2 symmetric stretching frequency, over a range of temperatures, it is possible to obtain a di-

rect picture of chain order and molecular organization of the components within a sample. An example of this technique is shown in Fig. 27.5 for ProLipid 141 and 151. Conformational order occurs at temperatures below 50°C.

27.1.5

Product Structuring with ProLipid® Lamellar Gels

As described previously (Sec. 27.1.3), the primary inspiration for the ProLipid lamellar gels was as a skin lipid replenishment system. However, there is a long history of the use of lamellar gel and liquid

Figure 27.4 Photomicrograph at 200X under cross polarization of the hydrated equimolar Ceramide 2/stearic acid/cholesterol skin lipid model system showing characteristic lamellar textures. Note the maltese-cross type pattern.

(a)

(b)

Figure 27.5 Thermotropic changes in the average methylene symmetric stretching (νsymCH2) frequency for (a) hydrated ProLipid® 141 and (b) hydrated ProLipid® 151. Conformational order is maintained below 50°C for both systems.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS crystal systems to structure and stabilize cosmetic and pharmaceutical oil-in-water emulsions.[1][7] Many classical fatty alcohol/glyceryl monoester emulsifiers have been found to form lamellar gels. This phenomenon was often due to the presence of low levels of free fatty acids that were products of the partial neutralization of the glyceryl monoester formed during the emulsification process. The actual structures of these emulsions, and the physico-chemical principles that drive their formation, are still not widely appreciated in the personal care industry. In view of this, these systems are often empirically designed for a specific formulation and, therefore, not generally applicable across a wide range of formulations. Some fatty alcohol/glyceryl monoester systems have been observed to build viscosity over time. For these reasons, lamellar gels have garnered a reputation for being difficult to work with and being limiting in their formulation flexibility. ProLipid lamellar gels are explicitly designed to address the above-stated concerns. Their compositions are selected to maintain stability of the lamellar gel structure across a wide range of pH, temperature, and oil phase composition. By maintaining product structuring over these varying conditions a considerable expansion in formulation flexibility is achieved. ProLipid lamellar gels provide a stabilizing external phase for suspended droplets in emulsions by virtue of their effect on the rheology of the external phase. The lamellar gels act to increase both apparent viscosity and yield stress, and thereby increase the suspending power of the external emulsion phase. The nature of their product structuring properties provides carrier/delivery functionality for actives making ProLipid lamellar gels especially versatile for personal care emulsions.

27.2 Formulating with ProLipid® Lamellar Gels 27.2.1

Selection of ProLipid® Lamellar Gel Systems

Currently, ISP offers two ProLipid lamellar gel systems. The first is ProLipid 141 (INCI: glyceryl stearate, behenyl alcohol, palmitic acid, stearic acid, lecithin, lauryl alcohol, myristyl alcohol, and cetyl

573

alcohol). ProLipid 141 contains globally approved ingredients and is compatible with anionic, nonionic, and cationic materials. It produces rich creams in oil-in-water personal care emulsions and leaves a dry silky after-feel on the skin. The second ProLipid lamellar gel system is ProLipid 151 (INCI: glyceryl stearate, cetyl alcohol, stearyl alcohol, behenyl alcohol, palmitic acid, and stearic acid). ProLipid 151 contains a small amount of cationic surfactant and is broadly compatible with nonionic, cationic, and low charge density anionic materials like xanthan gum. It forms stable, low viscosity lotions that provide a wetter feel on application, as well as leaving a lighter, conditioned skin after-feel. A use level of 3–5 wt% is recommended for both ProLipid systems, depending upon the volume and composition of the oil phase. ProLipid systems maintain their lamellar gels structure across the recommended pH range for skin care products of 3.8 to 8.0. Both ProLipid systems are compatible with commonly used personal care silicones such as dimethicones, cyclomethicones, and phenyltrimethicones.

27.2.2

Preparation of ProLipid® Lamellar Gel Emulsions

ProLipid lamellar gel emulsions are prepared by first melting the appropriate ProLipid system into the oil phase. The hot, liquid oil phase is then slowly added into the hot aqueous phase using high shear processing such as homogenization. High shear processing insures effective, homogeneous dispersion of the oil phase throughout the aqueous phase. Such processing at high temperatures insures that the ProLipid is in a fluid phase so that it can be readily and uniformly dispersed within the aqueous phase. Upon cooling, the ProLipid product transitions from its liquid state at high temperature into the lamellar gel phase (which has the oil phase dispersed within the lamellar gel). An alternative process to high shear mixing is to use a polymeric dispersant such as Ganex® P-904 LC (~0.15 wt%). Such polymeric dispersants serve to uniformly distribute the fluid lamellar gel/oil phase at high temperature with simple paddle mixing.

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27.3 Delivery of Functional Materials from ProLipid® Lamellar Gel Formulations 27.3.1 Demonstration of Lamellar Gel Structure in ProLipid® Emulsions A ProLipid 141 moisturizing cream formulation is shown in Formulation 27.1 and a ProLipid 151 moisturizing lotion formulation is shown in Formulation 27.2. Both of these formulations were evaluated for lamellar gel structure using FTIR spectroscopy. The resulting data showed that even in the presence of emollient esters, which exhibit random conformation of their hydrocarbon chains, the average methylene symmetric stretch for both formulations indicates a significant degree of conformational order below 40°C (Fig. 27.6). The observed conformational order shown in Fig. 27.6 is a very strong indication that the lamellar gel structure is present in these emulsion formulations.

(a)

27.3.2

Long Lasting Moisturization

Clinical Study with ProLipid® 141 Moisturizing Cream. The ProLipid 141 moisturizing cream shown in Formulation 27.1 was tested in a four week clinical moisturization study. For the first week, panelists washed with an alkaline soap twice per day in order to induce dry skin on their legs. During the second and third week of the test, the panelists treated one leg with the moisturizing cream while the other leg was left untreated. Both legs were washed with alkaline soap once a day. For the fourth week, product application was discontinued and washing was continued on both legs with alkaline soap once a day. As shown in Table 27.1, the product-treated leg was significantly more moisturized than the treated leg, even one week after discontinuing product use. Visual evaluation of the panelist legs was made by expert assessment at a clinical testing laboratory using a 0–4 (best–worst) scale. The fact that the moisturized leg remained significantly more moisturized after one week following discontinuing product application is a strong indication that the ProLipid 141 was effectively delivered to the stratum corneum where, as expected, it was incorporated into the native lipid structure. This incorporation repaired and enhanced the natural lipid moisture barrier of the stratum corneum thereby providing a long term moisturization benefit.

(b)

Figure 27.6 Thermotropic changes in the average methylene symmetric stretching (νsymCH2) frequency for (a) ProLipid® 141 moisturizing cream and (b) ProLipid® 151 moisturizing lotion. In spite of a large excess of conformationally disordered emollient esters, significant amounts of conformational order are observed below 35°C for both systems.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS Table 27.1. Averaged Clinical Results by Expert Visual Assessment for ProLipid® 141 Cream Moisturizer

Evaluation Point

Treated Leg p < 0.001

Untreated Leg

Baseline

1.60

1.60

One week treatment

0.61

1.65

Two week treatment

0.74

1.77

Regression

1.52

2.16

575

27.3.3 Delivery and Substantivity of Sunscreen Agents Effective sun protection is commonly measured by the parameter known as the sun protection factor (SPF). SPF is defined as the ratio of the minimal erythema dose (MED) of protected skin to the MED of unprotected skin. An MED is the smallest UV-B dose which produces perceptible erythema after 24 hours. Each person has their own MED since every individual’s skin has unique characteristics.

Dermatologists generally recommend that Clinical Study with ProLipid® 151 Moisturpeople use a sunscreen product with an SPF of 15– izing Lotion. A similar study was conducted with 30 during sun exposure. Providing these SPFs with the ProLipid 151 moisturizing lotion. Again, for the as low a level of sunscreen as possible can be a real first week, panelists washed with an alkaline soap formulation challenge. to dry their legs. Beginning on Monday of the second week, the panelists then treated one leg with The delivery of effective and efficient sun the moisturizing cream while the other leg was left protection requires that a product provide a comuntreated. Both legs were washed with alkaline soap plete, uniform film of sunscreen agents on the skin once a day. For the weekend following the five-day surface. ProLipid lamellar gel emulsions provide this treatment, product application was discontinued, highly desirable, uniform distribution of sunscreen while washing was continued on both legs with the agents on skin after application; they produce high alkaline soap. Both legs were then evaluated on the sun protection factors (SPF). The resulting film is Monday morning following the weekend washing. very hydrophobic and provides superior water reEvaluation of efficacy was performed using a sistance, when present in sufficient amounts. SkiCon® 200 instrument (IBS Company, Ltd.) which ProLipid lamellar gels also work synergistically with measures moisture content in the skin via electrical conductance. With this instrument, higher conTable 27.2. Averaged Clinical Results with SkiCon® 200 ductance values indicate greater retained skin for ProLipid® 151 Moisturizer Lotion moisture content. As shown in Table 27.2, the product treated leg was significantly more moisturized than the untreated leg after one Treated Leg treatment and throughout the remainder of the Untreated Leg Treatment Conductance study. Conductance -1 Day (ohms ) (ohms-1) This second study showed that ProLipid (p < 0.05) 151 provided both a rapid increase in Day One 55.0 28.5 moisturization, as well as delivering significant long term moisturization, after only five days Day Two 60.9 32.4 of product treatment. Again, there is a strong Day Three 63.6 36.1 indication that the ProLipid 151 was effectively delivered to the stratum corneum, where it inDay Four 58.5 39.5 corporated into the native lipid structure. This Day Five 53.8 30.5 incorporation resulted in the repair and enDay Eight hancement of the stratum corneum natural 38.4 28.6 (three days after lipid moisture barrier, and thereby provided a treatment stops) long term moisturization benefit.

576

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Ganex alkylated polyvinylpyrrolidone (PVP) polymers to provide excellent uniform, hydrophobic films with higher SPF and water resistance. SPF and water resistance results are significantly better than for products made with other technologies such as emulsion systems based on alcohol ethoxylate emulsifiers. Sample formulations are shown in Formulation 27.3, and corresponding SPF and water resistance performance data are shown in Table 27.3. Water resistance was measured with five panelists using the FDA protocol[8] that measures SPF after panelists undergo an 80 minute immersion in a whirlpool bath.

sion system. This formulation gave an average SPF of 14.6 (five panelists) after an 80 minute water immersion.

The benefits seen in Formulation 27.4 are also found in formulations having even higher SPF values. Formulation 27.5 shows a formulation for a ProLipid 141-based lotion that produces an SPF value of 28 after an 80 minute immersion. The incorporation of both Si-Tec™ DM 100 (dimethicone) and SiTec™ CM 040 (cyclomethicone) help reduce the product’s viscosity to that of a lotion by lowering the apparent viscosity of the lamellar gel network. This also improves esthetics by reducing product drag and decreasing rub-in time. ProLipid 141 at a concentration of 5 wt% with 0.5 wt% Table 27.3. SPF Values for ProLipid® 141 Formulations Ganex WP-660 provides the required water Before and After Water Immersion[8] resistance. Ganex P-904 LC, at 0.15 wt%, is used to make very small, uniform emulsion SPF after 80 min Formulation Initial SPF droplets. immersion

1

16.5

8.16

2

18.0

17.25

3

18.0

15.75

4

17.25

16.50

5 panelists, FDA protocol

When used at a level of 3 wt%, ProLipid 141 provides a good initial SPF value of 16.5, but only retains half of its sun protection after 80 minute water immersion. Increasing the ProLipid 141 level to 5 wt% raises the initial SPF value to 18, and at this level, retains virtually all of the skin protection after the 80 minute water immersion. Similar results are obtained when 1 wt% of either Ganex V-220 or Ganex WP-660 are added to the original 3 wt% ProLipid 141 formulation. These formulations clearly demonstrate the ability of ProLipid 141 to deliver excellent protection from the sun, as well as long lasting water resistance. Excellent sun protection and a high level of water resistance can also be obtained from a sprayable lotion based on ProLipid 151 as shown in Formulation 27.4. The combination of xanthan gum (Keltrol® T) and ProLipid 151 is again exploited in this system for its ability to make a low viscosity, stable emul-

27.3.4 Delivery and Substantivity of Ascorbic Acid Ascorbic acid (vitamin C) is a water-soluble material that is easily oxidized in aqueous solution. This property makes this antioxidant active a formulation challenge to deliver to the skin and retain its effective form. We have found that ascorbic acid can be incorporated into a non-aqueous stick structured by ProLipid 151, as shown in Formulation 27.6. After all the other components have been melted at 75°C, the ascorbic acid is added and, after about 5 minutes, the mix becomes transparent. Ascorbic acid does not crystallize upon cooling, nor does it oxidize. This product provides an excellent ascorbic acid delivery vehicle, especially for lip or eye area applications.

27.4 Extended Insect Repellency with a ProLipid® 151 Lotion Most of the area of a lamellar gel is occupied by hydrophobic hydrocarbon chains. Hydrophobic ma-

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS terials readily incorporate in the area of these chains. It has been found that the insect repellant IR3535® (ethyl butylacetylaminopropionate) incorporates very well into a ProLipid 151 lamellar gel in the presence of Ganex V-216. ProLipid 151, with xanthan gum as the rheology modifier, was chosen to make a sprayable emulsion system for easy application of this product. In mosquito cage testing, it was found that this formulation gave 2.5 times longer insect repellency than one made from a simple emulsion containing a greater level of IR3535. The formulation is shown in Formulation 27.7.

27.5 Extended Fragrance Release with ProLipid® Systems Anhydrous ProLipid 141 or 151 can be used to make solid fragrance sticks when an extended fragrance release on skin is desired. The fragrance is diluted within an ester blend, then structured with ProLipid 151 as shown in Formulation 27.8. Fragrance panelists report that these sticks release fragrance for extended periods of time. Similarly, ProLipid 141 or 151 can be used to structure petrolatum to produce a stick that can be used as a foot or lip balm. The material readily in-

577

corporates into the skin, where it is hydrated, and then acts to strengthen the native skin lamellar gel structure.

27.6 Conclusions ProLipid lamellar gels that mimic the native lipid structure in the skin have been shown to form a wide variety of stable oil-in-water emulsion products that effectively deliver themselves into the upper levels of the stratum corneum. The hydrophobic nature of these lamellar gels makes them highly effective in providing a uniform, water resistant film of hydrophobic materials for products such as sunscreens, insect repellant, and fragrances. Biofunctional materials such as ascorbic acid or tocopherol are also readily incorporated into these formulations, and are thereby made available for release over extended periods of time. Additionally, ProLipid lamellar gels reinforce the skin lipid barrier. They provide moisturization, and can prevent penetration of undesirable materials such as environmental allergens. In product use, ProLipid lamellar gels provide superior sensory benefits. Taken together, the multifunctional benefits of ProLipid lamellar gels suggest they are a powerful new technology for exploitation by personal care formulators.

The information contained in this document and the various products described are intended for use only by persons having technical skill and at their own discretion and risk after they have performed necessary technical investigations, tests and evaluations of the products and their uses. While the information herein is believed to be reliable, we do not guarantee its accuracy and a purchaser must make its own determination of a product’s suitability for purchaser’s use, for the protection of the environment, and for the health and safety of its employees and the purchasers of its products. Neither ISP nor its affiliates shall be responsible for the use of this information, or of any product, method, or apparatus described in this document. Nothing herein waives any of ISP’s or its affiliates’ conditions of sale, and WE MAKE NO WARRANTY, EXPRESS OR IMPLIED, OF MERCHANTABILITY OR FITNESS OF ANY PRODUCT FOR A PARTICULAR USE OR PURPOSE. We also make no warranty against infringement of any patents by reason of purchaser’s use of any product described in this document.

578

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

27.7 Formulations Formulation 27.1: ProLipid® 141 Moisturizing Cream

Phase

Ingredient

Function

Deionized water A

B

C

Supplier

67.50

Glycerin

Dispersant, humectant

1.00

Uniqema

Stabileze QM

Rheology modifier

0.20

ISP

Ceraphyl 230

Emollient

4.00

ISP

Ceraphyl 494

Emollient

6.00

ISP

Ceraphyl 368

Emollient

10.00

ISP

ProLipid 141

Lamellar gel

5.00

ISP

Deionized water 10% Sodium hydroxide

5.00 Neutralizer

0.50

Fisher

Germall Plus

Preservative

0.30

ISP

Liquapar PE

Preservative

0.50

ISP



D

Weight %

Procedure 1. Combine Phase A, except for Stabileze QM. 2. Sprinkle Stabileze QM into Phase A with stirring. Heat to 70°C–75°C. Mix until clear. 3. Combine Phase B with stirring. Heat to 75°C–80°C. Combine Phase C. 4. When Phase A is at 70°C–75°C and Phase B is 75°C–80°C, add Phase B to Phase A with homogenization. 5. Continue homogenization while adding Phase C, then switch to sweep agitation and begin cooling. 6. Add Phase D with stirring at 35°C–40°C. QS for water loss. 7. Mix and cool to room temperature.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS

579

Formulation 27.2: ProLipid® 151 Moisturizing Lotion

Phase

Ingredients

Function

Deionized water A

B

Supplier

73.80

Versene NA

Sequestrant

0.10

Dow

Glycerin

Dispersant, humectant

1.00

Uniqema

Keltrol T

Rheology modifier

0.50

Kelco

Ceraphyl 230

Emollient

4.00

ISP

Ceraphyl 494

Emollient

6.00

ISP

Ceraphyl 368

Emollient

10.00

ISP



C

Weight %

ProLipid 151

Lamellar gel

4.00

ISP

Liquid Germall Plus

Preservative

0.60

ISP

Procedure 1. Add Versene NA to the water. Pre-mix Keltrol T with glycerin and slowly add the premixture to Phase A with stirring. Heat to 70°C–75°C. 2. Combine Phase B with stirring. Heat to 75°C–80°C. 3. When Phase A is stirring at 70°C–75°C and Phase B is uniform at 75°C–80°C add Phase B to Phase A with homogenization. 4. When the batch appears uniform, turn off the heat and switch to paddle mixing. Add Phase C with stirring at 35°C–40°C 5. QS for water loss. Mix and cool to room temperature.

580

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 27.3: ProLipid® 141 Medium SPF Sunscreen Formulations

Phase

Ingredient

Function

Deionized water A

B

C

D

Weight % 1

2

3

4

69.3

67.3

68.3

68.3

Supplier

Hexylene glycol

Dispersant, humectant

2.0

2.0

2.0

2.0

Shell

Carbopol 940

Rheology modifier

0.2

0.2

0.2

0.2

Noveon

Escalol 557

Sunscreen

7.5

7.5

7.5

7.5

ISP

Escalol 567

Sunscreen

3.0

3.0

3.0

3.0

ISP

Escalol 587

Sunscreen

3.0

3.0

3.0

3.0

ISP

Ceraphyl 368

Emollient

6.0

6.0

6.0

6.0

ISP

ProLipid 141

Lamellar gel

3.0

5.0

3.0

3.0

ISP

Ganex V-220

Water resist agent

0.0

0.0

1.0

0.0

ISP

Ganex WP-660

Water resist agent

0.0

0.0

0.0

1.0

ISP

Triethanolamine

Neutralizer

0.2

0.2

0.2

0.2

Dow

5.0

5.0

5.0

5.0

Deionized water Germall Plus

Preservative

0.3

0.3

0.3

0.3

ISP

Liquapar PE

Preservative

0.5

0.5

0.5

0.5

ISP

Procedure 1. Combine Phase A and heat to 70°C–75°C. Mix until clear. 2. Combine Phase B with stirring. Heat to 75°C–80°C. Combine Phase C. 3. When Phase A is at 70°C–75°C and Phase B is 75°C–80°C, add Phase B to Phase A with homogenization. 4. Continue homogenization while adding Phase C, then switch to sweep agitation and begin cooling. 5. Add Phase D with stirring at 35°C–40°C. 6. QS for water loss. Mix and cool to room temperature.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS

581

Formulation 27.4: ProLipid® 151, Very Water Resistant Sunscreen Spray*

Phase

Ingredient

Function

Weight %

Deionized water

A

64.25

Keltrol T

Rheology modifier

0.50

Kelco

Versene NA

Sequestrant

0.10

Dow

Butylene glycol

Dispersant, humectant

2.00

Celanese

Lubrajel oil

Emollient

0.50

ISP

Escalol 557

Sunscreen

7.5

ISP

Escalol 567

Sunscreen

3.0

ISP

Escalol 587

Sunscreen

3.0

ISP

Ceraphyl 368

Emollient

2.0

ISP

Emulsynt GDL

Emollient

1.50

ISP

Lamellar gel

6.00

ISP

Water resist agent

0.50

ISP



B



ProLipid 151 

Ganex WP-660 Deionized water C

D

E

Supplier



5.00

Poviderm SK-3

Detackifier

0.50

ISP

Germall Plus

Preservative

0.30

ISP

Methylparaben

Preservative

0.20

ISP

Butylene glycol

Preservative

1.00

Celanese

Fragrance RR-82894

Fragrance

0.15

Ungerer

Procedure 1. Add Versene NA to the water. 2. Pre-mix Keltrol T with glycerin and slowly add the pre-mixture to Phase A with stirring. Heat to 70°C–75°C. 3. Combine Phase B with stirring. Heat to 75°C–80°C. 4. When Phase A is stirring at 70°C–75°C and Phase B is uniform at 75°C–80°C add Phase B to Phase A with homogenization. 5. Continue homogenization while adding Phase C. Continue to homogenize for 7 minutes after addition of Phase C is complete. 6. Turn off heat and switch to sweep agitation, cool to 45°C. 7. Add ingredients in Phase D individually, mixing well after each addition. 8. Add Phase E. QS for water loss. Mix and cool to room temperature. * SPF 14.6 after eighty-minute immersion (five-person FDA protocol).[8]

582

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 27.5: High SPF ProLipid® 141 Sunscreen Lotion*

Phase

Ingredients

Function

Deionized water

A

B

C

D E

F

Weight %

Supplier

42.72

Hexylene glycol

Dispersant, humectant

3.0

Shell

Aculyn 33

Rheology modifier

2.65

Rohm & Haas

Lubrajel oil

Emollient

1.50

ISP

Versene NA

Sequestrant

0.1

Dow

Escalol 557

Sunscreen

7.5

ISP

Escalol 567

Sunscreen

5.0

ISP

Escalol 587

Sunscreen

5.0

ISP

Escalol 597

Sunscreen

8.0

ISP

Ceraphyl 368

Emollient

3.0

ISP

ProLipid 141

Lamellar gel

5.0

ISP

Ganex WP-660

Water resist agent

0.5

ISP

Si-Tec DM 100

Skin protectant

0.75

ISP

Ceraphyl 55

Emollient

3.0

ISP

Deionized water 10% Sodium hydroxide

5.00 Neutralizer

1.68

Fisher

Ganex P-904 LC

Dispersant

0.15

ISP

Si-Tec CM 040

Detackifier

4.5

ISP

Germall Plus

Preservative

0.3

ISP

Liquapar PE

Preservative

0.5

ISP

Fragrance RA-36

Fragrance

0.15

Robertet





Procedure 1. Combine Phase A and heat to 70°C–75°C. Mix until clear. 2. Combine Phase B with stirring. Heat to 75°C–80°C. 3. In a separate vessel, combine Phase C and heat to 70°C–75°C. 4. Add Phase C to Phase B maintaining a temperature of 75°C. 5. Homogenize Phases B and C into Phase A. Shut off heat. 6. Add Phase D with homogenization. Continue homogenization for 2–5 minutes. 7. Sprinkle Phase E into homogenizing batch. After addition of Phase E is complete, homogenize for 5 minutes. Switch to sweep agitation and cool to 40°C. 8. Add Phase F with stirring at 35°C–40°C. QS for water loss. Mix and cool to room temperature. *SPF 14.6 after eighty-minute immersion (five-person FDA protocol).[8]

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS

583

Formulation 27.6: ProLipid® 151 Ascorbic Acid Stick

Phase

Ingredient

Function

Weight %

Supplier

Paraffin wax 160/165

Stick structure

12.0

Frank B. Ross Co.

Emulsynt GDL

Stick structure

20.0

ISP

Snow White Petrolatum

Stick structure

42.9

Penreco

Stick structure

9.0

ISP

Rheology modifier

7.5

ISP

Ceraphyl 28

Rheology modifier

2.0

ISP

Tocopheryl acetate

Antioxidant

0.2

Roche

ProLipid 151

Stick structure

5.0

ISP

B

Liquapar Oil

Preservative

0.4

ISP

C

Ascorbic acid, ultra fine powder

Skin health

1.0

Roche



Ceraphyl 424 A



Ceraphyl 375 



Procedure 1. Melt Phase A ingredients and heat until melted and uniform at 80°C. 2. Add Phase B at 80°C and mix until uniform. Begin cooling batch to 75°C. 3. Add Phase C and mix until clear. Pour samples at 75°C.

584

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 27.7: ProLipid® 151 Insect Repellant Lotion

Phase

Ingredient

Function

Deionized water

A

C

Supplier

70.6

Sodium citrate

Sequestrant, buffer

0.20

Fisher

Versene NA

Sequestrant

0.10

Dow

Glycerin

Dispersant, humectant

1.0

Uniqema

Keltrol T

Rheology modifier

0.50

Kelco

IR3535

Insect repellant

11.00

Merck

Ceraphyl 368

Emollient

5.50

ISP

Ceraphyl 494

Emollient

5.50

ISP

Ganex V-216

Emulsion stabilizer, film former

1.00

ISP

ProLipid 151

Lamellar gel

4.00

ISP

Liquid Germall Plus

Preservative

0.60

ISP



B

Weight %

Procedure 1. Add Versene NA and sodium citrate to water with stirring at room temperature. 2. Pre-wet Keltrol T with glycerin and slowly add to Phase A with stirring. Heat Phase A to 70°C– 75°C. 3. Combine Phase B with stirring. Heat to 75°C–80°C. 4. When Phase A is at 70°C–75°C and Phase B is 75°C–80°C, add Phase B to Phase A with homogenization until batch appears uniform, then turn off heat. Continue homogenization during cool-down. 5. Add Phase C with stirring at 35°C–40°C. QS for water loss. Mix and cool to room temperature.

REREK: PROLIPID® SKIN-MIMETIC LAMELLAR GEL CARRIER AND DELIVERY SYSTEMS

585

Formulation 27.8: ProLipid® 151 Fragrance Stick

Ingredient

Function

Weight %

Supplier

Ceraphyl 368

Emollient

10.00

ISP

Ceraphyl 31

Emollient

20.00

ISP

Ceraphyl 50

Emollient

20.00

ISP

ProLipid 151

Lamellar gel

45.00

ISP

Fragrance

Fragrance

5.00

Procedure 1. Combine ingredients and heat to 55°C–60°C. Stir until uniform liquid is achieved. 2. Pour into desired container and cool overnight.

586

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References

4. Forslind, B. Acta Dermato Venereologica, 74:1–9 (1994)

1. Eccleston, G. M., J. Soc. Cosmet. Chem., 41:1–22 (1990)

5. Tiddy, G. J. T., Physics Reports, 57:1–46 (1980)

2. Golden, G. M., Guzek, D. B., Harris, R. R., McKie, J. E., and Potts, R. O., J. Investigative Derm., 86:222–259 (1986)

6. Mendelsohn, R., and Moore, D. J., Chem. Phys. Lipids, 96:141–157 (1998)

3. Schaefer, H., and Redelmeier, T. E., Skin Barrier: Principles of Percutaneous Absorption, 1st Ed., Karger, Basel (1996)

7. Junginger, H. E., Surfactants in Cosmetics, 2 Ed., pp. 155–182, Marcel Dekker, New York (1997) 8. Federal Register, 58:28194–28302 (1993)

28 Intelligent Polymers and Self Organizing Liposome Gel Delivery Systems Wolfgang Meier and Jörg Schreiber Beiersdorf AG Hamburg, Germany

28.1 28.2 28.3 28.4

Introduction ................................................................................... 588 Chemical Structure of Lipids ........................................................ 588 Lamellar Phases .......................................................................... 588 Liposomes .................................................................................... 588 28.4.1 Liposomes and Human Skin ............................................. 590 28.4.2 Formation of Vesicles ....................................................... 590 28.4.3 Current Technologies for Preparation of Vesicles ............. 590 28.5 Spontaneous Formation of Liposomes from Lamellar Liquid Crystals .............................................................................. 591 28.6 New Product Delivery Vehicles Based on Fluid Liposomal Dispersions Obtained from Lamellar Phases .............................. 592 28.7 Stability Issues with Liposomes ................................................... 593 28.7.1 Current Approaches to Stabilize Liposomes .................... 593 28.7.2 Traditional Liposomal Gels................................................ 594 28.7.3 Current Liposomal Products with Enhanced Viscosity .... 594 28.8 New Liposomal Gels in the Presence of Intelligent Polymers ...... 595 28.8.1 Polymers for Attachment to the Liposome Surface .......... 596 28.8.2 Discussion of the New Liposome Gel Approach .............. 596 28.9 Summary ...................................................................................... 598 28.10 Formulations ................................................................................. 599 References .......................................................................................... 602

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 587–602 © 2005 William Andrew, Inc.

588

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

28.1 Introduction This chapter surveys some of the existing methods of liposome preparation and discusses a new technology to formulate fluid (low viscosity) liposome dispersions. Furthermore, a new approach to the formation of liposomal gels is described.

groups of PC try to minimize their contact with water and the hydrophilic head group is orientated towards the water phase. As a result, these individual lipid molecules build higher “structure units” called bilayer membranes. In the case of high concentrations of these amphiphilic lipids, several bilayer membranes will form in water-based systems. Multiple (more or less), flat bilayer membranes dispersed in water are called lamellar phases (Fig. 28.2).

28.2 Chemical Structure of Lipids

The formation of such lamellar phases depends upon both the temperature and concentration of the corresponding lipid used (Fig. 28.3).

Certain molecules, like phospholipids, have a specific chemical structure based on glycerol esterified with two long chain fatty acids (stearic and linoleic) and phosphoric acid [like phosphatidylcholine (PC)]. The chemical structure of PC can be simplified (Fig. 28.1). Phosphatidylcholine consists of a polar head group and two apolar hydrophobic chains. Other molecules, like glyceryl monoesters, differentiate from phospholipids because they only have one hydrophobic group.

28.3 Lamellar Phases The amphiphilic structure of the above-mentioned lipids leads to a specific interaction when these molecules are dispersed in water. Both hydrophobic

Figure 28.1 Overview of phospholipids.

28.4 Liposomes The curvature of the bilayer membranes in a lamellar phase is more or less flat, however, the membranes can also be curved in space. Such symmetrically curved bilayers are called vesicles or liposomes (based on phospholipids) or niosomes (nonionic surfactant vesicles, free of phospholipids). Other complex curved bilayer structures in space are called cubic phases (see Ch. 29). Liposomes (vesicles) usually consist of one or more concentric lipid bilayers enclosing an aqueous core (Fig. 28.4).[1] Often equilibrum structures exists between liposomes and lamellar phases (Fig. 28.3).

MEIER, SCHREIBER: INTELLIGENT POLYMERS AND SELF ORGANIZING LIPOSOME GEL DELIVERY SYSTEMS

Figure 28.2 Lamellar phase.

Figure 28.3 Binary phase diagram of a phospholipid.

Figure 28.4 Structure of liposomes in water.

589

590

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Particles containing only one bilayer have been termed unilamellar vesicles (ULV), while those containing many bilayers have been termed multilamellar vesicles (MLV) (Fig. 28.5).[2]

Encapsulation and release studies of personal care actives like salicylic acid,[4] retinoic acid,[5][6] and retinyl palmitate[7] have been published in the past.

28.4.2 28.4.1 Liposomes and Human Skin Human skin is a complex biomaterial consisting of layers identified as the stratum corneum, epidermis, and dermis (see Ch. 3). An intact barrier function is essential for a healthy skin. Diffusion of substances through stratum corneum is usually very slow. Personal care cosmetic formulations are generally designed to transport lipids, moisturizers, and actives into the skin. Current understanding is limited regarding which formulation factors have either a positive or negative influence on the adsorption of substances through the skin. The fascination of liposomes comes from the fact that the membrane in radial direction is only 3– 5 nm thick and, additionally, the size of the vesicles have similar dimensions to living cell membranes. Furthermore, liposomes are of interest for the personal care and pharmaceutical industries as delivery systems for actives of different solubility.[3] Liposomes can encapsulate water-soluble actives within the aqueous compartment (Fig. 28.6). Additionally, a lipid soluble, or amphiphilic ingredient, can be embedded within the bilayer membrane.

Figure 28.5 Structure of multilamellar liposomes in water.

Formation of Vesicles

The formation of a vesicle is a consequence of the molecular dimensions of the lipid bilayer molecules that dictate the self-assembly process. The critical packing factor, P, is defined as V/AL, where V is the volume of the lipid, A is the polar headgroup cross sectional area and L is the preferred length of the hydrophobic chain. These three factors can often be used to predict the morphology of surfactant aggregates based on solely geometrical properties of the molecules.[8]

28.4.3

Current Technologies for Preparation of Vesicles

Various techniques are available to form small unilamellar vesicles varying in size from 20 to 100 nm: • Sonication for periods of 15–60 minutes, to produce clear, slightly opalescent dispersions.[9] • Extrusion through polycarbonate membranes under high pressure.[10]

Figure 28.6 Liposomes as carriers for actives.

MEIER, SCHREIBER: INTELLIGENT POLYMERS AND SELF ORGANIZING LIPOSOME GEL DELIVERY SYSTEMS • Reverse-phase evaporation.[11] • Non-phospholipid vesicles (Novasomes), 0.1–1.0 microns in diameter, were formed by high velocity injection of an amphiphile mixture into an excess water phase.[12] The resulting vesicles form after the initial micellar solution has cooled. Other aqueous systems reported to spontaneously form vesicles are summarized in the literature.[13] Some of the above-mentioned techniques are time consuming, or not applicable on an industrial scale. To overcome those difficulties, a new strategy has been developed to formulate liposomes. This process is described below.[14][15]

28.5 Spontaneous Formation of Liposomes from Lamellar Liquid Crystals A liposome may be viewed as a fragment of the bilayer of a bulk liquid crystal phase that has been transformed into a closed spherical shape (Fig. 28.7). Dilution with water of a lamellar liquid crystalline phase containing bilayer-forming molecules (and single tailed surfactants) yields the corresponding liposomes in a single step. The patented process is illustrated in Fig. 28.8.[14] The single-tailed surfactants induce a curvature in the flat membrane, thus, formation of liposomes is easier to achieve.

591

Preparation of a liposome involves the selection of a bilayer-forming ingredient, such as phosphatidylcholine which is dissolved in water in the presence of a single-tailed surfactant. This process was studied at various temperatures prepared from 40°C to 80°C. Other variables included: the type of phospholipid, the surfactant, and the presence of other ingredients such as actives, antioxidants, and preservatives. Mechanism of vesicle formation. The mechanism of vesicle formation from a lamellar phase can be understood by an increase of the hydration of the polar head groups of the molecules during cooling the mixture. Water penetrates the bilayer membrane of the lamellar phase increasing the distance between the bilayers, thus inducing undulations in the membranes. The curvature of the membranes increases due to the presence of single-tail surfactants during the cooling process. This process facilitates the formation of liposomes (Fig. 28.8). Controlling vesicle size. The size of the vesicles can be controlled by the ratio of PC to surfactant. For example, it is possible to formulate liposomes of a PC/sodium lauroyl lactylate mixture with vesicle size of 130 or 200 nm. High pressure homogenization is not necessary for the process. This allows the production of relatively inexpensive formulations with only a small input of energy (simple stirring). Examples of such systems are given in the “Formulations” section at the end of this chapter (Sec. 28.10) and in a patent covering this technology.[15]

Figure 28.7 Liposomes as a fragment of the lamellar phase.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 28.8 Formation of liposomes from a lamellar phase.

28.6 New Product Delivery Vehicles Based on Fluid Liposomal Dispersions Obtained from Lamellar Phases A disadvantage of many hydroalcoholic-based personal care products (such as eau de toilettes, hair tonics, face tonics, cleansing products, insect repellents, anti-acne products, sun sprays, pharmaceutical dosage forms, and deodorant pump sprays) is their alcohol content. The alcohol reportedly causes dry skin, enhances penetration, and causes stinging in the eye and axilla regions. Current products based on the fluid liposomal dispersions described in this chapter solve the above mentioned problems because they can be formulated without alcohol and deliver the benefits explained below. Furthermore, the technology described is inexpensive since high pressure homogenization is not necessary. Products with a white (quasi lotions) or transparent appearance can be formulated with this technology. Phospholipid-containing liposomes, especially those with a high content of phosphatidylcholine

(PC) are of interest because they have GRAS status (generally regarded as safe). They are particulary valuable because of their high content of polyunsaturated fatty acids (linoleic acid and linolenic acid).[16] Furthermore, it has been reported that percutaneous absorption of liposomes is often related to the degree of unsaturation of the lipids from the bilayer membrane.[18] Advantages of the lamellar phase dilution approach. • Ease of preparation via a one-step process to liposome formation. • Formulation flexibility due to a broad choice of ionic or nonionic amphiphiles. • Encapsulation of lipophilic and hydrophilic actives in the liquid crystalline phase followed by dilution with water. • Controlled release of actives. • Low surfactant content. • Inexpensive formulations. • Good skin compatibility. • No high pressure homogenization necessary (inexpensive technology).

MEIER, SCHREIBER: INTELLIGENT POLYMERS AND SELF ORGANIZING LIPOSOME GEL DELIVERY SYSTEMS Benefits of using phospholipids (phosphatidylcholine). • PC is a source of linoleic acid and linolenic acid. • Hydrating and soothing properties. • Anti-acne properties. • Stabilization of foam structures. • Skin’s own active. • GRAS status. • Skin care and hair care ingredient. • Skin feel additive.

28.7 Stability Issues with Liposomes Depending on the choice and concentration of an insertion molecule (an active for example) the vesicle can be stabilized or destabilized. Stability problems of liposomes are known from unilamellar vesicles because they tend to fuse with other vesicles to form large unilamellar vesicles (Fig. 28.9).[18]

28.7.1

593

Current Approaches to Stabilize Liposomes

Several attempts to stabilize liposomes have been described in the literature. One possibility is to polymerize the lipids in the bilayer membrane.[19][20] Steric stabilization of vesicles by attachment of large hydrophilic groups (such as PEG) on the surface gives so-called “stealth liposomes” (Fig. 28.10).[21] This name is attributed to their reduced recognition and uptake by the immune system. Reports concerning sterical vesicle stabilization by addition of triblock copolymers of poly(ethlyene glycol) (PEG) and poly(propylene oxide) (PPO) have been described. In this case, the more hydrophobic group (PPO) adsorbs on the surface of the bilayer membrane (Fig. 28.11).[22] Furthermore, stabilization of a single vesicle by hydrophobically modified water-soluble polymers (Fig. 28.12) has been discussed in an overview by Ringsdorf, et al.[19]

Furthermore, surfactant or detergent-induced breakage of liposomes are often not sucessfully controlled.

Figure 28.10 Stealth liposomes.

Figure 28.9 Fusion of liposomes.

Figure 28.11 Sterical vesicle stabilization by triblock copolymers.

594

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Concentrated vesicle dispersions or vesicular phospholipid gels (VPG). Increasing the phospholipid concentration gives semisolid liposome formulations in which the vesicles are very densely packed.[23] One example of this technique is Natipide II (special phospholipid/water mixture).

Figure 28.12 Stabilization of a single vesicle by a hydrophobically modified water-soluble polymer.

28.7.2

Traditional Liposomal Gels

The viscosity of liposomal dispersions is often comparable to the viscosity of water. Because it is well-known that absorption of substances is one of the factors that determines the benefits of a delivery system, viscous liposomal formulations are more attractive compared to the fluid, low viscosity dispersions. Several techniques have been developed to formulate liposome gels. These techniques are mentioned briefly in the next section.

28.7.3

Current Liposomal Products with Enhanced Viscosity

An overview concerning strategies to increase the viscosity of liposomes is given in Table 28.1.

Brandl, et al., (1994) reported a technique to achieve VPGs by high-pressure homogenization of highly concentrated (phospho)lipid dispersions.[24]–[26] The VPGs primarily consist of small unilamellar vesicles. Both delivery systems are expensive if not diluted with water to conventional fluid dispersions. Fluid liposome dispersions in a gel matrix. Another approach to increase the viscosity of liposome dispersions is to incorporate the liposomes into a pre-formed gel matrix. Xanthan gum, carboxymethylcellulose, collagen, or alginates have been used as thickeners.[30]–[32] Topical liposome gels have been developed for the treatment of acne.[33] A Carbopol® (acrylic acid based thickener) was employed as thickener for these gels. Furthermore, it was demonstrated that hydrocortisone (HC) formulated into a liposome gel showed reduced absorption of the drug when compared to a conventional ointment formulation.[33] Nevertheless, higher and sustained skin concentrations of HC were found. In view of the fact that the vesicles are physically dispersed in the gel, sometimes their fusion cannot be controlled effectively (Fig. 28.9). Furthermore, uncontrolled interaction of the spherical vesicles with the polymer backbone may be a disadvantage in some cases because these interactions may increase the vesicle size during storage.

Table 28.1. Current Liposomal Products with Enhanced Viscosity

Product Delivery Vehicle

Viscosity Enhancing Principle

Literature

Vesicle dispersions or vesicular phospholipid gels (VPG)

High concentration of packed densely vesicles

Röding,[23] Brandl[24]–[26]

Ternary surfactant systems of sodium stearate/ octanol/water

Cubic phase of small, unilamellar vesicles

Hoffman, Gradzielski[27]–[29]

Fluid liposome dispersions incorperated into a gel matrix

Xanthan gum, collagen, carboxymethyl-cellulose, alginate, Carbopol®

Weiner,[30] Sentjurc,[31] Yotsuyanagi,[32] Marfatia[33]

MEIER, SCHREIBER: INTELLIGENT POLYMERS AND SELF ORGANIZING LIPOSOME GEL DELIVERY SYSTEMS Ternary surfactant systems. Another approach to vesicle gels was described by Gradzielski, Hoffmann, et al.[27]–[29] In this work, a ternary surfactant system of sodium stearate/octanol/water forms a cubic gel phase that contains small unilamellar vesicles of 10–20 nm radius. Cubic gel systems, or cubosomes are discussed in Ch. 29. Vesicles in emulsion-based product delivery vehicles. Incorporating fluid vesicle dispersions into emulsions is often a problem because the integrity of the bilayer membrane is usually disturbed during mixing of all the components. The surfactants and the oil phase can interact with the liposomes in an unforseeable way, thereby destroying the vesicle bilayer membrane. Only small concentrations of detergent or surfactant molecules can usually be added to vesicles. In this case, mixed liposomes (bilayer membrane-forming surfactants and detergent molecules) are formed. Increasing the detergent (surfactant) concentration in the membrane leads to saturation, and finally to formation of mixed micelles (monolayers instead of bilayer membranes).[34]

28.8 New Liposomal Gels in the Presence of Intelligent Polymers A different approach to the formation of liposomal vesicle gels has been described in a 1996 patent[35] and a subsequent publication.[36] These gels are formed in the presence of intelligent polymers whose synthesis and nomenclature is described in the patent.[35] It was expected that the stabilization approach of a single vesicle (illustrated in Fig. 28.12) could be modified into a polymer-mediated stabilization process in the presence of ABA-type triblock copolymers, or hydrophobically modified watersoluble polymers of the non-ABA type. In this case, where the length of the water-soluble part of the polymer (PEG as an example) exceeds the average distance between two vesicles (in a vesicle dispersion), a bridge is easily formed. The hydrophobic ends of the polymer (for example, stearic acic or cholesterol) have a strong tendency to insert into the bilayer membrane of the liposomes by a selforganization process (Fig. 28.13). In a way, the poly-

595

mers are expected to behave intelligently because they build up a more complex nanoscale structure without the assistance of the formulator. This network is transient because the polymer endgroups are able to leave the bilayer membrane. However, this is an unlikely process, because the hydrophobic endgroups of the polymer tend to minimize their contact with water. Further addition of such polymer molecules leads to a three-dimensional network of connected liposomes (Fig. 28.14). A similar network can be constructed in the presence of hydrophobically modified water-soluble polymers of the non-ABA type (Fig. 28.15).

Figure 28.13 Crosslinking of two liposomes by a hydrophobically modified water-soluble polymer (ABA type).

Figure 28.14 Gel formation by crosslinking of several liposomes with a hydrophobically modified watersoluble polymer (ABA type).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS liposomes. The size of the vesicles is not affected because this is a controlled liposome/polymer interaction process. Furthermore, typically observed stability problems with liposomes in emulsion-based products can be avoided because there is no excess oil or surfactant phase. Additionally, transparent gels or products with a white appearance (quasi emulsions) can be made with this approach because the formulator can run the process with either transparent vesicle dispersions (SUV) or liposomes having a milky appearance.

Figure 28.15 Gel formation by crosslinking of several liposomes with a hydrophobically modified watersoluble polymer (non-ABA type).

28.8.1

Polymers for Attachment to the Liposome Surface

The polymer nomenclature is explained here. PEG-800 Chol2(ABA type polymer). A: hydrophobic group (cholesterol, short name: Chol) B: hydrophilic group (polyethylene glycol, short name: PEG) PEG-800 (B block). This has two terminal hydroxyl groups. Chemical reaction with two parts cholesteryl chloroformiate (A block) yields the corresponding di-cholesteryl modified PEG-800 (CholPEG800-Chol; short name: PEG-800 Chol2). PEG-800 distearate (ABA type polymer). Chemical reaction of PEG-800 (B block) with two parts stearic acid (A block) yields the corresponding PEG-800 distearate.

28.8.2

Discussion of the New Liposome Gel Approach

Interestingly, simple mixing of liposomal dispersions with the polymers described in Sec. 28.8.1 gives the corresponding gels. This approach is of interest because the fusion of vesicles (Fig. 28.9) can now be effectively minimized, or avoided, because the polymer molecules serve as a spacer between the

Formation of liposomal gels/creams is also possible with commercial dispersions from different companies (such as Probiol 05018 from Kuhs, Vesisomes from Vesifact AG, or Rovisomes from Rovi). There are other companies manufacturing liposomal dispersions for the crosslinking approach to the corresponding gels. Additionally, the patented approach to formulate fluid liposome dipersions descibed in Sec. 28.6 is a suitable starting point for product development. The viscosity of the delivery system can be easily controlled by the amount of polymer, choice of hydrophobic end group, and type of polymer backbone. Liposomes can be loaded with different hydrophilic, lipophilic, or amphiphilic actives. Examples include vitamins, UV filters, unsaturated lipids, ceramides, unsaturated fatty acids, DNA, growth factors, stratum corneum lipids like cholesterol, or a cosmetic oil phase in the bilayer membrane. In these cases, formation of the corresponding active-loaded liposomal gels is easily achieved. One can also use other colloidal phases as a starting point for the final vesicle gel formation. Examples of such phases include micelles, hexagonal, inverted hexagonal, and cubic phases; dilution of colloidal phases; and change of pH. The proliposomes Natipide II from Nattermann can serve as suitable starting material to formulate the corresponding new liposomal gels. Sometimes, liposomal dispersions are in equilibrium with another phase, such as a lamellar phase (see Sec 28.3). In this case, the viscosity of the system will not change because the ABA polymers or the hydrophobically modified polymers of the non-

MEIER, SCHREIBER: INTELLIGENT POLYMERS AND SELF ORGANIZING LIPOSOME GEL DELIVERY SYSTEMS ABA type, are also able to stabilize and crosslink the bilayer membranes of the lamellar phase (Fig. 28.16). Pure lamellar phases can also be crosslinked to form the corresponding lamellar gels because the only difference from liposomes is that the bilayer membrane is not symmetrically curved. New product delivery vehicles based on liposomal (lamellar) gels/creams with intelligent polymers. Current liposomal products on the market can be replaced based with the new liposomal (lamellar) gels/creams described in this chapter. Among its many advantages (see below) is the fact that the liposome polymer self-organization process (lamellar-phase polymer self-organization process) for forming new gels/creams can be used to formulate new product prototypes. Examples of such products include sunscreens, hair care, cleansing products, insect repellents, body- or face-care gels and creams, anti-acne, and pharmaceutical dosage forms. This new delivery system is not comparable with current market products because it is a new approach to formulate liposomes (lamellar phases) with enhanced viscosity. Furthermore, the extremely homogeneous distribution of the liposomes (lamellar

597

phases) in the gel/cream matrix is attributed to the polymer that serves as a “spacer” between the liposomes (lamellar phases). This leads to a different type of skin/liposome gel interaction. Examples of such systems are given in the “Formulation” section (Sec. 28.10) and in the patent.[35] Advantages of liposomal systems containing intelligent polymers. • Alternative to the incorperation of liposomes into emulsion-based products. • Ease of preparation. • One-step process to the formation of new liposomal cosmetic gels. • One-step process to the formation of new liposomal cosmetic creams (quasi emulsions). • Improved stability of the liposomal bilayer membrane. • Improved stability of lamellar phases and enhanced viscosity. • Reduced fusion of vesicles. • Fresh sensation after topical application. • Formulation of gels/creams with good spreadability, low tack.

Figure 28.16 Gel formation by crosslinking of a lamellar phase with a hydrophobically modified water-soluble polymer.

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• Gels/creams with a different range of viscosity from sprayable to stiff gels/cremes. • Crosslinking of liposomes or lamellar phases with encapsulated actives. • Bilayer ingredient (PC) is a source of linoleic acid and linolenic acid. • Bilayer ingredient (PC) is a skins own active (GRAS status). • Controlled release of actives. • Skin care. • Inexpensive formulations. • Good skin compatibility. Benefits of the phospholipid (phosphatidylcholine). • PC is a source of linoleic acid and linolenic acid. • Hydrating and soothing properties. • Anti-acne properties. • Skin own active. • GRAS status. • Skin care and hair care ingredient. • Skin feel additive.

28.9 Summary This chapter gives an overview concerning the current understanding of formation of liposomal products based on the chemical structure of certain lip-

ids and their aggregation behavior in water-based systems. A new approach to fluid dispersions has been described; a vesicle may be viewed as a fragment of the bilayer of a bulk liquid crystal phase that has been transformed into a closed spherical shape. Dilution surfactant dispersions of a lamellar liquid crystalline phase (containing bilayer-forming molecules) yields, in one step, fluid liposome dispersions. The size of the resulting vesicles can be controlled by the type of surfactant and the ratio of phospholipid-to-surfactant. The formulation of liposomes by this method is inexpensive as compared with current technologies. Stability problems of liposomes have been described as well as current approaches to overcome these. An overview was given concerning liposomal gels and emulsions containing vesicles. A new approach to formulate liposomal gels/ creams or lamellar phases with enhanced viscosity has been described. Gel formation in liposome-containing systems is the result of the build-up of a nanoarchitecture of liposomes (lamellar phases) crosslinked with hydrophobically modified watersoluble polymers (self assembly of vesicles or lamellar phases and polymers). The resulting transient gel network structure leads to new, high performance controlled-release compositions that are not comparable to classical thickened liposomal gels or lamellar compositions. Controlled liposome-polymer interactions leading to three-dimensionally stabilized liposomal products are an attractive new approach for the formation of many new types of cosmetic/ pharmaceutical delivery systems.

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28.10 Formulations Formulations 28.1–28.4: Fluid Liposome Dispersions

Ingredient Sodium lauroyl lactylate (mg)

1

2

3

4

18

—

—

—

—

—

Cetyltrimethylammoniumbromide (mg)

—

Polyglycerin monoisostearate (mg)

—

—

49

—

Glyceryl stearate citrate (mg)

—

—

—

40

Phosphatidylcholine (mg) Propylene glycol (mg) Water (aqua), bidistilled, for liquid crystals (g) Water (aqua), bidistilled, for vesicle dispersion (g)

16

100

105

188

172

1041

500

1067

1230

1.0

0.5

1.5

1.5

11.5

11.5

18.5

13.5

Preparation: To illustrate the production of liposomes from a lamellar phase, we prepared these from four solutions using phosphatidylcholine and the four surfactants shown above according to the following procedure. The indicated amounts of surfactant and phosphatidylcholine were dissolved in the corresponding amount of propylene glycol at 80°C. The resulting clear solution was then slowly diluted at this temperature with an amount of double-distilled water, to yield a lamellar liquid crystalline phase. Upon addition of additional double-distilled water, the system was converted to a vesicle dispersion. Further examples of fluid liposome dispersions are given in Ref. 15. Disclaimer: The above given formulations are protected by Beiersdorf patents (e.g., WO 9924018). Similar examples in the scope of the invention and/or concerning the method of preparation are also protected. In case of licence interest contact the Intellectual Property Department of Beiersdorf AG/Hamburg/Germany. (Telephone: +49-(0)40-4909-3766)

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Formulation 28.5: Lamellar Gel

Ingredient Laureth-5 (g)

0.1

Sodium lauryl sulfate (mg)

0.1

200 mg PEG-800 Distearate (g)

0.2

Water (g)

5.0

Preparation: Mixing of the fluid lamellar gel composition with the polymer PEG-800 distearate gives the corresponding lamellar gels. Disclaimer: The above given formulation is protected by Beiersdorf patents (e.g., WO 9813025). Similar examples in the scope of the invention and/or concerning the method of preparation are also protected. In case of licence interest contact the Intellectual Property Department of Beiersdorf AG/Hamburg/Germany. (Telephone: +49-(0)40-4909-3766)

Formulation 28.6: Liposome Gel

Ingredients Dimethyldioctadecylammonium bromide (mg) PEG-800 Chol2 (mg) Water (g)

176.0 50.0 8.0

Preparation: Mixing of the cationic charged vesicle suspension with the polymer PEG-800 Chol2 gives the corresponding liposomal gel. Disclaimer: The above given formulation is protected by Beiersdorf patents (e.g., WO 9813025). Similar examples in the scope of the invention and/or concerning the method of preparation are also protected. In case of licence interest contact the Intellectual Property Department of Beiersdorf AG/Hamburg/Germany. (Telephone: +49-(0)40-4909-3766)

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Formulation 28.7: Liposome Gel

Ingredient Oleic acid (g)

1.0

KOH (1m) (g)

1.8

PEG-800 Chol2 (g)

0.2

Water (g)

8.2

Preparation: Mixing of the anionic charged vesicle suspension with the polymer PEG-800 Chol2 gives the corresponding liposome gel. Disclaimer: The above given formulation is protected by Beiersdorf patents (e.g., WO 9813025). Similar examples in the scope of the invention and/or concerning the method of preparation are also protected. In case of licence interest contact the Intellectual Property Department of Beiersdorf AG/Hamburg/Germany. (Telephone: +49-(0)40-4909-3766)

Formulation 28.8: Liposome Gel

Ingredient A proliposome dispersion (g) (consisting of a mixture of lecithin, water, ethanol)

3.3

PEG-800 Distearate (g)

2.0

Water

94.5

Preparation: Mixing of the proliposome dispersion with the polymer PEG-800 Distearate gives the corresponding liposomal gel. Further examples of lamellar or liposome gels are given in Ref. 35. Disclaimer: The above given formulation is protected by Beiersdorf patents (e.g. WO 9813025). Similar examples in the scope of the invention and/or concerning the method of preparation are also protected. In case of licence interest contact the Intellectual Property Department of Beiersdorf AG/Hamburg/Germany. (Telephone: +49-(0)40-4909-3766)

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References 1. Margalit, R., in R. Rosoff, Vesicles, pp. 527559, Marcel Dekker, New York, Basel, Hong Kong (1996) 2. Schubert, R., Liposomen in Arzneimitteln, pp. 167-185, Müller, R. H., Hildebrand, G. E., Pharmazeutische Technologie: Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart (1997) 3. Storm, G., Crommelin, D. J. A., Pharm. Sci. Technol. Today, 1:19–31 (1998) 4. Guenin, E. P., and Zatz, J. E., J. Soc. Cosmet. Chem., 45:229–238 (1994) 5. Montenegro, L., Panico, A. M., Ventimiglia, A., and Bonina, F. P., Int. J. Pharm., 133:89– 96 (1996) 6. Imbert, D., Kasting, G. B., and Wickett, R. R., J. Soc. Cosmet. Chem., 15:119–134 (1994) 7. Guenin, E. P., and Zatz, J. E., J. Soc. Cosmet. Chem., 46:261–270 (1995) 8. Engberts, J. B., and Kevelam, J., Curr. Opin. Colloid Interface Sci., 1:779–789 (1996) 9. Chapman, D., Liposome Technology, (G Gregoriadas, ed.) 1(1), CRC Press, Boca Raton, Fl (1984) 10. Hope, M. J., Bally, M. B., Webb, G., and Cullis, P. R., Biochim. Biophys. Acta, 812:55–65 (1985) 11. Szoka, F., and Papahadjopoulos, D., Proc. Nat. Acad. Sci., USA 75:4194–4198 (1978) 12. Wallach, D. F. H., and Phillippot, J., Liposome Technology, 2nd Ed., (G. Gregoriadis, ed.) CRC Press, Boca Raton, Florida (1992) 13. Kaler, E. W., Herrington, K. L., Murthy, A. K., and Zasadzinski, J. A. N., J. Phys. Chem., 96:6698–6707 (1992) 14. Diec, K. H., Meier, W., and Schreiber, J., Cosmet. Toil., 117(3):37–42 (2002) 15. Schreiber, J., and Meier, W., method for producing liposomes, WO 9924018. 16. Egbaria, K., and Weiner, N., Adv. Drug Delivery Rev., 5:287–300 (1990) 17. Cullel, N. P., Coderch, L., de la Maza, A., Parra, J. L., and Etelrich, J., Drug Delivery, 7:7–13 (2000)

18. Gibson, S. M., and Strauss, G., Biochim. Biophys. Acta, 769:531–542 (1984) 19. Ringsdorf, H., Schlarb, B., and Venzmer, J., Angew. Chem., 100:117–162 (1988) 20. Ringsdorf, H., and Schlarb, B., Makromol. Chem., 189:299–315 (1988) 21. Lasic, D. D., and Papahadjopoulos, D., Science, 267:1275–1276 (1995) 22. Kostarelos, K., Tadros, T. F., and Luckham, P. F, Langmuir, 15:369–376 (1999) 23. Röding, J., SÖFW, 116:509–515 (1990) 24. Brandl, M., Bachman, D., Reszka, R., and Drechsler, M., DE 4430592 (1994) 25. Brandl, M., Drechsler, M., Bachmann, D., and Bauer, K. H., Chem. Phys. Lipids, 87:65–72 (1997) 26. Tardi,C., Drechsler,M., Bauer, K. H., and Brandl, M., Int. J. Pharm., 217:161–172 (2001) 27. Gradzielski, M., Bergmeier, M., Müller, M., and Hoffmann, H., J. Phys. Chem. B, 101:1719– 1722 (1997) 28. Gradzielski, M., Grabner, D., Müller, M., and Strunz, P., Ber. Hahn-Meitner-Inst., HMI-B 559:163 (1999) 29. Gradzielski, M., Müller, M., Bergmeier, M., Hoffmann, H., and Hoinkis, E., J. Phys. Chem. B, 103:1416–11424 (1999) 30. Weiner, A. L., Carpenter-Green, S. S., Soehngen, E. C., Lenk, R. P., and Popescu, M. C., J. Pharm. Sci., 74:922–925 (1985) 31. Gabrijelcic, V., and Sentjurc, M., Int. J. Pharm., 118:207–212 (1995) 32. Takagi, I., Shimizu, H., and Yotsuyanagi, T., Chem. Pharm. Bull., 44:1941–1947 (1996) 33. Patel, V. B., Misra, A., and Marfatia, Y. S., Pharm. Dev. Technol., 5:455–464 (2000) 34. Neubert, R. H., Hildebrand, A., Janich, M., Mrestani, Y., and Plätzer, M., Pharm. Ztg., 145:3691-3697 (2000) 35. Schreiber, J., and Meier, W., WO 9813025 (1996) 36. Meier, W., Hotz, J., and Günther-Ausborn S., Langmuir, 12:5028-5032 (1996)

29 Cubosomes® and Self-Assembled Bicontinuous Cubic Liquid Crystalline Phases Patrick Spicer The Procter & Gamble Company West Chester, Ohio Matthew Lynch The Procter & Gamble Company Ross, Ohio Steven Hoath and Marty Visscher Children’s Hospital Medical Center Cincinnati, Ohio

29.1 29.2 29.3 29.4 29.5

Introduction ................................................................................... 604 The “Eureka!” Moment.................................................................. 605 Cubosome Applications ................................................................ 605 Liquid Precursor Process for Cubosome Manufacture ................ 606 Powdered Cubosome Precursors using Spray-Drying Technology and the Hydrotrope Method ........................................ 607 29.6 Functionalized Cubic-Phase Liquid Crystals ................................ 609 29.7 Clinical Evaluation of Skin Conditioning by Cubic-Phase Liquid Crystals .............................................................................. 611 29.8 Clinical Study Results................................................................... 611 29.9 Conclusions .................................................................................. 615 29.10 Formulations ................................................................................. 616 References .......................................................................................... 618

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 603–620 © 2005 William Andrew, Inc.

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29.1 Introduction Bicontinuous cubic-phase liquid crystals are newly discovered exotic materials originally found in the most unassuming places. The original observations of cubic liquid crystalline phase came during the study of polar lipids used as food emulsifiers,[1][2] such as monoolein (Fig. 29.1). The most studied binary system, monooleinwater, forms at least two types (diamond and gyroid)[3] of an optically clear, solid-like[4] bicontinuous cubic phase at water contents between 20%–40% (w/w) at room temperature.[5]–[8] Other aqueous surfactant systems self-assemble into thermodynamically stable bicontinuous cubic liquid crystalline phases as well.[9][10] Bicontinuous cubic liquid crystalline materials are an active research topic[11] because their unique structure lends itself well to controlled release applications. Amphiphilic molecules form bicontinuous water and oil channels, where “bicontinuous” refers to two distinct (continuous, but non-intersecting) hydrophilic regions separated by the bilayer.[12] This structure allows for simultaneous incorporation of water- and oil-soluble materials as well as amphiphiles. The unique phase structure provides a tortuous diffusion pathway for controlled release,[13][14] and lipid-based cubic-phase liquid crystals are biocompatible, digestible,[1][15] and bioadhesive.[16] Cubosomes are discrete, sub-micron, nanostructured particles of bicontinuous cubic liquid crystalline phase (Fig. 29.2). Cubosomes possess the same microstructure as the parent cubic phase but have much larger specific surface area. Their dispersions have much lower viscosity than the bulk cubic phase. The relative insolubility of cubic-phase-forming lipid in water allows cubosomes to exist at almost any dilution level, as opposed to most liquid crystalline systems that transform into micelles at higher levels of dilution. As a

Figure 29.2 Cryo-TEM photograph of cubosomes formed in the monoolein-water system using the conventional high shear dispersion technique.[36] Both micron-scale and sub-micron cubosomes can be formed, down to a lower limit of about 50 nm. Also visible are lamellar vesicles that are a common nonequilibrium by-product of the high shear-dispersion processes employed. (Reproduced with permission from Spicer, et al.[35] Copyright 2001, American Chemical Society.)

result, cubosomes can be easily incorporated into personal care and other types of product formulations. Cubosomes are typically produced by the high-energy dispersion of bulk cubic phase,[17][18] followed by colloidal stabilization using polymeric surfactants.[19] After formation of the cubosomes, the dispersion is formulated into a product and then applied to a substrate of interest, usually some body tissue. Thereafter, active materials contained in the cubosome are either absorbed or released via diffusion.

Figure 29.1 Molecular structure of the lipid most commonly used to form cubosomes, monoolein. Monoolein is a monoglyceride commonly used as a food emulsifier.

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29.2 The “Eureka!” Moment The thought to apply cubosomes in personal care products came following a lecture on the properties of surfactant liquid crystalline systems by Professor Stig Friberg, formerly of Clarkson University, now retired. The mention by Dr. Friberg of a material capable of solubilizing high levels of proteins[20] (~40% w/w) was intriguing and suggested further potential of such materials for solubilization and controlled release of active ingredients.

29.3 Cubosome Applications A common application for cubosomes is vehicles for drug delivery. The first patent describing cubosome usage specifies numerous medical and controlled release applications,[21] although controlled release is usually possible only for bulk cubic phases.[22] Consequently, self-assembled surfactant phases have been extensively examined for compatibility with numerous medical active ingredients and their applications.[23] The rapid expansion of the life-sciences industry is expected to drive previously “exotic” delivery vehicles and ingredients into broader marketplaces such as personal care and consumer products.[24] For example, an application area under current development by L’Oreal is the use of cubosome particles as oil-in-water emulsion stabilizers and pollutant absorbents in cosmetics.[25]–[30] These workers discovered that a second amphiphile, phytantriol (Fig. 29.3), has an aqueous phase behavior sufficiently close to that of monoolein to form cubosomes under similar conditions. Even more recent patent activity by Nivea points to cubosome use in personal care product areas as

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varied as skin care, hair care, cosmetics, and antiperspirants.[31]–[34] Despite recent activity on a lab scale, there remains a lack of practical manufacturing scalability and material customization information that is necessary to lead formulators to consider using cubosomes in commercial products. This chapter reviews the work on the optimization of manufacturing methods for cubosome production. It also discusses the physicochemical properties of cubosome particles and their performance in clinical evaluation settings. The driving force for the work described in this chapter is the extension of existing cubosome technology in order to make possible their manufacture on a large scale, as well as to develop techniques for the adjustment of important cubosome physical properties. The first part of the work described herein is the development of a process for spontaneously forming cubosomes via dilution of the monooleinethanol-water system.[35] The process avoids the traditional, high-energy dispersion of bulk cubic phase used previously.[17][18][36] A second process developed produces powder precursors that spontaneously form cubosomes upon hydration. The method avoids the need for transport and processing of bulk water and opens the door to a wider range of applications like drug delivery via inhalation.[37] Both processes make cubosome manufacture more broadly possible than previous technology because they require only standard processing equipment and materials. A third development described in this work discusses property enhancement of the native cubic phase. This is accomplished by means of ionic surfactants and polymers that strongly associate with solubilized active ingredients. Finally, the effects of the bicontinuous cubic phase on human skin are studied and the results compared to existing consumer skin treatments.

Figure 29.3 Molecular structure of phytantriol, a second amphiphile that forms cubosomes in aqueous systems. Phytantriol is often used in sunscreens and other personal care formulations.

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29.4 Liquid Precursor Process for Cubosome Manufacture In view of the difficulty and expense of the highshear processes originally required for dispersion of viscous bulk cubic phase to form cubosomes, it is desirable to seek less aggressive manufacturing processes. High-energy processes can be expensive, difficult to scale-up, and harmful to fragile temperature-sensitive active ingredients like proteins. In some product applications, it is also advantageous for cubosomes to form only upon use (for example, during hand washing or mouth rinsing). A strong driving force exists for development of a liquid phase precursor to cubosomes in order to avoid high-energy processing and produce them in situ. The hydrotrope dilution process[35] is found to

Diamond Bicontinuous Structure

consistently produce smaller, more stable cubosomes. In concept, particles are formed by nucleation and growth, as employed in crystallization and precipitation processes. This is achieved by dissolving the monoolein in a hydrotrope, such as ethanol, that prevents liquid crystalline formation. Subsequent dilution of this mixture spontaneously “crystallizes” or precipitates the cubosomes. This process is carried out without the need for high shear, thereby minimizing the risk of degrading the cubic liquid crystalline structure.[35] The liquid precursor process allows for easier scale-up of cubosome preparations and avoids bulk solids handling and potentially damaging high energy processes. The dilution process employed for manufacture of cubosomes using a liquid precursor is easily visualized using a ternary phase diagram of a hydrotrope like ethanol, water, and monoolein (Fig. 29.4).

Gyroid Bicontinuous Structure

Figure 29.4 Schematic diagram of the ternary phase behavior of the ethanol-monoolein-water system. The dilution trajectories indicate the cubosome-forming processes possible in such a system. Path A forms smaller, submicron, cubosomes upon dilution by starting from an isotropic liquid solution. Path B starts from a macroemulsion state and forms micron-scale cubosome particles upon dilution. Also shown are calculated approximations of the two bicontinuous cubic structures formed in this system. (Reproduced with permission from Spicer, et al. Copyright 2001 American Chemical Society.)

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES A large isotropic liquid region exists at high ethanol concentrations. The isotropic phase has a low viscosity and is easy to prepare. In addition to the isotropic liquid region, there are three single-phase liquid crystalline regions: the lamellar liquid crystalline phase, and the two bicontinuous cubic liquid crystalline phases: the diamond and the gyroid (calculated schematics of these two bicontinuous structures are also shown in Fig. 29.4). As seen in Fig. 29.4, the cubic-phase liquid crystals can tolerate about 10% by weight of ethanol, which acts as a hydrotrope. However, not all hydrotropes work this well, and Lynch and Spicer[38] provide a list of other materials that are very compatible with monoolein. Most importantly, as seen in Fig. 29.4, there is a large miscibility gap between the water apex and the cubic phase, where cubosomes form. Production of large and sub-micron cubosomes merely requires adding water to monoolein-ethanol precursor solutions until the mixture falls into this miscibility gap. The dilution pathway, as shown on the ternary diagram, determines the size of the cubosomes produced. Consider Path A (Fig. 29.4) that involves the dilution of an isotropic liquid (50% w/w monoolein, 50% ethanol) with a polymer/water solution. This procedure forms a colloidal dispersion of cubosomes in water with the composition: 89% w/w water, 5% monoolein, 5% ethanol, and 1% Poloxamer 407. The Poloxamer acts as a stabilizer to avoid aggregation of the cubosomes. This dilution pathway provides a fine dispersion of sub-micron cubosomes. An alternative, Path B in Fig. 29.4, results in the formation of larger cubosomes via dilution from the region of the phase diagram where emulsions of rich and lean isotropic liquid form. Such emulsions are also excellent precursors for cubosome dispersions because they can be easily dispersed and stabilized prior to cubosome formation. The particle size distribution of the precursor emulsion is easily tailored by exposure to low shear rates. The emulsion, thus formed, can be stabilized and diluted into the cubicliquid equilibrium region on the ternary diagram in order to form cubosomes. In fact, a macroemulsion (70% water, 20% ethanol, 10% monoolein), diluted with an aqueous solution of Poloxamer 407, forms a cubosome dispersion (90% water, 6% ethanol, 3% monoolein, 1% polymer) by means of simple hand agitation. Spicer, et al.,[35] find that additional shear

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beyond hand mixing aids in the uniform production of sub-micron cubosomes. However, much less shear is required in this process than that required for dispersion of bulk cubic phase without hydrotrope. Omission of the stabilizing polymer during dilution will obviously form bulk cubic phase instead of cubosomes, thereby allowing additional applications such as bulk surface treatments.

29.5 Powdered Cubosome Precursors using SprayDrying Technology and the Hydrotrope Method Powdered cubosome precursors are powders composed of dehydrated monoolein coated with polymer. Such precursors offer some process and performance advantages over liquid phase hydrotropic cubosome precursors. Hydration of the precursor powders forms cubosomes with a mean particle size of 600 nm, as confirmed by light scattering and cryoTEM.[37] The lipids typically used to make cubosomes are waxy, sticky solids. As such, these properties render them unable to form small discrete particles. It has been found that a water-soluble, non-cohesive starch coating on the waxy lipid prevents agglomeration and allows control of particle size. Spray drying is an excellent process to produce such particles. This commercially useful technique produces encapsulated particles from an emulsion of liquid droplets, or from a dispersion of solid particles in a concentrated aqueous polymer solution. The continuous and dispersed phases are sprayed through a nozzle in order to create suspension droplets. These droplets are then contacted with a heated, dry air stream flowing in the opposite direction. The excess water present immediately evaporates and leaves dry powder particles composed of the dispersed phase encapsulated by a shell of the formerly dissolved polymer. Spray-drying processes are easily scaled up and are already widely employed for manufacturing consumer products like detergents and foods. Further, the process provides a simple route to preload actives into the cubosomes prior to drying. Finally, the polymer coating on the powder imparts surface properties to the hydrated cubosomes that can be tailored by proper selection of the encapsulating polymer.

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In this manufacturing approach, the liquid feed to the spray-dryer can be tailored to adjust the resulting powder properties. Production of starchcoated cubosome powder precursors requires a high shear treatment of the monoolein in an aqueous starch solution. This treatment forms a coarse cubosome dispersion which is then pumped through a nozzle and spray-dried. Full operating conditions are described in Ref. 37. The initial composition pumped into the spray-drier is 60% w/w water, 30% starch, and 10% monoolein. Drying removes almost all the water present, and gravimetric tests of the finished powder generally indicate a final powder composition of about 4% w/w water, 72% starch, and 24% monoolein. Although the relative fraction of starch is high (3:1 starch:monoolein), this starch level is necessary in order to preserve powder quality. Figure 29.5 compares SEM photographs of starchencapsulated monoolein with a 3:1 (left hand side) and 1:1 (right hand side) starch:monoolein ratio. As seen in Fig. 29.5, the powder with the 3:1 ratio exhibits good encapsulation of the monoolein and small particle size. However, the 1:1 ratio product exhibits poor morphology and larger particle size. In the latter case, the bulk powder is undesirably more cohesive as a result of poor encapsulation of the sticky monoolein by the starch. The production of starch-coated powder precursors from a hydrotropic solution of monoolein emul-

sified in water makes the spray-drying step easier. Ethanol is known to act as a hydrotrope and dissolve viscous cubic liquid crystalline phase. This technique forms a low-viscosity liquid and eases processing.[35] Reapplication of the hydrotrope effect in the spray-drying process avoids formation of cubosome dispersions and eases spray drying. However, other changes in the formula are also required in order to accommodate the ethanol. For example, a new polymer is needed for encapsulation of the monoolein, since the insolubility of starch in ethanol prevents its use in this approach. A useful alternative to the starch is dextran. The material to be spraydried contains 37.5% water, 25% dextran, 22.5% ethanol, and 15% (w/w) monoolein. The quaternary system is prepared by first dissolving the dextran in water and the monoolein in ethanol. Thereafter, the two solutions are combined and mixed. Once mixed, the quaternary system forms an emulsion of two distinct phases. One phase is optically isotropic while the other phase is optically birefringent. The twophase emulsion has a low viscosity and is easily spray dried. The type of encapsulating starch also affects the powder precursor quality. Drying occurs as the dispersion is sprayed into droplets and moisture rapidly evaporates by convective heating. Cubosomes in the dispersion form the nucleus of many of the sprayed droplets and are surrounded by aqueous

Figure 29.5 SEM photographs of spray-dried powder precursors of cubosomes. The left-hand side photo shows powders with a 3:1 starch:monoolein ratio exhibiting desirable morphology and good encapsulation of the sticky monoolein. The right-hand side photo shows powders with a 1:1 starch:monoolein ratio. This ratio exhibits poorer encapsulation of the monoolein and much larger particle size because of agglomeration.

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES starch solution. As drying proceeds, the starch remains and it forms a coating around the cubic-phase particles, thereby encapsulating them. Since the cubic phase itself contains 40% (w/w) water, some drying must also occur within the core of the particles. Low molecular weight starches (84,000 MW) produce superior powders as compared to high (335,000 MW) molecular weight starches.[37] A more comprehensive listing of feasible polymers and other useful materials for encapsulation of cubosomes has been discussed elsewhere.[39] The application of the hydrotrope method to spray-drying for production of cubosome precursors significantly eases processing. Thermal gravimetric analysis indicates the presence of 16% w/w volatile materials remaining in the precursor powders following drying. Of this fraction, 3% w/w is water and 13% is ethanol. The volatile content remains constant for several months. This indicates that good encapsulation of both the ethanol and the monoolein has been obtained using the dextran. Depending upon the application, the powders can be produced with varying amounts of ethanol. This is accomplished by tailoring the film properties of the polymer in order to take advantage of the nucleation of small cubosomes from monoolein-ethanol solution during hydration.[35] The large proportion of polymer required for encapsulation (~75% w/w for starch and ~60% for dextran) limits the amount of active material that can be incorporated within the cubosomes for subsequent delivery. Assuming, as an upper feasible limit, a 10% w/w dispersion of starch-stabilized cubosomes is desired, and a 1:1 ratio of monoolein-to-active is used, the maximum weight percent of active in the cubosome dispersion is 1.25%. Such a low level is useful only for high value-added materials like pharmaceuticals, vitamins, flavors, or scents. The process described demonstrates the feasibility of forming dry powders with the ability to form cubosomes upon hydration.

29.6 Functionalized CubicPhase Liquid Crystals It is usually assumed that the loading and release properties from cubic-phase liquid crystals are

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solely governed by the solubilized active. However, loading properties are, in fact, governed by the partition of actives between existing phases. It has been noted[7] that active partitioning is driven by thermodynamic constraints that force the chemical potential of the active in each phase to be identical at equilibrium. In a more simplified view, the active has a higher affinity for the liquid crystal and, therefore, leads to higher loading. For example, it has been demonstrated[40] that changing the ionization state of an active alters its solubility and consequently its loading ability in liquid crystalline phases. At low pH, the active is more hydrophobic and can be loaded to higher levels. This phenomenon is observed for a wide range of actives including lidocaine, prilocaine, clomethiazole (CMZ), and phenol butylamine. However, it has been noted[41] that amphiphilic actives such as chlorpheniramine maleate, diltiazem-HCl, and propranolol-HCl bind differently from one another to the monoglyceride in cubic phase, thereby leading to further partition differences. The authors suggest that partition correlates more with surface activity of the actives than with their solubility. At short contact times, release is diffusion-controlled and is a function of the square root of time.[42] At longer contact times, however, release rates of actives such as chlorpheniramine maleate and pseudoephedrine-HCl follow a different rule. This is primarily due to the fact that they interact with the liquid crystal. The release rates are also seen to slow down as the concentration in each phase approaches its equilibrium partition value. Further, several temperature-jump experiments suggest that propranolol hydrochloride releases faster with temperature in view of its increased ability to diffuse through the matrix and its water solubility. The common thread that emerges from this body of work is that the active material’s physicochemical properties drive both the loading efficacy and the release properties. Obviously, both of these parameters can significantly affect the utility of the cubic phase as a delivery vehicle. The concept of functionalization is useful to control both the loading and release properties of the active. This is accomplished by changing the properties of the cubic phase. Functionalization is achieved by incorporating amphiphilic molecules into the liquid crystal. In this method, the hydrophobic portion of the amphiphile inserts itself into the

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bilayers of the cubic phase and the hydrophilic portions of the amphiphile extend into the water channels (the hydrophilic regions of the bicontinuous cubic phase). By customizing the specific properties of the hydrophilic portions, it is possible to control their interaction with the active ingredients to be incorporated. As an example, a positively-charged hydrophilic portion of an amphiphile is expected to increase the loading potential for a negativelycharged water-soluble active. It is expected that active release properties, at short contact times, will be altered because the active is grabbed by the positively-charged amphiphile during diffusion out of the liquid crystal. In contrast, release properties for long contact times will also be altered in view of the increased affinity between active and cubic phase and its effect on active partitioning. Taken together, these approaches for customizing the properties of the cubic phase are an alternative method to changing the loading and release properties of an active. The result offers a greater potential for tailoring active release properties over a broader range of applications and conditions. One useful approach for functionalization of cubic phase requires incorporating relatively small amphiphiles, such as surfactants, into the cubic phase. Surfactants used in this capacity are often termed “anchors,” and must be chosen with care. The addition of octyl glucoside,[43] sodium oleate,[44] cetyltrimethylammonium bromide,[45] and sodium cholate,[46] for example, all tend to convert the cubic phase to a lamellar phase, even with relatively small additions of amphiphile. It has been suggested[47] that these “conversions” reflect different locations of the anchors in the cubic phase. Low polarity anchors that incorporate directly into the cubic-phase bilayer are expected to force lamellar phase formation. In contrast, more polar anchors are envisioned to locate themselves at the interfacial regions of the cubic phase, and thereby tend to force reverse hexagonal-phase formation. An optimal set of anchor properties that maximize functionalization without significantly altering the underlying structure of the cubic phase has been presented.[48] Ideal anchors have low water solubility, low Krafft Temperature, an accessible hydrophilic group with which the active can interact, and a critical packing parameter (ratio of head group area to tail area) close to unity. Such surfactants typically

form vesicles in aqueous solutions. Other work reports that large amounts of surfactant can be added into the cubic phase if surfactants with these properties are chosen. For example,[49] it has been demonstrated that biological lipids with the properties listed above can be formulated into the monoolein cubic phase at a relatively large weight percentage with only minor increase of the liquid crystal unit cell dimension. Most importantly, several workers suggest that the inclusion of anchors alters the loading and release properties of actives solubilized in the cubic phase. It has been shown[50] that distearoyl phosphatidylglycerol, in cubic phase, retards the release of timolol maleate. In addition, the inclusion of dioleoyl phosphatidylcholine into cubic phase alters the loading of 4-phenylbutylamine.[40] Quaternary ammonium surfactants have been solubilized into the cubic phase and this approach affects the loading and release properties of ionized ketoprofen, an anti-inflammatory active ingredient.[48] Such anchors are added at concentrations greater than 20 % w/ w without altering the unique bicontinuous structure of the cubic phase. This work also provides discussion of the magnitude of the interaction based upon the molecular structure of the anchor’s hydrophilic portion. A second approach to functionalization is to incorporate large, amphiphilic polymers, or “tethers” into the liquid crystal. Although this approach has been studied to a lesser degree than surfactant incorporation, certain reports indicate that it is viable. For example,[19] it has been demonstrated, through a phase diagram, that high concentrations of Poloxamer 407 (an amphiphilic triblock copolymer) can exist in the monoolein cubic phase. It was suggested that this polymer is included in the internal bilayers and not just on the surface of the dispersed cubosomes. In fact, it has been demonstrated,[51] that at low concentrations of Poloxamer 407, most of the polymer adheres to the surface of cubosome particles. However, at high Poloxamer 407 concentrations, of the polymer, there is a conversion of the cubic-phase liquid crystal from the diamond to the gyroid bicontinuous structure. This suggests that the polymer partitions into the bulk of the cubic-phase matrix without destroying the structure. Further, the insertion of sodium alginate (a water-soluble polysaccharide) into the cubic phase changes the structure of the liquid crystal from diamond to gyroid but induces only moderate changes to the overall phase

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES diagram.[52] This phenomenon suggests that a polymer-rich cubic phase forms under such conditions. Inclusion of the polymer is also found to modify the release rate properties of proteins by forming an aqueous polymeric gel in the water channels of the liquid crystal structure. Addition of sodium citrate alters this behavior almost instantaneously by disrupting the gelling properties of the polymer. In summary, functionalization of cubic phases to control and optimize their loading, release, and partitioning of active ingredients is an effective approach to tailoring the properties of formulations. Given the relative cost of surfactant and pharmaceutical active ingredients, the functionalization approach seems quite feasible, especially in view of the need to produce formulations that are both practical and economical. Finally, the approach offers greater opportunity for developing systems with the capability of triggered active release. Useful triggers or stimuli include change in pH or salt levels, or the addition of a solvent. All of these powerful tools are at the discretion of the formulator.

29.7 Clinical Evaluation of Skin Conditioning by CubicPhase Liquid Crystals One application of cubic-phase liquid crystals, such as in the monoolein-water system, is their use as controlled release systems for delivery of selected water- and oil-soluble materials.[14] Such applications require an understanding of the interface between the bicontinuous cubic structure and the biological epithelia which they contact (e.g., the gut, oral mucosa, and the skin). In the case of skin, the ultimate biological interface is constituted by a thin (~20 µm thick) cross-linked biopolymer called the stratum corneum. Proponents of drug delivery across the barrier that human skin provides point to the stratum corneum as the chief obstacle and impediment to successful passage of a molecule, or drug, into the living epidermis and/or the bloodstream. Numerous strategies have been developed, therefore, to disrupt the architecture of the stratum corneum. Examples include the use of high energy ultrasound, laser ablation, electrophoresis, and chemical penetration enhancers. In all of these cases, the idea is to

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create momentary micropores or channels for drug passage.[53] Alternative approaches to improving passage of actives across the stratum corneum can be envisioned. For example, a nanostructured cubic phase can be nondestructively juxtaposed with the stratum corneum for therapeutic or drug delivery purposes. This approach implies the development of a seamless interface between the cubic phase and the underlying stratum corneum and, by extension, between the stratum corneum and the underlying epidermis. Recently, a membrane-folding model involving phase transitions from cubic-to-lamellar morphologies has been proposed to explain formation of the epidermal barrier.[54][55] These considerations emphasize the importance of understanding biophysical interfaces at the nanostructural level. Work on the thermal, mechanical, and electrical properties of cubic phases in contact with the stratum corneum must be performed in order to provide a foundation for all specific applications. A better understanding of the biological-biophysical interface of the skin-cubic phase systems is essential for cubic-phase applications involving transdermal drug delivery. Example applications include transdermal delivery with or without electrophoresis, the development of adhesive and skin protection strategies, and electrical sensing measurements of the skin surface. The biocompatibility of monoolein preparations or other conceivable cubic phases also needs to be explored. The more seamlessly such a material intercalates with the epidermal barrier, the more likely a practical “window” can be established for specific applications.

29.8 Clinical Study Results In this section, the results of two clinical studies involving acute (minutes-to-hours) and chronic (several weeks) exposure of human stratum corneum to monoolein-water cubic phases are briefly summarized. Both studies were conducted on normal, adult human female volunteers with consent and institutional review board approval. The first study contrasts the effects of two cubic-phase formulations with two standard barrier creams containing petrolatum as the primary lipid

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base. The water vapor permeability of the contact materials was assessed using an in vitro gravimetric system as described in Fig. 29.6. The results indicate that the cubic phases are highly permeable to water and fail to exhibit a clear dose response as a function of film thickness. The formulations in the clinical study include: 1. 75% monoolein, 25% water 2. 75% monoolein, 20% water, 5% glycerin 3. petrolatum (long chain hydrocarbon mixture, 0% water), and Eucerin cream® (petrolatum, mineral oil, lanolin alcohol, 17% water) Treatments were applied to one of six skin sites measuring 2.5 cm × 5 cm on the volar forearm at levels of 2.5 mg/cm2 in order to simulate typical concentrations of emollients in the skin literature. Ten subjects were enrolled and evaluated. The key focus of this study was to characterize water-related properties of the skin surface in contact with the standard emollients and the cubic phases. Figure 29.7 shows the clinical effects of the treatments on transepidermal water loss (TEWL), as measured in vivo with a Dermalab evaporimeter. The Eucerin water-in-oil emulsion demonstrated increased TEWL at 30 minutes post application presumably as a result of water loss from the formula itself. In contrast, the cubic phases showed no such behavior and TEWL is indistinguishable from control sites at this time. Petrolatum, as expected for an occlusive film, reduced TEWL. Two hours post application, there were no clear effects of any ointment that affected TEWL (data not shown). The effects of the various treatments on waterhandling properties are evaluated by means of a sorption-desorption test.[56] In this standardized test, surface electrical capacitance readings were measured prior to, and at measured intervals following, topical application and removal of exogenous water.[57] The area under the desorption curve indicates the degree to which the skin surface and adsorbed materials will bind exogenous water.[58] In this experiment, the bulk cubic phases demonstrated increased water binding to the skin surface as indicated by an increased area under the sorption-desorption curve (Fig. 29.8).

In a second experiment, the efficacy of a cubicphase test formulation consisting of 75% monoolein and 25% water was tested in a standardized model of xerotic (dry) skin. Twenty healthy adult female volunteers free of dermatitis but with visual skin dryness (grade > 2) on the lateral calf were evaluated. The bulk cubic-phase test formulation is compared to a glycerin-containing moisturizing lotion (Vaseline® Intensive Care Dry Skin Cream) versus a no-treatment control site. Following a one week washout period in which lotion treatment was discontinued, subjects applied 1 mg/cm2 of the cubosome formulation and 2.5 mg/cm2 of the glycerin-based product to the lower legs over a 10 cm × 10 cm treatment area, twice a day, for 14 days. The skin condition was evaluated by a combination of visual and biophysical methods.[59][60] Visual grades were assigned by trained experts using a 0–3 scale for dryness and a 0–4 scale for erythema. Table 29.1 summarizes the results of this preliminary study. Skin grades (dryness and erythema) were scored visually using a standardized scale. Transepidermal water loss and the moisture accumulation test were quantified using standardized instruments. The cubic phase initially appears to reduce visual skin dryness. However, continued treatment exacerbated the skin condition. Evidence of barrier damage was observed as increased TEWL and erythema. It was speculated that endogenous epidermal metabolism hydrolyzed some monoolein to form oleic acid, contributing to this effect.[61] In addition, one of the obvious findings of this study is the difficulty of applying the bulk cubic phase to the skin surface. In the study, the cubic phase was supplied to subjects in small syringes, and a measured aliquot was dispensed to the skin. Next, it was rubbed into the site until the subject believed that a uniform film was achieved. The application process was quite difficult because of the bulk cubic-phase viscosity. Some subjects briefly occluded the material in an attempt to spread it. During application, the water content may have decreased, thereby resulting in a conversion from the cubic phase to a lamellar phase. It is also possible that the application process itself results in increased friction and/or trauma to the xerotic (dry) skin site.

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Figure 29.6 Water vapor transport, measured in vitro, across petrolatum and cubic phases of varying thickness. In this experiment, a Gore-Tex® sheet was immobilized over a plastic weigh boat containing water. Water vapor transport was determined gravimetrically by observing the weight loss of the boat/Gore-Tex combination either alone (control), or following application of 0.5 (A), 1.0 (B), or 2.5 (C) mg/cm2 of a cubic phase containing 75% monoolein and 25% water. Column D indicates water transport across a cubic phase containing 75% monoolein, 20% water, and 5% glycerin. The petrolatum film was 0.5 mg/cm2. All cubic phases produced a small reduction in water vapor transport but there was no dose response effect observed. Petrolatum was highly occlusive.

Figure 29.7 Transepidermal water loss measured on normal adult human skin thirty minutes after topical application of 2.5 mg/cm2 of Eucerin cream® (petrolatum, mineral oil lanolin alcohol, 17% w/w water), petrolatum (long chain hydrocarbon mixture, 0% w/w water), and monoolein-based cubic phases containing 25% w/w water (A), 25% w/ w water at 1.0 mg/cm2 (B), and 20% w/w water + 5% w/w glycerin (C). At this time point, TEWL is significantly elevated over the Eucerin sites and reduced over the petrolatum sites (*). This result presumably reflects the slow evaporation of water from the formulation with Eucerin cream and occlusion with petrolatum. In contrast, the cubic phases behave similarly to the controls, but have higher TEWL than the petrolatum sites.

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Figure 29.8 Water-holding capacity of skin sites measured by the area under the sorption-desorption curve four hours after application of the same test ointments shown in Fig. 29.7. In this study, the Eucerin site was significantly less than controls; whereas all cubic phases exhibited significant increases in water-holding capacity when compared to the control sites (*).

Table 29.1. Summary of Results of a Clinical Study on the Effect of Glycerin-based Lotion vs the Effect of a Cubic Phase Preparation on Dry (Xerotic) Skin

Day

Skin Grades Dryness

1

Erythema

Transepidermal Water Loss

Moisture Accumulation Test

No differences among sites in either score

Baseline values not significantly different among groups

Baseline values not significantly different among groups

4

Cubic phase significantly less dry than control site and more erythematous than control and glycerin lotion sites

Groups significantly different with glycerin lotion < controls < cubic phase sites

No significant differences among groups

14

Cubic phase site drier than control and glycerin lotion sites; No difference in erythema among sites

Glycerin lotion significantly lower than control and cubic phase sites; cubic phase higher than control site

Values low indicating very dry skin in all groups; glycerin lotion higher than cubic phase

21

Cubic phase site visibly drier than control and glycerin lotion sites; cubic phase more erythematous than glycerin lotion site

Glycerin lotion < control < cubic phase sites

No significant differences among groups

Control Glycerin lotion Cubic Phase

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES These two preliminary studies allow the following general conclusions: 1. Bulk cubic phases are difficult to handle and difficult to apply to human skin. In contrast, the relatively anhydrous lamellar phase of the monoolein-water admixture is relatively fluid and easy to apply. The application of relatively dehydrated, starch-encapsulated cubosome particles offers another potential method for forming cubic phase nanometer-scale architectures on human skin.[37] 2. The paradoxical addition of exogenous water to the lamellar phase of a topically applied monoolein-water admixture results in the formation of a more viscous cubic architecture. Thus, the simple addition or removal of exogenous water provides a means of controlling the phase behavior and, thus, the physical nature of the topical application. 3. The cubic phase is highly vapor permeable when measured over a hydrated support structure such as Gore-Tex® (Fig. 29.6) as well as over human skin (Fig. 29.7). In the experiment shown in Fig. 29.6, variations in the film thickness do not decrease the water vapor gradient. A tantalizing, unanswered question that arises is: Does this unusual property reflect the bicontinuous nature of the water phase in the cubic material? Vapor permeability combined with a physical barrier is a desirable characteristic in wound healing applications.[58] High viscosity and high vapor permeability are two physical properties distinguishing monoolein-water cubic phases from occlusive skin ointments such as petrolatum. 4. The cubic phase is hygroscopic on human skin, as judged by instrumental tests such as the sorption-desorption test (Fig. 29.8). Thus, exogenous water is sequestered in the cubic-phase architecture and may result in a phase change. The amount of water can be ascertained by standardized electrical tests such as the sorption-desorption test.

615

5. The direct application of a cubic phase as a therapeutic agent for xerotic (dry) skin yields conflicting results (Table 29.1). In the study presented, twice-daily application of a cubic phase to the dry lower legs of normal adult females evoked increased erythema, increased visual dryness, and increased transepidermal water loss as compared to use of a standard glycerinbased lotion. Whether this response is the result of a potential irritating effect of the cubic phase, or a secondary effect due to repeated application of a very viscous and difficult to apply ointment, requires further study. In summary, it is anticipated that cubic-phase systems will find increasing application for both drug and personal care active delivery vehicles. They may also become platforms for adhesives, skin protectants, and biomonitoring devices. The utility of these nanostructured systems can be extended by the ability to control the physical phase of the system (e.g., the transition from lamellar to cubic phase[48] and the use of cubosome powder precursors[37]). Such systems will be particularly versatile if, as speculated, it can be demonstrated that the biological interface itself possesses a cubic architecture.[54][55]

29.9 Conclusions Bicontinuous cubic liquid crystalline phases, either in bulk or cubosome form, offer unique properties of particular interest to the personal care industry. Cubic-phase materials can be formed by the simple combination of biologically compatible lipids and water. Thus, they are well suited for use in treatments of skin, hair, and other body tissue. Some observations of skin irritation in clinical tests with bulk cubic phase point to a need for further study of alternative formulations that avoid the formation of residual oleic acid and employ cubosome dispersions having much lower viscosity. The ability to easily form cubosomes, either in use, during formulation, or during manufacture, offers greatly enhanced flexibility for product development efforts. Formulation of personal care products

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containing cubosomes often requires additional surface-active ingredients. For this reason the inherent capability to tailor the active ingredient loading of cubic phases and control the tolerance of cubic

phases for other ingredients using amphiphilic anchors or polymeric tethers is a crucial tool that needs to be further developed.

29.10 Formulations Formulation 29.1: Cubosome Dispersion Formed by Dilution of an Isotropic Solution

Phase

A

B

Ingredient

Function

Weight %

Monoolein

Amphiphile

10.0

Ethanol

Hydrotrope

5.0

Water

Hydrate amphiphile

1.8

Poloxamer 407

Stabilizing polymer

1.0

Water

Polymer solvent

82.2 Total

100

Mixing Instructions: • Weigh the Phase A ingredients into a suitable vessel equipped with a mixer. The materials form a clear, low-viscosity, isotropic liquid. • Combine the Phase B ingredients into a separate vessel and stir until all polymer is dissolved. • Inject Phase B solution into Phase A and mix only as much as needed to produce cubosomes of the desired size. A colloidally stable dispersion of cubosomes forms.

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES Formulation 29.2: Powder Cubosome Precursor

Phase

A

Ingredient

Function

Weight %

Monoolein

Amphiphile

10.0

HICAP 100 Starch

Encapsulant

30.0

Water

Hydrate amphiphile

60.0

Total

100

Mixing Instructions: • Weigh the Phase A ingredients into a suitable vessel equipped with a high-shear mixer. Upon shearing the materials will form a relatively low viscosity coarse dispersion of cubosomes. • Spray-dry to produce a powder with a final composition of about 4% w/w water, 72% starch, and 24% monoolein.

Formulation 29.3: Bulk Cubic Phase for Skin Treatment

Phase A B

Ingredient

Function

Weight %

Monoolein

Amphiphile

57

Glycerin

Skin softener

5

Water

Hydrate amphiphile Total

38 100

Mixing Instructions: • Melt Phase A ingredient into a suitable vessel by heating above 40°C and stirring. • In a separate vessel, mix the Phase B ingredients until completely homogeneous. • Add the Phase B ingredients to the Phase A ingredients and mix well. The mixture forms a very viscous, clear gel-like material that needs to be mixed well to ensure uniform incorporation of all Phase B ingredients.

617

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References 1. Lindstrom, M., Ljusberg-Wahren, H., Larsson, K., and Borgstrom, B., Aqueous Lipid Phases of Relevance to Intestinal Fat Digestion and Absorption, Lipids, 16:749–754 (1981)

13. Anderson, D. M., and Wennerström, H., SelfDiffusion in Bicontinuous Cubic Phases, L3 Phases, and Microemulsions, J. Phys. Chem., 94:8683–8694 (1990)

2. Andersson, S., Jacob, M., Ladin, S., and Larsson, K., Structure of the Cubosome - a Closed Lipid Bilayer Aggregate, Z. Krist., 210:315–318 (1995)

14. Engström, S., Lindman, B., and Larsson, K., Method of Preparing Controlled-Release Preparations for Biologically Active Materials and Resulting Compositions, Fluid-Carbon International AB (Malmo, SE), USA (1992)

3. Larsson, K., Two Cubic Phases in MonooeinWater System, Nature, 304:664, (1983) 4. Jones, J. L., and Mcleish, T. C. B., Concentration Fluctuations in Surfactant Cubic Phases: Theory, Rheology, and Light Scattering, Langmuir, 15:7495–7503 (1999) 5. Lutton, E. S., Phase Behavior of Aqueous Systems of Monoglycerides, J. Amer. Oil. Chem. Soc., 42:1068–1070 (1965) 6. Hyde, S. T., Andersson, S., Ericsson, B., and Larsson, K., A Cubic Structure Consisting of a Lipid Bilayer Forming an Infinite Periodic Minimal Surface of the Gyroid Type in the Glycerolmonooleat-Water System, Z. Krist., 168:213–219 (1984) 7. Laughlin, R. G., The Aqueous Phase Behavior of Surfactants, Academic Press (1996) 8. Briggs, J., Chung, H., and Caffrey, M., The Temperature-Composition Phase Diagram and Mesophase Structure Characterization of the Monoolein/Water System, J. Phys. II France, 6:723–751 (1996) 9. Fontell, K., Mandell, L., and Ekwall, P., Isotropic Mesophases in Systems Containing Amphiphilic Compounds, Acta Chem. Scand., 22:3209–223 (1968) 10. Luzzati, V., Tardieu, A., Gulik-Krzywicki, T., Rivas, E., and Reiss-Husson, F., Structure of the Cubic Phases of Lipid-Water Systems, Nature, 220:485–488 (1968) 11. Hyde, S., Andersson, A., Larsson, K., Blum, Z., Landh, T., Lidin, S., and Ninham, B. W., The Language of Shape, Elsevier, New York (1997) 12. Scriven, L. E., Equilibrium Bicontinuous Structure, Nature, 263:123–125 (1976)

15. Patton, J. S., and Carey, M. C., Watching Fat Digestion, Science, 204:145–148 (1979) 16. Nielsen, L., Schubert, L., and Hansen, J., Bioadhesive Drug Delivery Systems 1. Characterisation of Mucoadhesive Properties of Systems Based on Glyceryl Mono-Oleate and Glyceryl Monolinoleate, Eur. J. Pharm. Sci., 6:231–239 (1998) 17. Gustafsson, J., Ljusberg-Wahren, H., Almgren, M., and Larsson, K., Cubic Lipid-Water Phase Dispersed into Submicron Particles, Langmuir, 12:4611–4613 (1996) 18. Gustafsson, J., Ljusberg-Wahren, H., Almgren, M., and Larsson, K., Submicron Particles of Reversed Lipid Phases in Water Stabilized by a Nonionic Amphiphilic Polymer, Langmuir, 13:6964–6971 (1997) 19. Landh, T., Phase Behavior in the System Pine Needle Oil Monoglycerides-Poloxamer 407Water at 20°, J. Phys. Chem., 98:8453–8467 (1994) 20. Ericsson, B., Larsson, K., and Fontell, K., A Cubic Protein-Monoolein-Water Phase, Biochim. Biophys. Acta, 729:23–27 (1983) 21. Landh, T., andLarsson, K., Particles, Method of Preparing Said Particles and Uses Thereof, GS Biochem AB, USA (1996) 22. Boyd, B., Characterisation of Drug Release from Cubosomes Using the Pressure Ultrafiltration Method, Int. J. Pharm., submitted (2003) 23. Drummond, C. J., and Fong, C., Surfactant Self-Assembly Objects as Novel Drug Delivery Vehicles, Curr. Op. Colloid Int. Sci., 4:449–456 (2000)

SPICER, ET AL.: CUBOSOMES AND SELF-ASSEMBLED BICONTINUOUS CUBIC LIQUID CRYSTALLINE PHASES 24. Enriquez, J., and Goldberg, R., Transforming Life, Transforming Business: The Life-Science Revolution, Harvard Bus. Rev., pp. 96–104, (Mar.-Apr. 2000) 25. Ribier, A., and Biatry, B., Cosmetic Compositions Comprising a Stable Aqueous Dispersion of Phytantriol-Based Gel Particles Containing a Long-Chain Surfactant as Dispersant and Stabilizer, Eur. Pat. Appl. (Oreal S. A., Fr.), p. 13 (Ep, 1995) 26. Ribier, A., and Biatry, B., Cosmetic or Dermatologic Oil/Water Dispersion Stabilized with Cubic Gel Particles and Method of Preparation, Eur. Pat. Appl. (Oreal S. A., Fr.), p. 16 (Ep, 1996) 27. Ribier, A., and Biatry, B., Oily Phase in an Aqueous Phase Dispersion Stabilized by Cubic Gel Particles and Method of Making. L’Oreal (Paris, FR), USA (1998) 28. Biatry, B., Cosmetic and Dermatological Emulsion Comprising Oily and Aqueous Phase, Eur. Pat. Appl. (L’oreal, Fr.), p. 12 (Ep, 2000)

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bic Phases, Ger. Offen. (Beiersdorf AG, Germany), p. 30 (Dec, 2002) 35. Spicer, P. T., Hayden, K. L., Lynch, M. L., Ofori-Boateng, A., and Burns, J. L., Novel Process for Producing Cubic Liquid Crystalline Nanoparticles (Cubosomes), Langmuir, 17:5748–5756 (2001) 36. Ljusberg-Wahren, H., Nyberg, L., and Larsson, K., Dispersion of the Cubic Liquid Crystalline Phase - Structure, Preparation, and Functionality Aspects, Chimica Oggi, 14:40– 43 (1996) 37. Spicer, P. T., Small, W. B., Lynch, M. L., and Burns, J. L., Dry Powder Precursors of ‘Soft’ Cubic Liquid Crystalline Nanoparticles (Cubosomes), J. Nanoparticle Res., 4:297– 311 (2002) 38. Lynch, M. L., and Spicer, P. T., Cubic Liquid Crystalline Compositions and Methods for Their Preparation, Procter and Gamble Co., USA (2002)

29. Biatry, B., Use of Phytantriol as Anti-Pollution Agent in a Cosmetic Composition, Eur. Pat. Appl. (L’Oreal, Fr.), p. 14 (Ep, 2001)

39. Spicer, P. T., Small, W. B., and Lynch, M. L., Cubic Liquid Crystalline Compositions and Methods for Their Preparation, Procter and Gamble Co., USA (2002)

30. Afriat, I., and Biatry, B., Use of Cubic Gel Particles as Agents against Pollutants, Especially in a Cosmetic Composition, Eur. Pat. Appl. (L’Oreal, Fr.), p. 14 (Ep, 2001)

40. Engström, S., Norden, T. P., and Nyquist, H., Cubic Phases for Studies of Drug Partition into Lipid Bilayers, Eur. J. Pharm. Sci., 8:243–254 (1999)

31. Schreiber, J., and Albrecht, H., Hair Care Products with a Content of Disperse Phase Liquid Crystals Which Form Cubic Phases, Ger. Offen. (Beiersdorf AG, Germany), p. 28 (De, 2002)

41. Chang, C.-M., and Bodmeier, R., Binding of Drugs to Monoglyceride-Based Drug Delivery Systems, Int. J. Pharm., 147:135–142 (1997)

32. Schreiber, J., and Albrecht, H., Cosmetic Cleaning Products with a Content of Disperse Phase Liquid Crystals Which Form Cubic Phases, Ger. Offen. (Beiersdorf AG, Germany), p. 26 (De, 2002) 33. Schreiber, J., and Eitrich, A., Deodorant and Antiperspirant Products with a Content of Disperse Phase Liquid Crystals Which Form Cubic Phases, Ger. Offen. (Beiersdorf AG, Germany), p. 22 (De, 2002) 34. Schreiber, J., Schwarzwaelder, C., and Cassier, T., Skin Care Products with a Content of Disperse Phase Liquid Crystals Which Form Cu-

42. Chang, C.-M., and Bodmeier, R., Swelling of and Drug Release from Monoglyceride-Based Drug Delivery Systems, J. Pharm. Sci., 86:747–752 (1997) 43. Angelov, B., Ollivon, M., and Angelova, A., X-Ray Diffraction Study of the Effect of the Detergent Octyl Glucoside on the Structure of Lamellar and Nonlamellar Lipid/Water Phases of Use for Membrane Protein Reconstitution, Langmuir, 15:8225–8234 (1999) 44. Caboi, F., Borne, J., Nylander, T., Khan, A., Svendsen, A., and Patkar, S., Lipase Action on a Monoolein/Sodium Oleate Aqueous Cubic Liquid Crystalline Phase - A NMR and X-

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Cubic Phase, J. Phys. Chem., 97:11103–11107 (1993)

45. Gustafsson, J., Oraedd, G., Nyden, M., Hansson, P., and Almgren, M., Defective Lamellar Phases and Micellar Polymorphism in Mixtures of Glycerol Monooleate and Cetyltrimethylammonium Bromide in Aqueous Solution, Langmuir, 14:4987–4996 (1998)

53. Barry, B. W., Novel Mechanisms and Devices to Enable Successful Transdermal Drug Delivery, Eur. J. Pharm. Sci., 14:101–114 (2001)

46. Gustafsson, J., Nylander, T., Almgren, M., and Ljusberg-Wahren, H., Phase Behavior and Aggregate Structure in Aqueous Mixtures of Sodium Cholate and Glycerol Monooleate, J. Colloid Int. Sci., 211:326–335 (1999)

55. Norlen, L., Skin Barrier Structure and Function: The Single Gel Phase Model, J. Invest. Derm., 117:830–836 (2001)

47. Caboi, F., Amico, G. S., Pitzalis, P., Monduzzi, M., Nylander, T., and Larsson, K., Addition of Hydrophilic and Lipophilic Compounds of Biological Relevance to the Monoolein/Water System. I. Phase Behavior., Chem. Phys. Lipids, 109:47–62 (2001) 48. Lynch, M. L., Ofori-Boateng, A., Hippe, A., Kochvar, K., and Spicer, P. T., Enhanced Loading of Water-Soluble Actives into Bicontinuous Cubic Phase Liquid Crystals Using Cationic Surfactants, J. Colloid Interface Sci., 260:404–413 (2003) 49. Templer, R. H., Madan, K. H., Warrender, N. A., and Seddon, J. M., Swollen Lyotropic Cubic Phases in Fully Hydrated Mixtures of Monoolein, Dioleoylphosphatidylcholine, and Dioleoylphosphatidylethanolamine, Springer Proc. Phys., 66:262–265 (1992) 50. Lindell, K., Engblom, J., Jonstroemer, M., Carlsson, A., and Engstroem, S., Influence of a Charged Phospholipid on the Release Pattern of Timolol Maleate from Cubic Liquid Crystalline Phases., Prog. Colloid Polymer Sci., 108:111–118 (1998) 51. Nakano, M., Sugita, A., Matsuoka, H., and Handa, T., Small-Angle X-Ray Scattering and 13C NMR Investigation on the Internal Structure of Cubosomes, Langmuir, 17:3917–3922 (2001) 52. Puvvada, S., Qadri, S. B., Naciri, J., and Ratna, B. R., Ionotropic Gelation in a Bicontinuous

54. Norlen, L., Skin Barrier Formation: The Membrane Folding Model, J. Invet. Derm., 117:823–829 (2001)

56. Agache, P., Mary, S., Muret, P., Matta, A. M., and Humbert, P., Assessment of the Water Content of the Stratum Corneum Using a Sorption-Desorption Test, Dermatology, 202:308– 313 (2001) 57. Visscher, M. O., Chatterjee, R., Ebel, J. P., Laruffa, A. A., and Hoath, S. B., Biomedical Assessment and Instrumental Evaluation of Healthy Infant Skin, Pediatr. Dermatol., 19:473–481 (2002) 58. Visscher, M. O., Hoath, S. B., Conroy, E., and Wickett, R. R., Effect of Semipermeable Membranes on Skin Barrier Repair Following Tape Stripping, Arch. Dermatol. Res., 293:491–499 (2001) 59. Li, F., Conroy, E., Visscher, M., and Wickett, R. R., The Ability of Electrical Measurements to Predict Skin Moisturization. Ii. Correlation between One-Hour Measurements and LongTerm Results, J. Cosmetic Sci., 52:23–33 (2001) 60. Loden, M., Biophysical Methods of Providing Objective Documentation of the Effects of Moisturizing Creams, Skin Res. Tech., 1:101– 108 (1995) 61. Jiang, S. J., and Zhou, X. J., Examination of the Mechanism of Oleic Acid-Induced Percutaneous Penetration Enhancement: An Ultrastructural Study, Biol. Pharm. Bull., 26:66– 68 (2003)

30 Nonaqueous Delivery Systems with Controlled Rheological Behavior Lin Lu Healy Penreco Houston, Texas

30.1 Introduction ................................................................................... 621 30.2 Background .................................................................................. 622 30.2.1 Polymeric Rheological Additives for Nonaqueous Systems............................................................................ 623 30.2.2 Unique Characteristics of Thermoplastic Block Copolymers ...................................................................... 624 30.3 Thermoplastic Block Copolymers as Rheological Modifiers ........ 625 30.3.1 Mechanism ....................................................................... 625 30.3.2 The “Eureka!” .................................................................... 625 30.3.3 Rheological Properties ..................................................... 626 30.3.4 Primary Functions of Elastomeric Gels in Personal Care Applications .............................................................. 627 30.4 Formulating with Elastomeric Copolymers .................................. 628 30.4.1 Identify The Appropriate System ....................................... 628 30.4.2 Incorporating the Gelling Copolymer ................................. 629 30.4.3 Prototype Formulation ...................................................... 630 References .......................................................................................... 631

30.1 Introduction A review of the literature shows that most of the studies and experiments related to use of rheological modifiers in cosmetic applications have been primarily focused on aqueous-based systems. Approaches to thicken, or rheologically modify the nonaqueous phase in such systems has rarely been dis-

cussed. The purpose of this chapter is to review the basics of rheology modifiers used for oil-based systems or the oil-phase of emulsions used in personal care products. This work describes some novel developments in this field and compares them with traditional thickeners in terms of functionality and performance. Guidelines for formulating the newer systems are presented as well as prototype formu-

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 621–632 © 2005 William Andrew, Inc.

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lations and emerging applications. In order to understand the behavior and performance of rheologically modified oils useful for delivery systems in the personal care industry, we will first explain, in depth, the nature of thermoplastic elastomers and how they function.

30.2 Background For centuries, oils derived from the botanical plants or from petroleum distillates have been applied to skin for personal care purposes in order to provide lubrication and protection features. Such oils have commonly been used in their original physical form or have been incorporated into the oil phase of either oil-in-water or water-in-oil emulsions. Such emulsions typically contain thickeners as well as emulsifiers in the oil phase. Examples of such ingredients include the fatty acid soaps of lithium, calcium, and sodium; fatty alcohols; and solid waxes such as cetyl alcohol. For products that primarily consist of oil components, consumers have learned to accept they will be “runny,” and messy to apply. By contrast with the personal care products, many industrial applications also use oil and oil-based products as lubricants or protectants. However, unlike personal care products, these are routinely “thickened” to achieve the desired rheological behavior. For example, most automotive lubricants need to have a certain rheological behavior over a wide range of shear rates and temperatures. Under such conditions, it is critical that the oils not oxidize or breakdown prematurely in order to maintain the machinery in good operating condition. As advances in mechanical engineering have occurred over the years, the science that involves the study of the friction, wear, and lubrication between interacting surfaces in relative motion (i.e., tribology) has also advanced considerably.[1] While typical lubricants for such purposes consist of a base oil, they also contain an additive package that commonly incorporates ingredients such as dispersant-inhibitor blends, pour-point depressants, and viscosity index improvers. In order to better understand the functions of these additives, certain important parameters related to the fields of lubrication and tribology are defined here.

• Shear stability: The ability of a lubricant to withstand shearing without degradation as measured by a loss in viscosity.[2] • Shear thickening: An increase in apparent viscosity that occurs with increases of time, at constant shear rate.[2] • Shear thinning: A decrease in apparent viscosity that occurs with an increase of time, at constant shear rate.[2] • Viscosity: The bulk property of a fluid, semifluid or semisolid substance which causes it to resist flow.[3] Note: (1) Viscosity η is defined by η = τ/(dν/ds) where τ is the shear stress, ν is the velocity, ds is the thickness of an element measured perpendicular to the direction of flow, and dν/ds is shear. (2) Viscosity that is independent of shear rate and measuring time is known as Newtonian flow; such flow has also been termed the dynamic or absolute viscosity. (3) Kinematic, or static viscosity (ν), is the ratio of the dynamic viscosity to the density, at a specified temperature and pressure. It is given as ν = η/ρ. • Viscosity index (VI): A commonly used measure of describing the effect of temperature on viscosity.[3] • Viscosity index improver: An additive, usually a polymer, which reduces the variation of viscosity with temperature and thereby increases the viscosity index of an oil.[3] • Thixotropy:[4] A decrease in viscosity with increasing time, at constant shear rate. • Rheopectic:[4] An increase in viscosity while the material is being sheared and recovers to its original viscosity when allowed to rest. From a tribology standpoint, viscosity retention is critical for oils used as lubricants. An oil that thins out at high temperature (i.e., has lower viscosity) or under high shear rate will significantly increase the risk of poor lubrication since the lubricated surfaces can separate more easily under these conditions. On the other hand, an oil that is too viscous can cause

HEALY: NONAQUEOUS DELIVERY SYSTEMS WITH CONTROLLED RHEOLOGICAL BEHAVIOR excessive heat buildup, drag, and excess energy consumption. Certain polymers are commonly employed to improve the viscosity index and keep the viscosity of the oil within an acceptable operating range, regardless of the temperature, shear, and pressure. Viscosity index improvers function by assuming a compact, coiled structure at low temperatures and “stretching out” at high temperatures. This “stretching out” behavior increases the viscosity of the oil at higher temperatures and counteracts the normal tendency of the base oil to decrease in viscosity with increasing temperature. Viscosity index improvers usually consist of high molecular weight, oil-soluble polymers such as: • Ethylene-propylene copolymers • Polymethacylate esters • Hydrogenated styrene-diene copolymers Viscosity index improved oils usually contain only about one percent of such polymers.[5] In such systems, the polymer concentration is quite low; the polymer molecules can be visualized as working independently of each other with little or no interaction. In view of this behavior, conventional viscosity improvers that are typically linear are less resilient than multi-arm block copolymers when subjected to high shear. High shear rates can rupture conventional linear viscosity index improvers and reduce their molecular weight significantly even by cleaving the polymer molecule only once. Such ruptured polymers are much less efficient in protecting the oil since the considerable reduction in molecular weight results in a permanent viscosity loss. By the contrast, multi-arm block copolymers used as viscosity index improvers may only loose one or two arms under stress, and viscosity does not diminish as much as with the linear polymers, and the polymer integrity remains intact. Gelled oil is also widely used today in the telecommunication cable industry. Most of the cable fillers and flooding compounds that are used to fill cables are based on a combination of white mineral oil, petrolatum, and polymeric additives. This combination produces a very high viscosity at low shear rate. Such systems commonly have a yield stress at zero shear rate (i.e., solid-like behavior). For such rheological behavior, the term “gel” is frequently employed. Flooding compounds must have a high di-

623

electric constant and be able to repel moisture as well as insulate the copper wires should water migrate into the cable. The flooding compound is also required to be oxidatively stable, and pass a “drip test” at 80°C.[6] To meet these criteria, the gellants used for cable fillers are made from compositions of thermoplastic block copolymers and polyethylene wax. The thermoplastic block copolymers gel the oil and produce a flexible, semisolid state, and the polyethylene wax adds rigidity. The finished oil-gels have good flexibility over a wide range of temperatures. They provide excellent insulation for the metal wires, yet will not drip out of the cable casing.

30.2.1 Polymeric Rheological Additives for Nonaqueous Systems A number of homopolymers and copolymers have been used to thicken hydrocarbon systems for personal care and pharmaceutical applications. For example, polyethylene and its derivatives are the most familiar polymers of this type. Various grades of polyethylene were first introduced by Allied Chemical and other companies and are commonly used for coatings such as floor and furniture polishes. Useful polymers include homopolymers of polyethylene, oxidized homopolymers, ethylene-acylic acid copolymers, and ethylene-vinyl acetate copolymers. These polymers are compatible with a wide spectrum of resins, waxes, oils, and plasticizers used in such polish products. There are two grades of polyethylene polymers: low density (LDPE) and high density (HDPE). LDPE is produced by means of a radical polymerization process. This process produces highly branched molecules that have low crystallinity, low melting points, and low mechanical stability. HDPE contains unbranched molecules. HDPE properties include good crystallinity, high melting points, and good mechanical resilience. Polyethylenes form thixotropic gels when combined with the oils and esters typically used in personal care products. Rheological curves of such gels show a high yield-stress which is very useful for suspending pigments.[7] Polyethylene is commonly used in applications such as antiperspirant sticks, lipsticks, mascara, etc.

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The term thermoplastic elastomer is a description of a material that demonstrates a high degree of plasticity and is ductile under forming conditions. Such materials can be shaped at elevated temperatures, and then cooled. They can then be reheated and reformed into a different shape. This entire process can be accomplished without changing the basic structure or properties of the polymer making up the thermoplastic elastomer. There are four main types of thermoplastic elastomers. These are styrene-butadiene block copolymers; olefinic copolymers; urethanes, and polyester block copolymers. Most thermoplastic elastomers consist of two phases and in oil form as “phaseseparated” systems. One phase is hard and solid at room temperature while the other phase is an elastomer that has a low viscosity at room temperature. Often, the two phases are chemically bonded by block or graft copolymerization. The hard phase provides these materials with their strength. Without the hard phase, the elastomer would flow under stress, and would be unusable. When the hard phase is melted or dissolved in a solvent, flow can take place. Under these conditions, the thermoplastic elastomer can be processed. Upon cooling or evaporation of the solvent, the hard phase again solidifies and the thermoplastic elastomer regains its strength.[8] In such phase-separated systems, each of the two phases retain their own characteristics despite being combined together. Each phase of such systems has its own crystalline melting point (Tm) and glass transition temperature (Tg ). One example of a thermoplastic elastomer is SBS (styrene-butadiene-styrene). This material is a

Figure 30.1 SBS thermoplastic block copolymer.

block copolymer formed from butadiene in the middle of the polymer chain and styrene at the end. The polystyrene ends of adjoining chains are attracted to one another by strong polar association. This association produces domains that tightly hold the chains together. In between these rigid domains are rubbery areas comprised of polybutadiene. These rubbery areas are soluble in hydrocarbon oil and esters. The Tg for the hard phase styrenic block is 95°C and the Tg for the soft phase butadiene is –90°C.[9] Figure 30.1 illustrates a two-dimensional SBS structure,[10] while a representation of a similar structure in three-dimensional space is shown in Fig. 30.2.[11]

30.2.2

Unique Characteristics of Thermoplastic Block Copolymers

Thermoplastic block copolymers exhibit the unique two-phase morphology responsible for thermoplastic elastomeric behavior. However, not all block polymers are thermoplastic elastomers, and not all thermoplastic copolymers have the structures of block copolymers. The (polystyrene) domain theory described previously (Sec. 30.2.1) effectively relates the vulcanization process employed in the rubber industry to the properties of the resulting thermoplastic elastomers. Rather than using sulfur as the crosslinking agent, the end-styrenic blocks are employed as crosslinking agents. This configuration forms tightly knit domains at the ends of the polymers, while the mid-segment elastomers are more loosely configured and entangled together. Unlike vulcanization, which is a slow irreversible process

Figure 30.2 Three-dimensional pictorial representation of thermoplastic elastomers.

HEALY: NONAQUEOUS DELIVERY SYSTEMS WITH CONTROLLED RHEOLOGICAL BEHAVIOR that produces a rubber that cannot reverse back to the original, the domains of thermoplastic polymers can disassociate and reassociate almost infinitely. This capability results in thermal reversibility properties for the elastomeric copolymers. The polystyrene domains in styrenic copolymers fulfill three critical functions:[12] • They act as physically reversible crosslinks and tie the elastomer chains together. This behavior forms a network that is effective at ambient temperature, but allows flow at elevated temperature.

625

lene), and poly(ethylene-butylene). The basic structures for the styrenic block copolymers are: Diblock

S-E

(n = 1)

Triblock

S-E-x-E-S

(n = 2)

Branched (S-E)n-x (radio block)

(n > 2)

where S represents a polystyrene segment, E represents an elastomer segment, n represents the number of repetitive monomer structures, and x represents a junction point between segments with a functionality of n.

• They prevent the entangled elastomer chains in the network from disentangling. • They act as reinforcing fillers, just like the carbon black and silica used in SBR rubber. Since the styrenic blocks behave in accordance with the description above, the ratio of the styrenic/elastomer block determines the strength of the resulting copolymer. As the polystyrene content or molecular weight increases, the block copolymers change from a soft consistency to a hard consistency. The block copolymers are phase-separated systems, so their appearance is typically opaque. Indeed, a mixture of polystyrene and polybutadiene is opaque even though both polymers are clear in their individual states.[13] However, block copolymers such as SBS are quite clear because of the small size of the molecular domains. The diameter of the polystyrene domains is estimated to be around 400 angstroms, if not smaller, while the wavelength of visible light is about 5,000 angstroms. As a result of the polystyrene domains being so much smaller than a wavelength of light, they do not scatter light significantly and both SBS and similar copolymers are transparent.[14] Styrenic block copolymers do not exhibit any crystallinity and are soluble in almost all organic solvents. However, because the block polymers are based on different block segments, almost no solvent dissolves both segment types completely. Aliphatic hydrocarbons have better solvency for the elastomer segments while more aromatic solvents tend to dissolve the polystyrene blocks more effectively. Several elastomeric mid-segments have long been used for commercial purposes. These include polybutadiene, polyisoprene, poly(ethylene-propy-

30.3 Thermoplastic Block Copolymers as Rheological Modifiers 30.3.1

Mechanism

Thermoplastic block copolymers by themselves do not have significant application potential in personal care products. These materials are very rubbery and elastic, and the melting point is too high for use with other common ingredients or polymers and they are generally incompatible. The only way to take advantage of the unique properties of the block copolymers in personal care applications, without detrimental effects, is to use “diluted” polymers. As mentioned in the Sec. 30.2, thermoplastic copolymers are commonly used as rheology modifiers in lubrication and the base oil is usually composed of paraffin and napthen mineral oil or synthetic hydrocarbons.

30.3.2 The “Eureka!” In view of fact that most of the oils and emollients used in the personal care industry are longchain, fully hydrogenated hydrocarbons or fatty esters, it is an obvious extension to think of using thermoplastic polymers as rheological modifiers for emollients. Fully hydrogenated mineral oil (70 SUS white oil), such as baby oil, is the most common basic emollient used for personal care applications. The

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elastomeric segments of the copolymers are soluble in this white oil, while the styrenic block segments are not. Upon addition of such copolymers to mineral oil, a heterophase mixture is formed. The SBS type of “ABA” triblock copolymers, which has styrenic blocks on both ends of the molecule, will absorb the white oil and form a solid or semisolid clear rubbery material. This material has good tear strength but poor “payout” and spreadbility. Styrene/ ethylene or styrene/ethylene/butylene type of diblock copolymers have only styrenic blocks at one end of the molecule. They will form a clear, stringy, oil gel that is easy to spread, but has low tear strength. In view of these properties, it is foreseeable that a blend of di- and triblock copolymers can be made to achieve the desired balanced performance required for personal care systems. A patent published in 1993, by P. DesLauriers and W. Heilman,[15] confirmed that mineral oil gel compositions of certain blends of diand triblock copolymers would have advantageous properties. Such properties include the ability to form clear, anhydrous, thickened systems useful for personal care, health, and beauty aid applications. The state of a mixture of di- and triblock copolymers is illustrated in Fig. 30.3.[16] Diblock copolymers only have one polystyrene block at the end. This means the polymer is attached to one styrenic domain with a tail (elastomeric block) dangling free. A small amount of triblock copolymer acts as a crosslinking agent for the diblock polymers. With polystyrene blocks on each end, triblock copolymers connect polystyrene domains together. This process builds up a three-dimensional network where

Figure 30.3 Diblock plus triblock copolymers (1: diblock; 2: triblock).

the linear hydrocarbon oil (i.e., mineral oil) is enclosed inside the network. The polystyrene domains will disassociate when the temperature reaches about or above 95°C. The polystyrene domains may reassociate under the influence of chemical intermediates or thermal and mechanical stress. However, the styrenic domains will always regain their strength by forming newly associated styrenic domains due to the chemical affinities among the styrenic blocks. The reassociation of domains upon cooling is the reason why the block copolymer oil-gels are thermally reversible and able to withstand mechanical stress. The degree of crosslinking determines the strength of the gel and this is reflected in the resulting viscosity of hydrocarbon oil-gel when it is sheared.

30.3.3

Rheological Properties

The rheological properties of combinations of hydrocarbon oil and thermoplastic block copolymers are characteristics of a very unusual class of nonNewtonian fluid. Their viscosity increases with increasing shear rate (dilatant) and with time of shearing (rheopectic). The viscosity of the hydrocarbon-based thermoplastic gels is primarily controlled by the type of the polymers used and the degree of interpolymeric crosslinking. A gel that is solely based on diblock copolymers will have very little strength. On the other hand, a gel that contains only triblock copolymers will have high strength since it has a very tight network that almost resembles a solid material. Use of such materials for personal care applications requires careful selection of a suitable balance between the diblock and triblock copolymers. While the type of copolymer is the main contributor to the final rheological behavior, the nature of the oil base and its degree of compatibility with the elastomeric and the styrenic segments of the copolymer are also important. Figure 30.4 shows viscosity-versus-temperature curve comparisons between two of thermoplastic copolymer gels based on isohexadecane and hydrogenated polyisobutene. The viscosity of the gel based on the lower molecular weight hydrocarbon is seen to exhibit lower viscosity.

HEALY: NONAQUEOUS DELIVERY SYSTEMS WITH CONTROLLED RHEOLOGICAL BEHAVIOR

627

Figure 30.4 Hydrocarbon gels: viscosity vs temperature profile.

30.3.4 Primary Functions of Elastomeric Gels in Personal Care Applications Whether included in a completely anhydrous system or in an emulsion system, the thermoplastic polymer gels always play one or a combination of the following roles described here. Thickener. When a hydrocarbon gel is included in a personal care product, its ability to act as a rheology modifier is of prime importance. This is especially true for water-in-oil emulsions where thickening the external oil phase dramatically improves the stability of the emulsion and its ability to suspend the water droplets consisting of the internal phase. This ability reduces the need for waxy types of thickener or emulsifier normally employed as well as particulate thickeners such as colloidal silica or clay. When incorporated into such w/o emulsions, the block copolymers produce more cushioning, higher “body” and more “play-time.” In cases where fine particles may be included in the oil phase first, adding the copolymer gelling agents will assist in stabilizing the dispersion of the particles. For completely anhydrous systems, the thickening effect produced by the elastomeric copolymers is far more visual and apparent than in a two-phase emulsion system. If the system contains oil components that are compatible with the block copolymer gel, the polymer network will be

able to expand and enclose the oil, thereby forming a transparent gel. Applications such as baby oil gel, or massage oil gel are ideal candidates for use with elastomeric copolymers. Suspension vehicle. Suspending insoluble particles in an acceptable carrier employed to deliver the particles has been a common practice in the personal care industry for many years. In some cases, these suspensions are used for decorative purposes. Examples of such particles include mica or glitter, or a whole range of bimetallic pigments capable of providing spectacular iridescent and color changing effects. Often, the suspension involves insoluble solids or pharmaceutically active ingredients such as particulate sunscreen agents like zinc oxide or titanium dioxide. The high yield-stress provided by the thermoplastic block copolymer gels acts to improve product shelf life by reducing or eliminating pigment sedimentation. Stability tests conducted on a mineral oil based gel containing a zinc oxide suspension at 50% solids indicate the suspension stayed intact for a week at 100°C (Fig. 30.5). Film former. Like many polymeric ingredients, the cross-linking property of the thermoplastic elastomers provide an ability to form a thin layer when applied to substrates. This tendency depends upon the nature of the substrates and other ingredients involved. Resulting films will have varying degrees of affinity for the substrate, and this will directly

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Figure 30.5 Zinc oxide suspension stability test at 100°C.

impact how long the film will last. As long as the film remains intact, it acts as a barrier between the substrate and the surrounding media. In personal care applications involving skin care, such elastomeric films provide a barrier to water and reduce transepidermal water loss (TEWL). The human dermal structure requires a sufficient water content in order to remain supple and elastic. It has been shown that traditional emollients may cause flattening of the surface contours of the skin, plumping of the individual corneocytes, and general smoothing and diminishing of facial lines.[17] Excessive water loss is one of the main contributors to premature aging of the skin. While humectants may be employed to input water into skin, another effective practice is to use occlusive agents which prevent the water from escaping. Examples of such humectants include the use of oil-soluble emollients like hydrocarbon oils, silicone oils, alkyl esters, etc. It is believed that when the diblock and triblock polymers described in this chapter are included in such nonaqueous fluids, an enhancement of emolliency is achieved as a result of the film-forming property described. Figure 30.6 shows a comparison of a TEWL test comparing a neat mineral oil with that of a block copolymer-gelled mineral oil. The results clearly indicate that the gelled oil exhibited better TEWL reduction.

30.4 Formulating with Elastomeric Copolymers 30.4.1 Identify The Appropriate System Thermoplastic block copolymer-modified hydrocarbon fluids have a great deal of versatility and can be utilized in many cosmetic and personal care applications. It is important however to evaluate the potential formula as a whole in order to gain a true assessment of whether the diblock and triblock copolymer technology adds value in a specific formulation. Several critical questions need to be asked in advance of formulating: • Does the formulation contain anything that is extremely polar, such as ethanol or aldehyde, which will soften, or dissolve the styrenic blocks, and therefore impair the stability of the polymeric network. • Does the formulation contain an ample amount of oil, or oil phase, for the polymeric network to expand and stabilize itself? • Does the formulation require the benefits available by incorporation of the polymers?

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629

Figure 30.6 Transepidermal water loss (TEWL) comparisons.

For most anhydrous products, polymer-based gels are perfect candidates. Such gels are usually employed as the viscosity modifier of choice. Hydrocarbon oils are popular in view of their wide availability, long-term safety record and relatively low cost. Most hydrocarbon oils also have good compatibility with the thermoplastic block copolymers described. More often than not, at least one ester will be involved in the formula as a skin conditioning agent or a “feel” modifier. Most of the esters that contain C8 or longer carbon chains, and no more than one polar functional group (such as a carbonyl or carboxyl) have sufficient compatibility with the polymeric gels for them to act as thickeners. Long-chain fatty esters such as isopropyl palmitate, isopropyl myristate, C12-15 alkyl benzoate, and octyl palmitate, all have excellent compatibility with the thermoplastic block copolymers described. Certain types of esters and silicones, such as hexyl isostearate and cyclomethicone, are compatible with the thermoplastic block polymers to a limited degree. Vegetable oil and other plant-derived oils consist mainly of triglycerides and fatty alcohol that have poor compatibility with the polymeric elastomers. One exception to this is jojoba oil, which has excellent compatibility because of the presence of a long-chain fatty-ester structure. Overall, with the right balance of ingredients, one can easily achieve the desired product consistency and appearance in finished formulations.

30.4.2 Incorporating the Gelling Copolymer Incorporation of the thermoplastic block polymers into a completely anhydrous product requires unconventional techniques. As mentioned earlier, the styrenic blocks of the polymers have a tendency to form tightly held domains when these polymers are “dissolved” in a hydrocarbon oil environment and exist at room temperature. However, these domains will disassociate at an elevated temperature of about 95°C. This temperature is critical when the polymers are blended with other materials and the elastomer portion of the polymers is being incorporated into the oil. During this process, the gel structures formed have to go through a “reorganization” before they reach the next stabilized stage and can reassociate themselves to form new styrenic domains. For most hydrocarbon oils, it is recommended that the oil and the polymers be heated to at least 95°C during blending operations. If blended with esters, the styrenic domains of the copolymers may be softened tremendously. For esters, therefore, the required mixing temperature is slightly lower than 95°C. If the gelling polymers are used in the oil phase of an emulsion, the oil phase should first be heated to the required temperature in order to incorporate the gelling agent, and then cooled to the appropriate

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temperature for blending with the water phase. An improperly mixed polymer oil-phase, or an oil gel that contains improperly mixed polymers, will produce the emulsions with poor stability. Most of the time, an inconsistent viscosity reading for the oil phase, or an oil gel that contains elastomeric polymers, is a characteristic sign of a poorly mixed system.

30.4.3 Prototype Formulation Formulation 30.1 contains a prototype formulation for baby oil gel.[19] The formula is a gelled white mineral oil using the thermoplastic block copolymers. In order to obtain a more fluid product, additional 70 SUS white mineral oil was added to reduce the high viscosity of the gelling agent of Versagel ® M1600.

Formulation 30.1: Baby Oil Gel

Phase

Ingredient ®

A

B

Function

Weight%

Versagel M1600

Moisturizer

44.60

®

Drakeol 7

Moisturizer

30.00

Isopropyl isostearate

Feel Improver

10.00

Propylene glycol isoceteth-3 acetate

Co-solvent

10.00

Isopropyl isostearate

Co-solvent

5.00

Propylparaben

Presevative

0.10

Fragrance

0.30

Mixing Instructions 1. Combine Versagel M1600 and Drakeol 7 and heat the mixture up to 95°C while mixing. 2. When the mixture is uniform, lower the temperature to 75°C, then add the isopropyl isostearate and mix well. 3. Add the rest of the ingredients except fragrance. 4. Cool the blend to about 45°C for fragrance addition and packaging. Disclosure This formula was developed by Penreco based upon internal testing of non-market products containing Versagel M1600 and is being distributed only for the purpose of promoting the use of Versagel ME1600 as a component of secondary cosmetic products. All formulations, including the formula set forth herein above, should be thoroughly researched by the proper personnel prior to use, which research should include irritation, allergic reaction and toxicological testing, as well as the review of any patent or other intellectual property law restrictions or prohibitions. Because of varying manufacturing conditions and component mixtures, neither Penreco, nor any affiliates of Penreco, make any warranties, expressed or implied, as to the accuracy of the formulation or the actual results of its use and Penreco expressly disclaims any and all liability resulting from the use of this formula or any secondary cosmetic products produced thereby. Nothing contained herein is to be construed as granting permission or making recommendation to use any patent or other intellectual property law rights owned by Penreco, Pennzoil Products Company or any other company or individual. The use of the foregoing formula shall constitute a waiver and release of Penreco and any affiliates of Penreco, of any infringement violation or alleged infringement violation, whether direct or claimed to be through contribution or inducement, of any patent or other intellectual property rights relative to the formulation or any products derived from or produced through its use.

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References

631

1. Wear Control Handbook (M. B. Peterson and W. O. Winer eds.), p. 1188, ASME (1980)

11. Thermoplastic Elastomers- A Comprehensive Review (N. R. Legge, G. Holden, and H. E. Schroeder, eds.), p. 515, Hanser Publishers (1987)

2. Wear Control Handbook (M. B. Peterson and W. O. Winer eds.), p. 1183, ASME (1980)

12. Holden, G., Understanding Thermoplastic Elastomers, p. 19, Hanser Publishers (2000)

3. Wear Control Handbook (M. B. Peterson and W. O. Winer eds.), p. 1189, ASME (1980)

13. Holden, G., Understanding Thermoplastic Elastomers, p. 21, Hanser Publishers (2000)

4. Rheological Properties of Cosmetic and Toiletries (D. Laba, ed.), p.16, Mercel Dekker (1993)

14. Holden, G., Understanding Thermoplastic Elastomers, p. 22, Hanser Publishers (2000)

5. Alexander, D. L., The Viscosity of Lubricants, Lubrication, 78(3) (1992) 6. Product Brochure – Cable Filler, Penreco 7. Encyclopedia of Polymer Science and Engineering, Second Edition, John Wiley & Sons, Index Volume, p. 28 (1998)

15. DesLauriers, P. J., and Heilman, W. J., U.S. Patent 5,221,534, Health and Beauty Aid Compositions (1993) 16. DesLauriers, P. J., and Heilman, W. J., U.S. Patent 5,221,534, Health and Beauty Aid Compositions (1993)

8. Holden, G., Understanding Thermoplastic Elastomers, p. 10, Hanser Publishers (2000)

17. Rheological Properties of Cosmetic and Toiletries (D. Laba, ed.), p.12, Mercel Dekker (1993)

9. Holden, G., Understanding Thermoplastic Elastomers, p. 12, Hanser Publishers (2000)

18. Harry’s Cosmeticology, Seventh Edition, p. 65, Chemical Publishing Co., Inc. (1982)

10. Holden, G., Understanding Thermoplastic Elastomers, p. 16, Hanser Publishers (2000)

19. Formulation Guide for Versagel® Products, Penreco (2001)

Part X Silicones

Linear Silicone Fluid Delivery Systems With Controlled Volatility Features

Cationic Silicone Complexes as Delivery Systems

SILICONES

Silicone Technology as Delivery Systems for Personal Care Ingredients

"Pro-Fragrant" Silicone Delivery Polymers

31 Cationic Silicone Complexes as Delivery Systems Anthony J. O’Lenick, Jr. Siltech LLC Dacula, Georgia Charles W. Buffa Biosil Technologies Inc. Paterson, New Jersey

31.1 31.2 31.3 31.4

Introduction ................................................................................... 636 The “Eureka!” Moment.................................................................. 636 Group Opposites .......................................................................... 636 Silicone Compounds .................................................................... 637 31.4.1 Carboxy Silicone Polymers ............................................... 637 31.5 Fatty Quaternary Ammonium Compounds .................................. 639 31.6 Silicone Complex Improvements .................................................. 639 31.6.1 Organic Quats .................................................................. 639 31.6.2 Silicone Quat Complexes ................................................. 639 31.7 Desirable Properties of Cationic Silicone Complexes .................. 640 31.7.1 Compatibility with Anionic Surfactants .............................. 640 31.7.2 Compatibility with Anionic Surfactants Test ...................... 640 31.8 Fatty Quaternary, Carboxy Silicone Conditioner ........................... 641 31.8.1 Test Method....................................................................... 641 31.8.2 Test Results ...................................................................... 642 31.9 Recent Advancements ................................................................. 644 31.10 Conclusions .................................................................................. 644 31.11 Formulations ................................................................................. 645 References .......................................................................................... 666

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 635–666 © 2005 William Andrew, Inc.

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31.1 Introduction The ability to deliver actives to the hair and skin is a key area of interest to the cosmetic formulator. Water-soluble materials that have no affinity for the hair or skin will only be effective in providing a benefit if they are retained on the substrate of choice. To develop cost-effective formulations, it is imperative to increase the substantivity of actives to hair and skin. As we use the term actives, it relates to any material the cosmetic chemist wants to place onto the hair or skin, rather than being restricted to certain traditional actives. For example, if a cationic conditioner is in an aqueous product, it can be considered an active and anything that facilitates the delivery of that conditioner onto the hair or skin is, in the simplest terms, a delivery system. We have developed complexation technology that allows for enhanced delivery to hair and skin. We believe this will become a major new application area for the cosmetic chemist. The successful approach described in this chapter is accomplished by making a salt that, by virtue of its molecular weight, is delivered preferentially to the skin or hair. Since larger molecules disrupt more hydrogen bonding between water molecules in aqueous systems, large sparingly soluble molecules have a tendency to preferentially deposit on substrates to achieve the lowest energy level. This concept of delivery allows for the formulation of products that provide outstanding performance and ease of formulation.

31.2 The “Eureka!” Moment Complex delivery dates back to May 1981, when pioneering work was done by Lucassen and Giles.[1] They showed that when mixed surfactant systems (anionic/cationic) are evaluated, the mixed surfactant often gave synergistic surface activity. Simply put, when a cationic and an anionic surfactant are mixed, they form a complex. If one mixes sodium lauryl sulfate and stearalkonium chloride together, one obtains sodium chloride, and a stearalkoniumlauryl sulfate complex. This complex is insoluble in water and it will precipitate in order to produce the lowest free-energy state system. If the surfactant molecules are chosen so that the complex is not insoluble and, instead, exhibits a low solubility in wa-

ter in the presence of a substrate, it will then deposit on that substrate in order to achieve the lowest possible energy state. In short, by properly selecting the solubility of the complex, one increases deposition on hair or skin and obtains “delivery.” The reader is referred to the Journal of Colloid and Interface Sciences, Vol. 81, No. 1, pp. 150–157 for a detailed physical chemistry of this phenomenon. We initially became interested in this technique during the study of methods to deliver water-soluble dyes to textile fibers. Such dyes were not terribly substantive, and most of the product was lost in the waste water. Ideally, if there was a charge on the fiber, the opposite charge could be put onto the dye and the process efficiency improved. Most times, however, this was not possible, and we observed that water-insoluble color compounds could not be easily delivered to the textile surfaces. It turned out that the very same emulsifiers that emulsified the color compound in the water also acted as detergents, and could remove the color so deposited. In the textile area, when a hydrophobic treatment is required, one can treat the fiber with silicone or with a hydrocarbon. Both types of treatment will result in a hydrophobic finish. However, if treated with silicone, the fiber will also be oleophobic. If treated with oil, the fiber will also be siliphobic. Thus, for waterproofing fibers, selection of the proper molecule is critical, since improper selection will result in unacceptable oil staining. In search of a solution to this problem, we discovered that when a charged silicone compound was chosen and complexed with a surfactant having the opposite charge, a more efficient mechanism to deliver the active was achieved. We quickly modified this concept to allow for the delivery of many noncolor compounds to the hair and skin and thereby achieved a powerful new approach for the delivery of useful personal care actives to the hair and skin.

31.3 Group Opposites In order to understand the technology described in this chapter, one first needs to understand the concept of group opposites. This concept was developed recently and explained in terms of solubility group opposites.[2] Originally, there were two types

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS of “opposites”: oil-soluble and water-soluble. Now, with the growing availability of organosilicone materials in personal care products, a new type of “opposite” needs to be introduced. The presence of silicone groups in the molecule alters the solubility and can result in an improved deposition on hair and skin of silicone-modified materials. When compounds are least soluble in water, they will be more likely to deposit on substrates, or end up at an interface. The trick in designing an effective molecule with enhanced deposition capability is to generate sufficient water-solubility to allow for a cosmetically appealing aqueous product, yet, at the same time, to have limited the water-solubility so that it will preferentially absorb onto the substrate. Charged silicone polymers offer a very attractive delivery system for actives having the opposite charge. This concept extends to standard quaternaries as well as many other useful ionic actives such as polyacrylate type polymers. Table 31.1 describes some very useful definitions, and their opposites, which are critical for understanding and achieving delivery.

31.4 Silicone Compounds In the 1990s, there was a considerable expansion in the number of silicone surfactants available commercially. In fact, there has been a duplication of virtually all classes of compounds available as carbon-based surfactants in the world of silicone surfactants. Table 31.2 outlines a range of products with similar functionality available in both the world of fatty chemicals as well as that of silicone.

637

phosphates, sulfates, and sulfosuccinates. Having such an ionic charge is the first requirement for making a delivery complex. The second requirement for making a delivery system complex is to make the silicone compound barely water-soluble. Silicone polymers offer extraordinary opportunities to vary solubility and, therefore, improve delivery and attachment to the desired substrates. A series of new products have been prepared and commercialized that incorporate silicone, fatty, and water-soluble moieties. These materials demonstrate improved substantivity to hair and skin, as expected.

31.4.1 Carboxy Silicone Polymers As an example of the effective use and application of cationic silicone complexes for enhanced personal care delivery systems, we present below specific complexes obtained between carboxy functional silicone polymers and selected fatty quaternary compounds. Carboxy silicone polymers useful in making delivery complexes have a pendant carboxy group present and consequently are anionic surface-active agents. Appropriate selection of the silicone portion of the molecule, combined with the proper cationic portion, has been found to considerably improve delivery and deposition uniformity of actives on the hair and skin. The delivery complexes have the structure shown in Fig. 31.1. These complexes are large molecules that disrupt hydrogen bonding in water and, as such, are preferentially adsorbed on the substrate in order to obtain an aqueous solution with the minimum free energy.

The new silicone-based products have increased substantivity to hair and skin as a result of the presence of the silicone moiety. In fact, to predict the solubility of Table 31.1. Group Opposites products having oil-soluble, water-soluble, and silicone-soluble Hydrophilic (water loving) Hydrophobic (water hating) portions, an expansion of the wellOleophilic (oil loving) Oleophobic (oil hating) known HLB system has been proposed and has come to be Siliphilic (silicone loving) Siliphobic (silicone hating) known as the 3D HLB System.[3] Note: Many of the compounds listed • Hydrophobic materials can be either oleophilic or siliphilic. in Table 31.2 possess an ionic • Oleophobic materials may be either hydrophilic or siliphilic. charge, and these include func• Siliphobic materials may be either oleophilic or hydrophilic. tional groups like carboxylates,

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 31.2. Comparison of Hydrocarbon Compounds with Silicone-modified Compounds[4]

Hydrocarbon Products

Silicone Products

Anionic Compounds Phosphate esters

Silicone phosphate esters[5][6]

Sulfates

Silicone sulfates[7]

Carboxylates

Silicone carboxylates[8][9]

Sulfosuccinates

Silicone sulfosuccinates[10][11]

Cationic Compounds Alkyl quats

Silicone alkyl quats[12]

Amido quats

Silicone amido quats[13]

Imidazoline quats

Silicone imidazoline quats[14]

Amphoteric Compounds Amino proprionates

Silicone amphoterics[15]

Betaines

Silicone betaines[16]

Phosphobetaines

Silicone phosphobetaines[17]

Nonionic Compounds Alcohol alkoxylates

Dimethicone copolyol

Alkanolamids

Silicone alkanolamids[18]

Esters

Silicone esters[19][20][21][22]

Taurine derivatives

Silicone taurine[23]

Isethionates

Silicone isethionates[24]

Alkyl glycosides

Silicone glycosides[25]

CH3 CH3 CH3 CH3 | | | | CH3—Si—(—O—Si—)a—(O—Si)b—O—Si—CH3 | | | | CH3 CH3 (CH2) 3 CH3 | O—(CH2CH2O)xC(O)—R—C(O)—O– CH3 | R—N+—CH3 | CH3 Figure 31.1 The structure of a delivery complex (Cetylsil®) based on carboxy silicone polymers.

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS

31.5 Fatty Quaternary Ammonium Compounds Fatty quaternary compounds are commonly called quats. They are tetra-substituted ammonium compounds in which each of the four groups on the nitrogen atom are comprised of groups other than hydrogen. If any hydrogen groups are present, the compounds are not considered quaternary amines; they are then known as primary or secondary amines. There are several well-known, undesirable attributes of fatty cationic products. In each case, these attributes may be improved by complexation with an anionic silicone moiety. Examples of these undesirable attributes include: • Fatty quaternary compounds are incompatible with anionic surfactants since an insoluble complex is frequently formed when the two types of materials are combined. This problem frequently occurs using polyacrylates as thickeners since they are cationic. • Many fatty quaternary compounds are eye irritants;[26] such materials are minimally irritating to the eyes at concentrations of 2.5 weight percent.[27] This limits the useful concentration. • Fatty quats are generally hydrophobic and, when applied to a substrate, cause a reduction in water absorbency of the substrate. It is not an uncommon situation for a traveler staying in a hotel to encounter a very soft towel that totally fails to absorb water. This is because the fatty quaternary treatment provides softness, but also prevents rewetting as a result of its hydrophobic nature. This situation can be also observed on hair when the absorbed conditioner prevents the hair from rewetting. The phenomenon causes the hair to become “gunky” and results in undesirable buildup of the material.

31.6 Silicone Complex Improvements Making silicone complexes with carboxy silicone compounds can mitigate many of these undesirable

639

attributes of the fatty quaternary ammonium compounds. The complexes of carboxy silicones with quaternary compounds produce altered properties which make them highly desirable in personal care applications such as shampoos, body washes, and other cleansing products. A comparison of two such complexes with two well-known quats is described below.

31.6.1 Organic Quats Stearalkonium chloride is well known to be an excellent conditioning agent, and imparts outstanding substantivity to hair. The product has detangling properties and improves wet-comb properties when applied after shampooing. The FDA formulation data reports the use of this material in 78 hair conditioners. Of these conditioners, eight are used at levels of less than 0.1%, eighteen at levels of between 0.1% and 1.0%, and fifty-two at levels of between 1.0% and 5.0%. Cetyltrimonium chloride, or CTAC, is well known to be a very substantive conditioner. In addition to providing a non-greasy feel, the material also improves wet-comb properties and also provides a gloss to the hair. The product, however, is classified as a severe primary eye irritant and therefore its useconcentration is generally limited to less than or equal to 1.0% by weight.

31.6.2

Silicone Quat Complexes

By contrast to the organic quats described above, it has been found that silicone carboxy fatty quaternary complexes offer significant advantages in personal care applications. Surprisingly, these materials form clear, water-soluble complexes with anionic systems in aqueous solution. They have been demonstrated to provide outstanding wet-comb properties and antistatic properties on hair. Further, these materials also provide non-greasy, softening properties to hair and skin, are minimally irritating to the eyes, and can be used to formulate clear conditioners. Significantly, these properties are seen in shampoo systems at concentrations below 0.5% by weight because the energetics of the solution favor deposition onto hair rather than retention in solution. The

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

silicone-quat complex offers considerable enhancement in deposition and conditioning, and enables the formulator to maintain efficacy in shampoos, while significantly reducing the component concentrations.

Stearasil® is compatible with, and forms clear solutions over a range of concentrations.

Commercial examples of such products are described in Table 31.3

31.7.2

31.7 Desirable Properties of Cationic Silicone Complexes

A ten-percent-solids solution of sodium lauryl sulfate (Colonial SLS from Colonial Chemical) was prepared. Separately, a ten-percent-solids solution of the quat (or quat silicone complex) being tested was also prepared. The quat was titrated into 100 ml of the sodium lauryl sulfate solution. The formation of a white, insoluble complex, or a haze, is considered to be the end point of the titration.

Cationic silicone complexes demonstrate major improvements over the original quat precursors in a variety of key areas. These include anionic compatibility, reduction of eye irritation, improved rewetting, improved compatibility with polyacrylates, and improved conditioning and combability of hair.

31.7.1

Compatibility with Anionic Surfactants

Traditional fatty quats like stearalkonium chloride and cetyltrimonium chloride, form water-insoluble complexes when combined with sodium lauryl sulfate in aqueous solution. This phenomenon is due to the formation of an insoluble anionic/ cationic complex. Cetylsil®, like the traditional quats, also forms a complex, but surprisingly however,

Compatibility with Anionic Surfactants Test

As can be seen from the data in Table 31.4, Stearasil is unique in that it is compatible with sodium lauryl sulfate systems. Eye irritation. Eye irritation is a major concern in the formulation of personal care products, particularly when working with quaternary surfactants. Primary eye irritation was tested using the protocol outlined in FHSLA 16 Code of Federal Regulations 1500.42. The products were tested at 25% actives and the results obtained are outlined in Table 31.5. Rewetting properties. When complexes of fatty quaternary compounds and carboxy silicone are used to treat textile fabrics, they make the substrate soft, but they do not make them hydrophobic. This distinguishes their behavior from the standard fatty

Table 31.3. Commercially Available Products

Commercial Name

INCI Name

Fatty Quat

Stearasil

Stearalkonium dimethicone copolyol phthalate

Stearalkonium chloride

Cetylsil

Cetrimonium dimethicone copolyol phthalate

Cetyltrimonium chloride

Stearasil S

Stearalkonium dimethicone copolyol succinate

Stearalkonium chloride

CetylsilS

Cetrimonium dimethicone copolyol succinate

Cetyltrimonium chloride

Stearasil and Cetylsil are registered trademarks of Biosil Technologies Inc.

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Table 31.4. Compatibility with Anionic Surfactants Test

Test Compound

End Point (ml)

Appearance

Material Type

Stearalkonium chloride

0.3

White solid

Fatty quat

Cetyltrimonium chloride

0.2

White solid

Fatty quat

Cetylsil®

0.5

White solid

Silicone quat complex

35.8

Haze develops

Silicone quat complex

®

Stearasil

®

®

Stearasil and Cetylsil are registered trademarks of Biosil Technologies Inc

Table 31.5. Eye Irritation

Product Cetyltrimonium chloride Cetylsil® Stearalkonium chloride* Stearasil

®

Score 106.0 8.3 116.5 11.3

Irritation Level

Material Type

Severely irritating

Fatty quaternary

Minimally irritating

Silicone complex

Severely irritating

Fatty quaternary

Minimally irritating

Silicone complex

* At a concentration of 0.5%, stearalkonium chloride was minimally irritating. This rating of “minimally irritating” was the same rating achieved by Cetylsil® and Stearasil® when used at 25% (or 50 times the concentration). As the data clearly show, the irritation level for the silicone-quat complex is dramatically reduced when compared to the starting quat.

quats, which only make the substrate hydrophobic. This property is very important in the personal care area, and specifically to their use on hair. Hair treated with the silicone-complexed quat does not show evidence of any buildup on the surface of the hair.

31.8 Fatty Quaternary, Carboxy Silicone Conditioner The highly desirable properties of formulating a conditioner using a fatty quaternary, carboxy silicone compound can be demonstrated using the formulations and test methods described below. A base formulation and a commercial conditioner were selected as controls. Modifications were made to these by the addition of Stearasil and Cetylsil.

31.8.1 Test Method The test hair used was 7-inch, dark brown, virgin hair from DeMeo Brothers. Five two-gram tresses were used per product evaluated. All tresses were pre-washed three times with Prell original shampoo, rinsed in water at 25°C, and air-dried. Performance was rated using the scale shown in Table 31.6. Table 31.6. Numerical Scale Used to Rate Effects of Formulations on Hair

Rating

Description

1

Very poor

2

Poor

3

Satisfactory

4

Good

5

Excellent

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Test formulas T1–T6 (see Table 31.7) were produced, tested, and compared to demonstrate the effects of systems with organic quaternary compounds and their silicone counterparts. The components of the base formulation used in the tests are shown Table 31.8.

the advantage of inclusion of the fatty quaternary, carboxy silicone complex in this formulation. Dry comb properties. The formulas in Table 31.7 were also evaluated on dry hair. The qualitative test results are shown in Table 31.10. Dry comb conclusions.

31.8.2

1. Upon comparing Formulas T1, T3, and T5, the following trend emerges:

Test Results

Conditioning, wetability, and combability were evaluated for each of these systems according to the prescribed test method. The test results are shown in Table 31.9 and described here. Conditioning and wet combability. 1. Upon comparing Formulas T1, T3, and T5, the following trend emerges: Including stearalkonium chloride into the base formula did not improve the base at all (Formulas T1 and T5). However, inclusion of Stearasil® into the base formula improved residual feel, and wet combability (Formulas T1 and T3). This clearly shows the advantage of inclusion of the fatty quaternary, carboxy silicone complex in this formulation. 2. Upon comparing Formulas T1, T6, and T4, the following trends emerge: Inclusion of CETAC (cetyl trimethyl ammonium chloride) into the base formula did not improve the base at all. (Formulas T1 and T4). However, inclusion of Cetylsil® into the base formula, improved residual feel, and wet combability (Formula T1 and T6). This clearly shows

Inclusion of stearalkonium chloride into the base formula resulted in a marginal improvement (Formulas T1 and T5). However, inclusion of Stearasil into the base formula improved shine and dry comb characteristics, and provided a very significant improvement in fullness of the hair (Formulas T1 and T3). This clearly shows the advantage of including the fatty quaternary, carboxy silicone complex in this formulation. 2. Upon comparing Formulas T1, T6, and T4, the following trends emerge: Inclusion of CETAC into the base formula resulted in an improvement in shine and dry comb characteristics (Formulas T1 and T4). Inclusion of Cetylsil into the base formula improved all properties measured except curl retention (Formula T1 and T6). The above data clearly shows that the incorporation of cationic silicone complexes, called Stearasil and Cetylsil, into the base formula resulted in significant improvements in functionality. These improvements are a direct result of the usefulness of such adjuvants for enhancing delivery of personal care actives to the hair.

Table 31.7. Formulations Include Two Controls and Four Test Formulations

Test Formulation

Description

T1

Base Formula

T2

Commercial Conditioner

T3

Base Formula + 2% Stearasil®

T4

Base Formula + 2% CETAC added

T5

Base Formula + 2% Stearalkonium chloride

T6

Base Formula + 2% Cetylsil®

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Table 31.8. Base Formulation Used for Control and Test Formulations in Table 31.7

Phase

Ingredient

A

B

Function

% Weight

Water

Solvent

Qs 100.00

Tetrasodium ETDA

Chelating agent

0.15

Biosil Basics SPQ

Conditioner

0.55

Rice bran oil

Conditioner

4.00

Cetyl alcohol

Conditioner

3.00

Test ingredient

C

2.00

Glyceryl stearate

Conditioner

2.50

Propylparaben

Preservative

0.10

Germall 115

Preservative

0.20

Procedure 1. In a suitable container, weigh out all items in Phase A in order shown. 2. Mix well and heat to 75°C. 3. In a separate container, weigh out and combine all items in Phase B in the order shown. 4. Heat Phase B to 75°C. 5. Add Phase B to Phase A at 75°C, while agitating for at least 15 minutes. 6. Add Phase C. 7. Cool to 25°C–30°C.

Table 31.9. Hair Conditioning Performance Rating (See Table 31.6) of Formulas Listed in Table 31.7

Property

Formula 1

Formula 2

Formula 3

Formula 4

Formula 5

Formula 6

Residual feel

2

4

4

1

1

2

Squeaky feel

1

2.5

1

1

1

3

Shine

1

2

1

1

1

2

Wet comb

4

5

5

4

4

2.5

Spreadability

4

4.5

4

3

3

3

Smoothness

3

3.5

4

3

3

3

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Table 31.10. Dry Comb Performance Rating (See Table 31.6) of Formulas Listed in Table 31.7

Property

Formula 1

Formula 2

Formula 3

Formula 4

Formula 5

Formula 6

Residual feel

3

3

3

3

3

4

Shine

2

3

3.5

2.5

3

4

Dry comb

3

3

4

5

3

3.5

Fly away

2

2

2

2

2.5

2.5

Curl retention

3

2

2

3

2

3

Fullness

2

2

4

2.5

3

3

Manageability

3

3

2

2

2

3

31.9 Recent Advancements

31.10 Conclusions

There has recently been a patent awarded for the composition of complexes based upon alkylamidoquats, rather than the alkyl quats.[31] These complexes have a superior skin feel, and are better conditioners.

The use of silicone carboxy, fatty quaternary complexes as delivery systems offers the personal care formulator an enhanced ability to improve the cost-effectiveness of using water-soluble actives in formulations that provide a benefit to the hair and skin. This improvement is a direct result of the alteration of the original solubility of water-soluble actives. As a result of the described complex formation between anionic carboxy silicone compounds and cationic fatty quaternary actives, improved substantivity to hair in aqueous formulation is achieved. We believe this is a powerful formulation technique that is ripe for further development.

Recently a number of patents[32]-[34] have been issued in which the complexation phenomenon outlined in this chapter has been expanded to compounds in which neither the cationic compound nor anionic compound contain silicone. The anionic and cationic compounds are chosen so that the complex has minimal water solubility and is compatible with non-ionic silicone surfactants. The performance attributes mimic those of the complexes made from silicone anionic compounds and fatty quats.

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31.11 Formulations Formulations 31.1–31.22, provided by Biosil Technologies Inc., illustrate the efficacy of the carboxy silicone, fatty quaternary complexes in a number of personal care products. The formulations cover a range of hair and skin products:

Facial Cleansers

Formulation 31.17

Pomade

Formulations 31.18–31.19

Hair Growth Treatment

Formulation 31.20 Formulation 31.21

Shampoos

Formulations 31.1–31.4

Tanning Product

Body Wash

Formulations 31.5–31.7

Makeup Remover Formulation 31.22

Conditioners

Formulations 31.8–31.16

Formulation 31.1: Shampoo

Material

Function

Water

Weight % QS to 100.0

Ammonium lauryl sulfatea

Detergent

23.0

Cocamid DEAa

Viscosity builder

2.4

Cocamidopropyl betainea

Detergent

2.9

Tetrasodium EDTA

Chelating agent

0.1

Aloe vera gel

Active

0.1

Peg 6000 distearate

Opacifier

0.5

Cetylsil® b

Conditioning complex

2.5

Biowax 754

Emollient

4.0

Sodium chloride

Viscosity builder

Phenonip

Preservative

®

b

As desired 1.0

Mixing Procedure In a suitable container, heat water to 75°C, add each ingredient in the order shown, using good agitation, allowing 15 minutes between additions. Cool to 35°C and add preservative. To increase viscosity, add salt. Notes 1. Cetylsil® is the fatty quaternary, carboxy silicone, added for improved conditioning. 2. Biowax® 754 is added for improved combability. 3. Extracts like common nettle, henna extract, etc., can be added as desired. Sources a

Colonial Chemical, South Pittsburg, Tennessee

b

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.2: Shampoo

Material

Function

Water

Weight % QS to 100.00

Ammonium lauryl sulfatea

Detergent

25.00

Cocamide DEAa

Viscosity

2.40

Cocamidopropyl betainea

Detergent

2.90

Tetrasodium EDTA

Chelation

0.50

PEG-150 distearate

Emollient

2.50

Biosil® Basics SPQb

Conditioner

1.00

Dowicil 200

Preservative

0.30

Stearasil® b

Conditioner

2.00

Mixing Procedure 1. In a suitable container, begin to heat water to 70°C–75°C, adding one ingredient at a time with proper mixing during each addition. 2. Begin to cool to 35°C. Sources a

Colonial Chemical, South Pittsburgh, Tennessee

b

.

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.3: Clear Softening Shampoo

Phase

Material

Function

Water

Qs to 100.00

Sodium laureth-2 sulfate

30.00

Viscosity builder

2.50

Detergent

7.00

Emollient

2.00

Glucose quat

1.50

Cetylsil S

Conditioning complex

6.50

Phenonip

Preservative

1.00

Cocamide DEA

a

Cocamido betaine ®

Biowax 754 Special a

SugaQuat L ®

B

a

Detergent

a

A

Weight %

b

b

Mixing Procedure 1. In a suitable container, combine all ingredients together of Phase A with good agitation, without aerating. 2. Begin to heat to 70°C–75°C.When clear and uniform, stop heating and cool to 35°C–40°C. 3. Add Phase B. Mix well. 4. Adjust pH to 6.3–6.8, with 50% citric acid as needed. Sources a

Colonial Chemical, South Pittsburg, Tennessee

b

Biosil Technologies, Inc., Paterson, New Jersey

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 31.4: Two-in-One Conditioning Shampoo

Material

Function

Water

Weight % QS to 100.00

Ammonium lauryl sulfatea

Detergent

23.00

Cocamide DEAa

Viscosity build

2.40

Cocamidopropyl betainea

Detergent

2.90

Tetrasodium EDTA

Chelation

0.05

Biosil Basics SPQ

Conditioner

1.00

PEG- 150 distearate

Emollient

2.50

Stearasil® b

Conditioner

4.00

b

Conditioner

1.00

Preservative

1.00

®

Behenesil

b

Phenonip Mixing Procedure

1. In a suitable container, add ingredients and heat to 70°C–75°C while mixing. 2. When all ingredients are melted and product is uniform, cool to 35°C–40°C while stirring. 3. Pearlescence should appear while cooling.

Sources a

Colonial Chemical, South Pittsburgh, Tennessee

b

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.5: Clear Body Wash

Phase

Material

Function

Water

QS to 100.00

Sodium laureth sulfatea

Detergent

30.00

Cocamidopropyl betainea

Detergent

7.00

Methylparaben

Preservative

0.15

Preservative

0.10

Cocamide DEA

Viscosity builder

3.00

Cetylsil® b

Conditioner

3.00

Cucumber extract

Active

0.25

Elder extract

Active

0.25

Matricaria extract

Active

0.25

Ginkgo extract

Active

0.25

C

Imidazolidinyl urea

Preservative

0.30

D

Citric acid

pH adjustment

A

Propylparaben a

B

Mixing Procedure 1. In a suitable container weigh out Phase A. Heat to 70°C–75°C. 2. Mix until clear and begin to cool to 35°C–40°C. 3. At 35°C, add Phase B. Mix well. 4. Add Phase C. Mix well. 5. Adjust pH with Phase D to 6.3–6.8. Sources a

Colonial Chemical, South Pittsburgh, Tennessee

b

Weight %

Biosil Technologies, Inc., Paterson, New Jersey

QS to pH 6.3–6.8

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Formulation 31.6: Body Shampoo

Material

Function

Water

Weight % Qs to 100.0

Ammonium laurel sulfatea

Detergent

25.0

Cocamide DEAa

Viscosity builder

3.0

Tetrasodium EDTA

Chelation

0.1

Aloe vera gel

Active

0.5

Conditioner

1.5

Slip agent

2.5

Cetylsil

® b

Silamine C-100

c

Sodium chloride

Viscosity builder

As desired

Citric acid

pH control

As desired

Phenonip

Preservative

1.0

Mixing Procedure In a suitable container, heat water to 75°C. Add each ingredient in the order shown, under good agitation, allowing 15 minutes between additions. Cool to 35°C and add preservative. To increase viscosity, add salt. Notes 1. Cetylsil® is a fatty quaternary, carboxy silicone and is added for improved conditioning. 2. Silamine C-100 is dimethicone copolyol amine and is added for skin feel. 3. Extracts like common nettle, henna extract, etc., can be added as desired. Sources a

Colonial Chemical, South Pittsburg, Tennessee

b c

Biosil Technologies, Inc. Paterson, New Jersey

Siltech LLC, Dacula, Georgia

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Formulation 31.7: Exfoliating Body Scrub

Phase

Material

Function

Water

A

QS to 100.00

Sodium lauryl sulfatea

Detergent

30.00

Cocamide DEAa

Viscosity builder

2.50

Cocamidopropyl betainea

Detergent

7.00

Emollient

1.00

Conditioner

3.00

Carbopol 1342c

Viscosity builder

0.25

Chamomile extract

Active

1.00

Mallow extract

Active

1.00

Cucumber extract

Active

1.00

Jojoba beads 40/60

Active

5.00

Germaben 11d

Preservative

1.00

Triethanolamine (99%)

pH adjustment

0.30

Fragrance

Fragrance

0.50

®

b

Biowax 754 Cetylsil

B

C

D

®b

Mixing Procedure 1. In a suitable container, disperse Carbopol 1342. 2. Once mixed well, add remaining ingredients from Phase A. 3. Begin to heat to 55°C–60°C until homogenous, then cool to 35°C–45°C. 4. Add Phase B. Mix well. 5. Add Phase C. Mix well, then add Phase D. Sources a

Colonial Chemical, South Pittsburgh, Tennessee

b c

Biosil Technologies, Inc., Paterson, New Jersey

Noveon, Cleveland, Ohio

d

Weight %

ISP, Wayne New Jersey

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Formulation 31.8: Spray-on, Leave-on Conditioner

Material

Function

Water

Weight % Qs to 100.0

Imidazolidinyl urea

Preservative

0.30

a

Conditioner

1.00

Biosil® Basics SPQa

Conditioner

0.30

Phenonip

Preservative

1.00

Cetylsil®

Mixing Procedure In a suitable container add water. Add each ingredient in the order shown, under good agitation, allowing 15 minutes between additions. Add preservative. Notes 1. Cetylsil® is a fatty quaternary, carboxy silicone and is added for improved conditioning. ®

2. Biosil Basic SPQ is a silicone quat that contains panthenol, a pro-vitamin.

Sources a

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.9: Chelating Rinse-off Conditioner

Phase

Material

Function

Water A

B

D

Qs to 100.0

Phytic acid

Chelation

Triethanolamine (99%)

pH adjustment

Methylparaben

Preservative

0.2

Cetyl alcohol

Conditioner

3.0

Rice bran oil

Oil phase

4.0

Conditioner

2.0

PEG-100 stearate

Emollient

1.2

Glyceryl stearate

Emollient

3.5

Propylparaben

Preservative

0.1

Biosil® Basics C38 ester a

Oil phase

1.0

Biosil® Basics SPQa

Conditioner

0.55

Phenonip

Preservative

1.00

Stearasil® C

Weight %

a

0.3 As required

Mixing Procedure 1. Into a suitable container add water. 2. Add Phytic acid. 3. Add enough TEA to adjust the pH to 4.0–4.5. 4. Add Phase B. 5. Heat to 70°C. 6. In another container combine Phase C. 7. Heat to 75°C–80°C. 8. Add Phase C to the mixture of Phase A and B, under good agitation. 9. Cool to 40°C add Phase D. Notes 1. Stearasil® is the fatty quaternary, carboxy silicone and is added for improved conditioning 2. Biosil® Basic SPQ is a silicone panthenol quat. 3. Biosil® Basic C38 is a guerbet ester. Sources: a

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.10: Spray-on, Rinse-off Conditioner

Material

Function

Water

Weight % Qs to 100.0

Hydroxyethylcellulose

Viscosity builder

0.1

Dowicil 200

Preservative

0.2

Active

1.0

Polymeric conditioner

1.0

Conditioner

5.0

Biosil® Basics HMC-1a b

GafQuat 755 N Cetylsil

®a

Mixing Procedure 1. In a suitable container add water, and heat to 70°C–75°C. 2. Slowly add hydroxyethylcellulose. 3. Mix 20 minutes. 4. Cool to 45°C–50°C . 5. Add Dowicil 200. 6. Allow to cool to 35oC. 7. Add remaining ingredients in order shown under good agitation. Notes 1. Cetylsil is a fatty quaternary, carboxy silicone and is added for improved conditioning. Source a

Biosil Technologies, Inc., Paterson, New Jersey

b

ISP, Wayne, New Jersey

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Formulation 31.11: Exothermic Conditioner

Material Biowax 754 Special

a

Function Emollient

Weight % 20.0

PEG 1000

Exothermic additive

Qs to 100.0

Stearasil® a

Skin feel

1.0

Silwax WD-Fb

Slip agent

0.5

Mixing Procedure 1. In a suitable container combine materials in order shown. 2. Heat to 65°C. 3. Allow to cool under agitation. Notes 1. Stearasil is the fatty quaternary, carboxy silicone and is added for improved conditioning. 2. Silwax WD-F is a fluoro silicone product that is added to improve combability. 3. The product is a white solid. If a liquid product is desired, use a lower molecular weight.PEG like PEG 400. 4. When placed in wet hands, the PEG produces a mild warming effect. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

b

Siltech LLC, Dacula Georgia

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Formulation 31.12: Spray-on Conditioner

Phase

Material

A

Water

B

Dowcil 200

C

Biosil® Basics HMWa

D E

b

®a

Preservative

0.20

Actives

3.00

Polymeric conditioner

5.00

Conditioner

5.00

Mixing Procedure 1. In a suitable container, weigh water. 2. Heat to 45°C–50°C. Then cool to 35°C–40°C. 3. Add Phase B; mix well with good agitation before adding the next phase. 4. Add Phase C; mix well with good agitation before adding the next phase. 5. Add Phase D; mix well with good agitation before adding the next phase. 6. Add Phase E; mix well. 7. Filter product. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

b

Weight % Qs to 100.00

GafQuat 755N Cetylsil

Function

ISP, Wayne, New Jersey

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Formulation 31.13: Two-in-One Conditioner

Phase

Material

Function

Water

A

QS to 100.00

Triethanolamine lauryl sulfatea

Detergent

25.00

Cocamidopropyl betainea

Detergent

7.00

Cocamide DEAa

Viscosity builder

2.00

Methylparaben

Preservative

0.20

Propylparaben

Preservative

0.10

Tetrasodium EDTA

Chelation

0.05

Biosil® Basics Cocosilb

Conditioner

5.00

Conditioner

3.00

Cetylsil

®b

B

Citric acid, 50% solution

pH adjustment

QS to 6.30-6.80

C

Sodium chloride

Viscosity adjustment

As required for viscosity

Mixing Procedure 1. In a suitable container, heat Phase A to 60°C, while stirring. 2. Cool to 50°C–55°C. 3. Use citric acid solution to adjust pH to 6.30–6.80. 4. Cool to 45°C. Mix well. 5. Use sodium chloride to adjust viscosity.

Sources a

Colonial Chemical, South Pittsburgh, Tennessee

b

Weight %

Biosil Technologies, Inc., Paterson, New Jersey

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Formulation 31.14: Rinse-off Conditioner

Phase

Material

Function

Water

A

C

QS to 100.00

Methylparaben

Preservative

0.15

Biosil® Basics SPQa

Conditioner

0.50

Tetrasodium EDTA

Chelant

0.05

Conditioning complex

2.00

Rice bran oil

Oil

4.00

Cetyl alcohol

Oil

3.00

Propylparaben

Preservative

0.10

PEG-100 stearate

Emulsifier

1.15

Glyceryl monostearate

Emulsifier

2.50

Biosil® Basics Behenesila

Conditioning complex

2.00

Imidazolidinyl urea

Preservative

0.20

Stearasil

B

®a

Mixing Procedure 1. In a suitable container, weigh and combine ingredients of Phase A. 2. Begin to heat to 75°C–80°C. 3. In another container, weigh and combine all ingredients in Phase B. 4. Heat phase B to 75°C–80°C. 5. Add Phase B to Phase A. Mix well. 6. Begin to cool to 30°C–35°C. 7. Add Phase C. Mix well. Sources a

Weight %

Biosil Technologies, Inc., Paterson, New Jersey

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS

659

Formulation 31.15: Creamy Conditioner

Phase

Material

Function

Water

A

QS to 100.00

Methylparaben

Preservative

0.15

Biosil® Basics SPQa

Conditioner

1.50

Conditioning complex

2.00

Tetrasodium EDTA

Chelation

0.05

Rice bran oila

Oil

4.00

Cetyl alcohol

Oil

3.00

Propylparaben

Preservative

0.10

PEG-100 stearate

Emulsifier

1.15

GMS-450

Emulsifier

2.50

Behenesila

Conditioning complex

1.00

Actives

1.00

Biosil Basics DL-30

Actives

1.00

Phenonip

Preservative

1.00

Stearasil

B

®a

Biosil® Basics HMCa C

Weight %

®

a

Mixing Procedure 1. In a suitable container, combine Phase A and with good agitation begin to heat to 70°C–75°C. 2. In another suitable container, combine Phase B and begin to heat to 70°C–75°C. 3. At temperature, add Phase B to Phase A. Mix well, begin to cool to 35°C–40°C. 4. At temperature, add Phase C mixing well between additions. 5. Add Phase D at 35°C. Mix very well. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

660

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 31.16: Clear, Leave-in Conditioner Detangler

Phase A

B

Material Water

Weight % QS to 100.00

Hydroxyethylcellulose

Thickener

0.09

Propylene glycol

Solvent

4.00

Conditioner complex

2.50

Conditioner

1.00

Dowicil 200

Preservative

0.30

Biosil® Basics HMC-1a

Actives

1.00

Cocosila ®

Biosil Basics SPQ C

Function

a

Mixing Procedure 1. In a suitable container, weigh out water of Phase A and disperse hydroxyethylcellulose. 2. Mix until clear, begin to heat to 60°C–65°C. 3. Combine Phase B and heat until uniform (60°C–65°C). 4. Add Phase B to Phase A. Cool to 40°C–45°C. 5. Add Phase C and mix well. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS

661

Formulation 31.17: Facial Cleanser (Oily Skin)

Phase

Material

Function

Water

QS to 100.00

Propylene glycol A

Solvent

3.00

Preservative

0.20

Emollient

1.00

Cetylsil S

Conditioning complex

2.00

Rice bran oila

Oil

5.00

Stearic acid

Oil

3.50

GMS-450

Emulsifer

1.00

Propylparaben

Preservative

0.15

Cetyl alcohol

Oil

0.40

Biosil® Basics C-38a

Oil

1.00

Emulsifying wax

Emulsifier

3.00

TEA lauryl sulfate

Detergent

3.50

Unicide U-13

Preservative

0.30

Rhodofiltrat chondrus crispusa

Active

1.00

Coralline concentrate

Active

1.00

Witch hazel extract

Active

0.5

Grapefruit extract

Active

0.5

Chamomile extract

Active

0.5

Methylparaben Biowax 754 special ®

B

C

D

Weight %

a

a

b

Mixing Procedure 1. In a suitable container, weigh out and combine ingredients in Phase A and begin to heat to 70°C–75°C with light agitation. 2. In another container, weigh out and combine ingredients in Phase B and begin to heat to 70°C–75°C with light agitation. 3. At desired temperature, add Phase B to Phase A. Mix well and begin to cool to 35°C–45°C. 4. Add Phase D, one ingredient at a time; mix well between additions. Add Phase E. 5. Mix well. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

b

Colonial Chemical, South Pittsburgh, Tennessee

662

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 31.18: Hair Pomade

Material

Function

Weight %

Petrolatum-white IS

Oil

QS to 100.00

Zenigloss Sc

Oil

2.00

Biosil Basics C-38a

Oil

10.00

Behenesila

Conditioner

1.00

Silwax 418b

Silicone wax

2.00

Mixing Procedure 1. Combine all ingredients in a suitable container and heat to 70°C–75°C or until uniformly melted. 2. Mix well. Pour product at 65°C–70°C. 3. Allow to cool.

Sources a

Biosil Technologies, Inc., Paterson, New Jersey

b

Siltech LLC, Dacula, Georgia

c

Zenitech LLC, Old Greenwich, Connecticut

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS

663

Formulation 31.19: Hair Pomade Stick

Phase A

B

Material Cyclomethicone

Function

a

Solvent Oil

15.00

Castor Wax MP80

Wax

8.00

Gloss additive

2.00

Biosil Basics C-38

Oil

3.00

Behenesilb

Conditioner

1.50

Zenigloss

c b

Mixing Procedure 1. Combine all ingredients of Phase B and heat to 75°C–80°C. 2. Once uniform, cool to 60°C– 65oC and add Phase A. 3. Mix until uniform. Sources Siltech LLC, Dacula, Georgia

b c

QS to 100.0

Stearyl alcohol

®

a

Weight %

Biosil Technologies, Inc., Paterson, New Jersey

Zenitech LLC, Old Greenwich, Connecticut

664

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 31.20: Hair Growth Conditioner Treatment

Phase

Material

Function

Water

A

C

D

QS to 100.00

Phytic acid complex

Active

2.00

Biosil® Basics SPQa

Conditioner

0.75

Tetrasodium EDTA

Chelation

0.05

Methylparaben

Preservative

0.20

Conditioner

1.25

Cetyl alcohol

Oil

3.00

Propylparaben

Preservative

0.15

Rice bran oil

Oil

4.00

PEG-100 stearate

Emulsifier

1.15

Glyceryl stearate

Emulsifier

2.50

Imidazolidinyl urea

Preservative

0.30

Biosil® Basics HMC-1a

Active

5.00

Complex anti chute N

Active

3.50

Ginkgo extract

Active

0.10

Chamomile extract

Active

0.10

Henna extract

Active

0.10

Fragrance

Fragrance

0.50

Cetylsil

B

Weight %

®a

Mixing Procedure 1. In a suitable container, add water and phytic acid complex. 2. Add remaining ingredients of Phase A; one at a time with good agitation between additions. 3. Begin to heat to 75°C–80°C. 4. In another suitable container, weigh and combine Phase B. Heat to 75°C–80°C. 5. Add phase B to Phase A. Mix well and begin to cool to 40°C–45°C. 6. At 40°C, add Phase C, one ingredient at a time with good agitation between additions. 7. Add Phase D. Mix well. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

O’LENICK, BUFFA: CATIONIC SILICONE COMPLEXES AS DELIVERY SYSTEMS

665

Formulation 31.21: Self-Tanning Mousse

Phase A

Material Water Hydroxy celluose

Thickener

0.10

Preservative

0.30

Conditioner

1.00

Conditioner complex

1.25

Biowax 754 special

Emollient

1.00

DHA

Self tanner

5.00

Dermochlorella D

Active

1.00

Cocamido betaine

Surfactant

3.00

®

a

Biosil Basics SPQ Cetylsil

®a a

C D

Weight % Qs to 100.00

Dowcil 200 B

Function

Mixing Procedure 1. In a suitable container, slowly sprinkle hydroxy celluose into water of Phase A. 2. Once well dispersed, weigh and combine ingredients of Phase B and add to Phase A. Mix well. 3. Add Phase C, one ingredient at a time, with good agitation between additions. 4. Add Phase D. Mix well. (NO HEAT REQUIRED). Note: Must use AIRSPRAY BOTTLE to achieve mousse effect. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

b

Colonial Chemical, South Pittsburgh, Tennessee

666

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 31.22: Water-based Makeup Remover

Material

Function

Water

Weight % QS to 100.0

Cocosila

Conditioner complex

2.0

Chamomile extract

Active

1.0

Cucumber extract

Active

1.0

Dowicil 200

Preservative

0.3

Mixing Procedure 1. In a suitable container, weigh and combine all ingredients in the order they appear. 2. Mix until completely uniform. Sources a

Biosil Technologies, Inc., Paterson, New Jersey

References

17. Kollmeier, U.S. Patent 4,654,161 (Mar. 1987) 18. O’Lenick, U.S. Patent 5,237,035 (Aug. 1993)

1. Lucassen, E., and Giles, D., Journal of Colloid and Interface Science, Vol. 81, No. 1, pp. 150–157 (May 1981)

19. O’Lenick, U.S. Patent 5,070,171 (Dec. 1991) 20. O’Lenick, U.S. Patent 5,070,168 (Dec. 1994)

2. O’Lenick, A. J., Journal of Surfactants and Detergents, Vol. 3, No. 2, p. 229 (Apr. 2000)

21. Dexter, U.S. Patent 4,724,258 (Feb. 1988)

3. O’Lenick, A. J., Surfactants: Chemistry and Applications, p. 96, Allured Publishing (1999)

23. O’Lenick, U.S. Patent 5,280,099 (Jan. 1994) 24. O’Lenick, U.S. Patent 5,300,666 (Apr. 1994)

4. ibid 2, p. 26.

25. O’Lenick, U.S. Patent 5,120,812 (Jun. 1992)

5. O’Lenick, U.S. Patent 5,149,765 (Sep. 1992)

26. Hunter, A., Encyclopedia of Shampoo Ingredients, pp. 174–175, Micelle Press (1983)

6. Dexter, et al., U.S. Patent 4,724,248 (Feb. 1988) 7. O’Lenick, U.S. Patent 4,960,845 (Oct. 1990) 8. Haluska, U.S. Patent 3,560,544 (Feb. 1971) 9. O’Lenick, U.S. Patent 5,296,625 (Mar. 1994)

22. O’Lenick, U.S. Patent 6,338,042 (Dec. 2002)

27. “Sherex Formulary,” Witco Chemical, Greenwich CT 28. Hunter, A., Encyclopedia of Conditioning Rinse Ingredients, Micelle Press, p. 99 (1987)

10. Maxon, U.S. Patent 4,717,498 (Jan. 1988)

29. O’Lenick, U.S. Patent 5,296,434 (Mar. 1994)

11. Colas, U.S. Patent 4,777,277 (Nov. 1998)

30. O’Lenick, U.S. Patent 5,248,783 (Sep. 1993)

13. O’Lenick, U.S. Patent 5,098,979 (Mar. 1992)

31. O’Lenick, U.S. Patent 6,498,263 (Dec. 2002)

14. O’Lenick, U.S. Patent 5,153,294 (Oct. 1992)

32. O’Lenick, U.S. Patent 6,461,598 (Oct. 2002)

15. O’Lenick, U.S. Patent 5,196,499 (Feb. 1993)

33. O’Lenick, U.S. Patent 6,410,679 (Jun. 2002)

16. O’Lenick, U.S. Patent 5,073,619 (Dec. 1991)

34. O’Lenick, U.S. Patent 6,372,934 (Apr. 2002)

32 “Pro-fragrant” Silicone Delivery Polymers Robert J. Perry* GE Silicones Waterford, New York

32.1 Introduction ................................................................................... 667 32.2 Silicone-based Molecular Release of Fragrances ........................ 668 32.2.1 Hydrolytic Cleavage of Fragrant Silicone Copolymers ..... 668 32.2.2 Axilla Bacteria (Enzyme) Triggers for Fragrance Release ... 668 32.2.3 Hydrolytically Cleavable Si–O Bonds as Fragrance Release Mechanism ......................................................... 669 32.2.4 Hydrolysis of Silicone-Based Schiff Bases....................... 671 32.2.5 Hydrolysis of Fragrant Silicic-Acid Esters ........................ 671 32.2.6 Silicone Personal Care Active Delivery Polymers ............ 675 32.3 Silicone-Based Non-Releasing Delivery Polymers ...................... 675 32.3.1 Sunscreens ...................................................................... 675 32.4 Summary ...................................................................................... 677 32.5 Formulations ................................................................................. 678 References .......................................................................................... 682

32.1 Introduction The technical, trade, and patent literature is replete with examples of grafting chemical moieties onto a polymer backbone in order to alter its properties. A review of the literature shows this is true for silicone polymers as well, but there are only a lim-

ited number of examples where the grafted group is delivering a useful active ingredient onto a substrate like skin, hair, fibers, or into the environment. This active may be released, or remain bound to the silicone polymer in order to fulfill the task it was designed for. The actives capable of being used or delivered in this manner were found to range from

*Present address: GE Global Research, Niskayuna, New York Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 667–682 © 2005 William Andrew, Inc.

668

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

fragrances, to cosmetics, to sunscreens. The term which we have adopted to describe this new and emerging delivery system for personal care systems is “pro-fragrant silicone delivery systems.”

32.2 Silicone-based Molecular Release of Fragrances 32.2.1

Hydrolytic Cleavage of Fragrant Silicone Copolymers

The most common type of active that can be released from a silicone polymer is a fragrance. Early examples of this delivery mechanism were reported in the mid-1960s with the formation of fragrant alkoxy silicones via transesterification reactions (Fig. 32.1). In these cases, the R groups were derived from fragrant alcohols, the R' were methyl or lower alkyl groups, and the R" were organic groups. When monomeric or polymeric alkoxy silicones, such as those in Fig. 32.2, were applied to textiles, the Si-O bonds could be hydrolyzed to release the free fragrant alcohol, R'OH.[1][2] The slow hydrolysis and sustained release of the fragrance over extended periods of time gave a desirable aesthetic effect when compared to a control consisting of the incorporation of free fragrant alcohol only. An example of applying a silicone resin formulation consisting of such silicate esters to cloth in

Figure 32.1 Formation of alkoxy silanes via transesterification.

order to provide a crease-proofing effect is shown in Formulation 32.1. The emulsion was padded onto a swatch of cotton fabric and cured at 165°C for 70 seconds and then air dried. In another type of opportunity, perfumed soap and antiperspirant or deodorant compositions were among the first personal care compositions utilizing the silicone fragrance technology and were described in 1980.[3][4] In a similar fashion, compounds 1–3 (Fig. 32.2) were shown to provide a sustained, longerlasting release of fragrance than a control without the silicone. A formulation for an antiperspirant system is shown in Formulation 32.2. The mixture was charged to an aerosol container and this composition, as well as a control using neat geraniol in the same proportions as the fragrant silane, were sprayed on separate areas of human skin and the persistence of the geraniol smell was recorded. The fragrant silane lasted at least four times longer than the control. Other similar fragrant alkoxy silane and alkoxy silicone materials were described in 1985. These were made by the displacement of methoxy or ethoxy groups by the desired alcohols.[5]–[7] Again, these compounds relied upon the slow hydrolysis of alkoxy silanes to give the desired sustained fragrance release effect. Table 32.1 illustrates how the blend of a rosetype perfume, based on compound 1 (Fig. 32.2), gave a longer lasting and more controllable fragrance tone than the fragrances without reactive silicones.[5] Nearly a decade later, polysiloxane compounds 4 through 7 (Fig. 32.3) were prepared from alcohols, aldehydes, and ketones. They have also been prepared from esters or lactones from a combination of silyl hydrides, a metal salt, and a reducing agent as shown in Fig. 32.3.[8] Materials with compounds like 4 through 7 were the first reported to use silyl hydrides as the reactive sites for derivatization. Applications were cited in the textile treatment area.

32.2.2 Axilla Bacteria (Enzyme) Triggers for Fragrance Release (1)

(2)

(3)

Figure 32.2 Examples of monomeric and polymeric alkoxy silanes and silicones (compounds 1–3).

The examples cited thus far have all relied upon the release of a fragrance via a hydrolytic cleavage mechanism. In another approach, underarm axilla

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS Table 32.1. Comparison of the Strength and Tone of a Fragrance Composition

Fragrant Article

Control Article

Strength

Tone

Strength

Tone

1

+2

-

+3

-

5

+1

-

+2

-

10

+1

-

+1

*

15

+1

-

0

^

21

0

-

–1

^

30

0

-

–2

^

Time (days)

669 bacteria have been employed to produce cleavage of the active fragrance from the precursor silicone polymer. In these cases, ester linkages were enzymatically cleaved by underarm flora to liberate the alcohol.[9][10] The ester moiety was tethered to the silicone backbone by means of an alkyl spacer which could be of variable length (Fig. 32.4). Several formulations of antiperspirants and deodorants were provided based on this technology. These are shown in Formulations 32.3 and 32.4. The procedures for making these compositions are typical for those skilled in the art.

Strength: +3 = very strong; +2 = strong; +1 = slightly strong; 0 = not strong or weak; – 1 = slightly weak; – 2 = weak. Tone: - = no change; * = slight change; ^ = distinct change.

32.2.3

Hydrolytically Cleavable Si-O Bonds as Fragrance Release Mechanism

Yet another approach to attach a desired fragrance to a silicone backbone that utilizes hydrosilylation chemistry but also incorporates a hydrolytically cleavable Si-O bond is shown in Fig. 32.5. This approach allows for mono-, di-, or tri-functional fragrant precursors to be made easily, and then attaching them to the desired silicone backbone.[11][12] With this synthetic scheme, the fragrant alcohol (Frag-OH) may be primary or secondary, and the X and OR groups are easily displaceable groups such as chloro, alkoxy, or acetoxy. Aldehydes, ketones, and esters can also be used to make vinyl or other terminally unsubstituted silanes, useful in preparing fragrance silicone release polymers. Figure 32.6 shows the enolate of the active oxygen compound is made first and then allowed to react with the reactive silane. These fragrant silane precursors are then attached to the silicone backbone by hydrosilylation as shown in Fig. 32.7.

Figure 32.3 Silicones prepared by reductive coupling of silyl hydrides and fragrances (compounds 4–7).

By this method, terminal and grafted fragrances may be easily attached to a wide variety of silicone backbones in order to produce fragrance-silicone delivery systems.[13]–[16]

670

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 32.4 Fragrant silicone ester.

Figure 32.5 Preparation of alkenyl silanes with multifunctional fragrant alcohols.

Figure 32.6 Preparation of alkenyl silanes with multifunctional fragrant aldehydes.

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS

671

Figure 32.7 Fragrant silicone polymers.

The hydrolysis and release of the desired fragrance was found to be dependent upon both the pH of the system as well as the position of fragrance attachment and the number of bound fragrant moieties. Figure 32.8 shows a series of such alcoholderived fragrant silicones, compounds 8 through 11. Experimental fragrance release data shows that siloxane 9, containing two fragrant alkoxy groups bound to the ends of a silicone polymer, released phenethanol nearly quantitatively over a 24-hour period (Fig. 32.9). By contrast, the mono-substituted analog 8 only released about one-half of the available alcohol. The same effect was seen when the fragrant moieties were connected to an internal position of the fragrant silicone polymer as shown in compounds 10 and 11 of Fig. 32.9. Aldehyde hydrolysis to release a fragrance from a fragrant silicone polymer was also explored with the compounds shown in Fig. 32.10. Compounds 12 and 13 were tested in the fragrance release experiment shown in Fig. 32.11. The base-catalyzed release of the fragrance was much faster than that promoted by acid. It was also seen that these same fragrant silicones, 12 and 13, could be incorporated into oil-inwater emulsions. This capability opened the door to water-deliverable, controlled-fragrance release compositions.[17]

32.2.4 Hydrolysis of Silicone-Based Schiff Bases An alternate way of making a pro-fragrant silicone is to form a Schiff base from an amino substituted silicone. This can be done with an aldehyde or ketone, as illustrated in Fig. 32.12.[18] The amino groups can be in the terminal or internal positions. The amino groups may also be primary and monofunctional as shown in Fig. 32.12, or primary and difunctional when an aminoethylaminopropyl group is utilized. Personal care systems go beyond skin and hair and extend to having clean, fragrant-smelling clothes as well. An example of a granular laundry composition having the pro-fragrant silicone is illustrated in Formulation 32.5.

32.2.5 Hydrolysis of Fragrant SilicicAcid Esters Substituted silicic-acid esters, such as Fig. 32.13, have been noted as a vehicle for fragrance delivery,[19][20] as have carboxylic acid derivatives of silanes of the type shown in Fig. 32.14.[21]

672

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Compound 8

Compound 9

Compound 10

Compound 11

Figure 32.8 Alcohol derived fragrant silicones (compounds 8–11).

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS

Figure 32.9 Release of phenethyl alcohol from compounds 8–11 over time under basic conditions.

Compound 12

Compound 13 Figure 32.10 Aldehyde derived fragrant silicones (compounds 12–13).

673

674

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 32.11 Acidic and basic hydrolysis of fragrant silicone compounds 12 and 13.

Figure 32.12 Preparation of silicone-based fragrant Schiff Bases.

Figure 32.13 Fragrant silicic acid ester.

Figure 32.14 Fragrant carboxylic acid derivatives.

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS 32.2.6 Silicone Personal Care Active Delivery Polymers

675 tion. Prototypes of both a lotion and ointment using this technology have been shown in Formulations 32.6 and 32.7.[22]

Beyond the fragrant silicone polymers described, other silicone-derivitized personal care actives have been reported that are capable of delivering skin smoothing properties as well as anti-aging and antiacne benefits. These materials are based upon trimethylsilyl derivatives of lactic acid, glycolic acid, salicylic acid, stearyl alcohol, and retinol.[22]–[24] Specifically, alpha-hydroxy acids (such as lactic, glycolic, or salicylic) have been treated with hexamethyldisilazane and then distilled to provide the desired bis(trimethylsilyl)hydroxycarboxylates.[22]–[24] (See Fig. 32.15 and Table 32.2.) These materials have been shown to be capable of being delivered to preferred sites in the epidermis to promote new cell and collagen growth without irrita-

Similar derivatization was performed on long chain alcohols as shown in Table 32.3. In this work, pure trimethylsilylated compounds were compared to a commercially available mixture of trimethylsilylated and underivatized stearyl alcohol. The sensory profiles generated showed an increase in the wetness, spreadability, gloss, and oiliness for the pure silylated alcohols, and decreased residue and waxiness.[25]

32.3 Silicone-Based NonReleasing Delivery Polymers 32.3.1 Sunscreens

Figure 32.15 Preparation of siliconized alpha-hydroxy acids.

Table 32.2. Siliconized Hydrocarboxylic Acids

Acid

Structure

Some of the most popular actives attached to silicone or silane substrates have been photostabilizing groups for sunscreen actives. In one case, a variety of benzylidene-camphor derivatives were attached to silicon-based substrates to stabilize dibenzoylmethane UV screens.[26] (Table 32.4) These materials were formulated with Parsol 1789 (4-t-butyl-4’-methoxydibenzoyl-methane) into a composition and subjected to UV irradiation (Formulation 32.8). A greater percentage of the sunscreen Parsol 1789 remained in those compositions containing the silicone material than in the controls.

Table 32.3. Siliconized Long-chain Alcohols

TMS = trimethylsilyl

676

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 32.4. Silicon-based UV Screen Stabilizers Benzylidenecamphor Unit

Silicon-Based Substrate

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS In another similar case, the UV-screen photostabilizer material was a 2-hydroxybenzophenone silicon derivative as shown in Fig. 32.16.[27] Again, several different silicone-based substrates were employed and provided the same advantages as those previously described. In the same area, it was reported that certain benzimidazoyl-benzazole and benzofuryl-benzazole silicone containing compounds (Fig. 32.17) had improved properties over the base materials, especially in the area of cosmetic properties and solubility in oils.[28]

32.4 Summary A variety of derivatized silicones containing actives covalently attached to the silicone frame-

Figure 32.16 2-Hydrobenzophenone silicone derivatives (R = linking group to Si).

677 work have been described. These silicones range from monomeric materials to high molecular weight polymers. They each incorporate fragrances, personal care actives, and sunscreens that either remained tethered to the silicone or could be released with an appropriate trigger. Some of these technologies are over 30 years old, and yet, it has only been in the last few years that a deepening interest in this type of technology for enhancing personal care formulations has emerged. It has been found, as expected, that the silicone portion of the compound provides attributes that have made these polymers so attractive in a wide range of applications. These include softness, lubricity, thermal stability, and conditioning, etc. The active part of the siliconeactive copolymers provides additional performance attributes that set these polymers apart from the competition. The time is ripe for increased effort in this area.

Figure 32.17 Benizimidazole-benzazole silicone derivative (R = linking group to Si).

678

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

32.5 Formulations The formulations in this section represent a range of compositions for use in personal care applications. They were originally reported in the patents cited

and are reproduced here as examples of useful reductions to practice and as starting points for those interested in pursuing any of these areas.

Formulation 32.1: Formulation of Silicate Ester and Crease-proofing Resin

Component

Weight %

Mixture 50% dimethylol ethyl triazone and 50% dimethylol urea

12

.

50% solution of Zn(NO3)2 6H2O in water

2.5

Silicate Ester 1

1.6

®

Triton X-100

0.3

Water

83.6

Formulation 32.2: Antiperspirant Formulation Using Alkoxy Silanes

Component

Weight %

Aluminum chlorhydrate

4.8

Octamethylcyclotetrasiloxane

2.4

Talc

2.6

Silane A*

0.1

Propellant

90.1

* Silane A was composed of 2.4% methyltrimethoxysilane; 14.2% geraniol; 13.0% methyldimethoxygeranylsilane; 48.6% methylmethoxydigeranylsilane; and 21.9% methyltrigeranylsilane.

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS

679

Formulation 32.3: Antiperspirant Composition with Fragrant Silicone Esters

Component

Weight %

Ethylene glycol monostearate

7.0

Shea butter

3.0

Neobee 1053 (PVO International)

12.0

Generol 122 (Henkel)

5.0

Kesscowax B (Akzo)

17.0

Dimethicone Dow Corning 345

35.0

Aluminum sesquichlorhydrate

20.0

Delayed release fragrance

0.5

Formulation 32.4: Clear Deodorant Stick with Fragrant Silicone Esters

Component

Weight %

Witconol APM

43.0

Propylene glycol

20.0

Alcohol 30C

20.0

Demineralized water

7.0

Monamid 150ADD

5.0

Millithix 925

2.0

Ottasept extra

0.5

Delayed release fragrance

0.75

Fragrance

0.75

680

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Formulation 32.5: Granular Laundry Composition with Schiff Base Silicone

Component Pro-fragrant silicone polymer C11-C13 Dodecyl benzene sulfonate C12-C13 Alkyl ethoxylate EO 1-8

Weight % 1.0 21.0 1.2

Sodium tripolyphosphate

34.0

Zeolite Na 4A

14.0

Sodium silicate 2.0 ratio Sodium carbonate

2.0 23.4

Enzyme

1.4

Carboxymethylcellulose

0.3

Anionic soil release agent

0.3

Brightener

0.2

Silicone suds suppressor

0.2

Perfume

0.3

Sodium sulfate

0.5

Moisture balance

Up to 100

Formulation 32.6: Lotion Formulation Using Derivatized Lactic Acid

Component

Weight %

3-n-hexylheptamethyltrisiloxane

50

Bis(trimethylsilyl)lactate

25

Dimethiconol (HMW)

18

Polybutene

4

Caprylyl trimethicone

2

Pareth-15

0.5

Fragrance

0.5

PERRY: “PRO-FRAGRANT” SILICONE DELIVERY POLYMERS

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Formulation 32.7: Ointment Formulation Using Derivatized Lactic Acid

Component

Weight %

Bis(trimethylsilyl)lactate

25

C24-28 Alkylmethylsiloxane wax

24.5

Caprylic/capric/stearic triglycerides

25

3-n-hexylheptamethyltrisiloxane

20

Caprylic/capric triglycerides

3

Caprylyl trimethicone

2

Fragrance

0.5

Formulation 32.8: Sunscreen Formulation with Silicone Benzylidenecamphor Derivatives

Component Isopropyl myristate

Weight % 30

Parsol 1789

1.5

Silicone benzylidenecamphor

5

Ethanol

qs 100

Formulation 32.9: Sunscreen Formulation with Silicone Benzimidazolyl-benzothiazole

Component

Weight (grams)

Sinnowax AO (Henkel)

7

Cerasynt SD-V ISP

2

Cetyl alcohol

1.5

Polydimethylsiloxane 200 cS

0.5

Witconol TN Silicone benzimidazolyl-benzothiazole Octocrylene Titanium dioxide Glycerol

10 4 10 3 15

Mexoryl SX

0.6

Triethanolamine

0.6

Preservatives Demineralized water

qs 100

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References 1. Allen, T. C., and Watson, H. J., US 3,215,719 to Dan River Mills, Inc (11/2/65)

16. Perry, R. J., and Kilgour, J. A., US 6,322,777 to General Electric Company (11/27/01)

2. Allen, T. C., and Watson, H. J., US 3,271,305 to Dan River Mills, Inc (9/6/66)

17. Perry, R. J., and Liao, W. P. US 6,083,901 to General Electric Company (7/4/00)

3. Cooper, B. E., GB 2,041,964 to Dow Corning, Ltd. (9/17/80)

18. Ono, M., and Ishida, M., WO 99/46318 to The Proctor & Gamble Company (9/16/99)

4. Cooper, B. E., GB 2,042,890 to Dow Corning, Ltd. (10/1/80)

19. Gerke, T., Schaper, U. A., Faber, W., and Jesche, R., DE 19841147 to Henkel KgaA (3/ 16/00)

5. Yemoto, J., Tarao, R., and Yamamoto, Y., US 4,524,018 to Chisso Chemical (6/18/85) 6. Yemoto, J., Tarao, R., and Yamamoto, Y., US 4,500,725 to Chisso Chemical (2/19/85) 7. Ward, A. H., EP 273,266 to Dow Corning Corporation (6/7/88) 8. Mimoun, H., WO 96/28497 to Firmenich S.A. (9/19/96) 9. Anderson, D., and Frater, G., EP 878497 to Givaudan-Roure (International) S.A. (11/18/ 98) 10. Anderson, D., and Frater, G., US 6,262,287 to Givaudan-Roure (International) S.A. (7/17/01) 11. Perry, R. J. US 6,046,156 to General Electric Company (4/4/00) 12. Perry, R. J. US 6,153,578 to General Electric Company (11/28/00) 13. Perry, R. J., and Kilgour, J. A., US 6,077,923 to General Electric Company (6/20/00) 14. Perry, R. J., and Kilgour, J. A., US 6,054,547 to General Electric Company (4/25/00) 15. Perry, R. J., and Kilgour, J. A., US 6,075,111 to General Electric Company (6/13/00)

20. Gerke, T., Schaper, U. A., Faber, W., Jesche, R., and Meine, G., WO 00/14091 to Henkel KgaA (3/16/00) 21. Alexandrovich, D. V., Vasilievich, K. V., Mikhailovich, K. V., Antonovich, V. V., and Hartmut, H., WO 01/79212 to Kireev, V.V. (10/25/01) 22. LeGrow, G. E., and Terry, W. L. Jr., US 6,143,309 to Archimica (11/7/00) 23. LeGrow, G. E., and Terry, W. L. Jr., US 6,228,380 to Archimica (5/8/01) 24. LeGrow, G. E., and Terry, W. L. Jr., US 6,267,977 to Archimica (8/31/01) 25. LeGrow, G. E., and Latham W. I. III, US 5,847,179 to PCR, Inc. (12/8/98) 26. Forestier, S., and Richard, H., US 6,312,673 to Societe L’Oreal S.A. (11/6/01) 27. Forestier, S., and Richard, H., US 6,071,502 to Societe L’Oreal S.A. (6/6/00) 28. Richard, H., and Luppi, B., US 6,221,343 to Societe L’Oreal S.A. (4/24/01)

33 Silicone Technology as Delivery Systems for Personal Care Ingredients Stephanie Postiaux, Catherine Stoller, Anne-Marie Vincent, and Joanna Newton Dow Corning S.A. Seneffe, Belgium

33.1 Introduction ................................................................................... 684 33.2 Silicone as Delivery Systems ....................................................... 686 33.3 Technology Review ....................................................................... 687 33.3.1 Synergistic Effect: Silicones as Enhancers of Organic Ingredient Efficacy .............................................. 687 33.3.2 Silicone Elastomers: Entrapment and Controlled Release .......................................................... 693 33.3.3 Silicone Vesicles and Encapsulation ............................... 695 33.4 Silicone-Based Cosmetic Formulations as Delivery Systems ..... 699 33.4.1 Non-Aqueous Emulsions of Polyols in Silicone to Deliver Storage-Sensitive Personal Care Actives ........ 700 33.4.2 Multiple-Phase Emulsions ................................................ 700 33.4.3 Polyether Modified Silicone Elastomers for Multiple-Phase Emulsions ................................................ 702 33.4.4 Polar Solvent-in-Oil Emulsions and Multiple Emulsions .. 703 33.5 Formulations ................................................................................. 704 References ......................................................................................... 714

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 683–714 © 2005 William Andrew, Inc.

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33.1 Introduction[2][16][17] Silicones are among the high performance ingredient success stories of the 1990s. The aisles of stores selling personal care products tell the exciting story of silicone growth in this area from a look at their labels. In recent years, the use of silicones has been expanded to virtually all personal care product segments. The number of new personal care products containing a silicone-based material is significant and growing rapidly. In 1985, approximately 28% of these products contained silicone and at the date of this writing (2003), the percentage of such products has almost doubled. The expanding use of silicone materials is related to a unique combination of attributes. Silicones serve a variety of functions. They can act as emollients, water barriers, and emulsifiers. They also provide specific sensory characteristics. They are widely known for the smooth, silky, non-greasy feel produced by their incorporation; an effect highly desired by consumers. Finally, formulators can trust the safety of silicones as evidenced by a wide range of studies that document their low order of toxicity. The word silicone is an umbrella term. It designates materials based on the organosiloxane chemistry, and more frequently, it is an alternative name for polydimethylsiloxane (PDMS). (See Fig. 33.1.)

Figure 33.1 Polydimethylsiloxane (PDMS).

Polydimethylsiloxanes have a semi-organic molecular structure made up of a highly mobile siloxane backbone supporting a regular and non-polar arrangement of pendant methyl groups. The mobility and flexibility of the siloxane chain is truly unique. It allows an easy, low energy requiring orientation of the polymer on the surfaces upon which they can be adsorbed. The methyl substitution of the silicone polymer is spread out at interfaces thereby forming a low surface energy shield. This shield develops very low intermolecular interactions and provides

unique surface characteristics. As a result of the inherent chemical stability of Si-O and Si-C bonds contained within these polymers, they exhibit chemical inertness relative to many substances and are thermally stable, as well. As a consequence of these unique molecular properties, silicones have unique properties. In view of their low surface tension (+/- 20 dynes/cm), they are able to wet virtually any organic surface. They spread on a wide variety of substrates, which make them suitable for applications such as lubrication, coating, and antifoam applications. Silicones can be formulated to cover a broad range of rheological profiles from viscous fluid to visco-elastic thermoplastic (pressure-sensitive adhesive) and rubber-like thermoset (elastomer) products. The low intermolecular interactions combined with the high intramolecular mobility of silicone polymers provide outstanding anti-adherent properties (useful to make release coating). Furthermore, silicones exhibit a high level of permeability to various substances (including water vapor and drugs). By substituting organofunctional groups for some methyl groups, significant changes of properties occur. These modified silicones are very often referred as organofunctional silicones. Silicones occupy a versatile, yet unique role in skin care applications. Their properties are adaptable to a range of formulation and use requirements. As formulation aids, silicones can help to detackify other ingredients such as some antiperspirant salts. They can act either as emulsifying agents or as carriers that deliver active ingredients to the skin. Low molecular weight cyclic silicones can indeed quickly evaporate without leaving any residue. This combination of benefits makes them very useful in certain personal care products such as antiperspirants. When incorporated into skin care products, silicones impart a characteristic soft feel. They can also provide a protective barrier against irritants and provide both lubricity and emollient benefits. These materials are essentially physiologically and chemically inert. They show a low order of oral toxicity, are non-irritating, and non-sensitizing when applied to the skin. A wide array of silicone types exists. Each category has some particular features making them suitable for several applications (Fig. 33.2).

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS

685

Figure 33.2 Application for siloxane-based molecule in personal care; silicone classes and respective benefits.

Phenyltrimethicone is used in color cosmetics for its incomparable shine. This phenomenon is a result of its very high refractive index. Other organosilicone fluids make the creation of long-lasting lipstick possible, while at the same time conferring shine and soft feel. Silicone elastomers, crosslinked version of these polymers, have opened a new dimension in skin feel. They provide an extraordinary, instantly perceivable silk or velvet skin feel. Antiperspirants also benefit from the incorporation of silicones since they are able to reduce the wellknown and undesirable whitening effect on skin. In hair care, several types of silicone impart different degrees of conditioning to the hair. While silicone polyether copolymers are primarily used for lighter conditioning, amino silicone fluids provide medium to strong conditioning. Hair cuticle coat products are mostly composed of silicone gums. These form a film around the fiber that imparts protection. Generally, emulsions offer the ease of formulating the silicone in aqueous-based products. As a re-

sult, they offer both ease of formulation and softness/conditioning benefits. Recently, some studies have highlighted the ability of silicone-based technologies to enhance and/or deliver actives in final personal care formulations; while at the same time provide a range of additional desirable features and benefits. Overall, these novel techniques hold potential for a wide range of innovative personal care applications. Creative formulators now have the tool to develop almost limitless high-performance, multifunctional products based on combinations of selected silicones and desirable active ingredients. This chapter focuses on various silicone technologies that provide novel and innovative delivery systems for active ingredients in personal care. These technologies cover a wide range of capabilities to address common issues associated with the incorporation of actives into personal care products. In addition, such systems are capable of providing many of the well-known attributes of silicones.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

33.2 Silicone as Delivery Systems A delivery system is usually defined as any type of material that is capable of making an active available for a targeted site of action. Using this definition, personal care delivery systems range widely from the simplest concepts such as volatile carriers for actives to increasingly more sophisticated technologies like encapsulation with the capability of providing controlled or sequential release of the active (Table 33.1). Although numerous technologies are commercially available, specific silicone technologies targeted at delivery offer some unique and distinctive features. One of the key benefits of such silicone systems relate to the incomparable aesthetics achieved with their use as compared to conventional materials. Furthermore, silicones are easy to formulate and offer broad formulation latitude to the cosmetic chemists. Silicone delivery systems are available in a variety of modalities. The most basic example of such a system is when a physical association of ingredients in a formulation can be used to achieve a carrier effect. Volatile silicones (i.e., low molecular weight cyclomethicone) have often been used as vehicles for delivering antiperspirant actives. This approach has been expanded to actives* such as fragrances and conditioning agents as well.

In another type of system, silicone can be used to impart a synergistic effect. One example of such features is the enhanced conditioning effect achieved through the combined used of a dimethicone copolyol with organic quaternary compounds. Another example is the beneficial effect on the sun protection factor, the value of a sunscreen formulation resulting from the addition of a few percent of an alkylmethylsiloxane copolymer. The active delivery technique framed as “encapsulation with no release” is very often positioned as “ingredient coatings.” They offer the advantage of reducing negative effects that may be linked to the use of an ingredient (e.g., skin irritation or skin penetration) while at the same time keeping the desired physical properties of the actives when they are released. Typical examples of this approach are employed with pigment coating for color cosmetics and encapsulation of sunscreen agents. Entrapment or encapsulation is probably the most popular delivery system employed in personal care industry. It is used to release the active during application by means of a high shear rate associated with applications of alkylmethylsiloxanes and lotions. These systems can be used to protect actives that are sensitive to external factors, to deliver potentially irritating ingredients, and/or to keep actives from reacting/interacting with other ingredients in the formulation.

* In this context, actives are defined as any materials for which marketing claims for specific performances of an end product are either made or implied.

Table 33.1. Categories of Delivery Systems and Respective Features

Physical Association

Combination of ingredients.

Encapsulation with No Release

Encapsulation/ Entrapment with Release

Controlled and/or Sustained Release

Sequential Release

“Coating” of ingredients to protect active in pre- and postapplication.

Protection of active prior to use. Release on application – “one shot.”

Delivery of active at the site of action at desired time, level, etc., or over a long period of time.

Multiple actives that need to be released in a welldefined order, at some specific time.

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS In one form of encapsulation, silicone elastomers can be used to entrap or absorb polar and non-polar oils prior to their formulation into the end product. In this case, as we have described previously, release of the active material occurs under the shearing forces associated with the rubbing motion onto the face or body. Encapsulation of useful active materials can also be achieved by means of a new class of proprietary delivery systems known as silicone vesicles. This cutting edge technology is considered as an extension to conventional phospholipid-based liposomes and, as such, it offers multiple benefits. Controlled release and sequential release are among the most complex techniques for the delivery of actives. These methods can be used to protect or separate actives, combine incompatible actives; and provide long-lasting, substantive properties on the skin. While entrapment techniques allow for the complete release of an ingredient at a specified time, controlled release allows for sustained delivery of the active over time. By contrast, sequential release mechanisms allow for multiple actives to be isolated and then metered out at specific times for a long-lasting and substantive effect. As an example of this approach, multiple-phase emulsions can be employed to deliver a number of active ingredients. Water-in-oil emulsions based on alkyl dimethicone copolyols or polyether modified elastomers can be used to deliver vitamins A and E. In practice, those actives are incorporated into the silicone copolymer or elastomer which constitutes the external phase of the primary emulsion. Thereafter, vitamin C can be incorporated into the external aqueous phase which surrounds the w/o emulsion suspended in it. Overall, these techniques offer the potential for a broad range of innovative personal care products and applications. Creative formulators hold the key to almost limitless high performance, multifunctional products based on combinations of certain silicones and active ingredients. The next part of this chapter (Sec. 33.3) examines each of the categories described above. Examples of cosmetic formulations containing or applying these techniques are also illustrated (Sec. 33.5).

687

33.3 Technology Review 33.3.1

Synergistic Effect: Silicones as Enhancers of Organic Ingredient Efficacy

Enhancement of sun protector factor (SPF) with alkylmethylsiloxanes.[3] Recent market information report that the sun care market is evolving more and more towards higher SPF values as consumers become increasingly aware of the dangers of UV radiations resulting from excessive skin exposure to the sun. Modern sunscreen products are subject to ever increasing market demands including: • UV-A protection • UV-B protection • High SPF • Need for photostability • Safety/non-irritancy • Cost effectiveness • Water resistance • Improved aesthetics In order to achieve the above goals, formulators are increasingly turning towards additives that can be combined with UV filters in order to improve sunscreen efficiency and/or compensate for some of their negative attributes. Some cosmetic raw materials are able to enhance this performance and a variety of silicone-based polymers fall into this category. A prime example of these is the alkylmethylsiloxane (AMS) family. Alkylmethylsiloxanes are organo-modified silicones whose methyl groups have been partially replaced by long chain alkyl groups (Fig. 33.3). By varying the chain length of the silicone backbone (x + y) and the alkyl group (R), as well as the degree of substitution (y), it is possible to produce three classes of alkylmethylsiloxanes: volatile fluids, nonvolatile fluids, and wax silicones with melting points ranging between 25°C and 70°C. Several methods have been developed to assess the benefits of alkylmethylsiloxanes in sun care products; these include wash-off resistance, sun protection factor (SPF) enhancement, and sensory profile of the formula.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 33.3 Chemical structure of alkylmethylsiloxanes.

Three types of alkylmethylsiloxanes were evaluated to determine their effect on the SPF of selected oil-in-water formulations containing organic sunscreens. The formulation ingredients and mixing procedure are described in the formulation section (Sec. 33.5). Based on the evaluation of Formulations 33.1 and 33.2, it was determined that stearyl dimethicone contributed to increased SPF compared to the formulation without alkylmethylsiloxanes and to the other alkylmethylsiloxane types used for comparison (Tables 33.2 and 33.3). Values for thixotropy, a rheological parameter that indicates the product is easier to spread was higher with the former AMS material. This allows the product to be evenly dis-

tributed on skin, improving sun protection by the formation of a regular homogeneous film. Microscopic evaluation also confirmed the positive impact of stearyl dimethicone on SPF. Although the melting point of the wax is about 30°C, no birefringence is observed around this temperature in the final formulation. Instead, a melting point transition is observed around 48°C–50°C, resulting in an isotropic phase. This indicates that stearyl dimethicone is not present as pure phase in the formulation and it is likely that one or more of the additives in the formulation, or processing step, have allowed the alkylmethylsiloxanes and the cinnamate component to become more compatible.

Table 33.2. SPF and Thixotropy Results for Formulation 33.1 Containing 6% UVB Sunscreen

Alkylmethylsiloxane (AMS) (4%)

In Vitro SPF

In Vivo SPF

Thixotropy Pa/s 32°C

Cetyl Dimethicone

20

3.3

NA*

-

1,806

Stearyl Dimethicone

27

4.5

20.4

3.5

16,280

C30-45 Alkylmethicone

21

3.5

NA*

-

-

15

2.5

12.7

2.1

5,010

Control (no AMS) *NA: Not applicable

Table 33.3. SPF and Thixotropy Results for (i) Formulation 33.2 Containing 11% UVB Sunscreen

Alkylmethylsiloxane (AMS)

In Vitro SPF

In Vivo SPF

Thixotropy Pa/s 32°C

Cetyl Dimethicone (2.5 %)

28

3.3

29.4

2.7

10,810

Stearyl Dimethicone (2.0%)

43

3.9

49.7

4.5

21,000

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS Stearyl dimethicone also allows the use of less UV-B filter to achieve the same SPF value as that of the formulation with more UV-B but no alkylmethylsiloxanes. The impact of these results is the ability to decrease both cost and potential irritancy of the final sun care formulation but to retain the same level of sun protection. This is illustrated in Fig. 33.4. Another test was carried out with an inorganic sunscreen (i.e., titanium dioxide) to determine the effect of the three selected alkylmethylsiloxanes on the SPF of both oil-in-water and water-in-oil sun care formulations (Formulations 33.3 and 33.4). For the o/w emulsions, best SPF results were obtained with the semi-liquid alkylmethylsiloxanes cetyl dimethicone (Fig. 33.5). It was found with the physical sunscreen testing that no correlation existed between the fomulation rheology and the SPF value of the physical sunscreen. However, microscopic evaluation show that both the stearyl dimethicone and cetyl dimethicone containing formulations had very small particles of dispersed phase and were quite homogeneous emulsions. By contrast, this was not the case for the control and the higher C30–45 alkyl methicone variants. It is expected that such homogeneous emulsions are likely to facilitate an even distribution of the physi-

689

cal sunscreen on the skin, thereby ensuring improved sun protection. For the w/o emulsions studied, using the range of alkylmethyl modified silicones the best SPF results were obtained with C30-45 alkyl methicone (Fig. 33.6). In this case, there seems to be a better correlation of SPF behavior with the resulting rheological profiles. All of these formulations were observed to be uniform and homogeneous emulsions under the microscope. From the studies carried out, it is apparent that alkylmethylsiloxanes can help sun care formulators to meet most key requirements for modern sunscreen products; these include high SPF, good wash-off resistance, cost efficiency, improved aesthetics, and safety/non-irritancy. The semi-liquid, or low melting point alkylmethylsiloxanes are recommended for o/ w emulsion systems while the high melting point silicone wax copolymers are particularly suitable for w/o sunscreen emulsion systems. Synergy between silicone polyethers and organic quats.[6] One of the most appealing novelties in the personal care field relates to the introduction of clear/colorless products. This trend, which emerged several years ago, has given rise to the category of “clear and mild conditioning” shampoos. End users who look for clear products associate the

Figure 33.4 In vitro SPF Results for different levels of UV-B sunscreens.

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Figure 33.5 In vitro SPF results for o/w formulations containing 7.5% micronised titanium dioxide.

Figure 33.6 In vitro SPF results for w/o formulations containing 5% micronised titanium dioxide.

clarity with naturalness, lightness, freshness, and a young, modern image. Of course, mild products are well known to have a very broad and ever increasing consumer appeal. This is particularly true for people with sensitive skin and in frequent use applications. These clear, mild products claim many additional related features such as high purity, nongreasy feel, non-comedogenic, non-allergenic,

smooth and silky feel. Additionally, clear shampoos stand out on the shelves because of their crystal clear appearance. This gives them a distinct marketing advantage over other shampoo types. Dimethicone copolyols (silicone polyethers) (Fig. 33.7) can easily be incorporated into clear shampoo formulations without affecting their appearance.

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS

691

Figure 33.7 Chemical structure of dimethicone copolyols.

By contrast to opaque shampoos, clear shampoos are marketed as being mild and light. In addition to gentle cleansing, several other attributes must be built into such formulates in order to complete the creation of a clear, mild, and light conditioning shampoo. Mildness is associated with the generation of rich and creamy foam during the washing step and, after rinsing, the hair must appear natural and healthy. Additionally, a number of benefits must be built into the system. These include easy detangling and combing, body, good manageability, and strength with good elasticity. Other required properties are good tensile and torsional properties, shine, soft and smooth feel, and no fly-away. All of these properties must be designed into the shampoo to make it a success. In general, clear, mild, and light conditioning shampoos will contain milder surfactant types than the traditional more irritant anionic surfactants used in traditional formulations. Amphoteric co-surfactants such as betaines and sulphosuccinates are examples of such milder surface-active cleansing agents. Additional ingredients are also required such as foam boosters, thickening agents, and/or solubilizers. Conditioning benefits are well known to be enhanced by the use of moderate molecular weight quaternary ammonium polymers (quats). These include, for example, Amerchol’s Ucare® polymer range (based on hydroxypropylcellulose cationic modified) and Rhone-Poulenc’s Jaguar ® C162 (hydroxypropyl guar hydroxypropyltrimonium chloride). Both types of products enable the formulation of clear shampoos. Furthermore, these polymer types have various benefits, including improvement of both wet combing and hair manageability. The addition of certain silicone polymers to the above mentioned systems have been found to im-

prove conditioning performance. However, the synergy between these two types of materials has only recently been demonstrated. Silicone polyethers are a class of functionalized silicones that clearly can help to deliver some of the benefits expected by consumers from clear, mild, and light conditioning shampoos. The presence of pendant hydrophilic ethoxylated chains on the hydrophobic siloxane backbone provide surface active properties. Such properties enable certain silicone polyethers to be easily solubilized or dispersed in surfactant systems. Three Dow Corning silicone polyethers were selected for evaluation with the quaternary modified polymers described previously: • Dow Corning® 5324 fluid (dimethicone copolyol) characterised by a low molecular weight and (EO)n type functionality. • Dow Corning® 5200 formulation aid (lauryl dimethicone copolyol) characterised by a medium molecular weight, —(EO)n(PO)n and C12 pendant chains. • Dow Corning® 2501 cosmetic wax (dimethicone copolyol), water-soluble wax. To demonstrate that the dimethicone copolyols described produce useful synergistic effects when combined with quaternary polymers typically used in shampoo, a clear and light conditioning shampoo was formulated (Formulation 33.5). The performance of Formulation 33.6 with and without different polymeric quaternary polymers and selected silicone copolyols was evaluated for foam generation and stability, detangling ability, fly away (antistatic), feel, and shampoo viscosity. The detangling properties of the shampoos were evaluated by measuring the time needed for panelists to completely detangle hair tresses. All results are summarized in Figs. 33.8 and 33.9.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 33.8 Wet detangling results (time in sec) of hair treated with and without silicone polyethers/quaternary polymers.

Figure 33.9 Summary of synergistic effect of shampoos containing selected silicone polyethers and quaternary polymers.

Examination of Figs. 33.8 and 33.9 show that the dimethicone copolyols studied improve foam generation and the resulting sensory profile (density, creaminess, etc.). They had no negative effects on foam quality for systems either with or without the quaternary modified polymers tested. The benefits observed are believed to be related to the surface activity of silicone polyethers. It is well recognized that if properly chosen, certain silicone copolyols provide additional stabilization at the gas/liquid inter-

face. It is believed that by lowering the total free energy of a gas/liquid system, silicone polyethers increase the elasticity of the air/liquid interfacial film, leading to foam boosting effects. All the results shown indicate clearly that the combination of dimethicone copolyols and quaternary polymers in clear, mild, and light conditioning shampoos provides improved conditioning. Moreover, their combination brings synergistic benefits that are

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS not perceivable when the two materials are used separately in a shampoo. To explain this result, one hypothesis that has been proposed is that quaternary polymers form ionpair complexes in the presence of anionic surfactants. The complex coascervates precipitate when diluted (e.g., during the rinsing step) thereby allowing deposition of the quaternary polymer onto the hair. By reducing the surface tension to lower levels than achievable with organic surfactants, the silicone surfactant forms a more homogeneous film of quaternised polymer on hair since they are expected to modify the spreading coefficient. The silicone polyethers, which are partially water dispersible, have been demonstrated to deposit by flocculating along with the quaternary polymer. Due to their physico-chemical properties, silicone polyethers help the quaternary polymer forming an improved conditioning film thereby providing additional silicone feel benefits. Another hypothesis proposed is that the pendant ethoxylated chains of the silicone polyethers form weak hydrogen bonds with the amino acids of the hair shaft, thereby providing a light conditioning effect. In spite of such weak bonding forces, the greater affinity of silicone polyethers for water would allow them to be easily removed from the hair during the rinsing process when additional water is provided.

33.3.2

693

The silicone elastomers blends are comprised of lightly cross-linked siloxane chains swollen in diluents such as cyclomethicone or low viscosity dimethicone. Prior to crosslinking via hydrosilylation (Fig. 33.11), siloxane chains can be varied by length (x + y) and by the amount or reactive (SiH) sites versus non-reactive sites (Si-methyl).The siloxane chains can also be functionalized with various groups (R), such as polyether or alkyl. The remaining reactive sites (SiH) are then connected via a crosslinking (CH2)n mechanism. Modification of the ratios of the components impacting the degree of cross-linking (amount of functionality, degree of dilution, etc.), can be designed to produce a significant range of useful properties. Crosslinking in a diluted medium produces a very loose cross-linked network. Following the cross-linking process, the materials can be further diluted with cyclomethicone or other suitable solvent, to the desired viscosity/“texture.” Unlike conventional dimethylsiloxane polymers, the silicone elastomers are capable of significant swelling in the presence of a suitable solvent such as cyclomethicone. Materials can be made with properties ranging from pourable liquids; to very stiff, crumbly gels; or creamy pastes. This versatility enables targeting specified properties and designing the silicone elastomer to meet product specific needs.

Silicone Elastomers: Entrapment and Controlled Release[1][7]–[9]

Until the early 1990s, essentially all of the silicone used in cream and lotion formulations for topical application were liquids. These included both linear polymers such as dimethicone as well as low molecular volatile cyclomethicone. In addition, some silicone resins where also employed which, in pure form, are brittle solids. The recent introduction of the silicone elastomers blends (i.e., polymeric silicone molecules crosslinked together to such an extent that the material gels) (Fig. 33.10) have offered new perspectives to formulators. These silicone elastomers are soft solids and provide aesthetic properties to personal care products unlike any other class of silicones.

Figure 33.10 Chemical structure of silicone elastomers.

Figure 33.11 Hydrosilylation reaction.

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When the diluting solvent for the three-dimensional silicone elastomer is volatile, these crosslinked silicone elastomer blends can be dried down to form elastomeric films on the substrate. Further introduction of polyether (polyalkylene oxide) functionality onto the elastomer backbone changes the properties of the original elastomer gel. As expected, the polyether functionality facilitates the introduction of water as well as aqueous solutions of active ingredients into the elastomer blend. This increased absorption capability into a three-dimensional gelled matrix opens the door to new types of delivery systems. Typical examples of actives that can be absorbed into the silicone elastomer network are vitamins E and A acetate. Both of these vitamins are somewhat polar oils and, therefore, are not compatible with silicone elastomers based entirely on polydimethylsiloxane. However, the incorporation of polyether groups onto the silicone elastomers significantly improves the compatibility of polar oils with the elastomers and results in homogenous blends. Compatibility of such polar oils has been observed to improve with an increasing degree of polyether substitution. Structural characterization of these materials by has revealed the presence of chemical bonding of some active ingredients (i.e., vitamin E) to the silicone gel matrix of the elastomeric silicone polyether. 29Si

As reported earlier, oil-soluble vitamins such as vitamins A and/or E can be entrapped in the oil phase of an elastomeric silicone polyether (Fig. 33.10). This active containing oil phase can then be used as such, or emulsified and stabilized without the addition of a secondary other surfactant. Both vitamins can be delivered to various substrates (i.e., hair, skin, etc.) during the high shear application forces and the concomitant evaporation of the volatile cyclomethicone. One of the main advantages of such homogeneous blends of vitamin E in elastomeric silicone polyether gels is the lower tendency for oxidation, and the resulting increase in stability of the vitamin in the formulation. This benefit is illustrated in the following example of a simple skin moisturizer formulation. (Formulations 33.6 and 33.7)

Stability test. One bottle each of the formulas from Formulations 33.6 and 33.7 were placed in an oven set at 40°C and another set of samples was placed in an oven set at 50°C. For this testing, lowdensity polyethylene bottles were chosen because this type of plastic is permeable to oxygen in the atmosphere and would, therefore, provide little protection for the vitamin E in the formula. Oxidation of vitamin E is well known to be accompanied by a color change from yellow to dark brown over time. This color change is easily observed against the white background of the moisturizer formula that does not contain the vitamin. The samples were aged at an elevated temperature to accelerate changes that might occur over time. They were examined for changes in appearance after one month. A difference in color was apparent for both samples (40°C and 50°C), and this difference was even larger for the pair of samples kept at 50°C. The moisturizer sample that was made with the blend of non-functional silicone elastomer (Formulation 33.6) and vitamin E was darker for both sets of samples indicating a greater degree of oxidation in these samples. The set of samples (Formulations 33.6 and 33.7) stored at 50°C were examined again after approximately five months and the difference in appearance was much more noticeable than it was at one month. Aside from the change of color, there were no other signs of instability after five months, at 50°C, for either formula. Entrapment of vitamin E acetate (VEA), vitamin A acetate (VAA), or a mixture of VAA and VEA were carried out using a similar procedure as that described above. All of them confirmed the former results obtained with only vitamin E. The description of those additional formulations can be found in the European patent application EP 1 020 494. The polyether modified elastomer used to entrap and enable the formulation of vitamins into skin and cosmetic formulations can also be used to design less greasy, water-in-oil emulsions without requiring the use of additional surfactants. This phenomenon has a considerable value in the personal care arena where skin sensitivity, due to the presence of certain surfactants, can be an issue because of undesirable irritation. Additionally, polyether modified silicone elastomers can be used for preparing the “inner” oil phase

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of multiple-phase emulsions that are emerging as a new trend in cosmetic formulations.

and enable quantification of Estradiol concentration in each sample.

Both features are further elaborated in Sec. 33.4.2.

The results obtained are reported in Figs. 33.12 and 33.13 and highlight the beneficial properties of polyether modified silicone elastomer in controlling the release rate of Estradiol.

Silicone elastomers and controlled release. The crosslinked structure of silicone elastomers (unmodified and polyether modified) led to the idea that they might serve as a reservoir for a controlled release of useful actives. In order to confirm this potential controlled release feature, a series of experiments was carried out in the context of topical drug delivery systems. Estradiol-containing samples were prepared and release rates were evaluated over a 24-hour period. The typical drug release test employed was a Dow Corning Health Care Industries protocol and required the formation of patches. These patches were formed by drawing out the drug-loaded polyether modified elastomer onto a Scotchpak® release liner and drying for 1 hour in a oven at 65°C. The resulting film was, thereafter, covered with another sheet of Scotchpak release liner formed by drawing out a drug-loaded, diluent-swollen elastomeric silicone material onto a Scotchpak release liner using 30-mil shims and, thereafter, drying for 1 hour in an oven at 65°C.The film was then covered with another sheet of Scotchpak releaser liner and punched into 4-cm patches using a Carver Press. The resulting patches were then tested in quadruplicate for the Estradiol release rate over a 24-hour period. The characterization of the drug release was performed on a Franz diffusion system using four replicates and the Estradiol analysis was perfomed by high pressure liquid chromatography (HPLC). The receptor medium was a 40/60 blend of polyethylene glycol 400/deionized water. This medium was selected in order to improve the Estradiol solubility and facilitate measurements of concentrations in the solvent. Sampling times were established at one, two, four, six, eight, and twenty-four hours. The receptor fluid was completely replaced at each sampling interval. HPLC was then run immediately after the completion of each diffusion experiment. Estradiol standards of known concentration were also run before and after each set of samples as controls. These were employed to calibrate the instrument

The data shows noteworthy 24-hour cumulative release rates of 45% to 58% and zero-order kinetics are suggested by the fact that the release was at constant rate. By comparison, typical release rates from classical silicone usually are far lower and typically range from 1% to about 11.7% These results support the hypothesis that the degree, or tightness, of the crosslinked silicone matrix directly affects the drug release rate. The ability to achieve a constant release rate that can be controlled by altering the degree of crosslinking may be beneficial for applications where a high level and steady release rate is desired. Although this experiment was conducted on a drug, it is expected that similar results will be obtained with personal care actives having similar polarity and molecular size to Estradiol.

33.3.3

Silicone Vesicles and Encapsulation[4][5]

In the mid 1990s, some fundamental research highlighted the ability of a new class of proprietary silicone polyethers (dimethicone copolyol) to form vesicles. These silicone-based vesicles are structurally comparable to liposomes which are described elsewhere in this book (see Ch. 13). Silicone vesicles are surfactant-based structures and they demonstrate the self-organization phenomenon well known to micelles and liquid crystal phases. For example, surfactants can form various types of aggregates in water by rearranging their group structure in order to increase stability and achieve the lowest energy configuration in solution. Simple two phase oil-in-water emulsions consist of surfactants that arrange themselves at the oil/water interface. In these systems, the hydrophilic moiety is directed towards the external water phase while the hydrophobic moiety is directed towards the internal oil phase. This rearrangement produces spherical, unilayer surfactant structures surrounding the suspended oil droplets.

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Figure 33.12 Cumulative release of estradiol achieved with polyether-modified silicone elastomer.

Figure 33.13 Release rate of estradiol achieved with polyether-modified silicone elastomer.

A vesicle is a specific type of surfactant assembly wherein the surfactants rearrange themselves in a bilayer structure (lamellae). In these cases, the hydrophobic moiety of the surfactant is oriented towards the inside of the bilayer while the hydrophilic moiety is facing the outside of the bilayer. By contrast with the unilayer surfactant structure of oil-in-water emulsions, two layers of self-oriented surfactants form a membrane around an inner core in typical vesicles. Three types of vesicles exist (Fig. 33.14): • Small unilamellar vesicles (20–50 nm). • Large unilamellar vesicles (200–500 nm). • Multilamellar vesicles (200–1000 nm).

In contrast with unilamellar vesicles which consist of a unique bilayer only, multilamellar vesicles are formed from multiple concentric bilayers. They can have various shapes and may be spherical, globular, or tubular. As a result of the bilayer structure, the two phases are distributed in a particular orientation in space. The oil phase is distributed within the concordance of hydrophobic tails of the surfactants and are contained within the bilayer itself. By contrast, the water phase is on the outside of the bilayer and acts as the “external” phase and is also found in the “hollow” of the sphere formed, and/or in-between the bilayers.

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Figure 33.14 Structure of a multilamellar vesicle.

Liposomes are a specific type of vesicle in which the surfactants are phospholipids. These phopholipids are convenient and useful as surface active components because their lipid structure is similar to that found in the stratum corneum.

• Since silicone vesicles do not contain hydrocarbon chains, they show additional stability.

Based on their structure, in general, vesicles offer a wide range of opportunities, in both the cosmetics and pharmacological fields. Some applications have also been reported in the electronics industry.

• Silicone vesicles are stable up to an unusually high temperature (90°C) and have a wide tolerance for various active ingredients encountered in cosmetic formulations. The silicone bilayer formed is highly flexible as compared with conventional liposomes. As a result of their ability to deform and retain their structures, they can be sterilized by passing through membranes. The stability of silicone vesicles depends, in part, on the stability of the polyether and its tendency to hydrolyze under certain conditions of pH.

The structure of silicone vesicles opens a wide range of possibilities for the incorporation of useful active ingredients. For example, using silicone vesicles, hydrophilic and hydrophobic actives can be separated and protected from each other. This protection is obtained because the hydrophobic actives can be distributed inside the bilayer, while hydrophilic actives will necessarily be in solution in the water phase. It has been demonstrated that permeability of the bilayer to water-soluble actives can be very low and this phenomenon prevents the active from escaping from the silicone vesicle. This protection mechanism also offers a way to reduce skin irritancy when actives are employed that, by themselves, would be too irritating to the skin. Silicone vesicles can have a diameter from about 0.05 to 1 micron and an internal volume of 10-6 µm3. The membrane thickness of these vesicles is about 3 to 4 nm. They offer complementary advantages to traditional liposomes made of phospholipids. For example:

• Rearrangement of the silicone copolymers into vesicles occurs spontaneously.

Different methods may be used to prepare silicone vesicles. For silicone polyethers, gentle mixing, or sonication of the dispersion of the silicone polyether copolymer in water is sufficient to produce the vesicles. Encapsulation of actives within the silicone vesicles is possible for compositions containing 0.1% to 40% of silicone polyether, and 0.1% to 10% of the active substance. Size control of the vesicles can be achieved via membrane extrusion techniques. In these cases, the silicone vesicles are passed through a filter of precisely sized holes in order to obtain a narrow and controlled size distribution. The most commonly used method to observe silicone vesicles is Cryogenic Transfer Transmission Electron Microscopy (cryo-TEM) (Fig. 33.15).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS • Humectants such as glycerin, sorbitol, and propylene glycol. • Colorants such as Violet No. 2, D&C Red 22, and D&C Green 8. • Enzymes such as papain, trypsin, and chymotrypsin. • Drugs such as aspirin and nicotine. • Hydroxy carboxylic acids such as hydroxyacetic acid (glycolic acid).

Figure 33.15 Cryo-TEM of typical silicone vesicles.

Non water-soluble actives can also be chosen from the following list:

This method allows the observation of macromolecules and their aggregates in their original environment. A thin layer of sample is formed (by freezing) and observed. Small angle x-ray analysis and video enhanced optical microscopy may also be used to observe the morphology of silicone surfactant aggregates in vesicle configuation.

• Conditioning agents such as vitamin A, vitamin E acetate, and lanolin oil.

Incorporation of actives in silicone vesicles. Depending upon the hydrophilic/hydrophobic nature of the active to be incorporated into the silicone vesicle structure, different approaches may be employed. Water-soluble actives can be first diluted in the water phase. The silicone surfactant is then added and vesicles are spontaneously formed during this process. Excess water and actives are thereafter removed using centrifugation, dialysis, or size exclusion chromatography. By contrast, water-insoluble actives are first added to the siloxane surfactant itself and this mixture is then added to the water phase with stirring.

• Humectants such as lanolin alcohol, cetearyl octanoate, and sodium stearoyl lactylate.

Water-soluble actives can be chosen from the following list: • Conditioning agents such as vitamin C, vitamin H (biotin), gelatin, and hydrolyzed collagen. • Deodorant actives such as Triclosan. • Antiperspirant salts such as aluminium chlorohydrate and aluminium/zirconium glycine. • Preservatives such as salicylic acid, DMDM hydantoin, and cetyl trimethyl ammonium bromide. • Sunscreen agents such as 4-aminobenzoic acid (PABA) and 2-phenylimidazol-5-sulfonic acid.

• Preservatives such as 2-mercaptopyridine1-oxide. • Sunscreen agents such as homomethyl salicylate (homosalate) and 4-methoxy cinnamic acid isoamyl ester.

• Colorants such as stearamide DIBA stearate and ethylene glycol monostearate. • Emollients such as mineral oil, jojoba oil, and polydimethylsiloxane. • Drugs such as nitroglycerin. The use of silicone vesicles to encapsulate actives offers multiple benefits. These include, among others: • Reduced skin irritancy (e.g., preservatives or sunscreens). • Improved stability of the active, (e.g., enzymes or vitamins). • Controlled release of the active, (e.g., water-soluble active in a slight permeable vesicle). • Incorporation of incompatible types of actives by separating them from each other. Assessment of encapsulation efficacy. The use of dyes or fluorescent substances can help determine whether the active substance is incorporated into the hydrophobic bilayer or within the water phase. Sodium fluorescein, a hydrophobic substance, can be incorporated into a water solution where vesicles are formed. This chemical is useful as it disappears into the bilayer, causing a loss of color of the initial solution. Calcein, which is more hydrophilic

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS than fluorescein, remains in the water phase after the formation of vesicles and no loss of color is observed. Finally, bromocresol purple (water-soluble dye) is capable of distributing in the water phase as well as in the hollow and outside the vesicle. When sodium hydroxide is added to vesicles containing this dye, the purple color rapidly turns yellow in the external water phase, while the color remains for a longer period of time in the hollow of the vesicle. This sort of test is useful for demonstrating the permeability of the membrane surrounding and the hydroxide ion can penetrate more or less quickly into the vesicle (as assessed by oil immersion microscopy). Potential membrane leakage from silicone vesicles can be assessed by means of calcein. After vesicles are formed in an aqueous solution of calcein, external water and excess active substances can be removed and the resulting vesicles may then be re-suspended in clear water. The rate of reappearance of fluorescence is an indication of the permeability and leakage characteristics of the membrane. This phenomenon can then be used to evaluate the impact of additives on the modification of the membrane. The quantity of encapsulated active substance can be assessed by measuring the color of a given

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vesicle suspension, using a calibration curve generated with the substance. Figure 33.16 shows particle size results for vesicles prepared from a dimethicone copolyol and loaded with increasing amounts of vitamin E acetate (VEA) from 0% to 30% after 24 hours of aging. Low levels of added VEA are seen to behave in a manner to that of unloaded vesicles, with a peak at about 1.5 micron and a tail at smaller size particles. Similar data is obtained after approximately two months of aging. The loaded vesicles are seen to remain essentially stable at the larger size. This result is consistent with the concept that the presence of VEA in the membrane stiffens the bilayer somewhat and, therefore, inhibits spontaneous dispersion to smaller vesicles.

33.4 Silicone-Based Cosmetic Formulations as Delivery Systems In addition to delivery system technologies that entrap or encapsulate actives, other means to stabilize, protect, and deliver actives to the substrate are also available. A number of specific formulation bases can act as delivery systems for actives and provide solutions for their issues.

Figure 33.16 Particle size results for a dimethicone copolyol loaded with increasing amount of vitamin E acetate.

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In the following section, several examples of silicone-based formulations capable of being employed as active delivery systems are reviewed. These include:

By employing volatile silicones as the continuous phase and selecting the polyol, it is possible to manufacture personal care products that not only protect storage-sensitive actives but also:

• Non-aqueous emulsions of polyols in silicone fluids.

• Possess a selective mechanism for the transport of active substances.

• Multiple-phase emulsions.

• Exert a moisturizing effect via the nature of the polyol phase.

• Polar solvent-in-oil emulsions and their multiple phase variations.

• Are completely free of preservatives. • Do not leave an unpleasant, greasy film on the skin.

33.4.1

Non-Aqueous Emulsions of Polyols in Silicone to Deliver Storage-Sensitive Personal Care Actives[11]

Non-aqueous-based emulsion chemistries allow the delivery of storage-sensitive personal care actives in conventional creams, lotions, and gels. This technology is based on propylene glycol-in-silicone emulsions that incorporate dimethicone copolyols (Fig. 33.17), which were originally developed for formulating water-in-silicone emulsions. The manufacture and stabilization of these emulsion systems provide opportunities for many innovative applications in the field of emulsion technology. In particular, polyol-in-silicone emulsions offer a stable vehicle for transporting raw materials that are sensitive to hydrolysis. In the personal care marketplace, these emulsions offer a new, reasonably priced and efficient method for encapsulating enzymes, vitamins, and antioxidants in conjunction with their incorporation to oil-in-water emulsions. In view of the demonstrated capability of certain polyols, such as propylene glycol and glycerin, these materials offer similar capability to liposomes to deliver active ingredients onto the skin. This process can be carried out, for example, by means of a propylene glycol phase containing personal care actives.

Figure 33.17 Chemical structure of dimethicone copolyols useful for forming mutliple-phase emulsions capable of delivering actives.

• Create a pleasant “skin feel” during application to the skin. To demonstrate this concept, wherein multiplephase emulsions protect water-sensitive actives, vitamin C was chosen as a model system, shown in Formulation 33.8. Formulation 33.8 was tested for in vivo sun protection factor (SPF) following the standard Colipa protocol. A value of 3.4 was obtained. This demonstrates effective delivery of ascorbic acid to the skin and also protection. This formulation showed only a minimal decrease in vitamin C activity (99.5%) after storage for one month at 50°C.

33.4.2 Multiple-Phase Emulsions[12][13] Certain active ingredients that are useful in skin care products can benefit from a special type of delivery system known as a multiple-phase emulsion. These emulsions provide an interesting potential vehicle for targeted and/or controlled release as well as encapsulation of actives in cosmetic and pharmaceutical products. Although multiple-phase emulsions have a fairly long history, recent progress in their fundamental understanding and development of novel emulsifiers has made them more readily accessible to formulators. Such multiple-phase emulsions are often positioned as a cost-effective alternative to conventional encapsulation technologies. Multiple-phase emulsions are composed of droplets of one liquid dispersed in larger droplets of a second liquid (primary emulsion). This primary emulsion is then dispersed in a final continuous phase. Generally, the internal droplet phase will be miscible

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS with, or identical to, the outer continuous phase. For example, in a water-oil-in-water (the main type of multiple-phase emulsion), the internal and external phases are both aqueous. For the purpose of effectively describing these complex systems, and in accordance with recognized standards of nomenclature used for w/o/w systems, the aqueous phase of the primary emulsion is designated as w1 and the primary emulsion is designated w1/o. The primary emulsion w1/o includes an oil phase which is designated as o. After the primary emulsion w1/o has been further dispersed in the second and outer aqueous phase (designated as w2), the complete multiplephase emulsion system is designated as w1/o/w2. A schematic representation of a typical w/o/w is illustrated in Fig. 33.18.

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In general, at least two surfactants must be employed in order to form a multiple emulsion. One surfactant is used for preparing the primary emulsion (w1/o), while a second surfactant, generally significantly different in composition from the first surfactant, is used in the final step of emulsification to form the w1/o/w2 multiple emulsion. One interesting class of surfactants useful for forming multiple-phase emulsions is silicone copolymers. These emulsifiers are polydimethylsiloxane grafted with hydrophilic chains based on polyoxyethyleneoxide, thereby forming a class of dimethicone copolyol (represented in Fig. 33.17). The addition of hydrocarbon chains to the dimethicone copolyol backbone increases the oil solubility and therefore opens new perspectives for the formulation of multiple-phase emulsions (Fig. 33.19) Such silicone copolymers indeed exhibit high surface activity and provide an unique combination of features and benefits: • Their ternary molecular structure allows them to migrate to the emulsion interface and to effectively lower the interfacial tension of the system.

Figure 33.18 Schematic of a multiple-phase emulsion w1/o/w2.

Some of the main benefits of w/o/w emulsions are their ability to segregate actives in the various phases, and to protect sensitive actives (that need to be delivered from an aqueous matrix) onto the skin, underarms, or hair. For example, oil-soluble active ingredients such as vitamin A and vitamin E, can be emulsified in the oil phase of the primary emulsion. This primary emulsion can then be emulsified into an outer water phase (w2) , thereby forming a multiple-phase emulsion. Alternatively, water-soluble actives such as vitamin C, can be emulsified into the water phase (w1) of the primary emulsion, and the primary emulsion can then be emulsified into the external water continuous phase (w2), forming the multiple-phase emulsion.

• Their polymeric character allows them to remain at the interface and stabilize the emulsion by a steric repulsion mechanism. • The very flexible siloxane backbone allows all the polyether and alkyl functional groups to orient in an optimal fashion at interface.

An example of w/o/w formulation based on an alkyl dimethicone copolyol is illustrated in Formulation 33.9.

Figure 33.19 Chemical structure of an alkyl silicone polyether.

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33.4.3 Polyether Modified Silicone Elastomers for Multiple-Phase Emulsions Another unique class of silicone emulsifiers for making stable multiple-phase emulsions useful as a delivery system has been previously described in Sec. 33.3.2. The advantage of using an elastomeric silicone polyether (see chemical structure in Fig. 33.10) is that this tridimentional network is present at the interface of the primary dispersed phase, w1, and the secondary dispersed phase, o. Therefore, it is the only emulsifier required to form such multiplephase emulsions. As previously mentioned, multiplephase emulsion systems are highly useful in view of their ability to protect sensitive active ingredients being delivered from an aqueous matrix onto substrates such as hair, skin, and underarms.

Vitamins capable of being entrapped in multiplephase emulsions made with elastomeric silicones are oil-soluble vitamins as well as water-soluble vitamins. These include but are not limited to: Oil-soluble vitamins: • Vitamin A1 • Retinol • C2-C18 esters of Retinol • Vitamin E • Tocopherol • Esters of vitamin E Water-soluble vitamins can be used and include but are not limited to: • Vitamin C • Vitamin B1

Elastomeric silicone polyethers are useful for preparing the “inner” oil phase of w/o/w emulsions. These emulsions can be formed by simply shearing and diluting water-in-silicone oil (w1/o) emulsions which have been prepared using an elastomeric silicone polyether as the emulsifier.

• Vitamin B2

To illustrate how these silicone elastomers can be used as an emulsifier in a w/o/w emulsion, a simple hand and body lotion containing vitamin C was prepared. The vitamin C was included in the formula in the form of an aqueous solution that was first emulsified into cyclopentasiloxane (D5) using the elastomeric silicone polyether as the emulsifying agent. The resulting w/o emulsion was then added to a conventional lotion (o/w) formula where it forms a separate oil phase that contains vitamin C (Formulation 33.10). The examination of the formulation under a microscope confirmed the presence of a multiple emulsion (i.e., droplets of aqueous vitamin C could be observed inside larger droplets of cyclopentasiloxane) (Fig. 33.20).

• Biotin

The pH of the lotion was measured about five days and was found to be essentially the same as a comparable lotion that did not contain vitamin C. This provides further evidence that vitamin C was trapped within cyclopentasiloxane (D5). If this material had escaped into the main water phase, the pH would have been significantly lower than the analogous lotion without vitamin C.

• Vitamin B6 • Vitamin B12 • Niacin • Folic acid • Pantothenic acid Besides vitamins, other active ingredients can be entrapped in the polyether modified elastomers. Examples include, but are not limited to: • Antimicrobial agent [e.g., 5-chloro-2-(2,4dichlorophenoxy)phenol also known under the name Triclosan].

Figure 33.20 Microscopic picture of an elastomeric silicone polyether-based w/o/w emulsion

POSTIAUX, VINCENT, STOLLER, NEWTON: SILICONE TECHNOLOGY AS DELIVERY SYSTEMS • Sunscreen (e.g., octylmethoxy cinnamate). • Astringents (e.g., aluminium chlorohydrate, aluminium zirconium tetrachlorohydrex, etc.). • Anti-acne agents (e.g., benzoyl peroxide). • Antibacterial agent (e.g., chlorohexadiene gluconate). • Antifungal agents (e.g., miconazole nitrate). • Anti-inflammatory agents (e.g., salicylic acid).

in a second continuous non-aqueous polar solvent phase, ps2 in order to form the second class of multiple emulsion known as ps1/ o/ps2. Both types of these polar multiple-phase emulsions are particularly useful for delivering polar actives such as alpha-hydroxy acids, vitamin C, and others. In both cases, the emulsifier of choice is the polyether modified elastomer described in Sec. 33.3.2 (see Fig. 33.10). Non-aqueous, polar solvents intended for use in personal care applications include, but are not limited to:

33.4.4 Polar Solvent-in-Oil Emulsions and Multiple Emulsions[14]

• Propylene glycol

Two variations of multiple-phase emulsions can be distinguished while using the same polyether modified silicone elastomer.

• Glycerol esters

1. A non-aqueous polar solvent-in-oil (ps1) in water multiple emulsion of type ps1/o/w. In this type of system, the non-aqueous polar solvent ps 1 is dispersed in a polydimethylsiloxane oil as a first continuous phase (primary emulsion) ps1/o by an emulsifier. The primary emulsion ps1/o is then dispersed in a second continuous aqueous phase W in order to form the multiple emulsion ps1/o/w. 2. A non-aqueous polar solvent-in-oil (ps1) in a non-aqueous polar solvent (ps2) thereby forming a multiple emulsion of the type ps1/ o/ps2. In this second case, a non-aqueous polar solvent phase ps1 is first dispersed in the silicone oil as a first continuous phase of a primary emulsion ps1/o by an emulsifier. The primary emulsion ps1/o is then dispersed

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• Glycerol • Polyethylene glycol Non-aqueous polar solvent-soluble active ingredients for ps1/o and ps1/o/ps2 emulsion systems can be chosen, and are not limited to the following: • Vitamins: vitamin C; vitamin A; vitamins B1, B2, B6, and B12; Niacin; folic acid; Biotin; and pantothenic acid. Their concentration can vary from 0.01% to about 50% by weight. • Drugs: including activated antiperspirant salts such as aluminium-zirconium trichlorohydrate. • Alpha-hydroxy acids: glycolic acid, lactic acid, tartaric acid, and citric acid (i.e., fruit acids). An example of a propylene-glycol/oil/water multiple emulsion is illustrated in Formulation 33.11.

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33.5 Formulations Formulation 33.1 Oil-in-water Sun Care Formulation Containing Organic Sunscreens

Phase

A

B

C

Ingredients

Function

Parsol MCX

Sunscreen

4.00

Parsol 1789

Sunscreen

1.50

AMS

SPF Booster

4.0

Crodamol GMS

Emollient

4.0

Cithrol GMS

Emulsifier

3.0

Methyl/propyl paraben

Preservative

q.s.

BHT

Anti-oxidant

q.s.

Amphisol K

Emulsifier

2.0

Carbopol® 980 (1% solution)

Thickener

10.0

Propylene Glycol

Moisturizer

3.5

KOH (10% solution)

Neutralizer

q.s pH 7.

Disodium EDTA Distilled Water D

E

Weight %

0.1 Water phase

Cyclomethicone

Up to 100 4.0

Parsol HS

Sunscreen filter

Distilled water

Solvent

KOH (10% solution)

Neutralizer

2.0 20.0 q.s. pH 7

Mixing Procedure: 1. Mix ingredients of Phase C together and adjust pH to 7.0 with KOH (10% solution). 2. Heat to 75°C. 3. Mix ingredients of Phase A together and heat to 85°C. 4. Add Phase B into Phase A. 5. Add mixture from Step (1) into Step (2) mixture using vigorous agitation and continue mixing while cooling to 45°C. 6. Mix Phase D ingredients together and add to (4) with vigorous agitation 7. Mix ingredients of Phase E, except the dimethicone copolyol. Then adjust the pH 7.0 with KOH (10% solution) and heat the mixture to 30°C and add the dimethicone copolyol. 8. Add Step (6) mixture into (5). 9. Check the pH of the final formulation and adjust it to pH 7.0 if necessary with KOH. 10. Compensate for the water lost occurring during the heating phase.

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Formulation 33.2: Water-in-oil Sun Care Formulation Containing Organic Sunscreens

Phase

A

B

C

Ingredients

Function

Parsol MCX

Sunscreen

6.00

Parsol 1789

Sunscreen

3.00

Parsol 5000

Sunscreen

3.0

Phenyl trimethicone

Sensory agent

3.0

AMS

SPF Booster

Cithrol GMS

Emulsifier

3.0

Finsolv TN

Emollient

4.0

Cetyl alcohol

Emulsifier

0.25

Methylparaben/propylparaben

Preservative

q.s.

BHT

Anti-oxidant

q.s.

Amphisol K

Emulsifier

2.0

Carbopol 980 (1% solution)

Thickener

10.0

Propylene glycol

Moisturizer

2.5

KOH (10% solution)

Neutralizer

q.s. pH 7

Disodium EDTA Distilled water D

E

Weight %

2/2.5

0.1 Water phase

Cyclomethicone

Up to 100 4.0

Vitamin E acetate

Active

0.5

Parsol HS

Sunscreen filter

2.0

Distilled water

Solvent

KOH (10% solution)

Neutralizer

Dimethicone copolyol

Skin feel agent

20.0 q.s. pH 7 2.0

Mixing Procedure: 1. Mix ingredients of Phase C together and adjust pH to 7.0 with KOH (10% solution). 2. Heat to 75°C. 3. Mix ingredients of Phase A together and heat to 85°C. 4. Add Phase B into Phase A. 5. Add mixture from Step (1) into Step (2) mixture using vigorous agitation and continue mixing while cooling to 45°C. 6. Mix Phase D ingredients together and add to (4) with vigorous agitation 7. Mix ingredients of Phase E, except the dimethicone copolyol. Then adjust the pH 7.0 with KOH (10% solution) and heat the mixture to 30°C and add the dimethicone copolyol. 8. Add Step (6) mixture into (5). 9. Check the pH of the final formulation and adjust it to pH 7.0 if necessary with KOH. 10. Compensate for the water lost occurring during the heating phase.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 33.3: Oil-in-water Formulation Containing Titanium Dioxide

Phase

A

A or B

B

Ingredients

Function

o/w (weight %)

Dow Corning AMS

SPF booster

2-4

Mineral oil

Emollient

6.0

Crodamol ML

Emollient

1.5

Cetyl alcohol

Emulsifier

2.0

GMS/SE

Emulsifier

1.2

Emulgin B2

Emulsifier

0.4

Stearic acid

Emulsifier

1.0

Cyclopentasiloxane

Volatile carrier

3-5

Preservative

Preservative

q.s.

Glycerine

Moisturizer

1.0

Triethanolamine

Neutralizer

1.0

Aloe vera gel

Thickener and moisturizer

0.5

Water & Tioveil AQ

Sunscreen filter

Distilled water

Solvent

Mixing Procedure: 1. Heat Phase A ingredients to 70-75°C. 2. In a separate container, heat Phase B ingredients to 70-75°C. 3. Add Phase A to Phase B with gentle stirring. 4. Homogenize using a high shear mixer.

18.75 Up to 100

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707

Formulation 33.4: Water-in-oil Formulation Containing Titanium Dioxide

Phase

A

A or B

B

Ingredients

Function

w/o System (weight %)

Laurylmethicone copolyol

Emulsifier

Dow Corning AMS

SPF booster

Mineral oil

Emollient

5.0

Witconol TN

Emollient

3.1

Tioveil OP

Sunscreen filter

12.5

Preservative

Preservative

q.s.

Glycerine

Moisturizer

4.0

Aloe vera gel

Thickener and moisturizer

q.s.

Sodium chloride

Stabilizer

1.0

Distilled water

Solvent

Mixing Procedure: 1. Mix Phase A ingredients together until homogeneous. 2. Mix Phase B ingredients together until homogeneous. 3. Slowly add Phase B into Phase A under adequate agitation. 4. Homogenize through Silverson.

3.0 2

Up to 100

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 33.5: Mild and Light Shampoo Formulation

Phase

A

B C D

Ingredients

Function

Weight %

Empicol ESB3

Surfactant

30

Amonyl 380 BA

Surfactant

3.0

Rewoderm S1333

Surfactant

3.0

Water

Solvent

Comperlan KD

Refatting agent

Jaguar C13 S (or) Ucare C13 S Glucamate DOE 120

Conditioning agent

Up to 100 4.0 0.1–1.0

Viscosity builder

1–2

Conditioning agent

2.0

pH adjuster

q.s.

Dow Corning 5200, (or) E

Dow Corning 5324 fluid, (or) 

Dow Corning 2501 cosmetic wax If required

Citric acid

Mixing Procedure: 1. Add all the ingredients of Phase A into appropriate vessel and heat to 65°C with a water bath. Some water needs to be kept for dispersing the Phase C and Phase D ingredients (around 10 g for each ingredient). 2. Heat Phase B separately to 65°C with a water bath. 3. Disperse the Jaguar C13 S or Ucare C13 S in some water and heat at 65°C (Phase C). 4. Disperse the Glucamate DOE 120 in some water and heat to 65°C (Phase D). 5. Add Phase A to Phase B. 6. Add Phase C into Step (5) ingredients. 7. Add Phase D into Step (6) ingredients. 8. Add Phase E. 9. Neutralize with the acid if required.

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709

Formulation 33.6: Skin Moisturizer Formulation with Vitamin E and Silicone Elastomer

Phase

Ingredients

A

B

Weight %

Blends of vitamin E with silicone elastomer in cyclopentasiloxane (1:1)

Carrier and active

6.0

Glycerin

Moisturizer

4.0

DMDM hydantoin

Preservative

0.3

Deionized water

Solvent



C

Function

86.7

Emulsifier/thickener

Sepigel 305

3.0

Total

100.0

Mixing Procedure: 1. Mix the vitamin E with the selected silicone elastomer (Formula A or Formula B) 2. Disperse Phase A into Phase B using a rapid shear mixing action to disperse the elastomer/vitamin E/D5 blend into the water phase. 3.

Add Phase C slowly and increase the mixer speed to maintain a good agitation.

Note: Samples of Formula A and B were divided into four low-density polyethylene bottles (two bottles for each formula) to perform some stability test.

Formulation 33.7: Skin Moisturizer Formulation with Vitamin E and Silicone Polyether

Phase A

B

C

Ingredients

Function

Weight %

Blends of vitamin E with elastomeric silicone polyether in cyclopentasiloxane (1:1)

Carrier and active

6.0

Glycerin

Moisturizer

4.0

DMDM hydantoin

Preservative

0.3

Deionized Water

Solvent



Sepigel 305

86.7

Emulsifier/thickener Total

3.0 100.0

Mixing Procedure: 1. Mix the vitamin E with the selected silicone elastomer (Formula A or Formula B) 2. Disperse Phase A into Phase B using a rapid shear mixing action to disperse the elastomer/vitamin E/D5 blend into the water phase. 3.

Add Phase C slowly and increase the mixer speed to maintain a good agitation.

Note: Samples of Formula A and B were divided into four low-density polyethylene bottles (two bottles for each formula) to perform some stability test.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 33.8: Polyol-in-Silicone Emulsion Containing Vitamin C

Phase A

Ingredients

Function

Weight %

Dimethicone copolyol and cyclomethicone*

Emulsifier

20.0

Cyclomethicone

Volatile carrier

2.5

Propylene glycol with 5% ascorbic acid

Carrier/moisturizer + active

77.0

Sodium chloride

Stabilizer**

0.5

B Mixing Procedure:

1. Weigh the Phase A ingredients into a suitable vessel equipped with a mixer. 2. Heat the mixture to 80°C and mix until uniform. 3. Heat separately the Phase B ingredients to 80°C and add Phase B to Phase A while homogenizing with a Braun kitchen Stirrer of type 4961. 4. Continue to homogenize for one minute. 5. Continue stirring with a blade stirrer (850 rpm = 3.11 m/s) for 45 min at 25°C. * 10% dimethicone copolyol emulsifier and 90% cyclopentasiloxane. ** Several studies demonstrated the need for sodium chloride to reduce the tendency for diffusion of the dimethicone copolyol from the silicone oil phase into the propylene glycol phase. The salt was found to help stabilize the emulsion.

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711

Formulation 33.9: Formulation of a w/o/w Emulsion with Alkyl Dimethicone Copolyol

Phase

Ingredients

Function

Weight %

Primary w/o Emulsion

A

B

Cyclopentasiloxane

Oil phase

15

Lauryl methicone copolyol

Surfactant

2.0

Mineral oil

Oil phase

5.0

Jojoba oil or Crodamol GTCC

Oil phase

5.0

Deionized water

Water

Sodium chloride

Stabilizer

72 1

Mixing Procedure: 1. Mix the ingredients of Phase A together at 800 RPM for 3 minutes. 2. Quickly add Phase B to Phase A. Continue mixing at very high speed for another 10 min. w/o/w Emulsion Rhodarsurf L-790

Surfactant

Water

Water

Mixing Procedure: 3. Add Rhodasurf L-790 to the primary emulsion, under moderate shear. 4. Slowly add the remaining water, under moderate shear.

3 30

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 33.10: Hand and Body Lotion with Vitamin C

Phase A

Ingredients

C D E

Weight %

Stearic acid

Oil phase

2.06

Arlacel 165

Oil phase

2.06

Petrolatum

Oil phase

5.15

Carbopol ETD 2001

Thickener

0.10

Deionized water

Solvent

Triethanolamine

Neutralizer

1.03

Deionized water

Solvent

10.31

Polyether–modified elastomer (9%) in cyclopentasiloxane

Active carrier

0.59

Solution of vitamin C in water (10% solution)

Active

22.16

DMDM Hydantoin

Preservative

0.31



B

Function

Up to 100%

Mixing Procedure: 1. Phases A and B are heated in separate mixing containers to about 85°C. Each phase is mixed thoroughly. 2. Phase A is slowly poured into Phase B while mixing with a propeller mixer. 3. After a uniform dispersion was obtained, the dispersion is removed from the hot plate and Phase C (at room temperature) is added while the mixing is continued. 4. The mixer speed is increased as the mixture thickens to maintain good turnover. 5. The emulsion is allowed to cool to about 50°C and Phase D is mixed into the emulsion. 6. After the mixture is uniform, mixing is continued for another 5 minutes. Adding it back together with Phase E compensates for the water lost by evaporation. 7. Mixing is continued until the formula is cooled down at room temperature.

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Formulation 33.11: Propylene Glycol/Oil/Water Multiple Emulsion PS1/o/w

Phase

A

Ingredients

C

D

Weight %

Hystrene FG

Anionic surfactant

1.78

Arlacel 165

Nonionic surfactant

1.78

White protopet

Emollient

4.46

Carbopol EDT 2001

Thickener

8.93

Deionized water

Solvent

55.07

Triethanolamine

Neutralizing agent

0.89

Water

Solvent

8.93

Cyclopentasiloxane (and) PEG-12 dimethicone crosspolymer

Emulsifier

9.28

Propylene glycol

Polar solvent

8.60

®

Preservative

0.27

®

B

Function

Glydant

Mixing Procedure: 1. The ingredients of Phase A are mixed and heated in a hot water bath at 80°C. 2. The emulsion is prepared by pouring Phase A into Phase B and mixing at 200 rpm (21 rad/s) for 5 minutes. 3. The emulsion is then neutralized with Phase C (w), and mixed for about five additional minutes. During neutralization, the speed mixer is gradually increased from 200 to 350 rpm to ensure adequate mixing. 4. The sample is removed from the hot water and allowed to cool to 55°C while continuing to mix at 350 rpm (37 rad/s). 5. When the temperature of the sample reaches 55°C, 25 g of Phase D are then added with a pipette. 6. Mixing is continued, and the sample is allowed to cool to 50°C. 7. After cooling Glydant is added and water content is readjusted to compensate for water lost by evaporation. Mixing is continued for an additional five minutes. Note: Actives can be added in the propylene glycol.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References 1. Smith, J. M., Thomas, X., Gantner, D. C., and Lin, Z., Loosely Crosslinked Silicone Elastomer Blends and Topical Delivery Research Disclosure, Dow Corning (2001)

9. Lin, Z., Schulz, W. J., and Smith, J. M., Elastomeric Silicone Terpolymer, US Patent 6,200,581, Dow Corning Corp. (2001)

2. Starch, M. S., and Krosovic, C. R., Silicones in Skin Care Products, Dow Corning publication, 22:1174-01 (1982)

10. Zombeck, A., and Dahms, G. H., New Formulations Possibilities Offered by Silicone Copolyols Cosmetics and Toileteries, 110(3):91 (1995)

3. Van Reeth, I. M., and Blakely, J. M., Use of Current and New Test Methods to Demonstrate the Benefits of Alkylmethylsiloxanes in Sun Care Products, Dow Corning publication 22:1793-01 (1999)

11. Dahms, G., and Tagawa, M., Novel Multiple Phase Emulsions for Stable Incorporation of Vitamin C Derivatives and Enzymes IFSCC platform presentation, Sydney, Australia, Dow Corning (1996)

4. Hill, R. M., and Snow, S. A., Silicone Vesicles and Entrapment, US Patent 5,364,633, Dow Corning Corp. (1994)

12. Lin, Z., Schulz, W. J., and Zhang, S., Waterin-Oil-in-Water Emulsion, US Patent 5,948,855, Dow Corning Corp. (1999)

5. Hill, R. M., and Snow, S. A., Silicone Vesicles and Entrapment, US Patent 5,411,744, Dow Corning Corp. (1995)

13. Lin, Z., Schulz, W. J., and Smith, J. M., Polar Solvent-in-Oil Emulsions and Multiple Emulsions, US Patent 6,080,394, Dow Corning Corp. (2000)

6. Marchioretto, S., and Blakely, J., Substantiated Synergy between Silicone and Quats for Clear and Mild Conditioning Shampoos, SöFW (Oct 1997) 7. Lin, Z., Schulz, W. J., and Smith, J. M., Entrapment of Vitamins with an Elastomeric Silicone Polyether, EP 1 020 494, Dow Corning Corp. (2000) 8. Lin, Z., Schulz, W. J., and Smith, J. M., Elastomeric Silicone Containing an Active Ingredient, US Patent 6,168,782, Dow Corning Corp. (2001)

14. Disapio, A. J., Multi-Laminate Fragrance Release Device, EP 0 348 970, Dow Corning Corp. (1989) 15. Starch, M. S., Silicone in Hair Care Products Drug and Cosmetic Industry (Jun. 1984) 16. Urrutia, A., Silicones: the Basis of the Perfect Formulation for Hair Care, Dow Corning publication, 22-1553-01 (1993)

34 Linear Silicone Fluids for Controlled Volatility Delivery Systems Arndt Schlosser, Julie Boucher, and Hubert Yeboah Wacker Chemical Corporation Adrian, Michigan Claudius Schwarzwaelder Wacker Chemie GmbH Burghausen, Germany 34.1 The “Eureka!” Moment.................................................................. 716 34.1.1 Evaluation of Octamethylcyclotetrasiloxane (D4) ............ 716 34.1.2 The New VOC Rules ....................................................... 716 34.2 Introduction to Silicone Technology .............................................. 717 34.2.1 Silicone Manufacture ........................................................ 717 34.2.2 Dimethicones or Linear Polydimethylsiloxanes ............... 719 34.3 Linear Volatile Silicone Fluids with Controlled Volatility ................. 719 34.3.1 What is a Volatile? ............................................................ 719 34.3.2 What Volatile Silicones Have Been Known Previously?... 721 34.3.3 The New Linear Volatile Silicone Fluids ........................... 722 34.3.4 What are the Properties of the New Volatile Linear Dimethicones? ...................................................... 723 34.3.5 How Linear Volatile Dimethicones are Different from Other Volatiles ......................................................... 723 34.3.6 How to Use the Linear Volatile Silicones .......................... 724 34.4 Applications .................................................................................. 725 34.4.1 Hair Care .......................................................................... 725 34.4.2 Skin Care and Sun Care .................................................. 725 34.4.3 Color Cosmetics .............................................................. 725 34.4.4 Antiperspirants, Deodorants, and Perfumes .................... 725 34.5 Conclusions .................................................................................. 726 34.6 Formulations ................................................................................. 727 References ......................................................................................... 738 Acknowledgements ................................................................................. 738 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 715–738 © 2005 William Andrew, Inc.

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34.1 The “Eureka!” Moment Volatile fluids have been used in cosmetic formulations for a long time.[1] Most of these fluids are organic-based materials. The first volatile substances used in the chemical industry were aromatic molecules and alcohol. After evaluation of the toxicological risks of using aromatics like benzene or toluene in the mid twentieth century, these materials were banned from use in the cosmetics industry. The next trend in volatiles was to use low boiling point aromatic-free mineral spirit mixtures. In order to provide better-defined products, the industry introduced hydrocarbons with a defined molecular weight. Isododecane was commonly used at this time and the industry began to look for other high volatility synthetic products that could add beneficial properties to cosmetic formulations. At this point in time, the volatiles cyclomethicones and hexamethyldisiloxane were introduced to the cosmetic market. These materials provided many benefits and were accepted as standard carrier solvents. All such volatile products became well established in the market place, and each formulator knew what volatile fluid he or she had to use in order to obtain the desired formulation properties. In the cosmetic industry, a whole range of volatility is needed in order to achieve a variety of goals. High volatility is required for rapidly drying products. Low volatility materials can be used to achieve delivery over time such as required for a perfume. In the late 1990s, two emerging issues led Wacker towards thinking about developing a whole new class of volatile silicones. These issues were a discussion about the possible toxicity of cyclomethicone, D4, in the cosmetic industry and increasingly stringent volatile organic compound (VOC) regulations emerging in California and other states.

34.1.1

Evaluation of Octamethylcyclotetrasiloxane (D4)

In response to the first of these issues, the silicone industry initiated a large program designed to evaluate the toxicological effects of different types of silicones. In the volatile silicone area, this evaluation began with octamethylcyclotetrasiloxane, the

smallest volatile cyclomethicone. The study also included hexamethyldisiloxane, the smallest linear silicone fluid. The smallest molecules of both the cyclic and linear classes were chosen because they had the highest volatility of all the silicones used in the cosmetic industry. It was reasoned that more of these low molecular weight compounds could be inhaled in view of their high vapor pressure. These materials were also of interest because they represented the smallest and, therefore, the lowest molecular weight molecules of the two classes. Since it is well known that fluids with a molecular weight below about 500 Dalton typically can penetrate the stratum corneum, these materials were ideal candidates for toxicological testing. Based on the toxicology data and risk assessment results[2] obtained from this study, the silicone industry has concluded that cyclics are safe for their intended use and this includes their incorporation into personal care products. The fact that reproductive effects have been seen for rats is not believed to be relevant to humans. Continuing research supports this conclusion and additional testing is ongoing. Despite the above assessment, and in view of prior history with other volatiles, the personal care industry, for the most part, has opted to minimize its usage of D4. As a result of this decision, and in view of the importance and large use of volatile silicones in the cosmetic industry, an alternative was needed and requested by customers. This need was the main reason that Wacker Chemicals, as a customer driven company, initiated its project to identify new volatile silicones with a totally acceptable toxicological profile. Studies carried out on hexamethyldisiloxane, the base of the class of linear volatile silicone fluids, show no indication of negative effects that are relevant to humans.[3]

34.1.2 The New VOC Rules In the 1990s, California and other Ozone Transport Commission (OTC) states in cooperation with the California Air Resources Board (CARB), began to legislate limitations as to the amount of volatile organic compounds that were allowed in formulations. Since silicones are defined by this legislation

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

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as non-organic, they do not fall within these limitations for use in cosmetic formulations. When this OTC model rule for Consumer Products[4] was discussed in the late 1990s, the only volatile silicones on the market were hexamethyldisiloxane and the cyclomethicones. The idea of linear volatile silicones with evaporation rates designed to meet the needs of the personal care market was an idea which had not been thought of before. In response to both the personal care market’s reaction to D4 and the upcoming VOC legislation, Wacker initiated a project to provide linear volatile silicones with evaporation rates designed to meet the range of customer needs.

34.2 Introduction to Silicone Technology

Figure 34.1 Silicone backbone.

Silicones are molecules built from a helical backbone (Fig. 34.1) of alternating silicon and oxygen atoms, polydimethylsiloxanes, or in cosmetic language (i.e., CTFA regulations) “dimethicones,” (Fig. 34.2) having three methyl groups at the ends of each molecule, and two methyl groups covalently bonded to each silicon atom between the ones at each end. The whole molecule can vary considerably in molecular weight. To transform a dimethicone to a functional silicone the methyl groups can be partially or completely substituted by other groups. These include polyethers, hydroxyl groups, different hydrocarbon chains of varying length, amino-modified hydrocarbons, and many other types of functional groups.

34.2.1

Silicone Manufacture

After oxygen, silicon is the most abundant element in nature. It makes up more than 25% of the earth’s crust and is, therefore, an inexhaustible raw material. Due to its high affinity for oxygen, silicon is quite unlike carbon. It cannot be found in a pure form, as carbon can, and only exists in nature in bonded compounds such as silicates, silica, and quartz.

Figure 34.2 Dimethicone.

The Mueller-Rochow process. The primary raw material used for the manufacture of silicones is quartz. This material is a crystalline modification of silicon dioxide. Base silicon metal is commercially made by means of an electrothermal reduction process employing carbon. In the “direct synthesis” of chlorosilanes, a precursor of dimethicones, finely powdered silicon is reacted with chloromethane in

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

the presence of a copper-based catalyst at a temperature of about 300°C. The “Direct Synthesis” technology (Fig. 34.3) is based upon the MuellerRochow process[5] and is named after its developers. The stoichiometric reaction of the process is quite simple. One silicon atom combines with two molecules of chloromethane and produces one molecule of dimethyldichlorosilane.

Figure 34.3 Direct synthesis of chlorosilanes.

In practice however, the target molecule dimethyldichlorosilane is only obtained in yields of 80%–90% and many silicon-containing by-products are also formed. Examples of these by-products include methyltrichlorosilane, trimethylchlorosilane, hydrogen-containing silanes, and other useful raw materials for manufacturing a broad range of silicones.[6] (See. Fig. 34.4.) One key side product of the Mueller-Rochow process is trimethylchlorosilane. This molecule is required as an “end capper” in the preparation of polydimethylsiloxanes. In view of the narrow boiling point differences between methyltrichlorosilane (66°C) and dimethyldichlorosilane (70°C), as well as the formation of azeotropes, a sophisticated distillation system is necessary in order to achieve the required high purity for individual silanes and, in particular, for separating dimethyldichlorosilane. The material is a critical component employed for chain extending and increasing the molecular weight of linear polydimethylsiloxanes.

The silicon-chlorine bonds of the chloromethylsilane monomers can easily be hydrolyzed by water. This results in the subsequent formation of hydrogen chloride and polymeric silanol compounds that are stable only under specific conditions. Typically, the hydroxyl groups of the silanol react with each other. In doing so, they split off water and form oligosiloxanes in a process known as condensation reaction. The combination of trimethylchlorosilane with dimethyldichlorosilane, in special ratios, allows the synthesis of linear, trimethyl end-capped polydimethylsiloxane chains with specific molecular weights. The complexity of these polymers has led to a simplification of their chemical description. In the literature, trimethylsiloxy units are often referred to as “M-units” while dimethylsiloxy units are called “D-units.” Thus using the simplified nomenclature a dimethicone is described as MDxM., where “x” is simply the number of repeating D-units in the resulting polymer. (See Fig. 34.6.)

Figure 34.4 Silanes derived from the Mueller-Rochow process.

Hydrolysis/condensation. At this point, our discussion of the process for manufacturing volatile linear silicones has brought us to the class of materials known as monomeric chloromethylsilanes. However, the required linear silicone materials are polymeric compounds and further processing is required to transform these chloromethylsilane monomers into the desired low molecular weight linear volatile silicones. (See. Fig. 34.5.) Figure 34.5 Hydrolysis/condensation.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

719

cosmetic industry the viscosity of these products is the prime method for classifying them. (See Fig. 34.9.) This property is a function of the molecular size and is proportional to chain length. The chain length of linear polydimethylsiloxanes can be adjusted by varying the ratio of D- to M-units in the linear equilibration reaction. Unlike the process for separating hydroFigure 34.6 Chemical equation of dimethicone reaction. carbons of different molecular weight, the boiling points of different silicone As an example of this process, hydrolysis and oligomers are so close together that it is not possible condensation of dimethyldichlorosilane is carried out to use distillation for separating molecules with difat Wacker in a continuous manner utilizing a loop ferent chain lengths. As a result, all dimethicones reactor. Dimethyldichlorosilane and water are reare comprised of mixtures of a more or less narrow acted together with the evolution of hydrogen chlodistribution of different linear polydimethylsiloxanes. ride. The result of this reaction is a mixture of linear The only exception to this rule, where it is possible polydimethylsiloxane and cyclic silicone polymers. to obtain a pure material, is the smallest molecule in After an optional equilibration step, these cyclics, the series. This compound consists simply of the water, and the last traces of hydrogen chloride are combination of two M-units and has no D-units. The then removed. The final result is a neutral, linear molecule is known as hexamethyldisiloxane or “MM” polydimethylsiloxane that is endcapped with OHor “HMDS.” (See Fig. 34.10.) groups. This material represents one of the most MM has a molecular weight of 164 Daltons and important basic intermediate products for synthesis a Newtonian viscosity of 0.65 cSt. As might be exof useful organosilicones. (See Fig. 34.7.) pected from its very low molecular weight, MM is a Wacker’s special process is focused on the forhighly volatile substance! mation of linear polydimethylsiloxanes, rather than cyclic siloxanes. The process is unique to Wacker Chemie and is known as the “linear technology.”[6] Upon equilibration of these linear materials with some 34.3 Linear Volatile Silicone M-units, trimethyl end-capped polydimethylsiloxanes Fluids with Controlled can be produced with a wide range of molecular Volatility weight. (See Fig. 34.8.) Wacker’s linear technology is quite different from the standard process for obtaining polydimethylsiloxanes (i.e., the “cyclic” process). In the cyclic process,[7] the target products are cyclic polydimethylsiloxanes. These are first isolated, and later transformed, in an additional equilibration step to linear polydimethylsiloxane with a range of molecular weight.

34.2.2

Dimethicones or Linear Polydimethylsiloxanes

The chemical name for dimethicone is linear, trimethyl end-capped polydimethylsiloxane. In the

In order to describe the new type of linear volatile silicone fluids developed by Wacker-Chemie, it will be useful to first provide a definition of volatility.

34.3.1 What is a Volatile? Basically, a “volatile” is a material that evaporates quickly under standard conditions of pressure and temperature. Relative volatility can be quantified by means of the “evaporation number.”[8] (Eq. 34.1.) This parameter is defined in Eq. (34.1) as the “evaporation time” of a given amount of material, divided by the evaporation time of a similar amount of diethylether.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 34.7 Linear siloxane technology process.

Figure 34.8 Complete reaction mechanism of dimethicone production.

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721

Figure 34.9 Viscosity vs molecular weight of dimethicones.

disiloxane, D4, and ethyl acetate. It can be seen that water is far less volatile than these materials, since it has a higher evaporation number of about 80.

Figure 34.10 Hexamethyldisiloxane.

It should be pointed out that the evaporation number is useful to describe the physical-chemical properties of a volatile but it has nothing to do with the legal definition of a volatile organic compound (VOC).

Eq. (34.1) Evaporation number =

evaporation time material X evaporation time diethylether

 Temperature : (293 ± 2)K     Humidity : (65 ± 5)% 

The use of the evaporation number to quantify volatility involves comparing the volatility of a material to the behavior of diethylether, a highly volatile substance. Highly volatile substances have an evaporation number of less than 10. Examples of these include methanol, ethanol, acetone, hexamethyl-

34.3.2

What Volatile Silicones Have Been Known Previously?

The most commonly used volatile silicone fluids in the cosmetic industry are the group known as cyclomethicones. Different products on the market include pure cyclics, octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6 ), and mixtures thereof. Of these, only D4 is a highly volatile substance since D5 and D6 have a relative volatility higher than water. (See Fig. 34.11.)

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 34.11 Evaporation rates of commonly used sovents at 25°C.

The volatility of mixtures of cyclic silicones can be controlled by mixing cyclics of different molecular weights. In the past, the only linear volatile silicone fluid used by the cosmetic industry was hexamethyldisiloxane. This material has a relative volatility even higher than that of D4 (see Fig. 34.11). Since hexamethyldisiloxane is a pure material, the evaporation rate is fixed and cannot be adjusted. As such, it has only been used in small quantities when compared to much larger amounts of the different cyclomethicones and their mixtures utilized by the personal care industry. Hexamethyldisiloxane is the only pure volatile linear silicone and the next “standard” linear silicone fluid has an average viscosity of 5 cSt, with a molecular weight average of 756 Daltons. At this molecular weight, the material is not volatile. In view of this, no mixtures of linear volatile silicones have been commercially available. Prior to Wacker’s project for the development of a range of linear silicones with different but defined evaporation rates, some mixtures had been developed. However, these mixtures were focused on providing a viscosity between 1 cSt and 3 cSt. Since the primary focus for these products was the specified viscosity, controlled volatility was not a target. As such, Wacker’s goal of producing a range of volatile linear silicones needed further process development.

34.3.3

The New Linear Volatile Silicone Fluids

The newly developed materials providing a range of controlled evaporation rates are mixtures of linear trimethyl end-capped dimethylsiloxanes (dimethicones) with a molecular weight from 164 Daltons to about 539 Daltons. Technically, it is not possible to isolate all the different molecules required in a production scale process. However, one way to obtain these mixtures is to develop a process that allows exact control of the mixture composition. This process differs significantly from that for making standard dimethicones. The latter process is targeted at obtaining very narrow molecular weight distributions around the average molecular weight of the target product. By contrast, Wacker’s new process is not targeted at viscosity. Instead, it is focused on achieving narrowly defined evaporation rates. Thus, the goal of Wacker’s process has shifted from generating a standard narrowly molecular weight distribution around a median, to creating compositions having defined ratios of different molecular weight linear silicone fluids. Wacker has been successful at developing this new process and has created the following linear volatile silicone fluids having specific evaporation rate properties (Fig. 34.12):[9]

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

723

Figure 34.12 Evaporation data of the new developed volatile dimethicones at 25°C.

• Wacker-Belsil® DM 1 Plus, with an evaporation rate close to D4. • Wacker-SLM 28038, with an evaporation rate closer to D5. • Wacker-SLM 28033, with an evaporation rate performance comparable to a commonly used D5/D6 mix. • Wacker-SLM 28032, having an evaporation rate similar to that of D6. Together with hexamethyldisiloxane, the complete range of evaporation rates commonly employed in the personal care industry is now covered by Wacker’s linear volatile silicone fluids. All of these have the INCI name dimethicone.

34.3.4

What are the Properties of the New Volatile Linear Dimethicones?

The newly developed volatile linear dimethicones have the following general properties (Table 34.1):[9] • Clear and colorless liquids. • Density between 0.8 and 0.9 g/cm3. • Refractive index between 1.384 and 1.391. • Boiling point > 100°C.

• Low viscosity between 1 cSt and 3 cSt. • Flash point from 32°C to 70°C (90°F to 160°F). • Low heat of evaporation; means no cooling effect during evaporation. • Quick but controllable evaporation. • Water insoluble, but miscible with mineral oils, lower alcohol, ester, and other commonly used cosmetic ingredients.

34.3.5

How Linear Volatile Dimethicones are Different from Other Volatiles

The new linear materials differ from the existing volatile materials in the following ways: • According to the current version of the California definition of VOC they are classified as NON VOC. • They are the first dimethicones that are designed to match the criteria of having a different specific volatility and not a specific viscosity. • Different evaporation rates can be achieved so alternatives for existing organic volatiles or volatile cyclomethicones can be created.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 34.1. Miscibility Data for the Group of Volatile Dimethicones

Ingredient

Wacker-Belsis Volatile Dimethicone

Mineral Oil

Ingredient

Wacker-Belsis Volatile Dimethicone

Emulsifier

C9-13 Isoparafin

∆

Peg-75 Lanolin oil

∆

Mineral oil, high viscosity

√

Peg-7 Glyceryl cocoate

∆

Mineral oil, low viscosity

√

Alcohols

Ester Oil

Octyldodecanol

∆

Ethyl acetate

√

Oleyl alcohol

∆

C12-15 Alkyl benzoate

√

Propylene glycol

∆

Isopropyl myristate

√

Isopropanol

∆

Decyl oleate

√

Alcohol

∆

Oleyl oleate

√

Glycerin

∆

Ethylhexyl methoxycinnamate

√

PPG-5-Laureth-5

P

Ethylhexyl salicylate

√

Keytones

Triglycerides

Benzophenone-3

P

Caster oil

∆

4-methylbenzylidene camphor

∆

Olive oil

√

Water

∆

Wheatgerm oil

√

Lanolin oil

∆

√ – miscible (>10%) P – partially miscible (1%–10%) ∆ - inmiscible

• Since linear volatile silicones have a very low heat of evaporation, they do not show a cooling effect during evaporation. This is an advantage as compared to most organic volatiles. • Linear volatile silicones are dimethicones. No health issues relevant to humans are known for the group of dimethicones. • The new materials provide the expected typical silky skin feel during application on skin and hair. • The availability of different evaporation rates provides the opportunity of product-specific skin feel, based on easy rub-in characteristics.

34.3.6

How to Use the Linear Volatile Silicones

These new volatile dimethicones can be used as pure volatile oils, or in mixtures, as a carrier for high molecular weight polymers like dimethiconols. The primary use of these products is as delivery systems and carriers. Their use enables the achievement of an even, homogenous distribution of actives and polymers. In blends with silanol endblocked polymers like dimethiconols, the new linear materials also produce mixtures with a low viscosity that makes the dimethiconol polymer easier to handle during production. The dimethiconol polymers provide all of the expected effects of the high molecular weight silicone polymer (i.e., film forming in the final application) after the volatile part of the mixture has evaporated.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS The new materials can also be used as the solvent portion of silicone elastomer resin gels, or in blends of different silicone fluids and silicone resins. Volatile dimethicones can be used as delivery carriers in clear products like perfumes as well as being emulsified with most standard emulsifier systems.

725

UV filters. They also reduce the tackiness of thickeners, provide a silky skin feel, and act as emollients during application. An additional beneficial effect is the improvement of rub-in characteristics.

34.4 Applications

The new materials are also known to reduce friction on the skin during the application of creams. This effect is a result of the low coefficient of friction characteristic of the class of linear volatile silicones. Example formulations are given in Formulations 34.2 through 34.6.

Volatile dimethicones can be used in many different cosmetic applications. These include hair care, skin care, antiperspirants, and deodorants.

34.4.3 Color Cosmetics

34.4.1

Hair Care

In hair care applications, the volatile dimethicones are used as carriers in shampoos in order to achieve a more uniform distribution of high molecular weight polymers along the hair fiber. This is a result of their low surface tension and high spreading pressure. • In conditioners, they are used to provide wet combing benefits prior to the time they evaporate. • In hair and styling gels, the volatile dimethicones act as plasticizers for the resins and polymers used in these products. • In hair gloss sprays, the new materials act as a delivery system and distribute the higher molecular weight phenyl-modified silicone gloss enhancers more evenly over the hair fiber. Volatile dimethicones can depress foam in shampoos, conditioners, and mousses because of their high volatility. In these cases, a foam stabilizer should be added to overcome this effect.[10] Based on their high volatility, there is no build up on hair from these products. An example of this type of use is given in Formulation 34.1.

34.4.2

Skin Care and Sun Care

In creams and lotions, including sun care products, the volatile dimethicones are used as a typical delivery system for active ingredients like resins and

In color cosmetics, the volatile dimethicones are used as a vehicle for pigments and to reduce the drying time of lipsticks, foundations, and mascara. In view of their good spreading properties on skin, very uniform and consistent pigment distribution can be achieved. The new materials also enhance the free flow of powders by reducing particle agglomeration. Another advantage of these materials is they can be used as a plasticizer for silicone resins. This property helps to form thin films, thereby maximizing the effect of long lasting products. Example formulations are shown in Formulations 34.7 through 34.9.

34.4.4

Antiperspirants, Deodorants, and Perfumes

In antiperspirants and deodorants, linear volatile silicone fluids are primarily used to improve the “payout” in all varieties of sticks, and as a delivery system for actives. The major advantage in such systems is high volatility and that evaporation occurs without any cooling effect on the skin. In perfumes, these products are used because they typically have a very low odor. By adjusting the evaporation rate, they can be used as a delivery system having a temperature controlled, time-release of the fragrance. In alcohol-based perfumes these new NON VOC products can be used as partial substitutes for currently used solvents. Additionally, they provide a silky skin feel. The superior spreadability properties of these materials provide an improved distribution of the an-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

tiperspirant and deodorant actives. For all antiperspirant and deodorant formulations it is an advantage that the newly developed products not only provide lubricity during application but also provide an increase in lubricity in aerosol valves.

Controlled volatility of products in this new class can be achieved by optimizing the ratio of different low molecular weight linear silicone fluids and combining them to produce newly available volatile dimethicone mixtures with different volatility.

An antiperspirant stick formulation is shown in Formulation 34.10.

The controlled volatility characteristic of these materials enables these products to provide properties ranging from having a rapid drying time to slower evaporating mixtures useful for the release of fragrances. They also provide reduced friction advantages in wet combing forces, so important for hair care products.

34.5 Conclusions In this chapter we have introduced a new delivery system concept based on the use of linear volatile dimethicones with controlled volatility. These products are not considered to be VOC under the US law and therefore can be used as substitutes for VOC’s in current formulations, as well as in low VOC systems. The INCI name of this new class of linear volatile silicone fluids is the well-known and toxicologically acceptable INCI name dimethicone.

Other important properties of the volatile linear dimethicones include good spreadability and noncooling behavior during evaporation. These characteristics provide formulators and consumers with an opportunity to generate product destinations in all areas of personal care ranging from hair, sun, and skin care, as well as color cosmetics and deodorants/antiperspirants.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

727

34.6 Formulations Formulation 34.1: Hair Shine Spray

Phase

A

Ingredient

INCI Designation

Weight %

Function

Supplier

Wacker-Belsil® SLM 28038

Dimethicone

Carrier, skin conditioning agent and 32.25 solvent

Wacker Chemicals

Wacker-Belsil® DM 1 plus

Dimethicone

Carrier, skin conditioning agent and 57.25 solvent

Wacker Chemicals

Wacker-Belsil® PDM 1000

Trimehtylsiloxy phenyl dimethicone

Hair and skin conditioning agent

Wacker Chemicals

Perfume

10.50 q.s.

Total

100

Mixing Procedure: Combine all silicone ingredients of Phase with moderate propeller agitation until solution is homogenous. Slowly add fragrance. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 34.2: Sunscreen Oil

Phase

Ingredient

INCI Designation

Weight %

Supplier

Eusolex 4360

Benzophenone-3

Sunscreen, UV filter

3.00

Merck

Finsolv TN

C12-C15 Alkyl benzoate

Emollient

10.00

R&H

Upamate DIPA

Diisopropyl adipate

Skin conditioning agent

10.00

UniversalPreserv-AChem

Parsol MCX

Octylmethoxycinnamate

Sunscreen, UV filter

7.00

Roche Vitamins, Inc.

Wacker-Belsil® CM 1000

Cyclomethicone, dimethicone

Skin and hair conditioning agent

10.00

Wacker Chemicals

Wacker SLM 28033

Dimethicone

Provides smooth silky skin feel

60.00

Wacker Chemicals

Color

Pigment

Colorant

q.s.

Preservative

q.s.

A

B

Function

Preservative Perfume

q.s. Total

100.00

Mixing Procedure: Mix all ingredients and filter. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

729

Formulation 34.3: Bath Oil

Phase

Ingredient Mineral Oil

A

C

Mineral oil

WackerStearoxy Belsil® SDM dimethicone, 6022 dimethicone

Weight %

Emollient, skin conditioning agent

69.00

Supplier Penreco

Skin conditioning agent

1.00

Wacker Chemicals

Skin conditioning agent

5.00

Uniqema

Wacker SLM Dimethicone 28038

Skin conditioner, spreadability enhancer

25.00

Wacker Chemicals

Preservatives

Preservative

q.s

Color

Colorant

q.s

Arlamol E B

Function

INCI Designation

PPG-15 Stearyl ether

Perfume

q.s Total

100.00

Mixing Procedure: Heat Phase A to 50°C (mix in Wacker-Belsil SDM 6022 homogenous). Mix Phase B into Phase A. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 34.4: Body Lotion

Phase

Function

Weight %

Skin conditioning agent

0.50

Merck

Methylparaben NF Methylparaben

Preservative

0.15

Rita

Propylene glycol

Propylene glycol

Humectant; skin conditioning agent

0.90

Rita

Fluilan

PPG-12-PEG-65 Lanolin Oil

Emollient; skin conditioning agent

1.03

Croda

Veegum

Magnesium aluminum silicate

Thickener

0.30

Vanderbilt

Wacker-Belsil® DMC 6031

PEG/PPG-25/25 Dimethicone

Coemulsifier

0.40

Wacker Chemicals

Deionized water

Aqua

Acetol 1706

Cetyl acetate, acetylated lanolin alcohol

Skin conditioning agent

1.10

Cognis

Emersol 210

Oleic acid

Cleansing agentsurfactant

0.50

Cognis

Nikkol CO 50T

PEG-50 Castor oil

Emollient

0.50

Nikko

Protameen PGR

Propylene glycol ricinoleate

Skin conditioning agent and emulsifying agent

0.95

Protameen Chemicals

Propylparaben NF

Propylparaben

Preservative

0.05

Protameen Chemicals

Wacker SLM 28032

Dimethicone

Solvent, skin conditioning agent, carrier

1.45

Wacker Chemicals

Wacker-Belsil® PDM 20

Trimethylsiloxy phenyl Skin and hair dimethicone conditioning agent

1.50

Wacker Chemicals

Pemulen TR 2

Emulsion stabilizer, Acrylate/C10-30 Alkyl viscosity increasing acrylates crosspolymer agent

0.15

Noveon

EDTA

Versene acid

Chelating agent

0.10

DOW

Germall II

Diazolidinyl urea

Preservative

0.20

ISP

Triethanolamine

pH Adjuster

0.17

Merck

Ingredient Glycerin

A

B

C

D

INCI Designation Glycerin

Supplier

90.05

Perfume TEA

Total 100.00 (cont’d.)

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

731

Formulation 34.4: (cont’d.)

Mixing Procedure: Combine all ingredients in Phase A with gentle stirring until solution is homogenous. Combine all ingredients in Phase B in separate vessel. Mix until homogenous. Add Phase C to Phase B and continue mixing until uniform. When both phases are homogenous, add Phases B and C to Phase A with good agitation. Mix at high shear for a minimum of 30 minutes. Add ingredients of Phase D separately and continue mixing at moderate speed for 15–20 minutes. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 34.5: Body Lotion Spray

Phase

A

Ingredient

INCI Designation

C

Supplier

White Beeswax NF

Beeswax

Emulsion stabilizer and skin conditioner

3.00

Hostacerin DGI

Polyglyceryl-2 sesquiisostearate

Skin conditioning and emulsifying agent

3.00 Clariant

Wacker-Belsil® CM 1000

Cyclomethicone, dimethiconol

Hair and skin conditioning agent, emollient

5.00

Wacker Chemicals

Wacker-Belsil® DM 1 plus

Dimethicone

Solvent and skin conditioning agent

7.00

Wacker Chemicals

Hair and skin conditioner

4.50

Wacker Chemicals

Cyclopentasiloxane, Wacker-Belsil® SPG caprylyl dimethicone Coemulsifier 128VP ethoxy glucoside

12.00

Wacker Chemicals

Wacker-Belsil® PDM Trimethylsiloxy 20 phenyl dimethicone

B

Weight %

Function

Sodium chloride

Sodium chloride

Thickener

Deionized water

Aqua

Kathon CG

Methylchloroisothazolinone, Preservative methylisothiazolinone

Koster Keunen

2.00 Merck 63.25 0.05 Rohm & Haas

Perfume

0.20 Total 100.00

Mixing Procedure: Heat Phases A and B up to 70°C, add Phase B to Phase A and homogenize. Cool down to 40°C while stirring. Add Phase C and cool down to room temperature. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

733

Formulation 34.6: After Shave Cream

Phase

Ingredient Carbopol Ultrez 10

A

B

Germaben II Deionized water Arlacel 85 Isopropyl Myristate Tween 80 Wacker-Belsil® CM 3092 Wacker SLM 28033 Wacker-Belsil® PDM 1000 Camphor Ethanol Hydagen B

INCI Designation Carbomer

Function

Weight %

Supplier

Emulsion stabilizer, thickener

0.30 Noveon

Preservative

0.20 ISP

Propylene glycol, diazolidinyl urea, methylparaben Aqua Sorbitan trioleate

Emulsifying agent

Isopropyl myristate

Emollient

5.00 Cognis

Polysorbate 80 Cyclomethicone, dimethiconol

Emulsifying agent

1.20 Uniqema Wacker 5.00 Chemicals Wacker 8.00 Chemicals Wacker 4.00 Chemicals 0.10 Merck 2.80 Merck 1.00 Cognis Jeen 0.10 International 0.50

Skin conditioning agent

65.20 0.60 Uniqema

Skin conditioning agent, solvent, carrier Trimethylsiloxy phenyl Hair and skin dimethicone conditioning agent Camphor External analgesics Ethanol Astrigent Bisabolol Skin conditioning agent C External nalgesics, Menthol Menthol flavoring agent Perfume Perfume Sodium hydroxide Sodium hydroxide D pH adjuster 6.00 (2% solution) (2% solution) Total 100.00 Mixing Procedure: Add water in a beaker and disperse Ultrez 10. Add preservative (Phase A). Mix Phases B and C into Phase A while stirring. Finally add Phase D to neutralize Ultrez 10. Stir until gel becomes homogenous. Dimethicone

We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 34.7: Liquid Foundation

Phase

Ingredient Wacker-Belsil® MM 8030 VP

INCI Designation C30-C45 Alkyl methicone

Wacker SLM 28038 Dimethicone

A

Wacker-Belsil® SPG 128 VP

Caprylyl dimethicone ethoxy glucoside, cyclopentasiloxane

Wacker-Belsil® DM 5

Dimethicone

Hostacerin DGI

Polyglyceryl-2 sesquiisostearate

Wacker-Belsil® TMS 803 Iron oxides B

Alpine Talc

Iron oxides Talc

Sodium chloride

Sodium chloride

Wacker Chemicals Wacker 10.00 Chemicals

Coemulsifier

11.00

Wacker Chemicals

2.30

Wacker Chemicals

Solvent and skin conditioning agent Skin conditioning and emulsifying agent

E

Germaben II Deionized water Cavamax W8Complex+ tocopherol

Propylene glycol, diazolidinyl urea, methylparaben, propylparaben Aqua Cyclodextrine, tocopherol

2.70

2.40 Clariant Wacker Chemicals 1.50 Sun Chemicals Wittaker, Clark 5.00 & Daniels 7.00 Presperse 51.00 Aldrich 2.00 Chemicals 0.30 1.50

Colorant Absorbent and skin protectant Sunscreen Thickener

Fragrance D

Supplier

Skin conditioning agent Carrier, solvent, skin conditioning agent

Trimethylsiloxysilicate Film former

Ti-Sphere AA 1515 Titanium dioxide Deionized water Aqua C

Weight %

Function

Preservative

1.00 ISP 2.00

Vitamine E delivery system

0.30

Wacker Chemicals

Total 100.00 Mixing Procedure: Heat Phase A to 75°C. Add Phase B to Phase A while homogenizing with Turrax. Check pigment dispersion. Heat Phase C to 75°C, then slowly add Phase A under homogenization with Turrax. Cool down to 40°C while stirring with air mixer. Add Phase D and Phase E while stirring. Cool down to room temperature while stirring. Homogenize mixer with Turrax and package. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

735

Formulation 34.8: Long-lasting Lipstick

Phase A

B

Ingredient Permethyl 99A Dermol IPM C33-5138 D&C Red #7 Calcium Lake Titanium dioxide Carnauba

C

Brij 52 Microcrystalline wax Polyethylene glycol 300

INCI Designation

Function

Weight Supplier % 10.00 Presperse 12.00 Alzo 3.50 Sun Chemical

Isododecane Isoproyl myristate Pigment

Solvent Emollient Colorant

Pigment

Colorant

1.00

Sun Chemical

Titanium dioxide Copernicia cerifera (carnauba) wax Ceteth-2

Sunscreen, UV filter

3.50

U.S. Cosmetics

Epilating agent

8.50

Ross

Emulsifying agent Bulking agent and emulsion stabilizer

3.50

Uniqema

6.00

Bareco Products

Humectant

3.00

Union Carbide

5.50

Koster Keunen

Microstalline wax PEG-6

NF White Beeswax Beeswax

Emulsion stabilizer and skin conditioning agent Carrier and solvent for resins and skin conditioning agent

Wacker SLM 28032

Dimethicone

Wacker-Belsil® TMS 803

Trimethylsiloxysilicate Film former

4.50

E

Alpine Talc

Talc

Bulking agent

3.50

F

Vitamine E

Tocopherol acetate

Anitoxidant; skin conditioning agent

0.20

BASF

G

Mica (white)

Mica

Colorant

4.00

Wittaker, Clark & Daniels

D

31.30

Wacker Chemicals Wacker Chemicals Wittaker, Clark & Daniels

Total 100.00 Mixing Procedure: Caution, do not over heat. Heat Phase A to 70°C in a glass kettle in a water bath on hot plate using temperature controller and air mixer. When Phase A reaches 70°C, add Phase B and mix until homogenous, 2–3 minutes. Melt Phase C and add to Phases A/B and mix for 2–3 minutes. Add Phase D and mix for 3–5 minutes. Add Phases E, F, and G simultanously and mix for additional 5 minutes. Mold immediately. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 34.9: Face Powder

Phase

A

B

C

Ingredient

Weight %

Function

Supplier

Carbopol 1342

Akrylates/C10-C30 Alkyl akrylate crosspolymer

Binder; provides good skin feel

3.00

Noveon

Unichem MS

Magnesium stearate

Anticaking agent

6.00

Universal Preserv.

Alpine talc

Talc

Absorbent and anticaking agent.

74.00

Wittaker, Clark & Daniels

AC Hydrolyzed collagen

Hydrolyzed animal protein

Hair, nail, and skin conditioning agent

2.00

Active Concepts, LLC

Wacker SLM 28033

Dimethicone

Skin conditioning agent and carrier

Methylparaben NF

Methylparaben

Pigments Alpine talc

D

INCI Designation

Color

Talc

12.20

Wacker Chemicals

Preservative

0.20

Protachem

Colorant

0.70

Absorbent and anticaking

1.90

Wittaker, Clark & Daniels

Colorant

Perfume Total

100.00

Mixing Procedure: Mix Phases A and B slowly. Add Phase C to Phase AB and mix until homogenous. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

SCHLOSSER, ET AL.: LINEAR SILICONE FLUIDS FOR CONTROLLED VOLATILITY DELIVERY SYSTEMS

737

Formulation 34.10: Anti-perspirant Stick

Phase

A

B C

Ingredient

INCI Designation

Weight %

Function

Supplier

Crodacol C 95

Cetyl alcohol

Emulsifier

18.00

Merck

Reach 101

Aluminum chlorohydrate

Anitperspirant and deodorant agent

24.00

Reheis

Pristerene 4911

Stearic acid

Emulsifying agent

18.00

Uniqema

Wacker-Belsil® DM 1 plus

Dimethicone

Carrier, skin conditioner

40.00

Wacker Chemicals

Color

Pigment

Colorant

q.s.

Perfume

q.s. Total

100.00

Mixing Procedure: Mix Phase A and heat to 75°C–80°C. Add Phase B to Phase A and stir. Add color and fragrance. Package at 65°C. We advise our customers on technological matters to the best of our knowledge under given circumstances. Our information and recommendations are without obligation. Existing laws and regulations are to be observed in all cases. This also applies in respect to any right of third parties. Our suggestions do not relieve our customers of the responsibility of checking the suitability of our products for the envisaged purpose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References 1. Berthiaume, M., Silicones in Cosmetics, Marcel Dekker, NY (1999) 2. CES Fact Sheet on D4, Cefic, Brussels, Belgium (2004) 3. SEHSC Fact Sheet HMDS, SEHSC, Reston VA, USA (2002) 4. OTC Model Rule for Consumer Products, OTC (2001) 5. Tomanek, A., Silicones & Industry, Hanser, Munich (1990)

6. Weidner, R., Roesch, L., Schlosser, A., Wacker Shanghai Tech-Center Opening, WackerChemie (2001) 7. O’Lenick, A. J., Wiegel, K. N., O’Lenick, T. G., C&T, 119(5):89 (2004) 8. Falbe, J., Regitz, M., Roempp Chemie Lexikon, G. Thieme, Stuttgart (1996) 9. Wacker-Chemie technical data sheets, www.wacker.com (2004) 10. Berthiaume, M., Silicones in Hair Care, SCC Monograph Series, NY (1997)

Acknowledgements First of all, I want to say thank you to all the chemists and technicians in our laboratories in Adrian, Burghausen, and Nuenchritz who worked on the Wacker project to develop linear volatile silicones. Without their help, we would not have been able to complete this chapter in the form we did. I also thank Meyer R. Rosen, the editor, who invited us to contribute this chapter to his book.

As for discussions of the basic silicone technology, I thank Dr. Weidner and Professor Roesch of Wacker-Chemie GmbH. To all my coauthors, I thank you for the patience you have had with me and acknowledge everybody for delivering her/his part in time to complete our work on schedule. Dr. Arndt Schlosser Adrian, MI

June 2004

Part XI Starch-Based Systems

Starch-Based Delivery Systems

STARCH-BASED SYSTEMS

Thixogel: Novel Topical Delivery Systems for Hydrophobic Plant Actives

35 Starch-Based Delivery Systems Susan O. Freers Grain Processing Corporation Muscatine, Iowa

35.1 Background .................................................................................. 741 35.1.1 Starch Chemistry ............................................................. 742 35.1.2 Formulation History .......................................................... 743 35.2 Trends ......................................................................................... 744 35.2.1 Ingredients from Natural/Botanical Resources ................ 744 35.3 Starch Modifications: Chemical and Physical .............................. 745 35.3.1 Modification Benefits ........................................................ 745 35.3.2 Starch Modification Chemistry and Functionality ............. 746 35.3.3 Starch Granule Gelatinization .......................................... 747 35.3.4 Functionality in Formulations ........................................... 747 35.4 Novel Starch-Based Delivery Systems ........................................ 747 35.4.1 Introduction....................................................................... 747 35.4.2 Absorbent Starch Delivery Systems ................................ 748 35.4.3 Film-Forming Starch Delivery Systems ........................... 750 35.4.4 Film-Forming/Viscosifier Starch Delivery Systems ......... 752 35.5 Future Innovation .......................................................................... 754 35.6 Formulations ................................................................................. 754 References ......................................................................................... 760

35.1 Background Basic, unmodified corn starch was first employed for powder applications and provided absorbency and cost effectiveness in body and cosmetic facial powders. The use of starch for personal care applications has evolved considerably over the years. More recent and sophisticated applications have now emerged. These applications include the use of

starch-based systems as functional ingredients and novel delivery systems that rely on chemical and physical modifications of starch. This chapter focuses on the development of new, starch-based delivery systems and their use in personal care formulations. Starches can function as oil carriers, carriers of sticky, aqueous ingredients, or carriers of active ingredients in powdered formulations such as body

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 741–760 © 2005 William Andrew, Inc.

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powders, dispersing bath powders, or powdered personal wash products. They can provide thickening or film-forming properties for aqueous systems like creams, lotions, body washes, and shampoos. Starches may be used to absorb moisture in a formulation, or to provide a soft, powdery feeling to the skin. Delivery systems can be based on starch and may be designed in the form of a powder, solution, gel, or even as a film.

the starch granules are extracted from the corn kernel.[1][2] Starch granules are a highly structured, semicrystalline organization of two polymers: amylose and amylopectin. Both amylose and amylopectin are composed of repeating anhydroglucose units. Amylose. Of the two polymers in the starch granule, the amylose polymer is a lower molecular weight, linear polymer. It contains α-D-(1 → 4) glucopyranosyl linkages and has a degree of polymerization of about 100 to 2,000 glucose units. (See Fig. 35.1.)

Although it has excellent properties as dusting powder, native corn starch has limited absorbency when used in certain formulations. In spite of this, starch is the perfect raw material to work with due Amylopectin. The second type of polymer in to its cost effectiveness and consumer-friendly lastarch is a branched glucose polymer, and has a much beling claims based on its natural origin. In order to higher molecular weight than amylose. Approxiovercome the limited absorbency, starch granules mately 97% of the glucose linkages in amylopectin can be modified to physically change them and, are α-D-(1 → 4) linkages, and the remaining linkthereby, improve the absorbency. This improvement ages are α-D-(1 → 6) glucopyranosyl linkages. The can be made during the processing of the starch, branching that is found in the amylopectin polymer and without chemical modification. The result is a is due to the α-D-(1 → 6) linkages. Amylopectin final starch product that is more absorbent and still has a degree of polymerization larger than about contains intact starch granules. While this latter tech2,000 and can range in molecular weight as high as nique is quite effective, in some cases, it is more several hundred thousands. (See Fig. 35.2.) desirable to chemically modify the starch in order to provide film-forming or rheology modifier properties. Chemical modification can also be employed to create a starch product that provides stable viscosity under harsh product or process conditions such as extreme low pH or high shear conditions. These physical or chemical modifications result in a variety of novel starch-based delivery systems that enable formulators to create unique, functional personal care products which allows delivery of useful active ingredients. Figure 35.1 Amylose is a linear glucose polymer with α -D-(1 → 4) glucopyranosyl linkages.

35.1.1

Starch Chemistry[1][2]

Before one can begin to understand novel starch-based delivery systems, an understanding of the starch granule is essential. The starch granule develops during the actual growing process of the corn kernel. Inside the corn kernel is a very complex, organized development of starch, protein, oil, and nutrients. Using a corn wet-milling production process,

Figure 35.2 Amylopectin is a branched glucose polymer with α -D-(1 → 4) linkages, and α -D-(1 → 6) glucopyranosyl linkages.

FREERS: STARCH-BASED DELIVERY SYSTEMS Corn starch. Corn starch is comprised of about 24% to 30% amylose and 70% to 76% amylopectin. As previously at the beginning of this section, the amylose and amylopectin polymers are tightly bound in a semicrystalline structure within the starch granule. Starch granules are generally insoluble at room temperature. When viewed under an optical microscope, using polarized light, corn starch granules will demonstrate a phenomenon called birefringence. This phenomenon shows up as a dark cross in the center of the starch granule. When a starch granule is hydrated, it loses this birefringence. Hydrated starch is also known as gelatinized, or pregelatinized starch. An intact starch granule generally demonstrates hydrophilic properties due to the presence of hydroxyl groups on the glucose polymers. These glucose polymers attract water by means of hydrogen bonding. Heating aqueous starch granule dispersions weakens the hydrogen bonds between the glucose polymers, thereby resulting in swollen starch granules. This swelling is the onset of gelatinization. The hydration of the starch granule can be controlled in order to produce various degrees of gelatinization in the final starch product. The state of the starch granule is very important to the functionality of the starch. This is especially true for modified starch and its use and application in final personal care formulations. Starches can be modified to change the chemical and physical characteristics of the amylose and amylopectin. These modifications change the functional properties of the starch and provide for a range of performance variations in personal care formulations. The physical state of the starch granules (i.e., whether they are gelatinized) will also affect how they are used in personal care formulations. Starches can be obtained and used in a wide variety of granular states. These range from intact, nonhydrated granules to fully hydrated, ruptured granules. A wide range of products with varying degrees of rupture and hydration are also technically feasible and commercially available. Retrogradation. When corn starch is slurried in water and heated in order to rupture the starch granule, it is then cooled, and, on cooling, it will “set back” to form a rigid gel. This gelling phenomenon is called starch retrogradation. In starch retrogradation, it is the linear amylose polymers that realign themselves to set back into a rigid starch gel. Unlike

743 amylose, however, amylopectin is a very complex polymer and does not demonstrate retrogradation properties like amylose. Some reassociation of amylopectin does take place when it is heated and cooled, but, it forms a more flowable gel unlike the rigid gel formed by amylose.

35.1.2 Formulation History Technology transfer. The technology of starches has been evolving for many years. The use of modified starches in the paper, textile, and food industries is widespread. This body of knowledge is a powerful base for the personal care industry and there is much opportunity for effective technology transfer. Many personal care starches are chemically modified based on the same technology employed in other industries. However, the specifications for the final starch products used for personal care applications will differ considerably from those used in industrial applications. The film-forming starch delivery systems discussed in this chapter fall into this latter category. While similar starch-based products have been used in the food and pharmaceutical industries, their use in personal care applications has provided some unique and specific functional properties required by this market that are not achieved by other ingredients. The “Eureka!” moment. To illustrate the development of unique starches for personal care applications, the discovery moment of the particular film-forming starch delivery system is discussed in this chapter. A scientist was working with a new, modified starch in the applications lab in order to better understand its properties. The scientist was interested in viscosity and was measuring it at several starch concentrations in water contained in clear glass beakers. After a short break from the lab, the scientist came back to find part of the starch had dried on the side of the beaker. It turned out that the dried starch had formed a clear, flexible film that was easily peeled off. This particular scientist worked in the pharmaceutical area and was involved in a tablet coating project. In a flash, the scientist recognized the opportunity of being able to coat tablets with this starch-based film and it quickly became part of the coating project.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Film-forming technology. The film-forming technology discovered by the scientist’s careful observation of an unanticipated property, later evolved into broad use in many pharmaceutical, food, and industrial applications. The technology also found its way into many personal care applications, as well as a wide range of applications requiring formation of a polymeric film. These applications included paper coatings, adhesives, textile coatings, tablet coatings, food coatings, etc. Water-soluble delivery films have become increasingly popular as a means of delivering active ingredients or flavors in the food and pharmaceutical industries. Beyond these industries, it was quite apparent that the personal care industry had the need for unique film-forming delivery systems as well. Thus, the principles of technology transfer were eloquently expressed and utilized in the evolution and application of these film-forming polymers for many industries. Rheology modifiers. Modified starches have long been used as rheology modifiers in personal care applications. Some modified starches provide filmforming properties along with stable viscosifying properties. Starches with these capabilities are of particular value in formulas where viscosity stability at a high or low pH has been an issue. Important examples of such formulations are those that require active ingredients such as alpha- or beta-hydroxy acids. Typically, thickeners used previously in skin and hair care products lose viscosity under extreme pH conditions typical of those required for alphahydroxy acids. When these new “active-acid” ingredients entered the personal care formulation arena, the formulator had very few alternatives to choose from. At first, the industry turned to gums such as xanthan gum in order to solve the problem. However, such gums are very high in molecular weight and tend to exhibit a high degree of elongational viscoelasticity. In industry parlance, this phenomenon is called “long textured” or pituitous. By contrast with pituitous xanthan gums, starches can be modified to provide stable viscosity under a wide range of pH conditions, and can be designed to have minimal or no elongational viscoelasticity! Such materials provide a “short,” creamy texture, which greatly enhances the physical form and consumer friendliness of final formulations. The behavior achieved is similar to that obtained by the use of modified starch in the food in-

dustry. In this venue, the extremely low pH conditions of certain food products, like lemon pie fillings, require an acid-stable thickener that doesn’t produce “stringiness.” Specification requirements. Although the starch modification technology described has adapted from industry to industry, the actual raw materials themselves may differ greatly. While the use of starch chemistry can be transferred from industrial applications to food applications to pharmaceutical applications and personal care applications, the starch product employed is rarely the same. Manufacturing processes, and ingredient specification requirements for the starch products used, differ greatly for the different industries. Moreover, the microbiological requirements for starches used in each of the industries cited differ widely. For example, based on typical product specifications for the industry, a modified starch used in the food industry may have an allowable standard plate count of 10,000 Colony Forming Units per gram (CFU/g). This degree of microbial activity is not acceptable in the personal care industry, for example, where requirements for standard plate count are usually less than 1,000 CFU/ g and often less than 500 CFU/g. It is of critical importance to understand that just because the features and benefits of starches used in other industries may be similar to those required in personal care, the use of these same materials is not simply transferable from one industry to another. In fact, there is much technology required to produce starchbased products that will conform to all the requirements of personal care formulations.

35.2 Trends 35.2.1 Ingredients from Natural/ Botanical Resources The personal care industry reacts to the everchanging needs of consumers by providing new products and novel formulations, based on novel ingredients. For example, obtaining functionality in a finished formula, while retaining mildness, has been a considerable challenge. In order to address this important issue, formulators have moved from the more chemically based ingredients to botanically

FREERS: STARCH-BASED DELIVERY SYSTEMS based products. Raw materials from renewable resources have become far more attractive to formulators and consumers alike than those derived from nonrenewable sources. The starch delivery systems discussed in this chapter are manufactured from such a renewable resource. Zea Mays (or corn) can be either physically or chemically modified to provide the functional properties required by personal care products. Besides novel actives from renewable resources, formulators are also looking for ways to deliver their active (or essential) ingredients to the skin and hair. New delivery systems are needed to act as vehicles for such actives and provide consumers with safe, effective formulations.

35.3 Starch Modifications: Chemical and Physical 35.3.1

Modification Benefits

As mentioned in Sec. 35.1, unmodified corn starch has long been used as a cost-effective, absorbent powder in personal care applications. While it is an excellent workhorse of the industry, the material has its limitations, especially when used in aqueous formulations. Unmodified corn starch is not used as a thickener in personal care formulations because when it is slurried in water, heated, and then cooled, it retrogrades to form an undesirable rigid gel. Such gels also will undesirably exude water over time, and this process of water separation is called syneresis. Also, the intact corn starch granule is insoluble in water at room temperature (see Sec. 35.1.1). As heating of the aqueous dispersion of starch granules takes place during processing, the hydrogen bonds between the anhydroglucose polymers are weakened, thereby allowing water to enter the starch granule. As water enters the starch granule, the starch granule begins to swell and the viscosity of the starch slurry increases. A fully swollen, but unruptured, starch granule coincides with achieving the maximum viscosity potential of the starch dispersion. This swelling phenomenon is not reversible. If heating of an unmodified starch dispersion continues after the fully swollen granule condition has been reached,

745 the starch granules will then burst and release the amylose and amylopectin forming a “solution” of the two polymers in water, along with fragments of the granules. (See Fig. 35.3.) As the starch solution is cooled, the two types of anhydroglucose polymers, amylose and amylopectin, begin to realign and reassociate and the process of retrogradation begins to occur. Since amylose is a linear polymer, it will realign itself and precipitate out at lower temperatures forming rigid gel. This retrogradation process exudes water from the gel as it sets up, and syneresis of water occurs. By contrast, the amylopectin will reassociate as well. However, it does not form as rigid a gel because of the nonlinear stereochemical structure, i.e., the branches on the amylopectin polymers do not let them get close enough to each other to form an insoluble gel network. Starches can be modified to ensure that the starting granules remain intact and avoid both retrogradation and syneresis. Unmodified starch solutions such as those just described can be cast into films. However, such films are cloudy, inflexible, have a weak tensile strength, and are generally unacceptable to the personal care formulator.

Figure 35.3 When stained with an iodine solution, the hydration of the starch granule is shown in each of four stages: the intact, insoluble granule (upper left); a partially hydrated granule (upper right); a fully swollen, fully hydrated starch granule (lower left); and a ruptured starch granule (lower right).

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

The deficiencies cited above for unmodified starch can be overcome. By suitably modifying a starch, the functional properties can be altered to enhance its utility in aqueous-based personal care formulations. Modified starches can provide clear, flexible, film-forming properties. They can also be modified to provide pH stability, shear resistance, heat stability, and emulsion stability through freezing and thawing. This not only gives personal care products made with such starches stability during processing, but it also provides finished product stability for aged materials. Particular rheological properties can be created by the way a starch is modified. Starches can also be modified to alter their retrogradation properties, and thereby control the behavior of the final viscoelastic gel produced following retrogradation and its rheological behavior.

35.3.2

Starch Modification Chemistry and Functionality

To fully understand how the range of modified starches available can function in a personal care formula, one must first understand the wide range of chemical modifications available. The most common types of chemical modification include hydrolysis, esterification, etherification, and oxidation. Various combinations of these chemical modifications can also be used.[4] Acid or enzyme starch modification. Acid or enzyme modifications are typically used to decrease the molecular weight of starch. This molecular weight degradation has the effect of decreasing the viscosity of the hot starch solution, as well as the viscosity of the final, cooled starch solution obtained during the starch hydration process. Typical reagents used to acid-modify a starch are hydrochloric or sulfuric acids. In the presence of water, these acids hydrolyze or cleave the α-D-(1 → 4) linkage in the long chain anhydroglucose polymers (both amylose and amylopectin) thereby creating shorter polymer lengths. This hydrolysis phenomenon occurs within the starch granule and the degree of hydrolysis can be controlled to produce various average molecular weight, modified starches. Enzymes can also be used to cleave the glucosidic linkages of both the amylose and amylopectin structures and thereby produce lower molecular weight starch molecules. Acid- or enzyme-modified starches will still retrograde and

form firm gels when cooled because the basic starch polymer interaction remains unchanged even though the molecular weight has been altered. Cross-linked starch modification. Crosslinking of polymers within a starch granule will increase the stability of the granule and its resistance to stressors like heat, acid, and shear. When the polymers in the starch granule are crosslinked, the granule becomes more resistant to hydration, and cannot swell as easily. The degree of crosslinking determines the extent to which the starch granule is able to swell. Crosslinking protects the integrity of the swollen starch granule by making it stronger and more resistant to mechanical rupture. Many reagents can be used to produce cross-linked starches. Examples of these include phosphorus oxychloride, sodium trimetaphosphate, adipic anhydride, and, less frequently, epichlorohydrin. Cross-linked starch granules are more resistant to acid and shear degradation. These types of modified starches generally provide more processing latitude and increased product stability. These improved attributes provide increased flexibility for formulators when developing a personal care product. Cross-linked starches are less sensitive to pH, agitation, homogenization, elevated temperature, and aging. Chemical starch modification. The chemical addition of functional groups to the anhydroglucose molecules comprising a starch granule can be used to inhibit starch retrogradation. Equally important, chemical modification, or substitution, is used to alter starch properties. Examples of such alteration include changing the ionic charge or making a starch more hydrophobic. Starch granules can be reacted with succinic anhydride, acetic anhydride, octenyl succinate, propylene oxide, or cationic reagents. Such substituted starches will form gels at lower temperatures, thereby allowing the modified starch to hydrate and achieve its functional properties without using extremely high production processing temperatures. Substitution will also improve the water-holding capacity of the starch granules and thereby inhibit the retrogradation and reassociation that would be noted in an unmodified starch as it cools. For example, final gels produced from starches modified with propylene oxide are highly flowable, and syneresis is reduced or eliminated. Such gels, and films produced from them, have improved clarity and flexibility. Stabilized starches. Modified starches, which are both crosslinked and substituted (to maximize

FREERS: STARCH-BASED DELIVERY SYSTEMS the stability of the starch granule), are called “stabilized starches.” Stabilized starches have a low gelatinization temperature and thereby require less heat to hydrate them. They produce clearer gels and provide maximum stability to acidic conditions, high shear, high temperature, and freeze/thaw stressors. Such products and their characteristics are highly appealing to personal care formulators. Oxidized starch modification. Lightly oxidizing a starch creates a whiter product due to a bleaching effect. Typical bleaching reagents include hydrogen peroxide, peracetic acid, ammonium persulfate, sodium hypochlorite, potassium permanganate, and sodium chlorite. Treatment with these reagents not only bleaches the starch, but also acts as a microbiological treatment that lowers the starches bioburden. Higher levels of these reagents will go beyond simple bleaching and modify the starch granules. In this case, properties such as improved adhesion and a lower gelatinization temperature are achieved. Increasing the degree of oxidation of starch granules, beyond producing simple bleaching effects, is a complex chemistry that alters several properties of the starch. Oxidation causes some glucosidic bond breakage, which decreases the molecular weight and, therefore, reduces the viscosity of the final starch gel. It decreases the gelatinization temperature of the starch granules and increases the adhesive properties of the starch. Combinations of all the above mentioned starch modifications are commercially employed to create novel ingredients with desirable multifunctional properties.

35.3.3

Starch Granule Gelatinization

An intact starch granule generally demonstrates hydrophilic properties due to the presence of hydroxyl groups on the amylose and amylopectin polymers. These polymers attract water which associates in the hydroxyl groups by means of hydrogen bonding. Heating aqueous starch granule dispersions weakens intramolecular hydrogen bonding between these polymers, and thereby results in swollen starch granules. This swelling has been called gelatinization (see Sec. 35.11). A central focus for the effective use of starch by formulators is to determine the processing condi-

747 tions required to obtain its ultimate functional properties. Sometimes, in the production of personal care products when heat is not readily available, it can be difficult to achieve the most advantageous level of starch gelatinization. Starch manufacturers can alleviate this problem by partially or totally swelling the starch granules before they are dried to produce what is known as pregelatinized starches. These starches may also be termed cold-water swellable, cold-water soluble, or instant starches. Thus, starches are available commercially in a variety of states including an intact granular state, a ruptured granular state, a swollen granular state, or a combination of these. Some starches have the potential to be hydrated in water at room temperature, while others require heating to best access their benefits. Discussions with the starch supplier are critical to understanding the types of modified starch available and how best to select and optimize product choice for achieving optimal formulation benefits.

35.3.4

Functionality in Formulations

Physically or chemically modified starches provide flexibility and stability to personal care formulations. Starches are very mild ingredients. They often allow the formulator to remove chemical, astringent ingredients (such as harsh salts) and replace them with less irritating materials. Starches are a cost-effective, environmentally friendly, label-friendly way to enhance the properties of personal care products. Physical modifications can provide the starch powder properties that emulate talc or even siliconecoated products. Chemical modifications to starch are used to alter rheological behavior and stability of the starch in aqueous formulations. The additional stability available is not only process related but also product related.

35.4 Novel Starch-Based Delivery Systems 35.4.1 Introduction Having covered some of the basic chemistry of starch granule modification, we turn now to their

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use and application in starch-based delivery systems. Understanding the chemistry of the starch granule, the chemical and physical properties of both unmodified and modified starches, the gelatinization process of the starch granule, and the functionality built into the molecule all provide insight into why starchbased delivery systems have such versatility in finished personal care formulations. The novel starchbased delivery systems discussed in this chapter include a physically modified starch developed to deliver oil or aqueous active ingredients, a film-forming starch designed to deliver active or nonactive ingredients to the skin or hair, and a film-forming starch that also acts as a rheology modifier.

35.4.2 Absorbent Starch Delivery Systems PURE-DENT corn starch. The absorbent properties of corn starch have justified its use in many powder applications, including body powders, foot powders, and baby products. While providing a pleasant, soft feeling to the skin, basic corn starch tends to be less absorbent than talc, the other widely used body powder raw material. Absorbency is extremely important in formulas designed to absorb body fluids such as foot and underarm products. A new, physically unique starch called PURE-DENT B836 corn starch USP is a fine-particle-size corn starch designed to absorb higher quantities of aqueous or nonaqueous substances than a typical corn starch. Since the starch granule is intact, this starch is not soluble in water at room temperature. As a result, the material can carry aqueous substances as well as oily substances. This product can act as a delivery system, a carrier of other ingredients in a formulation, or as a functional ingredient in a personal care formula. PURE-DENT B836 corn starch USP is manufactured by means of a unique, proprietary process that increases its surface area. As a result, the starch granule remains intact, but provides a higher surface area to absorb not only hydrophobic materials, but also aqueous ones. This starch can be used in formulations to absorb body fluids, enhance flow properties, and/or stabilize powder formulations by managing the moisture in the finished product.

In general, starches are very cost-effective, functional ingredients and PURE-DENT B836 is no exception. Although priced higher than a basic corn starch, the functional properties provide unique benefits at a much lower cost than those obtainable with typical synthetic polymers. Absorption properties. Materials absorbed onto PURE-DENT B836 are not only adsorbed onto the surface of the starch, but they are also partially absorbed and internalized by the starch granule, thereby providing enhanced stability to the absorbed active. This absorption is a physical phenomenon, and as a result, the absorbed material may be readily released from the PURE-DENT B836 starch. This phenomenon allows a substance to be carried and deposited onto the skin or hair, or into a formula, and yet be deliverable and, therefore, available to provide its benefit. Aqueous-based ingredient absorption. The quantity of active material that PURE-DENT B836 can retain following absorption is dependent upon the type of substance and the desired properties of the final product. When the substance is water, an industry test can usually be employed to quantify the amount of water absorbed. The M/K Systems Gravimetric Absorbency Testing System (GATS)[7] has been used to quantify the amount of water capable of being absorbed by PURE-DENT B836 versus the amount of water absorbed by a basic corn starch. This test measures the amount of water absorbed over time in a two-gram sample. Figure 35.4 shows the results of this study. As seen in Fig. 35.4, PURE-DENT B836 can absorb, and hold 150% of water based on the weight of the B836 as compared to a typical corn starch. Oil absorption. PURE-DENT B836 also has the ability to carry large quantities of oils and still remain a powder. Laboratory studies have shown the product can carry between 30% and 50% oil loads and still retain its powder flow properties! Useful oils range from the mineral oil type to vitamin oils. Other active oils or even oily substances are also capable of being absorbed in such quantities. The level of oil employed on the starch can be increased until a level is reached at which point the starch becomes a paste and loses its ability to carry oil while retaining its free-flowing powder characteristics. Some ointment or jelly-type products such

FREERS: STARCH-BASED DELIVERY SYSTEMS

749

Figure 35.4 PURE-DENT B836 corn starch USP absorbs significantly more water than an unmodified corn starch when tested using the GATS industry test to quantify the amount of water absorbed.

as petrolatum have been carried at levels of 75% load and still remain a powder. The acceptable loading and final physical form of the starch/oil system is dependent upon the type of substance carried and the desired properties of the end product. Other substances such as sticky, high-viscosity materials may also be carried within PURE-DENT B836. For natural formulations, materials such as honey have been absorbed on this unique starch. Formulation enhancement. In certain types of production and packaging equipment, powders are typically easier to handle than liquids or pastes. They can also be used to accurately measure minute quantities of ingredients into a formula. Powdered formulations are often more stable than emulsions or suspensions. A personal care powdered formula may utilize the absorption capabilities of PURE-DENT B836 to carry a difficult ingredient and enable its effective placement in the formula. The PUREDENT B836 product may also be used as the bulking agent in the powder, thereby contributing to the absorbing properties of the final formula. Foot products, skin products, underarm products, bath products, etc., all can benefit from the absorption properties of this starch. Formulation 35.1 (Sec. 35.6) demonstrates how PURE-DENT B836 corn starch can be used to carry numerous oils and oily substances into a bath product. This dispersing bath powder exhibits ideal flow

properties in spite of the heavy oil load carried. PURE-DENT B836 starch also disperses in the bath water, thereby releasing the carried emollients and moisturizers into the bath and making them available for the recipient’s skin. Formulation 35.1 is an example of a complex, dispersing bath powder. Other simpler formulas may be produced using PUREDENT B836, oils, and a flow agent, such as fumed silica. To enhance the silky feel of creams and lotions when rubbed into the skin, insoluble powders are typically added. PURE-DENT B836 can be added to such personal care formulas in order to contribute a silky, powdery skin feel. Since the properties of PURE-DENT B836 are based on the physical structure of the starch granule, this particular starch should be added during the cooling cycle in the processing operation in order to keep the starch granule intact. Due to the fine particle size of PUREDENT B836, it provides the consumer with a smooth feeling when it is rubbed onto the skin. Formulation 35.2 (Sec. 35.6) is a mild body-lotion formula. In this system, the PURE-DENT B836 is added after the heating cycle in order to preserve integrity of the starch granule. The starch provides a powder after-feel to the lotion when it is rubbed on the skin, as well as increasing the stability of the formula by means of its absorption properties.

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35.4.3 Film-Forming Starch Delivery Systems Zeina® hydroxypropyl starch. The concept of using a modified starch as the primary polymer for film formation is intriguing to the personal care industry. Many personal care formulations rely on the formation of a film to deliver desired functional effects to the skin or hair. Personal wash products, facial masks, lotions, creams, shaving products, as well as liquid makeup and mascara, employ filmforming polymers as a way to deliver these attributes to the consumer. Zeina B860 hydroxypropyl starch. A newer concept in film formation technology creates a delivery film that operates as a stand-alone vehicle to deliver active, or nonactive ingredients, to the skin or hair. Such products can be produced and sold as an actual free-standing film, and not as a lotion or paste that must dry out in order to create a film on the body or hair. Of course, Zeina B860 can also be used to create a film on the body or hair in a more traditional way such as through its use as a lotion or mask formulation. Still another use for the product is to use the film it makes to protect the active ingredient. This can be accomplished by encapsulating the material with a film-forming polymer such as the hydroxypropyl starch, thus creating a protective barrier film around a droplet of the active material. Product information. Zeina B860 hydroxypropyl starch, is a modified starch designed to deliver active or nonactive ingredients by way of a filmforming delivery system. It is a modified starch created by using the substitution process discussed in Sec.35.3.2). Zeina B860 is a hydroxypropyl starch. Hydroxypropylation inhibits starch retrogradation and enhances film-forming and clarity properties. The exact production process is proprietary, but the end result is a modified starch with a low gelatinization temperature, low viscosity, and little-to-no retrogradation. This unique polymer can produce watersoluble delivery films, or provide film-forming properties for a wide range of personal care formulations. Zeina B860 is ideal for formulations requiring these water-soluble film properties. It contributes mildness to personal care formulas and adds both functionality and a smooth, silky skin feel. The lowviscosity characteristics of Zeina B860 solutions allow for using a higher solids content so there is less water to dry when forming the film. This modified

starch is a pregelatinized or “instant” starch. This form makes it is easy to process since it does not require heat to produce the film properties. When Zeina B860 is viewed under an optical microscope, no intact starch granules are seen. A combination of polymers is often used to introduce film properties to a particular formula. Zeina B860 can be used alone, or in combination with other polymers, to develop the exact properties desired in the final formulation. Compared to other expensive, synthetic polymers, Zeina B860 is a highly cost-effective material for achieving desired properties, such as film formation. Formulation challenges. There are no major formulation manufacturing hurdles to overcome when using Zeina B860 film-forming starch. The product can be easily hydrated in cold, warm, or hot water. It can be dispersed in water with good agitation that continues for about twenty to thirty minutes. For best results, the starch should be added to the top edge of the liquid vortex created by the mixer. This allows the polymer to quickly hydrate with minimal lumping. Unlike some starch polymers that are hard to pump due to very high viscosity, the lowviscosity characteristics of Zeina B860 provide for ease of handling when making formulations. As a water-soluble polymer, Zeina B860 is typically added to the aqueous phase of personal care formulations. The polymer can be preblended with other ingredients to enhance the dispersibility of other ingredients. Examples of such ingredients include gums, such as xanthan gum, or cellulosic products. Applications of water-soluble delivery films. As we have noted previously, Zeina B860 is an excellent film-forming polymer. It creates a watersoluble film that can easily be washed off the skin or hair. This polymer can be used to add film-forming properties to formulations or to create unique delivery films. These delivery films are clear, glossy, water-soluble, and fairly flexible. Zeina B860 films can be made to be very elastic and flexible by formulating with plasticizers such as glycerin. Such films can be used to deliver actives, or nonactives, to the skin or hair. Formulas can range from a very simple system with Zeina B860, plasticizer, water, and the ingredient to be delivered, to very complex systems containing various polymers, plasticizers, detackifiers, emulsifiers, soluble and insoluble actives, as well as color, fragrance, or flavor.

FREERS: STARCH-BASED DELIVERY SYSTEMS To create a delivery film with Zeina B860, a flowable gel must first be produced. A typical concentration to accomplish this is about 10% to 20% Zeina B860 in water. However, the concentration can range from about 5% to 30%, depending upon the other ingredients in the formula. Other polymers can be used to enhance the film properties of the Zeina B860. These polymers can be natural rheology modifiers, such as guar gum, xanthan gum, locust bean gum, acacia gum, etc., carrageenan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or many others. Concentration levels of such adjuvant polymers can range from 1% or 2%, to 10% or 20%, to even 50%, of the polymer in the film, depending upon the desired end properties. Plasticizers are employed to provide Zeina B860 films with desired flexibility and elasticity. The type and concentration of plasticizer employed is dictated by the final properties of the film desired. While glycerin and propylene glycol are the plasticizers of choice for the Zeina B860 polymer, a wide range of other plasticizers are also useful—especially when a combination of polymers are employed. Plasticizer concentrations can vary from about 5% based on the polymer to as high as 50% of the polymer. Shorter chain length polymers such as sugars, polyols, or maltodextrins can also be used to plasticize the film. These films can be tested for tensile strength and elasticity properties, and the level and type of plasticizers can be varied to achieve the desired end result. Water-soluble, or water-insoluble active ingredients can also be added to Zeina B860 films. Emulsifiers, preservatives, detackifiers, or sweeteners may be added as well. For example, if the active ingredient to be delivered is an oil, an emulsion needs to be created before the film is cast. This requires using an emulsifier, such as polysorbate 80, in order to create a homogenous mixture and thus a homogenous film. Colors, fragrances, or flavors can be added to the films in order to make them aesthetically pleasing to the consumer. In each of these cases, the Zeina B860-based starch film acts as a carrier/delivery system for this broad range of useful personal care actives. Due to their adhesive properties and water solubility, Zeina B860 films can be applied to the skin by wetting the skin or the film, then adhering the film to the skin. These properties makes these films an ideal delivery system, and they can then be rinsed away

751 by simply using water, thereby leaving the skin feeling silky and smooth. In situations where it is appropriate for an active to remain on the skin for longer delivery of the active, the Zeina B860 film can remain adhered to the skin instead of being washed away. Specific formulations for Zeina B860 delivery films are not cited in this chapter due to the sensitivity and confidentiality of specific projects currently in progress. Film formation in personal care formulas. Zeina B860 hydroxypropyl starch is ideal for personal care applications where a washable gel or film is desired. An obvious application for the product is in personal wash products and facial masks. The smooth skin feel and mildness of Zeina B860, combined with its unique water-soluble, film-forming properties, make it an outstanding choice for such formulations. Besides the use of Zeina B860’s film properties in washable products, it can also be used to add body and skin feel to other formulations, without acting as a primary thickener! In such cases, it can be used by itself, or in combination with other polymers. Creams and lotions, shave products, liquid makeup, and mascara are all types of products that can benefit from the film-forming properties of Zeina B860 modified starch. While Zeina B860 is frequently used for its film-forming ability, it provides a noticeable smooth feel to formulations when used at higher concentrations. Personal wash products have increased in popularity over the past ten years. Formulation 35.3 (Sec. 35.6) demonstrates how Zeina B860 hydroxypropyl starch is used in a body wash formulation. It provides body and film formation properties, while maintaining the desirable smooth after-feel attributed to modified starches. This is an example of using Zeina B860 in combination with another modified starch (PURE-GEL® B990) to create a water-soluble film on the body, delivering the cleaning surfactant (i.e., detergent), and then allowing the film to be washed away. Facial masks can be removed from the skin by peeling them off or by gently washing them away. Zeina B860 is ideal for such formulations because of its film-forming properties, as well as its water solubility. Formulation 35.4 (Sec. 35.6) uses Zeina B860 at a 10% concentration in order to provide film-forming properties to the product. It also contributes rheological enhancement and smoothness to

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

the formulation, as well as providing the mildness characteristics often desired in facial products. The low viscosity of Zeina B860 allows the starch to build solids in the formulation so less water can be used. As a result of the need for less water, facial masks can dry faster. Again, the water-solubility contributed to the film by the starch enables the mask to be easily and gently washed away. Personal care products that are not washed away from the skin or hair can also benefit from the film-forming properties of Zeina B860. Formulation 35.5 (Sec. 35.6) is a liquid makeup formulated with Zeina B860 as the primary film former. Once again, this starch provides body and suspending properties for the formulation, along with film-forming properties. In this case, the film is delivering both pigments and emollients to the skin.

and then attaching the dusting particulate, or powder, to the Zeina-coated particulate. Examples of applications for these processes include bath powders, bath crystals, and powdered cleansing products.

35.4.4

Film-Forming/Viscosifier Starch Delivery Systems

PURE-GEL® hydroxypropyl starch phosphate. While Zeina B860 hydroxypropyl starch is a low-viscosity polymer designed to deliver film-forming properties without the negative effects of high viscosity, some film-forming starches are designed

Encapsulation of active ingredients. The film-forming properties of Zeina B860 allow it to be a perfect polymer for use in encapsulating and, therefore, protecting particulates or actives in oil droplet form. The modified starch acts as a film-forming polymer by forming a water-soluble film around an “active” oil droplet. This encapsulating film provides barrier properties and protects the oil droplet from environmental stressors. The water-soluble nature of the outer, encapsulating film allows the oil to be released when the encapsulated product comes in contact with water. A typical manufacturing process for encapsulation by Zeina B860 is spray drying. A basic encapsulating formula includes this filmforming polymer, an emulsifying agent, such as gum arabic, a carrier, such as maltodextrin, and the active oil to be encapsulated. Zeina B860 solutions are often sprayed on particulates to form water-soluble, protective coatings. A fluid bed process is often used to apply these coatings. This process involves suspending the particulates in a bed of air and spraying the starch coating solution onto the particulates using a spray gun. The starch solution droplet hits the particulate, spreads to form a film on the particulate, and then dries quickly because of the air flow in the fluidized bed of product. (See Fig. 35.5.) The low-viscosity nature of the polymer allows for increased solution concentration and shorter production times. Under certain conditions, Zeina B860 is used to adhere particles or powders onto other particulates by applying a Zeina B860 film to the recipient particulate

Figure 35.5 In the fluid bed top spray coater, the particulates are suspended in a bed of air. The coating solution is sprayed onto the particulates using a spray gun. (Diagram courtesy of Vector Corporation, Marion, IA.)

FREERS: STARCH-BASED DELIVERY SYSTEMS to function as rheology modifiers or thickeners. For example, PURE-GEL® modified starches illustrate this type of multifunctional polymer. PURE-GEL is a family of modified starches that are used as thickeners and rheology modifiers in personal care products. As stabilized starches, they provide both product and process stability. Due to hydroxypropylation, this starch does not retrograde and, therefore, provides a smooth, rheologically pleasant gel with little or no elongational viscoelasticity. They also form excellent films and are used in a wide range of personal care products from creams and lotions, to shaving products, to cleansing products. Product information. PURE-GEL starches are hydroxypropyl starch phosphates. Chemically, they fit into the category of stabilized starches (see Sec. 35.3.2). The starch granules have been crosslinked and substituted and are therefore “stabilized.” Once the desired formulation viscosity is reached, PUREGEL starches maintain that viscosity and therefore provide stability to the formulation. These starches are comprised of intact granules and are not pregelatinized starches. This stable viscosity is created during the formulation process by applying heat in order to hydrate the starch granules. The unique stability of this product with regard to: pH, shear, heat, and freeze/thaw cycling relies, to a great extent, on the ability of the starch granules to maintain their integrity. Even though heat is required to hydrate the starch during formulation processing, PURE-GEL starches easily hydrate at typical processing temperatures due to their low gelatinization temperature. These starches have an unusually good ability to hold onto water under extreme conditions, thereby providing personal care products with significantly improved stability. PURE-GEL modified starches also act as film formers in such formulations. Formulation challenges. As described above, PURE-GEL polymers are stabilized starches and, therefore, provide stability during the formulation process as well as to the finished personal care product. Low pH formulations, high heating conditions, or high shear processing can cause many commonly used thickeners to lose viscosity and stability. In such cases, the result can be emulsion breakage and the fact that the personal care product can be ruined or rendered inappropriate for sale. By contrast, PUREGEL starches provide stability to formulations that allow them to withstand harsh conditions and produce a beautiful appearing end product. Freeze/thaw

753 stability has recently become very important to the personal care formulator since personal care products are now shipped and stored globally, under a wide range of temperature cycling conditions. It is highly undesirable for the consumer to open a premium personal care product container, only to find a broken emulsion and a film of water on the top. PURE-GEL starches are crosslinked and substituted. As such, the integrity of the starch granule is protected, and they hold on to the water in the formulation, thereby preventing syneresis. Thus, PURE-GEL starches contribute freeze/thaw stability to final formulations and are a powerful tool for enhancement of product stability. PURE-GEL modified starches can be used in combination with other polymers and rheology modifiers. They are extremely cost-effective, functional ingredients and are often used to reduce the overall cost of the formulation. These polymers are “short textured” (i.e., little viscoelastic effects) and, by blending them with “longer-textured” viscosifying agents, such as gums, the formulator can achieve the optimal combination of viscoelasticity and rheological behavior required for a particular application. Applications. The versatility of the PURE-GEL family of starch products allows its use in a wide range of personal care products. These include: alpha-hydroxy acid creams or lotions, mild shaving creams, and personal wash products. One of the PURE-GEL modified starches, called PURE-GEL B990, can be used in combination with Zeina B860 in order to provide the desired combination of filmforming properties and rheological behavior in the body wash formula previously cited. (See Formulation 35.3.) In Formulation 35.3, the PURE-GEL B990 is creating viscosity and creaminess while enhancing the film formation of the product. It also aids in the delivery of the detergent to the skin. Formulation 35.6 employs PURE-GEL B990 in a low-pH, alpha-hydroxy acid skin cream. In this case, PURE-GEL B990 stabilizes the viscosity of the formula and delivers the emollients with a light, film-forming property to the skin. This modified starch also provides mildness and smoothness characteristics. Because it is a stabilized starch, PUREGEL B990 has the ability to maintain the cream’s viscosity even under the product’s low-pH conditions and the heat of processing. It also provides the cream with freeze/thaw stability.

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35.5 Future Innovation

35.6 Formulations

Many products and projects utilizing the new starch-based delivery systems described in this chapter are in development by numerous companies. Details of this work necessarily cannot be discussed in this chapter due to the sensitive, proprietary issues involved. Application patents are pending and intellectual property rights should always be reviewed when working with any new raw material. Generally, however, such materials provide film-forming products that can range from treatment products to simple flavor or fragrance delivery systems.

Formulations 35.1–35.6, courtesy of Grain Processing Corp., are provided as starting formulations to demonstrate examples of how the unique starch delivery systems described in this chapter are used in personal care products. The information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

Formulation 35.1: Dispersing Bath Powder

Phase

Ingredient

Function

B

INCI

Kukui nut oil

Emollient

1.0

Aleurites moluccana seed oil

DC 556 fluid

Emollient, couple oil

1.0

Phenyl trimethicone

DC 244

Emollient, couple oil

2.0

Cyclomethicone

Fragrance A

Weight %

1.5

Transcutol

Solvent, couple oil

2.0

Ethoxydiglycol

Brij 93

Emulsifier, couple oil

2.5

Oleth-2

Lexquat AMG-O

Skin conditioner

2.0

Oleamidopropyl PGdimonium chloride

Tocopheryl acetate (vitamin E)

Emollient, moisturizer

0.5

Tocopheryl acetate

PURE-DENT B836

Carrier, dispersant

Cab-O-Sil M5

Flow agent

86.0 1.5

Corn (Zea Mays) starch Silica

Manufacturing instructions 1. Mix Phase A ingredients together with good agitation. 2. Slowly blend Phase A into Phase B. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

FREERS: STARCH-BASED DELIVERY SYSTEMS

755

Formulation 35.2: Mild Body Lotion

Phase

A

Ingredient

Function

Weight % 82.90

Water

Solvent

MALTRIN M100

Build solids, skin feel

5.00

Maltodextrin

Carbopol Ultrez 10

Thickener

0.15

Carbomer

Disodium EDTA

Preservative

0.05

Disodium EDTA

SF96-100

Emollient, slip

1.00

Dimethicone

Montanov 68

Emulsifier

1.50

Cetearyl alcohol and cetearyl glucoside

Lipomulse 165

Emulsifier

1.50

Glyceryl stearate and PEG-100 stearate

Mineral oil 65/75

Emollient, moisturizer

5.00

Mineral oil

Triethanolamine 99%

Neutralize carbopol

0.15

Triethanolamine

PURE-DENT B836

Powdery skin feel

2.00

Corn (Zea Mays) starch

0.75

Phenoxyethanol, methylparaben, butylparaben, ethylparaben, propylparaben

B

C

D

INCI

Phenonip

Preservative

Water

Manufacturing Instructions 1. Combine Phase A ingredients and heat to 75°C with agitation. 2. Combine Phase B ingredients and heat to 75°C with agitation. 3. Add Phase B to Phase A with agitation. 4. Add Phase C to combined Phases A and B with agitation. 5. Cool to 40°C and add Phase D with agitation. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 35.3: Body Wash Formula

Phase

A

B

Ingredient

Function

Weight %

Water

Solvent

Tetrasodium EDTA

Preservative

0.1

Tetrasodium EDTA

Zeina® B860

Film former, skin feel

3.0

Hydroxypropyl starch

PURE-GEL® B990

Thickener, skin feel

3.0

Sodium hydroxypropyl starch phosphate

BIO-TERGE® AS-40

Detergent, foamer

30.0

Sodium C14-16 olefin sulfonate

Plantaren 2000

Foamer, detergent

12.0

Decyl glucoside

Velvetex BK-35

Foam booster & stabilizer

2.0

Cocamidopropyl betaine

Sepiperl N

Surfactant

3.0

Coco-glucoside and coconut alcohol

Monamid CMA

Emulsifier, thickener

3.0

Cocamide MEA

Glycol stearate

Emulsifier, pearlant

2.0

Glycol stearate

Dowicil 200 (10% solution)

Preservative

1.5

Quaternium-15

Citric acid (25%)

Conditioner, buffer

0.5

Citric acid

Fragrance and color

39.9

INCI Water

as desired

Manufacturing Instructions 1. Mix Phase A ingredients together and heat to 75°C with good agitation. Hold for 10 minutes. 2. Cool to 45°C and add Phase B ingredients. 3. Adjust pH to 4.5–5.5 with citric acid. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

FREERS: STARCH-BASED DELIVERY SYSTEMS

757

Formulation 35.4: Washable Facial Masque Formulation

Phase

Ingredient

Function

Weight %

Water

Solvent

Veegum Ultra

Thickener

Zeina B860

Film former, body

10.0

Plantaren 2000

Foamer, detergent

5.0

Decyl glucoside

Butylene glycol

Solvent, solubilizer

5.0

Butylene glycol

Arlacel 165

Emulsifier

5.0

Glyceryl stearate and PEG-100 stearate

Vitamin A palmitate

Vitamin, conditioner

0.1

Retinyl palmitate

Stearic acid

Emollient, thickener

3.0

Stearic acid

Oleic acid

Emulsifier

2.7

Oleic acid

C

Zeosyl 200

Abrasive, absorbant

2.0

Hydrated silica

D

Kaolin

Absorption base

E

Titanium dioxide

Abrasive

1.9

F

Fragrance

Fragrance

0.3

A

B

G

47.99

INCI

2.50

13.0

Water Magnesium aluminum silicate Hydroxypropyl starch

Kaolin Titanium dioxide

Germaben II

Preservative

1.0

Propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

Tea tree oil

Anti-bacterial, disinfectant

0.01

Melaleuca alternifolia, (tea tree) leaf oil

Bois oil

Emollient, moisturizer

0.50

Hydrogenated vegetable oil

H

Manufacturing instructions: 1. Heat water to 75°C and add Veegum Ultra with rapid agitation. Add remaining Phase A ingredients with good agitation. 2. Heat Phase B to 75°C. 3. Add Phase B to Phase A with good agitation. Transfer to a mixing unit with vacuum capabilities. 4. Add Phases C, D, E, and F to Phase A and B mixture. 5. Run under full vacuum until smooth and air free cool to 40°C. 6. Add Phase G and Phase H and mix until smooth. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 35.5: Liquid Makeup

Phase

A

Ingredient Water

Function Solvent

Veegum K

Thickener

Keltrol T (2% solution) Disodium EDTA Hexylene glycol

Permethyl 99A

Thickener, polymer Preservative Solvent Polymer, film former Opacifier Anti-caking, absorption Pigment Pigment Pigment Absorption, powder Emollient, conditioner Solvent, emollient

Montanov 68

Emulsifier

2.0

Promulgen D

Emulsifier

2.0

Cerasynt IP

Emollient

1.0

Gransil GCM

Conditioner, emollient

1.0

Germaben II

Preservative

1.0

Zeina® B860 Titanium dioxide Kaolin B

Yellow iron oxide Red iron oxide Brown iron oxide Talc Dow Corning 245 fluid

C

D

Weight % 39.95

INCI

20.0 0.1 4.0

Water Magnesium aluminum silicate Xanthan gum Disodium EDTA Hexylene glycol

3.0

Hydroxypropyl starch

6.0

Titanium dioxide

1.0

Kaolin

0.23 0.40 0.50 1.82

Iron oxides Iron oxides Iron oxides Talc

2.0

10.0 4.0

Cyclopentasiloxane Isododecane Cetearyl alcohol and cetearyl glucoside Cetearyl alcohol and Ceteareth-20 Stearic acid and aminomethyl propanol Cyclomethicone and polysilicone-11 Propylene glycol, diazolidinyl urea, methylparaben, and propylparaben

Manufacturing Instructions 1. Heat water to 75°C and add remaining Phase A ingredients with good agitation. 2. Add Phase B to Phase A. 3. Heat Phase 3°C to 75°C. Add Phase C to Phase A and B mixture. 4. Cool to 40°C and add Phase D. 5. Pass through a colloid mill. 6. Cool to room temperature with gentle agitation. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

FREERS: STARCH-BASED DELIVERY SYSTEMS

759

Formulation 35.6: Alpha Hydroxy-acid Cream

Phase

Ingredient

Function

Weight %

A

Water

Solvent

B

Disodium EDTA

Preservative

0.1

Disodium EDTA

C

PURE-GEL B990

Thickener, skin feel stabilizer

2.0

Sodium hydroxypropyl starch phosphate

Lipomulse 165

Emulsifier

3.0

Glyceryl stearate and PEG-100 stearate

Eutanol G

Emulsifier, emollient

4.0

Octyldodecanol

Cetearyl alcohol

Thickener

1.5

Cetearl alcohol

Montanov 68

Emulsifier

2.0

Cetearyl alcohol and cetearyl glucoside

Dow Corning 344

Emollient, skin feel

5.0

Cyclomethicone

Dow Corning 200-100

Emollient, skin feel

1.0

Dimethicone

Lactic acid 85%

Exfoliant

3.0

Lactic acid

Water

Solvent

5.0

Water

Glydant

Preservative

0.2

DMDM hydantoin

D

E F

73.2

INCI Water

Manufacturing Instructions 1. Heat Phase A (water) to 75°C. 2. Slowly add Phase B and Phase C with agitation. 3. Combine Phase D and heat to 75°C. 4. Add Phase D to Phase A, B, and C. 5. Cool to 45°C and add Phase E and Phase F. 6. Adjust pH to 3.5 to 3.8 with NaOH sloution. This information is presented in good faith but it is not warranted as to accuracy of results. Also, freedom from patent infringement is not implied. This information is offered solely for your investigation, verification, and consideration.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References

5. Fleche, G., Starch Conversion Technology, Marcel Dekker, Inc., New York (1985)

1. Whistler, R. L., BeMiller, J. N., and Paschall, E. F., STARCH: Chemistry and Technology, 2nd Edition, Academic Press (1984)

6. Grain Processing Corporation Technical Bulletin, PURE-DENT® B836 for Personal Care Applications, Muscatine, IA (2001)

2. Watson S. A., and Ramstad, P. E., Corn: Chemistry and Technology, American Association of Cereal Chemists, Inc., St. Paul, MN (1987)

7. MK Systems, Inc., Literature, Gravimetric Absorbency Testing System, www.mksys tems.com.

3. Urbano, C. C., Cosmetic Bench Reference, Cosmetics & Toiletries, Allured Publishing Corporation, Carol Stream, IL (1996) 4. Wurzburg, O. B., Products of the Corn Refining Industry: Seminar Proceedings, Corn Refiners Association, Inc., Washington, DC (1978)

8. Grain Processing Corporation Technical Bulletin, Zeina™ B860 for Personal Care Applications, Muscatine, IA (2002) 9. Wenninger, J. A., McEwen, G. N., CTFA International Buyers’ Guide 2002, Vol. 2, The Cosmetic, Toiletry, and Fragrance Association, Washington, DC (2002)

36 Thixogel™ Novel Topical Delivery Systems for Hydrophobic Plant Actives John J. Wille Bioderm Technologies, Inc. Trenton, New Jersey

36.1 Introduction ................................................................................... 762 36.1.1 Genesis of Concepts: The “Eureka!” Moment ................. 762 36.1.2 Statement of the Problem ................................................ 763 36.1.3 Thixogel Technology ......................................................... 763 36.2 Thixogel Formulations .................................................................. 763 36.3 Delivery System Technology ........................................................ 764 36.3.1 Essential Elements of Thixogel Delivery System ............ 764 36.3.2 Thixogel Processing ........................................................ 765 36.3.3 Surface Science and Interfacial Principles ...................... 767 36.3.4 Emulsification Studies on Thixogel Formulations ............ 768 36.3.5 Role of Key Ingredients .................................................... 769 36.3.6 Key Formulating Factors.................................................. 771 36.4 Thixogel Applications .................................................................... 773 36.4.1 Current Applications ......................................................... 773 36.4.2 Skin Hydrating Thixogel Formulations .............................. 773 36.4.3 Skin Protecting Thixogel Formulations ............................ 774 36.4.4 Reversible Hydration Effects of Topically Applied Thixogels .......................................................................... 774 36.4.5 Delivery of Oxygen from Thixogel .................................... 775 36.4.6 Antimicrobial Thixogel Formulations ................................ 776 36.4.7 Antioxidant and Antiirritant Hydrophobic Plant Actives ..... 777 36.4.8 Hydro-Alcoholic Extracts of Plants Rich in Flavonoids .... 779 36.4.9 Antioxidant Plant Extracts ................................................ 779

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 761–794 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 36.5 Summary ..................................................................................... 779 36.5.1 Benefits to Formulators and Customers.......................... 780 36.6 Formulations ................................................................................. 780 Acknowledgments ................................................................................... 793 References ......................................................................................... 793

36.1 Introduction 36.1.1 Genesis of Concepts: The “Eureka!” Moment At first glance, starch mixed with oil does not appear to be a very promising mixture for use as an ingredient in cosmetic or personal care products. Therein lies a story of technology transfer from agricultural applications to skin care and topical drug delivery systems. The story starts in 1997 when, as Director of Skin Physiology and Biomaterials Research at ConvaTec (a division of Bristol MyersSquibb Company), the author met two scientists: Dr. Ken Eskin (deceased) and Dr. George Fanta, at the United States Department of Agriculture (USDA). They had invented Fantesk™ technology, a jetcooking process for producing stable dispersions of oil in an aqueous starch matrix.[1]–[7] Such dispersions were produced without the need for an emulsifier. In the Fantesk process, starch molecules migrating from the aqueous phase to the oil-water interface are adsorbed around micron-sized oil droplets thereby encapsulating them. Depending on the starch-to-oil ratio, a wide range of viscosities and oil contents can be prepared. These range from pourable liquids to semisolid gels. Typically, a slurry of cornstarch in water is introduced into the jet cooker and heated under steam pressure in a Venturi chamber. This first pass pre-gelated starch is then reintroduced into the cooker along with hot oil. The hot oil is then agitated with the gelated starch under steam pressures sufficient to create turbulence. This jet cooking action totally solubilizes the cornstarch carbohydrate molecules, which are homogeneously adsorbed onto the dispersed oil droplets. By this means, the carbohydrate-coated oil droplets are prevented from coalescing and remain dispersed in the starch matrix even when cooled to ambient temperatures. Moreover, the solubilized starch is prevented

from undergoing retrograde gelation during the cooling phase, which results in a system that is stable. This technology has many applications. The broad range includes food processing techniques for coating low-fat potato chips and preserving the pleasing lingual texture of fat in ice cream, to industrial uses such as recovery of residual oil from depleted oil wells. Although ConvaTec/Bristol Myers Squibb decided not to proceed with the Fantesk technology for wound care applications, the author retained his interest in it. Upon leaving the company, he joined Hygene Inc. as its President and COO. Hygene Inc. then contacted Drs. Eskins and Fanta, and entered into a Cooperative Research and Development Agreement to study possible medical device applications for their work. In particular, Hygene Inc. was interested in its potential utility as a drug delivery vehicle. This interest and preliminary studies led to the award of a Small Business Innovative Grant by the USDA. As the principal investigator, the author undertook work to further develop the Fantesk technology towards its use as an oxygen gel delivery vehicle for chronic ulcer treatment. Coincident with the work on oxygen gel delivery vehicles, the Fantesk technology was also studied for its potential capability as a topical delivery system for drugs. Skin permeation studies showed that a 1% hydrocortisone starch-oil dispersion vehicle was as effective as the leading over-the-counter hydrocortisone cream.[8] Other work demonstrated its utility as a protective and greaseless skin barrier lotion. Pilot clinical trial testing demonstrated its ability to prevent contact irritation due to 24-hour occlusion with sodium lauryl sulfate.[9] The unique attributes of the Fantesk technology also began to emerge in the form of other applications. These included an antimicrobial hand lotion and a greaseless topical disinfectant lotion. The material was also found to act as a highly effective “glove-within-a-glove” for health care workers. In

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES this application, Fantesk incorporated both a skinderived natural fatty acid and benzalkonium chloride.[10] Finally, considerable efforts were made to develop a cosmetically acceptable moisturizing lotion. This application, however, was replete with technical difficulties. For example, adding xanthan gums and lowering the starch concentration reduced tackiness, but addition of humectants such as glycerol reintroduced high skin tack. Ingredients that plasticize starch for moisture introduce undesirable tackiness of Fantesk starch-oil mixtures. Further, all formulations, with or without thickeners or glycerol, left an undesirable rigid film on the skin. As with the inception of many creative ideas, all of the work described above set the stage for the invention of a new technology based on Fantesk. The deficiencies of this system led to focused efforts on its irresolvable issues. Resolution of these issues was critical in order to develop a cosmetically acceptable moisturizing lotion.

36.1.2

Statement of the Problem

In attempting to overcome the problems with Fantesk starch-oil composites, fundamental changes were made in formulating and processing the starch that led to the Thixogel™ technology described in this chapter. The new approach abandoned the jetcooking process of the Fantesk system, and employed entirely new and novel methods.

36.1.3

Thixogel Technology

Thixogel technology produces useful material with the following features and benefits: • Stable emulsion can be formed without irritating surfactants, alcohol, or fatty acid esters. • Aesthetically, these systems have the greaseless feel of an oil-in-water emulsion. • Ease of spreading on skin. • Rapid drying without undesirable skin tack. • Protective film-forming properties. • Softens dry and rough skin. • Vehicle for hydrophobic drugs/plant actives.

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Thixogel technology employs a low concentration of nonirritating surfactants in order to achieve oil dispersion in an aqueous starch matrix (i.e., a hydrocolloid sol in a surfactant disperse medium). This method is far superior to the prior art, the jet cooking process employed in the Fantesk process. In addition, in the Thixogel technology, silicone oils have been either substituted for, or combined with, mineral oil and petrolatum in order to achieve finer dispersion of oil droplets and reduce the stickiness of the humectant-plasticized starch. Thixogel is formed in a simple two-step process. A cornstarch slurry is prepared in cold water containing a specified low concentration of the surfactant and, if desired for moisturization, a specified amount of glycerol. The mixture is then heated with continuous stirring until all of the starch is dissolved. The clarified starch is removed from the source heat, and allowed to cool to 65°C. The oil phase ingredients are then blended into the aqueous starch phase by low-shear mechanical mixing. The resulting starch-based emulsion has been proven to be superior as a cosmetic vehicle, a skin protectant, and a vehicle for the delivery of hard-to-formulate lipophilic plant actives. It also behaves as a stable lotion and is useful for delivery of novel cosmetic actives that provide anti-irritant and anti-aging activities.

36.2 Thixogel Formulations All Thixogel formulations are oil-in-water emulsions. More than a hundred Thixogel-based formulations have been made and tested to date. The basic ingredients of all Thixogel formulations are water, starch, oil, and an emulsifying agent. To this basic formula one may optionally include a variety of other ingredients. These can include, for example, humectants, one or more silicone oils, organosilicone, active agents such as an antimicrobial, antioxidant plant actives, as well as natural preservatives. The starch component may be comprised of different natural and modified starches. A variety of natural vegetable and synthetic oils can be used, and anionic, cationic, and non-ionic surfactants are all useful in various formulations. A common feature of all the exemplar formulations presented at the end of this chapter (see Sec. 36.5) is the stability of starch-oil dispersions formed by heating and mixing the starch and oil un-

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der controlled temperature and mixing conditions. Thixogel formulations are so-called because they display thixotropic viscosity changes (i.e., they form semisolids upon standing but with moderate mechanical agitation or low shear, they become pourable gels and lotions). A hypothetical multistep process underlying the interaction and “physical state” of starch, endogenous phospholipids, surfactants, and oil during both gel formation and surfactant emulsification is presented below. Gel formation. Thermal dissociation of starch molecules promotes the helix to random coil transition, thereby, exposing polar groups and enhancing polar-polar water solvation, intermolecular hydrogen bonding between starch molecules. This allows extensive hydration by water molecules. Apolar groups remain buried inside the apolar regions of the starch associated phospholipids and proteins. Surfactant-gel interactions. Upon dissociation in water, benzalkonium chloride forms positively charged benzylalkyl ions, and negatively charged chloride ions. The former migrate to the negatively charged colloidal sol particles, conferring on them a positive charge. To counterbalance this, negatively charged chloride ions form a double layer of charges, the so-called Helmholz double layer. An equilibrium is established between starch-ion complexes and yet undissociated surfactant, resulting in a net positively charged solution. Due to the stereochemically unfavorable interactions between water and the hydrocarbon tail of the benzalkonium molecule, micelles are formed with hydrophobic chains of the benzalkonium molecule oriented toward apolar regions in the starch molecule, while the polar and hydrogen bonded groups in starch are oriented towards water. In this way, the total energy of the system is reduced and entropy increased through disordering of the water molecules. The equilibrium so formed stabilizes the surfactant-starch colloidal gel. Emulsification step. Upon addition of oil droplets to the solvated gel, the oil droplets interact at the oil-water interface with the hydrophobic regions of the starch molecules and are stabilized by agglomeration of starch molecules that coalesce around individual oil droplets. At equilibrium, the overall stability of these starch-oil-surfactant complexes is brought about by long-range Van der Waals forces acting between the apolar regions of the starch molecules.

36.3 Delivery System Technology 36.3.1

Essential Elements of Thixogel Delivery System

Most creams and lotions in the cosmetic market are emulsions. They may exist as microemulsions, multiple emulsions, fluorocarbon emulsions, and hydrocolloid gels.[18] Thixogel is a novel oil-in-water type hydrocolloid emulsion comprised of starch, water, oil, and an emulsifying agent. The starch may be a natural starch, or a modified starch. The oil may be a paraffin oil, mineral oil, or polydimethylsilicone oil. The oil may be a perfluorodecalin, a vegetable oil, and can be various combinations of these oils. The emulsifying agent may be an anionic, cationic, or non-ionic surfactant. Thixogel hydrocolloid emulsions are highly stable for at least three years at room temperature. The viscosity of such systems is a function of the starchto-oil ratio. Low viscosity fluids are usually formed when the starch concentration is below 1 wt%. Gels are seen at concentrations of starch in the range of 1 wt% to 4 wt%, and at oil concentrations below 10 wt%. Starch-oil dispersions are achieved by processing at temperatures above 75°C. Dispersions are stabilized by high-speed mechanical blending, in the presence of low surfactant levels. Scanning electron microscope pictures of Thixogel systems reveal the presence of oil droplets within a starch matrix with an average size distribution clustered around 0.5–2.5 microns. Previous studies have shown that oil droplets in Thixogel systems are coated with a polysaccharide shell. This shell prevents coalescence of the oil droplets and insures emulsion stability by means of two mechanisms. The first is the tendency of high molecular weight polysaccharide (i.e., starch) to precipitate due to their low water solubility, because it reduces surface tension at the oil-water interface; the second is the favorable increase in entropy and energy reduction of the reoriented molecules at the water-oil interface. Thixogels are soluble in the hydrocarbon oil-phase layer that develops on the surface of the skin when mechanical breakdown of the polysaccharide shell surrounding the oil droplets produces oil droplets that coalesce and rapidly form a continuous oil film.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES

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Thixogel is considered to be a poor delivery vehicle for hydrophilic cosmetic actives. However, Thixogel formulations may be readily incorporated into the bulk water phase of formulation and actives contained in them released on the skin surface at a constant rate and according to zero-order kinetics. Because they are water soluble, the actives are generally not able to penetrate the stratum corneum by means of passive diffusion.

Batch performance quality control is typically characterized by viscosity measurements made with a Brookfield Thermosel instrument. Thixogel formulations made with DRY-FLO/AF® starch (4 wt%), mineral oil (8 wt%), and benzalkonium chloride (1 wt%) generally have a viscosity of 13, 200 ± 100 cP at 20°C and 2.5 rpm using a #27 SPDL spindle. Under the same test conditions, a Thixogel formulation with 3.3 wt% DRY-FLO/AC® starch, 10 wt% petrolatum, and 0.5 wt% benzalkonium chloride had a viscosity of 8,500 ± 100 cP.

36.3.2 Thixogel Processing

Effect of surfactants on Thixogel emulsion stability. Stable Thixogel emulsions can also be formed by heating ungelated starch solids in the presence of sodium lauryl sulfate (0.5 wt%) or Triton X100 (0.1 wt%) at starch:oil ratios of 1:1, 1:2, 1:3, and 3:1. The gelatinized starch in the presence of an aqueous surfactant solution is then blended with paraffin oil using either natural starches, (e.g., pure foodgrade powders, waxy starch, or modified starches, such as StaMist-365, Solance and DRY-FLO/AF). Stable gel emulsions can also be formed as described above by heating the starch above 75oC and blending in mineral oil at starch:oil ratios of 1:1 and 1:2. This can be accomplished using either pure foodgrade powders or waxy maize-type starch. Finally, stable gel emulsions can be formed by heating the starch above 75°C in the presence of benzalkonium chloride (1 wt%) at a starch:oil ratio of 1:1 (using either pure food-grade powders or a hydrophobic starch e.g., StaMist-365). In special cases, lecithin can be substituted for benzalkonium chloride at a starch:petrolatum ratio of 1:2. It is unlikely that the gelatinized starch and surfactants interact directly but rather interact through micelle formation between starch-associated phospholipids and proteins and the oil ingredients.

The first step during manufacturing of a Thixogel formulation is to gelatinize the starch component in water. Starch is first mixed with cold water in order to form a slurry. The slurry is then heated in the presence of the chosen surfactant, benzalkonium chloride, to near the boiling point of the solution. Clarification occurs within minutes, and the clarified aqueous starch solution is then cooled to 65°C. Polydimethylsiloxane and other oil phase ingredients are, thereafter, blended into the starch solution with continuous stirring. The agitation is continued until all of the oil phase ingredients are thoroughly dispersed into the starch matrix. This step is accompanied by the development of an opalescent-to-opaque white color. The mixture is thereafter allowed to slow-cool under constant stirring conditions, and poured into suitable containers for later skin testing and product application. Effect of temperature and mixing on Thixogel formulations. Good control of both temperature and mixing conditions are essential for reproducible production and consistent Thixogel formulation. Uniformity and gel consistency are compromised when these conditions are not met. Effect of starch concentration on formulation viscosity. As noted above, changes in starch concentration directly affect the viscosity of the formulation. Low starch concentrations fail to produce a stable emulsion, while concentrations above 4 wt% result in ultraviscous unusable gels. Within the optimal range of usable starch concentrations, the concentration of oil phase ingredients also affect rheological properties. Oil concentrations below 1 wt% produce watery emulsions with an oily skin feel. High oil concentrations above 12 wt% are less stable, and require increased levels of emulsifier with undesirable skin-associated reactions such as skin irritation.

Effect of silicone oils on starch gel properties. Polydimethylsiloxane fluids (viscosity range 10,000 to 60,000 cP) can be substituted for petrolatum at starch:oil ratios of 1:1 and 1:2 in the presence of benzalkonium chloride (1 wt%). The addition of organosiloxane oils to Thixogel formulations provides a smoother texture, water-resistance, and aids in the reduction of the undesirable tackiness imparted by starch as an emulsion thickener. Oxygen-carrying oils: perfluorocarbons. In other Thixogel formulations where oxygen-carrying oil was required, perfluorodecalin was substituted

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for petrolatum at a 1:2 starch:oil ratio in the presence of 1.6 wt% benzalkonium chloride. This and all of the other above formulations are generally useful as skin protectant gels. They may be made into moisturizing gels by simply incorporating 10% to 20% glycerol in the aqueous phase ingredients prior to heating and blending with the oils. Using hydrophobic plant-derived actives. The basic Thixogel starch:oil-in-water hydrocolloid emulsions provide ease of spreading on skin, and long-lasting skin protection against waterborne chemicals and skin irritants. More sophisticated formulations are required for the delivery of hydrophobic plant actives in view of their potential benefits as biochemical modulators of skin reactions. In such cases, the active must first be incorporated into the oil phase without traces of organic solvents in order for the final gel to be cosmetically acceptable. The residual organic solvent issue has been solved by first dissolving the hydrophobic plant active into mineral oil. The delivery of hydrophobic plant-derived active agents, incorporated into Thixogel is enhanced by the fact that not all of the oil is encapsulated in the polysaccharide shell. Excess oil is thus available to carry hydrophobic active in the disperse phase. These solutes are able to penetrate into the stratum corneum intercellular lipid upon application of the hydrocolloid gel emulsion on skin. Regarding the use of hydrophobic plant ingredients, for example, carrot extracts enriched in carotenes are totally insoluble in water. Likewise, tomato paste-derived lycopenes are also completely insoluble in an aqueous phase. To obtain such materials as active ingredients, they first must be extracted into an organic solvent such as hexane, and thereafter dried to a powder. The powder may then be solubilized in mineral oil. This technique is highly useful because it allows the formulation of such materials directly into the oil phase ingredients of Thixogel. In addition, dimethicone (DC-200 Fluid) and decamethyl cyclosiloxane (DC-245 Fluid) can be added to the oil phase ingredients in order to obtain a smoother skin feel. In the formulations found at the end of this chapter (Sec. 36.5), Thixogels have been employed to deliver other hydrophobic plant-derived actives including retinoids and flavonoids. General considerations. Thixogel personal care delivery systems can be designed to alter the delivery of active components and control the re-

lease rate from the vehicle by interacting with the active agent. Such systems may also incorporate permeation enhancers. These enhancers are capable of altering the flux of the active ingredients as it penetrates the stratum corneum. In fact, in some cases, there is actually an enhancement of the hydration of the stratum corneum as a result of this alteration in flux. For example, oleic acid has been combined with palmitoleic acid alone, or in combination with ethanol and employed as vehicle components that can alter the rate of movement of active agents (e.g., hydrocortisone) through the stratum corneum (Wille, unpublished). The Food and Drug Administration (FDA) clearly differentiates between cosmetics and drugs. Drugs require FDA approval and regulation to certify claims and indications for a drug. By contrast, cosmetics are legally restricted to claims that affect the beauty and appearance of skin without altering skin structure. Recently, consumers have become more sophisticated in choosing cosmetic products in the hope of slowing the effects of skin aging and degree of facial wrinkling. Cosmetic companies have sought to provide the consumers with a sound scientific rationale and clinical research to underpin their product’s superiority in affecting the skin appearance. Among the active agents approved for topical use by the FDA are vitamins A, E, and K (i.e., fatsoluble vitamins), alpha-hydroxy acids (AHAs, e.g., glycolic acid and lactic acid at or below 5%); antiwrinkling and skin exfoliants; and retinoids (i.e., vitamin A derivatives like retinoic acid, 0.01% creams, for example, Retin A). The use of active agents has been a prime source of confusion since such materials are legally neither drugs nor cosmetics. Such materials were first termed cosmeceuticals by the dermatologist, Albert Kligman, M.D. Other such controversial active compounds include glucans, enzymes, and antioxidants. By and large, the cosmeceuticals now being marketed in the U.S. have been “grandfathered in” by the Cosmetic Fragrance and Toiletries regulatory approval process. A general review of cosmeceuticals suitable for cosmetic products is available.[18]–[21] In view of consumer demands and market pull, the cosmetic industry has come to believe that conventional cosmetic formulations are technically insufficient to deliver active agents, and novel

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES high-technology solutions are required in order to protect the efficacy of sensitive actives, as well as their shelf-life. This trend has led to an explosion in the cosmetic-related patent literature of more than four hundred issued patents per year over the last decade. The majority of these patents are concerned with novel and innovative cosmetic delivery systems. Although the majority of cosmetic products today are based on oil-in-water or water-in-oil emulsions, much effort has been expended improving the “feel” of such formulations through changes in rheological properties. This has primarily been accomplished by attempting to eliminate an undesirable “oily feel” by compositional changes, or by optimizing pH and surfactant emulsifier systems in order to reduce skin irritation. Reduction is skin irritation has been obtained by using milder emulsifying surfactants and emulsion-stabilizing chemicals. This trend has been well underway for many years, and some systems have been developed without surfactants at all. While it is highly probable that some ideal cosmetic delivery system could be formulated to accomplish all of the desirable phenomena described, such systems might still be unsatisfactory because many cosmeceutical agents are themselves skin irritants. This is especially true when they are used at or near concentrations required to deliver true activity. This is particularly important today when consumers are demanding products that really do work and go beyond claims without substance. It is for this reason those new natural compounds and botanical agents have been vigorously sought after. These plant-derived anti-irritants can be added to personal care formulations in order to reduce the skin irritation caused by other, more common, actives such as AHAs and retinoids.[12] Similar approaches to reducing irritation include the use of bisabolol, a known natural anti-irritant[13][15]–[17] and attempts to normalize irritated skin function with artificial mixtures of skin lipids.[14]

36.3.3 Surface Science and Interfacial Principles In order to determine what surface and interfacial science principles are involved in the Thixogel delivery system, many studies have been carried out to uncover the role of various emulsifiers in producing the stable hydrocolloid gel emulsions. While it is

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known that starch powders can, themselves, absorb oil; the amount of oil absorbed by natural starch powders is very limited, indeed. By contrast, hydrophobically modified starches such as DRY-FLO/ AC® can readily be dispersed in an oil phase. However, these starch granules remain in the oil phase when mixed with water unless an emulsifying agent is present. It is, of course, known that oil and water do not mix unless the interfacial tension between them is minimized. The required work of dispersion for an oil to be comminuted into fine droplets required to form an oil-in-water emulsion is minimized by reducing interfacial tension between the oil and water. Macromolecular polymers such as proteins (e.g., gelatin solution) are known to reduce the surface tension of water. Molecules like phospholipids will also reduce the overall interfacial tension at the oil and water interface. It is proposed that phospholipids adsorbs at the interface between the oil and the water and thereby cause a decrease in stereochemical ordering of water molecules at the oilwater interface. The presence of the phospholipids provides an opportunity for polar-polar interactions between the polar groups of water and the polar head group of the phospholipid. By this means, the reduction in the number of degrees of freedom of the polar substituents causes the overall energy of the system to be reduced. As a consequence of this interfacial tension is reduced. By the same token, emulsification of oils is aided by the apolar (i.e., lipophilic) side chain interactions of the phospholipid. These side chains interact with the apolar groups present at the surface of the oil phase, thereby reducing the number of degrees of freedom of the oil molecules. The result of this reduction is a decrease in entropic contribution of the phospholipids, and the creation of a more ordered system. One consequence of this decrease in entropy is seen in selfassembling phenomenon in lipid bilayers and micelles. This is not a violation of the second law of thermodynamics as energy is fed into the system by the input of mass in the form of phospholipid molecules.[62] It is particularly relevant to note here that natural starches contain up to a few percent of natural phospholipids. This fact may help to explain the oilbinding properties of natural starches.[5] In the case of Thixogel, preparation of the hydrocolloid gel emulsion is accomplished by addition of surfactants and providing sufficient mechanical

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mixing such that an increase in surface area occurs through oil droplet size reduction. Stabilization of these emulsions is accomplished by interaction of starch molecules with the oil droplets. It is thought that this occurs as a result of the phospholipid contained in semi-purified natural starches and that these phospholipids act as “emulsifiers.” Deposition of starch molecules at the oil interface occurs because the large starch molecules (>106 Daltons) are less soluble in the water phase and, by interacting with oil molecules reduce the overall interfacial energy of the system.

36.3.4 Emulsification Studies on Thixogel Formulations Table 36.1 presents a summary of results evaluating the ability of various surfactants, fatty acids, and oils to form stable Thixogel-type emulsions. The test results indicate that benzalkonium chloride alone, at concentrations below 1 wt% is ineffective unless combined with oleic acid at a concentration of 0.5 wt% or higher. The combination of benzalkonium chloride and DRY-FLO (20 wt%) is capable of forming a stable emulsion of soybean oil and water, even at 0.1 wt% of benzalkonium chloride. Lastly, the combination of oleic acid (1 wt%) and citricidal (0.5 wt%) was found to be effective in producing a stable oil-in-water emulsion.

By contrast, oleic acid, by itself, was found to be ineffective at stabilizing such emulsions. In another series of investigations, the ability of several formulations to act as emulsifiers, themselves, were examined. In this assay, 0.2 ml of each formulation was added directly to a test tube containing 2.0 ml of soy bean oil carefully layered on top of 2.0 ml of water. The mixture was then shaken in order to thoroughly mix the two phases. A control containing just the two phases was used as a reference for measuring the extent of emulsification and the resulting emulsion stability. The addition of 0.2 ml of a Thixogel formulation containing starch (DRY-FLO/ AC®) and mineral oil in a 1:2 ratio, in the presence of benzalkonium chloride, led to the appearance of an interface after 60 minutes. A transfer of 20 wt% of the water phase into the oil phase was accomplished with this approach. Thereby demonstrating the ability of Thixogel to act as an emulsifier. In a second formulation, starch (DRY-FLO/AC®) and petrolatum (in a 1:2 starch:oil ratio), in the presence of 0.1 wt% of benzalkonium chloride and 0.5 wt% palmitoleic acid, generated only a 10% shift of water into the oil phase. Finally, a similar formulation containing 4 wt% of dimethicone produced a 5% transport of oil across the oil/water interface and into the water phase. These results suggest that emulsification can be brought about by both movement of oil into the water phase and by movement of water into the oil phase of such systems.

Table 36.1. Combinations of DRY-FLO Starch, Oils, and Surfactant that Emulsify a Two-phase Oil and Water Mixture

Benzalkonium Chloride (wt%)

Oleic Acid (wt%)

Citricidal (wt%)

20% DRY-FLO

1.0

0

0

None

1.0

0

0

Added

0.5

1.0

0.5

None

0.5

5.0

5.0

None

0.1

0.5

0

Added

0.1

0

0

Added

0.0

1.0

0.5

None

Note: The assay system consisted of 2.0 ml of soybean oil layered on top of 2.0 ml of water in a test tube. Each of the combinations above in each row was added at zero time and test tubes shaken to thoroughly mix the phases. The test was considered positive for emulsification if there was incomplete separation of phases at 60 minutes.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES 36.3.5 Role of Key Ingredients Starch as a cosmetic and personal care ingredient. Natural starches are high molecular weight (> 1–2 × 106 Daltons) polysaccharide polymers. Pure food-grade starch is composed of 70% amylose and 30% amylopectin. A natural corn mutant variety produces an amylose-free starch known as Waxy cornstarch. In general, natural starches are not soluble in cold water and must be heated above 70°C in order to make them dissolve completely. Upon cooling, natural starches at concentrations above 2 wt% of solids form semi-translucent rigid gels. These are referred to as pre-gelatinized starch. Gel formation in natural cornstarch is due to the rapid re-association, upon cooling, of intra- and intermolecular hydrogen bonds between different polymer side chains. Once starches are subjected to a heating and cooling cycle in water, and gel formation begins, they are too rigid and sticky to be used directly on skin. For this reason, such starches are to be considered poor candidates as bulk carriers for personal care actives. Natural starches are known to have a limited capacity to bind oils.[6]-[7] As such, they have been limited to use as thickeners and emulsifiers in the food industry. Finely milled starches adhere well to skin and, like talc, possess a slippery skin feel. Indeed, starches have a long and venerable place in the personal care market as a basic ingredient of dusting powders for babies. Modified starches have also been used as aqueous rheology modifiers and as bulk carriers in protective skin care lotions such as Vaseline® Constant Care. As a result of their undesirable gel and film-forming properties, natural starches have generally been passed over as cosmetic ingredients in favor of modified starches. Two commercially available chemically modified starches are Structure® Solance and DRY-FLO/AC®. The former is a hydrophobized potato starch achieved by chemical addition of 2-N, N- bis (2-carboxyethylamino) ethyl ether, while the latter is a calcium salt of an amylopectin starch carrying hydrophobic dodecenylbutanedioate pendant groups. One advantage of DRY-FLO/AF® for personal care applications, is it can be formulated into oil-in-water emulsions without heating. Yet another hydrophobically modified starch used in Thixogel formulations is StaMist-365™, and this has been broadly used in Thixogel formulations.

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Starch is a common excipient in solid tablet dosage forms for many drugs in the pharmaceutical industry. Recently, starch has been used to encapsulate drugs for enteric delivery and as a means of increasing the clearance time of the drug in the digestive tract.[20]–[22] There is also recent interest in the possibility of employing starch coatings for delivery of drug-containing liposomes. Natural cornstarch has been chosen as a key ingredient of Thixogel formulations: • It is a natural ”Generally Recognized As Safe” (GRAS ) plant polymer. • It is an inexpensive ingredient (bulk price <10 cents/pound). • It is a good aqueous phase thickener with thixotropic and viscoelastic rheological properties. • It binds oil. • It forms a transparent “leave behind” protective film on skin. It also provides a greaseless, smooth feeling lotion/gel when formulated into oil-in-water emulsions. Such formulations can be made over a wide range of starch: oil ratios. • It forms a stable hydrocolloid gel emulsion with a wide variety of natural and synthetic oils and combinations of different starches and oils. Such systems may be widely useful for many cosmetic and drug delivery applications. Choice of oils in Thixogel formulations. The choice of oil to form hydrocolloid gel emulsions with starch presents no serious limitation. Saturated hydrocarbons such as mineral oil and petrolatum jelly, which are standard ingredients for formulating emulsions in the cosmetic industry, readily form stable Thixogel emulsions in the presence of low levels of emulsifying agents. Indeed, natural fatty acids have been substituted for common oils as the “oil phase:” examples include oleic acid, a major constituent of soybean oil; and linoleic acid, a constituent of olive oils. Another natural oil that forms Thixogel emulsions and has unique benefits for skin is meadowfoam oil. This oil has a virtually pure C22- chain length hydrocarbon compound. Finally, starch thickened oil-in-water emulsions have been prepared using Triacetin®, a natural triacetate glyceride. Triacetin forms a stable emulsion in the presence of benza-

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lkonium chloride (1 wt%) or sodium lauryl sulfate (0.5 wt%), but not with Triton X-100 (0.1 wt%). Of critical importance to applications in the personal care industry is the fact that Thixogel emulsions can be formulated with silicone oils, including a high viscosity dimethicone (60,000 cP), less viscous poly(dimethyl)siloxanes (200® Fluid), and volatile dimethylpentanecyclosiloxanes (245® Fluid). These silicone oils reduce stickiness, improve spreading, lubricate surfaces, and improve the gloss of skin care formulations. [48] Their incorporation into Thixogel formulations provide an elegant skin feel when formulated in combination with starch, petrolatum jelly, and mineral oil. Moreover, silicone oils are accepted by the CTFA as waterproofing ingredients as well as for establishing skin protection claims. Silicone oils are generally permeable to small molecules such as oxygen and water vapor.[48] This deficiency is remedied in Thixogel formulations containing silicones by the addition of starch. Upon drying, the starch forms films on skin that are impermeable to oxygen, and by the addition of mineral oil and petrolatum, they are made impermeable to water vapors. Effect on delivery of hydrophobic plant-derived actives. The development of a topical delivery system for plant-derived actives was greatly aided by modification of the Thixogel starch:oil hydrocolloid gel emulsions. Studies have shown that hydrophobic plant-derived actives can be formulated into the mineral oil phase of Thixogel emulsions. Among the hydrophobic plant actives so formulated are antioxidants such as flavonoids, beta-carotene, and lycopenes. Other active agents include retinoids (e.g., retinyl palmitate); vitamins A, E, and K; plant sterols; and a variety of medicinal and herbal oils (such as sea buckthorn oil). Emulsifier role in Thixogel emulsion formation. As noted previously, natural starches are not composed entirely of pure polysaccharide polymers; small amount of proteins and polysaccharides are present as well. These materials are interfacially active, but they are not present in sufficient quantities to provide commercially stable emulsions. Since starch, by itself, is a poor emulsifying agent for oilin-water emulsions, emulsifiers must generally be added to form a stable oil-in-water emulsion embedded in gelated starch.

We have chosen to prepare starch-in-oil dispersions by formulating the starch ingredient into an aqueous surfactant solution. As mentioned earlier (Sec 36.3.2), useful surfactants include all three classes: anionic, cationic, and non-ionic; these are typically present at concentrations below 1 wt%. Most Thixogel formulations employ the cationic emulsifier, benzalkonium chloride. In principle, the anionic surfactant (sodium lauryl sulfate) and the non-ionic surfactant (Triton X-100) are useful in forming Thixogel emulsions, but the former is a well-known skin irritant, and the latter is not a very effective antimicrobial agent and did not work when formulated with one of the oils. A potential, but surmountable difficulty in using benzalkonium chloride in Thixogel formulations is its ability to form ion pairs with fatty acid compounds. Such ion pairs do form if the benzalkonium chloride and fatty acids are heated together during processing. However, the ion-pair formation may be prevented. This can be accomplished by adding the fatty acid during the cooling phase after emulsification has occurred, or by holding the pH at or above pH 6 during processing. Lecithin, a natural phospholipid, is also a good emulsifier for Thixogel systems. It can be formulated as a 5 wt% ethanol solution with pure foodgrade cornstarch and forms a stable hydrocolloid gel emulsion with petrolatum at a starch:oil ratio of 1:2. Humectants employed in Thixogel formulations. A common issue with any starch-based lotion is its drying effect on skin. This drying effect can be overcome by the addition of a moisturizing agent or humectant. One such widely accepted cosmetic humectant is the simple sugar, glycerol.[35] As a poly (alcohol), glycerol has a strong affinity for water and is well tolerated on skin even at high concentrations. Other sugars such as Trehalose, as well as sugar esters, have also been used as cosmetic humectants. They have enjoyed recent popularity, but they are less effective than glycerol. Natural moisturizing factor (NMF) (e.g., pyroglutamic acid) may also be employed as a humectant either alone or in combination with glycerol. Since NMF is typically high in cost, it can add considerably to the price of the finished product. Preservatives employed in Thixogel formulations. Starch is subject to both bacterial and

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES fungal degradation. Unpreserved starch in Thixogel emulsions is primarily subject to contamination by molds. Several effective, all-purpose, natural preservatives are tea tree oil and citricidal. Tea tree oil has recently been shown to be an effective antimicrobial agent for dermatological and veterinary applications.[47] This natural preservative is readily incorporated into the oil phase ingredients of Thixogel formulations. Likewise, citricidal, an oil from grapefruit seeds is a very effective antimycotic agent. Citricidal appears to be superior to tea tree oil as a long lasting preservative, because it is less volatile and less aromatic than tea tree oil. Aside from its primary use as an emulsifier in Thixogel, the use of low levels of benzalkonium chloride serves the dual purpose of inhibiting the growth of both bacteria and yeast. Thixogel starch formulations containing both benzalkonium chloride (0.5 wt%) and citricidal (0.5 wt%) have been shown to remain uncontaminated for several years. Plant-derived actives employed in Thixogel formulations. The uses of natural ingredients,[36] botanicals,[37] medicinal herbs,[38] and plant oils have all drawn significant attention from formulators in the cosmetic industry. In particular, vitamin E is present in many skin care products and serves as a fat-soluble antioxidant, (e.g., Lubriderm, advanced therapy lotion), and as a possible anti-aging agent. Ascobic acid (vitamin C), which is derived from citrus fruits, is also included frequently in skin care formulations. However, this water-soluble vitamin is very unstable in aqueous solutions. To overcome this deficiency, vitamin C is often paired with another redox partner such as the tocopherols (vitamin E) in order to slow its oxidation. The instability of vitamin C has also been improved by its use in the form of a fatty acid ester such as ascorbyl palmitate. Ascorbyl palmitate has been chosen for use in Thixogel formulations, and is typically incorporated into the mineral oil phase. Preliminary in silico experiments showed that it could be slowly released from the starch-oil emulsion matrix and act as an antioxidant.[32] The principal plant actives under development in Thixogel formulations are hydrophobic plant actives derived from carrot extracts (carotenes) and tomato paste (lycopenes). Both actives are known anti-cancer agents and regulators of epithelial homeostasis. Their role in epidermopoeisis and skin care is still under investigation. For both materials, ex-

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tracts have been prepared and enriched by sequential extraction with ethyl alcohol and organic solvents. These extracts are then dried to a powder form and solubilized in mineral oil. A clear necessity for the preparation of such formulations is to prevent the photo-bleaching effect that occurs in mineral oil solutions exposed to visible light and oxygen. This may be accomplished by addition of mineral oil solutions of vitamin E (0.1 wt%). Figure 36.1 presents results of studies showing the photo-protective effect of vitamin E on photo-bleaching properties of lycopenes. Similar encouraging results have also been obtained with the addition of vitamin E to prevent the photobleaching of carotenes derived from carrot extracts. Corn tassel extract: another Eureka! moment. Perhaps, the most interesting plant active formulated in Thixogel delivery systems is an extract of corn tassels.[60] The story behind this ingredient began several years ago, when the author was driving to work along a country road on a warm August day. The car window was down, and, at a particular spot along the road, there came a strong aroma, slightly reminiscent of the pungent odor from blossoms of the Mimosa tree. Later, the author was able to determine that the smell came from the cornfield, and, in particular, from the corn tassels. Sometime later, some corn tassels were removed and extracted with methanol. The aromatic material was identified by HPLC (high pressure liquid chromatography) methods a esnd seen to be largely comprised of esters of phenoxyacetic acid. Characterization of the corn tassel extracts is underway, and as yet unpublished. The presence of these esters was quite intriguing, in view of previous studies by the author, which had shown that phenoxyacetic acid derivatives were potent anti-irritants.[33] For commercial purposes, the corn tassel active material was named Tasselin. Hydro-alcoholic extracts of Tasselin can be concentrated to an oil by rotary evaporation followed by dissolution in mineral oil. This mineral oil solution of Tasselin can then be later added to the oil phase ingredients of Thixogel delivery system formulations.

36.3.6 Key Formulating Factors Choice of starch. Unlike modified starches, natural cornstarch, including waxy cornstarch, are

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Absorbance at 470 nm (OD)

0.6 0.5 0.4 LL +VitE 35°C

0.3 0.2 0.1 0 0

1

2

3

4

5

6

7

Time (days)

(a)

Absorbance at 470nm (OD)

0.6 0.5

LL, unsealed 35°C

0.4 0.3 0.2 0.1 0 0

1

2

3

4

5

6

Time (days)

(b)

Figure 36.1 (a) Effect of vitamin E on photo-bleaching of Lycopene dissolved in mineral oil, and (b) photobleaching of AO Lycopene-2 in mineral oil.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES preferred for Thixogel. They form high yield stress gels and are better thickeners than modified starches because of their higher molecular weight. These polysaccharides will encapsulate dispersed oil droplets more readily than low molecular weight, degraded starch molecules. By boiling natural cornstarch in 1N sodium hydroxide to hydrolyze it, followed by recovering the treated starch, it has been demonstrated that the starch had lost its ability to form a hydrocolloid gel emulsion (with oil) even in the presence of an emulsifier. Choice of oil. The choice of an oil, or combination of oils, in the Thixogel formulations is solely determined by the application. Petrolatum is a good skin protectant and provides some moisturization relative to mineral oil and other vegetable oils. Likewise, the use of viscous silicone oils can enhance the skin protectant action of Thixogel formulations when combined with petrolatum. Less viscous lotions and gels can also be formed by using liquid oils such as mineral oil and vegetable oils. Soybean oil, for example, provides oleic acid, which is known to enhance skin permeation of hydrophilic drugs. The mechanism for this enhancement is believed to be fluidization of the lipid bilayer associated with the intercellular epidermal lipids in the stratum corneum. Another useful oil in Thixogel formulations is linoleic acid. This material is present in linseed and cottonseed oils. Yet, another useful oil is olive oil, which contains omega-3 fatty acids. These fatty acids are known to have antibacterial and can help repair the damaged lipid skin barrier perturbed by dietary insufficiency of essential fatty acids (i.e., linoleic acid). Artificial sebum, a mixture of ceramides, fatty acids, triglycerides, cholesterol, cholesterol esters, and squalene may also be substituted for the oil phase ingredients in Thixogel formulations. Palmitoleic acid is the most active antimicrobial monooxygenated fatty acid present in sebum.[34] This fatty acid has been used in Thixogel formulations in order to design a greaseless, spreadable antibacterial hand gel. Choice of emulsifying agent and effect on skin irritation. As described previously (Sec. 36.5.2), the cationic surfactant, benzalkonium chloride, was chosen for most Thixogel applications and formulations. It is approved for use as a preservative for certain external personal care applications.[59] Starch-in-oil type Thixogel formulations containing 0.5 wt% benzalkonium chloride have been

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found to be only marginally irritating in a standard ocular irritancy test. No skin irritation was observed when applied as a single dose application to human skin in a panel of human volunteers.[51] Effect of emulsifier combinations. In an attempt to lower the concentration of benzalkonium chloride below 0.5 wt%, pairs of emulsifiers have been substituted. One pair consisted of 0.5 wt% oleic acid combined with 0.1 wt% benzalkonium chloride. Another emulsifier pair examined was palmitoleic acid (0.5 wt%) and benzalkonium chloride. To a limited extent, addition of 0.5 wt% citricidal in combination with benzalkonium chloride can also lower the overall concentration of required emulsifiers. Ionpair formation was avoided during processing of such combinations by maintaining the pH above 6.

36.4 Thixogel Applications 36.4.1

Current Applications

The model formulations provided at the end of this chapter (see Sec. 36.5) cover a range of personal care applications. Since the time of this writing none of these models have been commercialized, and a partner in the personal care and cosmetic industry is being sought to either manufacture, and/or market them. The basic technology is covered by a pending patent application.

36.4.2 Skin Hydrating Thixogel Formulations Four of the formulations (Formulations 36.1 through 36.4) are basic skin barrier gels and lotions, having skin protection and/or skin moisturization as their main attributes. These model formulations have been evaluated by a variety of tests including skin hydration using a skin capacitance-measuring device, the Corneometer (Model CM 825, Courage & Khazaka, Koln, Germany). Figure 36.2 shows that Formulation 36.1 has virtually no effect on skin hydration, while Formulation 36.2 significantly elevates skin moisture to levels 50% greater than that seen in normally hydrated skin. The elevated skin moisture obtained persisted for at least

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

one hour after application of this formulation at 26°C and a relative humidity of 28%. Similarly, Formulation 36.5, with 10% glycerol, provides significant elevation of skin moisturization.

36.4.3

Skin Protecting Thixogel Formulations

The skin-protecting effect of Formulation 36.1 was demonstrated by the crystal violet stain test as described below. Several 2.5 cm2 circles were drawn on the volar arm surface of a human subject. The encircled areas were then coated with test material [A, Vaseline; B, Formulation 36.1 (Tx-1D), or C, no coating material (unprotected control)]. Discs of filter paper were then dipped into a 0.2 wt% crystal violet stain solution, drained of excess dye, and applied to the treated areas for five minutes. The discs were then removed and the excess dye washed off by several water rinses. The resulting stained skin areas were then photographed. A typical result is shown in Fig. 36.3. Clearly, both Vaseline and DermSeal (Formulation 36.1) were effective at enhancing skin protection. The skin-protecting effect of Formulation 36.1 was also demonstrated by conducting a modification of the aluminum foil deterioration test.[61] In this assay, pieces of aluminum foil are first coated with 50 microliters of the test gel and then air dried for 10 minutes. The coated foil area is then exposed to 100 microliters of 3N HCl acid for 30 minutes. The results of one such test is presented in Fig. 36.4. Both the control (A) piece of foil and the foil coated with petrolatum developed holes. By contrast, two Thixogel systems, Formulations 36.1 and 36.5, did not develop any holes (see Sec. 36.5 for ingredients).

36.4.4

Figure 36.2 effect of three Thixogel-type formulations: DermSeal (Formulation 36.1), EktaSeal (Formulation 36.2), and UltraDerm (Formulation 36.5) on elevation of skin hydration.

Figure 36.3 Protective effect of applying Vaseline (A), Thixogel Formulation 36.1 (B), or no lotion (C), on volar arm skin, stained after these applications with a solution of crystal violet stain and washed with water to remove excess stain.

Reversible Hydration Effects of Topically Applied Thixogels

A remarkable property of Thixogel formulations is their ability to be air-dried and then to rehydrate back to their original volume, upon addition of water. In this respect, Thixogel conforms to the definition of an elastic gel. This is seen for a sample of Formulation 36.5 (see end of chapter for ingredients) as shown in Fig. 36.5.

Figure 36.4 Protective effect afforded by application to aluminum foil of Thixogel Formulation 36.1 against the corrosive effect of 3N hydrochloric acid.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES

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of formulators for cosmetic, skin care, and woundhealing applications. It is known that starch (amylose) films are virtually impermeable to oxygen and air.[11] (See Formulation 36.6) We speculated that starch-coated oil droplets might bind and then slowly release dissolved oxygen. However, preliminary studies showed that starch-coated oil droplets do not significantly bind oxygen. An alternative approach is to incorporate an oxygen-carrying molecule into the dispersed phase of Thixogels (i.e., oil). Oxygen may be incorporated in such systems by using perfluorodecalin as the oil. This material is widely used to bind oxygen and is employed as a blood substitute. Its incorporation into emulsions has been described in a number of patents.[52]–[58]

Figure 36.5 Effect of air-drying and rehydration with water on the reversible uptake of water and gel consistency of Thixogel Formulation 36.5.

This hydration phenomenon occurs when the gel is applied to normally hydrated skin. After drying, it can then be rehydrated with water. This process can be repeated through many cycles of drying and rehydration. Moreover, upon drying on the hands, the Thixogel formulations may even be rinsed in 95% ethanol and air-dried without preventing rehydration upon subsequent exposure to water. This unique property of Thixogels has been termed a “glove-ina-glove.” It may have wide-ranging benefits for healthcare workers who get dry irritated skin because they repeatedly wash their hands multiple times a day often employing intervening alcohol washes.

36.4.5

Delivery of Oxygen from Thixogel

A topical gel conveying oxygen to the skin via a controlled release delivery system is one of the goals

Dissolved oxygen was incorporated into Thixogel Formulation 36.6 (OxyDerm) by replacing all other oil phase ingredients with 10 wt% perfluorodecalin (PFC). In order to achieve this effect, various aqueous solutions were first oxygen charged. These were composed of just one added component of OxyTega gel, or OxyTega gel, itself. Oxygen was then bubbled directly into the solution for five minutes at 20 psi in an open-air container. The oxygenated solutions obtained were then continuously stirred at 25°C, at moderate rpm and dissolved oxygen was continuously monitored with an oxygen electrode connected to an oxygen meter. The results are summarized in Fig. 36.6. The kinetic release curves for all Thixogel components, with or without perfluorodecalin share a similar oxygen release rate and have an approximate half-life of 15 minutes. By contrast, OxyTegabased systems (Formulation 36.6) retained the dissolved oxygen for a period of 30 minutes. There is, in fact, a trend toward increased duration of release of oxygen beyond the 30-minute period. Similar tests conducted on Thixogel emulsions employing mineral oil and 1 wt% benzalkonium chloride show a half-life of approximately 90 minutes. The most favorable starch:mineral oil ratio for achieving slow oxygen release occurred at a 1:3 ratio. Although, still somewhat speculative, it is proposed that once oxygen is released onto the skin, following the breakdown of the carbohydrate shells encapsulating the oil, the oxygen molecules bound to the perfluorodecalin oil would be trapped between the skin and the starch film, thus, assuring an oxygen depot available to damaged skin by passive diffusion.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

7

Water Water plus 10% PFC Starch (4%) + PFC Starch (4%) OxyTega

Dissolved Oxygen (ppm)

6

5

4

3

2

1

0 0

5

10

15

20

25

30

35

40

Mixing Time (minutes)

Figure 36.6. The kinetics of oxygen release. Data are shown for water, water plus 10% PFC, starch (4%), starch (4%) + PFC, and OxyTega.

36.4.6

Antimicrobial Thixogel Formulations

Benzalkonium chloride, at 0.5 wt%, acts as both a surfactant and an antibacterial agent in Thixogel formulations. Given concerns about possible skin irritation at or above 0.5 wt%, the concentration of this cationic surfactant was reduced to 0.1 wt%. Palmitoleic acid was added to supplement the emulsifying action of the benzalkonium chloride and, at the same time, to increase the overall antimicrobial action of the benzalkonium chloride/palmitoleic acid combination. Human sebum contains a special isomer of palmitoleic acid (C16:1∆6) that this isomer as well as the C16:1∆9 are both highly effective antibacterial agent against gram-positive bacteria. These isomers also acts synergistically with alcohols (ethanol and isopropyl alcohol) and, thus, effective as a broad acting antimicrobial agent.[32] SanoSeal gel (Formulation 36.8) was tested for its bactericidal action on a clinical isolate of Staphylococcus aureus. The bacteria were applied at a level of 5 × 105 cells to a saline-moistened sterile filter paper and exposed for 20 minutes to Formulation 36.8 (100 µL per filter) to completely cover the

bacterized paper. Controls included sterile filter papers with an equal number of bacteria. These were covered with a sterile starch/oil dispersion lacking palmitoleic acid (positive control). Sterile filter papers, with no bacteria, and covered with sterile SanoSeal gel were also employed as controls. After treatment, the filter papers were aseptically transferred to a sterile broth and incubated on a rotary shaker overnight. It was found that bacteria-containing paper without palmitoleic acid in the Thixogel was clouded by growth of bacteria. By contrast, filter papers either without bacteria, or coated with SanoSeal gel, were as clear (i.e., uncontaminated) as uninoculated sterile broth. Small aliquots from each broth were then transferred to a fresh sterile broth and incubated again overnight at 37°C. Only the cloudy broth from the bacteria-containing Thixogeltreated flask grew out bacteria. These results show that SanoSeal gel (Formulation 36.8) kills an amount of applied bacteria up to five-logs in a 20-minute exposure. Since the formulation contains no toxic chemicals, and no drying alcohol, it is effective and safe to use. Further, the formulation is not harsh or irritating to skin.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES 36.4.7

Antioxidant and Antiirritant Hydrophobic Plant Actives

In a review,[12] only a small number of patents were listed for anti-irritant plant extracts. A summary of these patents is shown in Table 36.2. One deficiency of many plant-derived ingredients with potential medicinal and cosmetic uses is that they are only soluble in organic solvents or oils. Several patents have been filed to overcome this deficiency and aid in the delivery of oil-soluble plant actives.[43]–[46] Some of the key botanical oils that are commercially available include almond, avocado, cottonseed, olive, corn, menhaden, safflower, soybean, peanut, sesame, and polyunsaturated fatty acids. The latter contain linoleic acid, gamma-linolenic acid, alpha-linolenic acid, and stearidonic acid. These polyunsaturated acids also contain omega-3-fatty acid, eicosaoentanoic acid, and docosahexaenoic acid. Other botanical extracts useful in personal care applications include lithospermum offiinale (napthoquinones), thyme (thymol), hypercium peforatum (hypericin), seabuckthorn (carotenoids), rosmarinus (phyosterols), and walnut (juglone). Still other botanical extracts include ginger (zingiberol, gingerol), Chamomilla recutita (α-bisabolol), carrot (β-carotene), and marigold-Calendula officinalis (calendulin, quercetin). Plant extracts are well-known sources of polyphenols in view of their polyphenol content. Plant extracts that are rich in polyphenols include grapeseed, honeysuckle, cranberry, and green tea (Camellia sinensis leaves). These materials are also rich in flavonoids (quercetin and apigenin), chloro-

777

genic acid, and epigallocatechingall-ate and caffeine. All of these agents have potent antioxidant activity.[38][40] Other plant extracts with claimed anti-irritant properties include aloe vera, Chamomilla recutia, Urtica dioica, Betula alba, Arnica montana, and Cinchona persea gratissima. Still other plant extracts in this class include Aloe barbadensis, Chamomilla recutia, Melissa officinalis, Mentha piperita, Rosmarinus officinalis, Biscus sabdariffa, and Althea officinalis. The long list continues with Artemisia absinthium, Primula vulgaris, Salvia officinalis, Santalum album, Viscum album, and Ilea millefolium. Plant extracts derived from fruits also contain high levels of flavonoids. Examples include Pyrus malus, Camellia sinensis, Ribes nigrum, Vaccinium macrocarpon, Citrus grandis, Paulinia cupana, and Actinidia chinesis. Other examples of fruit derived extracts include Citrus aurantifolia, Citrus aurantium, Carica papaya, Passiflora edulis, Prunus persica, and Ananas sativus. Flavonoid compounds are of particular importance as antioxidants that interfere with growth factor receptor regulated signal transduction.[41] Tables 36.3–36.5 present data on plants and herbs that are rich in flavonoids. These materials can be isolated from Spanish honeybee pollen. For example, rutin, quercetin, myricetin, and trans-cinnamic acid all were present at levels greater than 350 mg/100 g. Recently, it was reported that Kaempferol is the major flavonoid derived from lyophilized extracts of the flowering buds of capers (capparis spinosa L). This material was shown to have both antioxidant and photo-protective effects in human skin.[30]

Choosing the right vehicle. Once desired plant actives have been selected for Table 36.2. Anti-irritant Plant Extracts: Published Patents an intended formulation, a proper vehicle for their delivery must be dePlant Extract Patent Reference Assignment signed. UltraDerm (Formulation 36.5) was chosen as the best delivery sysRosmarinic acid US 5,393,526 E. Arden tem for hydrophobic plant actives for (Sage) (Castro, 1995) the following reasons: Cola nitida

EPA 3554554A2 (Smith et al,1989)

E. Arden

Yerba Oil, bisabolol, Chamazulene

WO 9,114,441 (Parnell, 1991)

Parnell Pharma

Yarrow

US 4,908,213 (Govil & Kohlman, 1990)

Schering Plough

• Hydrophobic plant active compounds are soluble in the oil phase ingredients. • Dry powders can be prepared by exhaustive venting of volatile solvents.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 36.3. Flavonoids in Indian Foodstuffs

Flavonoid Content* High (>100 mg)

Medium (50-100mg)

Low (< 50 mg)

Indian gooseberry

Kidney beans

Apple

Omum

Soybeans

Guava

Cumin

Grapes

Fenugreek seeds

Cardimum

Ginger

Mustard seeds

Betel leaf

Coriander powder

Brandy

Bajra

Tea, coffee

Cinnamon Red Chili

Brinjal

Cloves Tumeric * Modified from data in: Nair, S., Nagar, R., Gupta, R., Anti-oxidant Phenolics and Flavonoids in Common Indian Foods, J Assoc Physicians of India, 8:708–710 (2001) (Flavonoid is sum of quercetin, kaempferol, luteolin, pelargonidin)

Table 36.4. Flavonoids in Various Plants* (concentration, mg/kg)

Plant

Myricetin

Onion leaves

Quercetin

Kaempferol

Luteolin

1498

832

391

Apigenin

Semambu leaves

Total 2041

Bird chili

1035

1663

Black tea

1491

Papaya shoots

1264

Guava

579

Chinese cabbage

187

Wolfberry leaves

547

Fruits

1129

glycosides

* Modified from data in: Mean, B., K. H., and Mohamed, S., Flavonoids in Tropical Plants, J Agricult & Food Chemistry, 49(6):3107–3112 (2001)

Table 36.5. Flavonoids in Herbs: Composition of Flavonoids in Fresh Herbs and Calculation of Flavonoids* (concentration, mg/100g)

Herb Parsley

Apigenin 510–630

Lovage Mint Dill

Quercetin 1

18–100 48–100

* Modified from data in Justesen, U., Food Chemistry, 73(2):245 (2001)

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES • Dry powders of hydrophobic plant active compounds are soluble in mineral oil. • Plant actives dissolved in mineral oil are also soluble in the combined oil phase ingredients of UltraDerm. • Protection of plant antioxidants from light and air can be achieved by adding tocopherol (vitamin E) directly to the mineral oil prior to dissolving the plant active.

36.4.8 Hydro-Alcoholic Extracts of Plants Rich in Flavonoids

As noted in Table 36.3, green onion leaves are a rich source of the flavonoid Quercetin. A hydroalcoholic extract of green onion leaves here designated “allin,” was prepared and tested for its effect on the proliferation of normal human keratinocytes cultured in a serum-free medium containing insulin and retinyl acetate. Both of these materials are the sole growth factors required for autocrine growth of keratinocytes.[49] Our results showed that allin inhibited autocrine growth of proliferating keratinocytes. The effect was equivalent to use of 10 µM quercetin dihydrate, a standard control flavonoid. These results indicate that green onion leaf containing flavonoids, like quercetin, block autocrine growth of serum-free cultures of keratinocytes by inhibiting the mitogenic signal transduction cascade. This action occurs through the insulin-like growth factor receptor (IGFR), which itself, is activated by retinoid stimulation and inhibited by inhibitors of tyrosine protein kinases.

36.4.9 Antioxidant Plant Extracts Depletion of antioxidants is well known to cause oxidative damage to human skin.[31] Flavonoids are known to be potent antioxidants. It is feasible, therefore, that topical replacement of skin antioxidants may help to alleviate oxidative stress due to ultraviolet radiation and ozone exposure. Since flavonoids are themselves oxidatively unstable, they require stabilization against oxidation by the addition of co-reductants such as vitamin E (α-tocopherol) or vitamin C (ascorbic acid). No mechanism exists to reduce

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oxidized vitamin E since there is no ascorbic acid in the upper layers of the epidermis (stratum corneum). To address this issue, we have sought good antioxidant plant extracts as candidates for incorporation into our chosen Thixogel hydrophobic delivery system (Formulation 36.5, UltraDerm). Moreover, it is our idea that plant extracts with strong antioxidant activity will be useful sources of plant-derived antiirritants. In order to test this hypothesis, the antioxidant activity of anti-irritant plant extracts were assayed by the diphenylpicrylhydrazyl radical test.[31] Table 36.6 summarizes some of these results. In our search for an effective plant-derived antioxidant, autumn olive (elaeagnus umbellata) was found to be a rich source of antioxidants. Two other sources of antioxidants also identified were hydroalcoholic extracts of corn tassels (Tasselin) and tomato paste. In addition, we have also isolated lycopenes from both tomato paste and autumn olive berries since both are rich sources of carotenes. They have been incorporated into Formulations 36.10 and 36.11 (PhytoDerm Gels). Similarly, hydroalcoholic extracts of green onion leaves and red Swiss chard have demonstrated modest but significant antioxidant activity. Green onion leaf extract, allin, was therefore incorporated into Formulation 36.12 along with retinyl acetate in order to enhance the antioxidant properties of this formulation.

36.5 Summary This chapter has described a process for producing stable dispersions of oil droplets in an aqueous natural starch gel matrix. The process first requires gelatinizing natural starch at a temperature sufficient to dissolve the starch in an aqueous solution containing one or more emulsifying agents. This procedure is then followed by blending of one or more oils with the gelatinized starch phase at a temperature sufficient to prevent gel formation. The use of petrolatum, mineral oil, and silicone oils, in various combinations in the oil phase ingredients, is employed in specified amounts, to produce a greaseless and tackless gel having good spreadability, rapid drying, and water-resistance. Such materials form a protective film on skin.

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Table 36.6. Relative Antioxidant Activity of Plant Extracts

Plant Extract (% Ethanol)

Relative Antioxidant Potency, P = (EC50 × Conc. Factor, kg/L)*

Activity Relative to Vitamin E (EC50 of 46 µM = 1 unit)

Indole acetic acid (0)

2.0

4.1

Green onion leaf (50)

3.1

6.7

Red swiss chard (50)

4.0

5.2

Tomato paste (50)

13.3

1.6

Corn Tassel (95)

16.5

1.3

176.0

0.1

Autumn olive berry (50)

*EC50 – defined as the concentration that reduced absorbance of a diphenylpicryl hydrazine standard solution by 50% when measured in a spectrophotometer at 595 nm.

Glycerol, a humectant, has also been used in the aqueous phase of the Thixogel formulations to provide for skin moisturization. Hydrocolloid gels prepared by the above process are capable of topically delivering plant-derived hydrophobic extracts such as cosmetic and medicinal ingredients into the oil-phase ingredients of the starch-in-oil gel systems. These hydrocolloid gel emulsions confer antioxidant, anti-aging, and antiirritant properties. These properties have been obtained with the formulations set forth in Sec. 36.6. One Thixogel system, based on the above concepts, is UltraDerm (Formulation 36.5). This formulation is a novel topical delivery system with diverse personal care applications.

36.5.1

Benefits to Formulators and Customers

It should be readily apparent that Thixogel emulsions are both easy to formulate and cost-effective. The major ingredients such as cornstarch, mineral oil, and petrolatum are relatively inexpensive. Since a stable hydrocolloid gel emulsion of starch-in-oil requires only very low levels of an emulsifying agent, the formulator can avoid the use of expensive fatty acid alcohols, fatty acid esters, thickeners, and emulsion stabilizers that are generally required to produce stable oil-in-water emulsions. Unlike many cosmetic emulsions, Thixogel emulsions are completely greaseless, and leave no oily residue on the skin. Furthermore, they are completely

resistant to alcohol and thus do not wash off when body skin is rinsed or decontaminated with alcohol. This property makes them highly useful to healthcare workers. Such workers can avoid the irritant effects of multiple cycles of water and alcohol washes during the course of their sanitary protocols. Finally, Thixogel formulations lend themselves to the enhanced formulation of oil-soluble active ingredients. Plant extracts that are only soluble in organic solvents can be readily dried, re-dissolved in mineral oil, and employed with the chosen oil phase. It has been it has been shown that lycopenes (derived from tomato paste), and carotenes (derived from carrots), can both be solubilized in mineral oil and then added directly to the oil-phase ingredients during the formulation of UltraDerm type gels.

36.6 Formulations There many diverse applications of the Thixogel technology in personal care and skin care areas. We have chosen twelve exemplary formulations, which reflect this diversity. The basic formulation always is comprised of a starch, an oil, and an emulsifier. The simplest formulations form a smooth opaque gel that spreads easily on skin and forms a protective film that is alcohol resistant and water resistant, but washes off with soap and warm water. The next level of formulation complexity is the addition of a humecant to starch, oilc and emulsifiers. We have chosen glycerol for this purpose.

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Other formulations utilize the properties and benefits of modified rather than natural starches. Another formulation takes advantage of the encapsulation and solubility of fatty acids in the oil phase ingredients. In particular, we have chosen palmitoleic acid because it has good activity against gram-positive bacteria such as Staphylococcus aureus.

delivery of skin actives. Hard-to-dissolve hydrophobic plant actives such as lycopenes and carotenes are first dissolved in mineral oil phase before emulsification with the starch gel aqueous phase. There is virtually no limit to the cosmetic active or dermatological drugs that can be incorporated into the bulk water phase or the encapsulated oil phase.

Still another application is the delivery of oxygen to damaged or compromised skin. This was accomplished by incorporating an oxygen carrying oil, Perfluorodecalin, as the oil phase ingredient. Probably, the most important application area is the

Each formulation has been given a trade name that describes its general application. The manufacturing procedures are appended at the bottom of each formulation along with a disclaimer.

Formulation 36.1: DermSeal—Basic Skin Barrier Gel: Hydrophobic Topical Gel Delivery System

Phase A

B

C

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

7.5

Deionized water

Water phase (hydration)

Cornstarch

Thickener, film-forming gel

3.5

Benzalkonium chloride

Emulsifier (preservative)

0.5

Citricidal

Natural preservative

0.5

88.0

Manufacturing Procedure 1. Weigh the Phase A ingredient and heat at 50°C until thoroughly melted in a suitable vessel equipped with a mixer Add C ingredient to pre-heated Phase A ingredient. 2. Weigh the Phase B starch ingredient, and place in a suitable vessel equipped with low-shear mixer. 3. Add a sufficient volume of deionized water to produce a 0.5% concentration of benzalkonium chloride. 4. Heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 5. Remove from heat, add directly to heated Phase A ingredient and then heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 6. Tip: Keep the gelated starch above its boiling point during the petrolatum jelly blending step. Store the gel in a sealed container away from heat and air. 7. The ratio of starch to petrolatum can be varied from 1:1 to 1:3 to 3:1 and still result in a stable homogenous emulsified gel. 8. A variety of pure food grade cornstarches have been tried in these type of formulations. These include Staley, Pure Food Powder, Decatur, IL., and DRY-FLO® AF, a modified starch from National Starch & Chemical, Co. Mineral oil can be substituted for petrolatum jelly. 9. A non-ionic surfactant (e.g., Triton-X100 at 0.1 wt%) or an anionic surfactant (e.g., sodium lauryl sulfate at 0.5 wt%) can be substituted for benzalkonium chloride. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.2: EktaSeal—Skin Barrier and Moisturizing Gel: Hydrophobic Topical Delivery System

Phase A

B

C

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

8.8

Deionized Water

Water phase (hydration)

Corn Starch

Thickener (gel and film-forming agent)

3.7

Benzalkonium chloride

Emulsifier (preservative)

1.0

Glycerol

Humectant

Citricidal

Natural preservative

73.0

20.0 0.5

Manufacturing Procedure 1. Weigh the Phase A ingredient and heat at 50°C until thoroughly melted in a suitable vessel equipped with a mixer and add Phase C ingredient. 2. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 3. Add a sufficient volume of deionized water, glycerol, and benzalkonium chloride, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 4. Remove from heat and add to pre-heated Phase A and Phase C ingredients. 5. Heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 6. Tip: Keep the gelated starch above its boiling point during the petrolatum blending step. Store the gel in a sealed container away from heat and air. 7. The ratio of starch to petrolatum can be varied from 1:1 to 1:3 to 3:1 and will still result in a stable homogenous emulsified gel. 8. A variety of pure food grade corn starches can be used including Staley, Pure Food Powder, National Starch & Chemical Co., and Argo. Mineral Oil, USP may be substituted for petrolatum jelly. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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Formulation 36.3: VegaSeal—All Natural Skin Moisturizing Gel: Hydrophobic Topical Delivery System

Phase A

B

C

Ingredients

Function(s)

Weight %

Soy Bean Oil

Oleophilic phase (skin softener/anti-irritant)

3.5

Deionized Water

Water phase (hydration)

82.0

Corn Starch (StaMist 365)

Thickener, oil absorber

3.0

Lecithin

Vegetable emulsifier

1.0

Glycerol

Humectant

Citricidal

Natural preservative

10.0 0.5

Manufacturing Procedure 1. Weigh the Phase B cornstarch ingredient and place in suitable vessel equipped with a mixer. 2. Add a sufficient volume of deionized water and glycerol. 3. Heat these Phase B ingredients at 90°C until the starch is entirely dissolved. 4. Remove from heat and add the remainder of Phase B ingredient (Lecithin in 5% Ethanol). 5. Mix the combined Phase B ingredients with Phase A (soy bean oil) and Phase C ingredients. Heat the combined oil-water mixture at 65°C with continuous mixing until a homogeneous emulsion is formed. 6. Tip: Keep the gelated starch above its boiling point, during the soy bean oil blending step. Store the gel in a sealed container away from heat and air. 7. Sta-Mist 365 is a hydro-phobically-modified cornstarch from Staley Manufacturing Co., Decatur, IL. Meadowfoam oil, oleic acid, olive oil, and canola oil can be substituted for soy bean oil. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.4: HydraSeal—Moisturizing Skin Barrier Gel: Topical Delivery System

Phase A

B

C

Ingredients

Function(s)

Weight %

Dimethicone-200® Fluid

Oleophilic skin protectant

Deionized water

Water phase (hydration)

Corn starch

Thickener (gel/film-forming agent)

3.4

Benzalkonium chloride

Emulsifier

1.0

Glycerol

Humectant

10.0

Citricidal

Natural preservative

5.6 79.5

0.5

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add sufficient volume of deionized water, glycerol, and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. Remove from heat and add citricidal to Phase A ingredient (dimethicone). 3. Heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 4. Tip: Keep the gelated starch above its boiling point during the dimethicone blending step. Store the gel in a sealed container away from heat and air. 5. Dimethicone is (dimethyl polysiloxane, 60,000 cP). A variety of pure food-grade cornstarches can be employed including those from Staley, National Starch, and Argo. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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Formulation 36.5: UltraDerm—Basic Topical Delivery System for Hydrophobic Plant Actives

Phase

Ingredients Poly(dimethylsiloxane)

Function(s)

Weight %

Skin protectant

0.8

®

DC-200 Fluid

Decamethylpentane A

Skin protectant

Cyclosiloxanes

0.33

DC-245 Fluid®

B

C

Mineral Oil

Oleophilic phase

4.1

Petrolatum jelly

Oleophilic phase

9.3

Deionized water

Water phase (hydration)

Corn Starch

Thickener (gel/film-forming agent)

3.1

Benzalkonium Chloride

Emulsifier

0.8

Glycerol

Humectant

10.0

Citricidal

Natural preservative

68.1

0.5

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, glycerol and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 3. Remove from heat and cool to 65°C. 4. Weight out Phase A ingredient (mineral oil, DC-200, DC-245 and petrolatum jelly) and add directly to pre-heated Phase B ingredients. 5. Stir in Phase C ingredient, and mix continuously until a homogeneous emulsion is formed. 6. Tip: Keep the gelated starch above its boiling point during the addition of Phase A ingredients. Store the gel in a sealed container away from heat and air. 7. A variety of pure food-grade cornstarches can be employed including Staley, National Starch, and Argo. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.6: OxyTega Gel—Skin Barrier and Oxygen Topical Delivery System

Phase A

B

C

Ingredient

Function(s)

Weight %

Perflurodecalin

Oleophilic phase (oxygen binding agent)

9.5

Deionized water

Water phase (hydration)

Cornstarch

Thickener (gel/film-forming agent)

4.0

Benzalkonium chloride

Emulsifier

1.5

Citricidal

Natural preservative

0.5

84.5

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, and add the benzalkonium chloride. 3. Mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 4. Remove from heat and add Phase C ingredient to Phase A ingredient (perfluorodecalin) and heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 5. Tip: Keep the gelated starch above its boiling point during the perfluorodecalin blending step. Store the gel in a sealed container away from heat and air. 6. A variety of pure food-grade cornstarches can be employed including those from Staley, National Starch, and Argo. Perfluorodecalin (95%). Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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Formulation 36.7: Soothex-Itch-Relief Gel—Skin Barrier: Witch Hazel Delivery System

Phase A

Ingredients Petrolatum jelly

C

Weight %

Oleophilic phase (skin protectant)

8.0

Skin protectant

1.0

Rheology modifier

4.0

Benzalkonium chloride

Emulsifier

1.0

Hammelis water (86%, Witch Hazel)

Water phase (astringent)

71.5

Isopropyl alcohol

Skin disinfectant

14.0

Citricidal

Natural preservative

Poly(dimethylsiloxanes) Potato starch (Structure Solance)

B

Function(s)

®

0.5

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of Hammelis water (14% isopropyl alcohol), and benzalkonium chloride. 3. Mix thoroughly and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 4. Remove from heat and add Phase C ingredient to Phase A ingredient (petrolatum jelly) and heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 5. Tip: Keep the gelated starch above its boiling point during the petrolatum and dimethicone blending step. Store the gel in a sealed container away from heat and air. 6. Structure Solance is 2-(N,(N-bis(2-carboxyethylamino)ethyl ether-derivatized potato starch from National Starch & Chemical, Bridgewater, NJ. Witch Hazel, U.S.P. 200 Fluid from Dow Corning, Midland, MI. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.8: SanoSeal Gel—Antimicrobial Hand Lotion: Hydrophobic Plant Active Delivery System

Phase

A

B

C

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

6.6

Poly(dimethylsiloxanes)

Skin protectant

5.0

Palmitoleic acid

Anti-microbial agent

0.5

Deionized water

Water phase (hydration)

Cornstarch (DRY-FLO® AF)

Rheology modifier

3.3

Benzalkonium chloride

Emulsifier

0.1

Citricidal

Natural preservative

0.5

84.0

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 3. Remove from heat and add Phase C ingredient to Phase A, and heat at 65°C with continuous mixing until a homogeneous emulsion is formed. 4. Tip: Keep the gelated starch above its boiling point during the petrolatum and dimethicone blending step. Store the gel in a sealed container away from heat and air. 5. Palmitoleic acid provides antibacterial activity, and oleic acid (0.5%) can be substituted for palmitoleic acid. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES

789

Formulation 36.9: PhytoSeal L—Anti-Aging Plant Active Topical Delivery System

Phase

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

9.3

Poly(dimethylsiloxanes)

Skin protectant

0.8

Decamethylpentane cyclosiloxane

Skin protectant

3.2

Mineral oil

Oleophilic solvent

4.0

Deionized water

Water phase (hydration)

Cornstarch

Rheology modifier (film/gel forming agent)

3.2

Benzalkonium chloride

Emulsifier

0.8

Glycerol

Humectant

10.0

C

Tomato paste extract

Plant active (anti-aging agent)

0.1

D

Citricidal

Natural preservative

0.5

E

Tocopherol

Anti-oxidant

0.1

A

B

68.0

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, glycerol and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. 3. Remove from heat and add Phase D and E ingredients (Tocopherol and Citricidal) to Phase A ingredient (Petrolatum jelly, 200® Fluid, 245® Fluid). 4. Phase C ingredient (Lycopene solution in mineral oil) is added to Phase A ingredients and heated at 65°C and then added to Phase B ingredients with continuous mixing until a homogeneous emulsion is formed. 5. Tip: Keep the gelated starch above its boiling point during the Phase A ingredients blending step. Store the gel in a sealed container away from light, heat, and air. 6. Corn starch from Staley, Decatur, IL. 200® Fluid and 245® Fluid from Dow Corning, Midland, MI, a Lycopene-enriched extract, was purified from tomato paste and a saturated solution of it dissolved in mineral oil, USP. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.10: PhytoSeal C/L—Photo-Aged Skin Repair Gel: Hydrophobic Plant Active Delivery System

Phase

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

9.2

Poly(dimethylsiloxane)

Skin protectant

0.8

Decamethylpentane cyclosiloxane

Skin protectant

3.2

Mineral oil

Oleophilic solvent

4.0

Deionized water

Water phase (hydration)

68.0

Cornstarch

Rheology modifier (film/gel forming agent)

3.2

Benzalkonium chloride

Emulsifier

0.8

Glycerol

Humectant

10.0

Carrot extract

Plant active (antioxidant)

0.1

Tomato paste extract

Plant active (antioxidant)

0.1

D

Citricidal

Natural preservative

0.5

E

Tocopherol

Antioxidant

0.1

A

B

C

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, glycerol, and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. Remove from heat. 3. Add Phase D and E ingredients (Tocopherol and Citricidal) to Phase A ingredients (petrolatum jelly, 200® Fluid, 245® Fluid, mineral oil) at 65°C and mix Phase B ingredients with continuous stirring until a homogeneous emulsion is formed. 4. Phase C ingredients (carrot and tomato paste extracts) in mineral oil were added to Phase A ingredients prior to mixing with Phase B ingredients at 65°C until thorough mixing is achieved. 5. Tip: Keep the gelated starch above its boiling point during the petrolatum, mineral oil, and silicone oil-blending step. Store the gel in a sealed amber container away from light, heat, and air. 6. Cornstarch was from Staley, Decatur, IL. 200® Fluid and 245® Fluid was from Dow Corning, Midland, MI. Carotene–enriched and lycopene-enriched preparations were prepared as saturated solutions in mineral oil. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES

791

Formulation 36.11: PhytoSeal T—Anti-Aging Plant Active Topical Delivery System

Phase

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

9.2

Poly(dimethylsiloxanes)

Skin protectant

0.8

Decamethylpentane cyclosiloxane

Skin protectant

3.2

Mineral oil

Oleophilic solvent

4.0

Deionized water

Water phase (hydration)

68.0

Cornstarch

Rheology modifier (film/gel forming agent)

3.2

Benzalkonium chloride

Emulsifier

0.8

Glycerol

Humectant

10.0

Corn tassel extract (Tasselin®)

Plant active (anti-irritant)

0.1

Retinol

Anti-aging agent

0.1

D

Citricidal

Natural preservative

0.5

E

Tocopherol

Antioxidant

0.1

A

B

C

Manufacturing Procedure

1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, glycerol, and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. Remove from heat. 3. Add Phase D and E ingredients (Tocopherol and Citricidal) to Phase A ingredients (petrolatum jelly, 200® Fluid, 245® Fluid, mineral oil) at 65°C and mix Phase B ingredients with continuous stirring until a homogeneous emulsion is formed. 4. Phase C ingredients (Tasselin and Retinol) were prepared separately as solutions in 95% ethanol and added to the combined Phase A, Phase B, and Phase D mixture at 65°C until thorough mixing is achieved. 5. Tip: Keep the gelated starch above its boiling point during the petrolatum, mineral oil, and silicone oil-blending step. Store the gel in a sealed amber container away from light, heat, and air. 6. Cornstarch from Staley, Decatur, IL. 200® Fluid and 245® Fluid from Dow Corning, Midland, MI. TasselinTM, a phenoxyacetic acid ester-enriched from hydroalcoholic extract of tassels from corn plants, was dissolved in 95% ethanol. Note: No guarantee is given or implied to meet any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 36.12: PhytoSeal R/O—Anti-Wrinkling: Plant Active Topical Delivery System

Phase

Ingredients

Function(s)

Weight %

Petrolatum jelly

Oleophilic phase (skin protectant)

9.2

Poly(dimethylsiloxane)

Skin protectant

0.8

Decamethylpentane cyclosiloxane

Skin protectant

3.2

Mineral oil

Oleophilic solvent

4.0

Deionized water

Water phase (hydration)

Cornstarch

Rheology modifier (film/gel forming agent)

3.2

Benzalkonium chloride

Emulsifier

0.8

Glycerol

Humectant

10.0

Retinyl acetate

Anti-wrinkling agent

0.1

Onion leaf extract

Plant active (antioxidant)

0.1

D

Citricidal

Natural preservative

0.5

E

Tocopherol

Antioxidant

0.1

A

B

C

68.0

Manufacturing Procedure 1. Weigh the Phase B starch ingredient and place in suitable vessel equipped with mixer. 2. Add a sufficient volume of deionized water, glycerol, and benzalkonium chloride, mix thoroughly, and heat the Phase B ingredients at 90°C until the starch is entirely dissolved. Remove from heat. 3. Add Phase D and E ingredients (Tocopherol and Citricidal) to Phase A ingredients (petrolatum jelly, 200® Fluid, 245® Fluid, mineral oil) at 65°C and mix Phase B ingredients with continuous stirring until a homogeneous emulsion is formed. 4. Phase C ingredients (retinyl acetate and onion leaf extract) were prepared separately as 1% solutions in 95% ethanol and added to the combined Phase A, Phase B, and Phase D mixture at 65°C until thorough mixing is achieved. 5. Tip: Keep the gelated starch above its boiling point during the petrolatum, mineral oil, and silicone oil-blending step. Store the gel in a sealed amber container away from light, heat, and air. 6. Cornstarch from Staley, Decatur, IL. 200® Fluid and 245® Fluid from Dow Corning, Midland, MI. A quercetin-enriched extract was purified from onion leaf extract and dissolved in 95% ethanol. Note: No guarantee is given or implied to met any specific performance criterion assigned to this formulation. Further, use of certain ingredients may be covered by other patents, and subject to prior licensing agreements.

WILLE: THIXOGEL: NOVEL TOPICAL DELIVERY SYSTEMS FOR HYDROPHOBIC PLANT ACTIVES

Acknowledgments The author wishes to acknowledge the following people and organizations for their help and for supply of some materials used for this study. • Dr. George Fanta, Senior Chemist, United States Department of Agriculture, 1815 North University Street, Peoria, IL 616043999. • Jerry Burke, Marketing Manager, CRODA, Inc., Skin -Care & Make-Up, 7 Century Drive, Parsippany, NJ 07054-4698. • Dr. Klaus Stanzl, DRAGOCO, Inc., Corporate Vice President, Cosmetic Division Worldwide, 10 Gordon Drive, Totowa, NJ 07512. • Michael Mercier, President, MMP, Inc., 3470 So. Clinton Ave., South Plainfield, NJ 07080. • Scott Cardinali, National Starch & Chemical Co., Inc., Personal Care Technical Services, 10 Finderne Ave., Bridgewatrer, NJ 08807.

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26. Loeffler, M., et al., Household and Personal Care Products Industry, p. 58 (Jul. 2002)

44. Zulli, F., et al., US Patent Application No. A1 200120160064 (2002)

27. Thiele, J., J., et al., Oxidants and Antioxidants in Cutaneous Biology, pp. 26–42, Karger, Basel (2001)

45. Lui, J. C., et al., US Patent Application No. A1 20010055597 (2001)

28. Drehert, F., and Maibach, H., Oxidants and Antioxidants in Cutaneous Biology, pp. 157– 164, Karger, Basel (2001)

46. Robinson, L. R., et al., US Patent Application No. A1 20020022040 (2002) 47. Koh, K. J., et al., Br. J. Dermatol., 147(6):1212 (2002)

29. Gupta, S., Household and Personal Care Products Industry, p. 56, (Jul. 2001)

48. Wille, J. J., 29th Intl Symp. Controll. Rel & Bio. Mater., Glasgow, UK (in press)

30. Bonina, B., et al., J. Cosmet. Sci., 53:321 (2002)

49. Wille, J. J., J. Cosmet. Sci., 54(1):106 (2003)

31. Podda, M., et al., Free Radic. Biol. Med., 24:55 (1998) 32. Wille, J. J., F.O. Cope, FASEB J., 15(5):A916 (2001) 33. Wille, J. J., et al., Skin Pharm. & Appl. Skin Physiol., 13(2):65 (2000) 34. Wille, J. J., and Kydonieus, A., Skin Pharm.& Appl. Skin Physiol.,16(3):176 (2003) 35. Thau, P., J. Cosmet. Sci., 53:229 (2002) 36. MacDonald, V., Household and Personal Care Products Industry, p. 67, (Jun. 2002) 37. MacDonald, V., Household and Personal Care Products Industry, p. 87, (Jun. 2000) 38. Gupta, S., Household and Personal Care Products Industry, p. 10 (Dec. 2001) 39. Wenli, Y., et al., J. Amer Oil Chem. Soc., 78(7):697 (2001) 40. McBride, C., Ag. Res., p. 18, (Feb. 2001) 41. Wenzel, U., et al., J. Pharmacol. and Exptl. Therapeut., 299(1):351 (2001) 42. Runge, F., et al., US Patent Application No. A1 20030031706 (2003)

50. Starch, M., et al., Controll. Rel Soc., Newsletter 20(2):18 (2003) 51. Company data on file. 52. Moore, R. E., US Patent No. 4569784 (1986) 53. Gianladis, G., US Patent No. 3277013 (1966) 54. Rosano, A., et al., US Patent No. 3778381 (1973) 55. Samejima, H., et al., US Patent No. 3823091 (1974) 56. Yokoyoma, H., et al., US Patent No. 3993581 (1976) 57. White, D. C., US Patent No. 4366169 (1982) 58. Arnaud, P., and Mellul, M., FR No. 2688006A1 (1993) 59. The Standard Draize Test on human skin of 50% benzalkonium chloride was mild as quoted in the MSDS supplied by Acros Organics, Fairlawn, NJ. 60. Rosen, M., Global Cosmetic Ingredients, 171(5):42-46 (2003) 61. Aluminum Test - Cosmetic Handbook Methods. 62. Morowitz, H., Entropy in Biological Systems.

Part XII Activated Delivery Systems

Smart Vectorization: Enzymatically Activated Encapsulation Technologies

ACTIVATED DELIVERY

Simultaneous Delivery Systems for Unit Dose, Topical Delivery of Complimentary and/or Incompatible Actives: "Thinking Outside the Jars & Bottles"

37 Smart Vectorization Enzymatically Activated Encapsulation Technologies Eric Perrier Coletica, SA Lyon, France Janice Hart Coletica, Inc. Northport, New York

37.1 37.2 37.3 37.4

Introduction ................................................................................... 798 The “Eureka!” Moment.................................................................. 799 Limits of Current Technologies ..................................................... 799 Overview of Trigger Release Mechanisms ................................... 800 37.4.1 Release with Change in Pressure ................................... 800 37.4.2 Release with Change in Temperature .............................. 800 37.4.3 Release with pH Change ................................................. 801 37.4.4 Release by Osmotic Pressure ........................................ 801 37.4.5 Molecular Encapsulation and Release ............................. 802 37.4.6 Release by Enzymatic Digestion ..................................... 802 37.4.7 Enzymatic Release: An Exact Approach ......................... 802 37.5 Encapsulation Technologies Applicable to Enzymatic Release ... 803 37.5.1 Formaldehyde- or Glutaraldehyde-Based Techniques ..... 803 37.5.2 Non-Formaldehyde- or Non-Glutaraldehyde-Based Techniques ....................................................................... 803 37.6 Micro- and Macrosized Particles for Enzymatically Activated Technologies ................................................................................. 805 37.6.1 Marine Collagen ............................................................... 805 37.6.2 Plant Proteins ................................................................... 806 37.6.3 Polysaccharide-Based Encapsulation ............................. 806 37.6.4 Nanoencapsulation .......................................................... 806 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 797–816 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 37.7 Properties and Performance of Micro- and Nanospheres and Capsules ............................................................................... 807 37.7.1 Enzymatic Digestion In Vitro ............................................ 807 37.7.2 Penetration vs Storage .................................................... 808 37.7.3 Pharmacokinetic .............................................................. 811 37.7.4 In Vivo Results ................................................................. 812 37.7.5 Membrane Selection ........................................................ 813 37.8 Perspectives and Conclusions ..................................................... 813 37.9 Formulations ................................................................................. 814 References ......................................................................................... 816

37.1 Introduction

not fit with the limitations of daily life and, therefore, this approach is not a sensible solution.

The development of the first liposomes in the 1930s led to their first use for cosmetic applications in 1984 by Louis Vuitton Moet Hennessy and L’Oréal. Later, the development of the first microspheres and microcapsules in the 1960s set the stage for their first industrial development for cosmetics in 1986 by Coletica, and their first use for cosmetic applications in 1987. With the passage of time it has become evident that encapsulation is an excellent method to modify the bioavailability of many beneficial active compounds and to overcome the inherent instabilities of some active compounds. Encapsulation technologies have provided consumers with visible innovations in formulations containing already known and commonly used ingredients. This leap in technology has provided additional marketing flexibility to increasingly educated consumers.

In this chapter we will discuss the benefits of encapsulating active ingredients followed by their release to the skin by means of an enzymatically activated mechanism. Typically, the high shear forces during rubbing application act as a trigger for active release for many encapsulation systems, but this phenomenon is critical for achieving skin protection and providing availability of the active compound.

Today, encapsulation of active ingredients is becoming imperative in the design and formulation of cosmetic products.[9][11] The primary challenge in adding an active compound to a formulation is in the short duration of the compounds effectiveness following its application to the skin. Typically, if the active is not protected by encapsulation, it may react spontaneously with other ingredients in the formulation, as well as with oxygen in the air. Such interaction can greatly inhibit the active compound’s efficacy and bioavailability to the skin. It is often difficult to use higher levels of the active compound in the formulation because this may cause skin irritation or toxicity as a result of the strong cellular metabolization. Repeated product application using low active levels may effectively solve such problems, but application of a cream every two to three hours does

The enzymatically activated encapsulation technology that is described in this chapter is a true biodegradable-drug delivery system (Bio-DDS). In this system, there is no modification of the physical or chemical properties of the formulation. Further, the system is environment insensitive and no change in the environment can induce release of the active compound. This specific encapsulation approach provides formulations that are stable in the challenging environment that the cosmetic chemist must address. This approach provides a high level of comfort that the active compound will only be released when the formulation containing the encapsulate is applied to the skin. Enzymatically activated encapsulates can be considered as very small reservoirs comprised of biodegradable polymers. Such systems have considerable advantages. For example, they are biocompatible and provide a non-toxic transport system for the actives chosen. They act as an active compound protector, and enable the development of a progressive release system for active ingredients. The approach also provides a tool for modulation and control of active ingredient penetration. It is a perfectly adapted delivery system for innovative and effective cosmetic formulations.

PERRIER, HART: SMART VECTORIZATION

37.2 The “Eureka!” Moment Coletica was founded in 1985 by researchers who were working on collagen research for the leather industry. This work was carried out in the French Technical Research Center, located in Lyon, France. One of the most abundant by-products of the leather industry is collagen obtained from the animal’s skin. Since the 1970s, this research team had been evaluating different applications for leather by-products and found some very interesting applications for collagen. One main application uncovered was the production of collagen dressings or collagen powders. These could be used as medical devices, in view of the high haemostatic properties of this molecule. During surgery, the collagen dressings were used to prevent bleeding. Further, the collagen dressings had the advantage of being biodegradable and could be kept in the body after surgery. Due to the high filmogenic properties of the collagen molecule, the research team found another interesting application in the cosmetic industry using the solution of collagen for many of its unique properties. Originally, the collagen employed was extracted from bovine skin but in view of the trends for less use of animal-based materials, the collagen is currently extracted from the skin of flat fish. Collagen spontaneously produces a strong, mechanically resistant film after drying. This is a phenomenon that only occurs with this protein and, as such, provides an unusual utility in personal care applications. Interestingly, during the same time as the leather research work, Coletica had the opportunity to meet Professor M. C. Levy (CNRS, University of Reims, France), who was working on microencapsulation for pharmaceutical applications. The professor’s process employed human serum albumin as a main ingredient to produce the core of the microspheres she was making. These microspheres were being used for the encapsulation of drugs in order to provide a slow delivery profile when ingested in the human body. Albumin was the protein of choice in this work because it was the only one acceptable for pharmaceutical-grade microspheres. Coletica had the idea to substitute collagen for the human serum albumin in the same process. The main obstacle in accomplishing this was that it was impossible to obtain a collagen solution at pH above 7.5 without precipitating it. For this reason, and in view of

799 Coletica’s previous experience in medical device preparation, glycosaminoglycans were added to the collagen solution. With this approach, a perfectly stable complex was obtained between the two polymers that was allowing a process to be successful at a pH above 9. This breakthrough made it possible to use collagen for the encapsulation process. The replacement of human serum albumin by collagen was successfully demonstrated on a lab scale and samples were presented to two companies in the cosmetic industry. Both of these companies then decided to use them immediately. Since the process had only been tried on a lab scale, it then became urgent to produce large batches suitable for commercial purposes. After much development work, Coletica was finally successful in 1986, two products were being marketed and “microencapsulation for cosmetic applications” was born. Since 1986, patents have been broadly filed on this technology. These patents cover the use of different natural proteins, peptides, natural polysaccharides and oligosaccharides, and synthetic polymers, using the initial encapsulation technology. The work has also been extended to production of microcapsules (and spheres) as well as nanocapsules (and spheres). In view of this key intellectual property foundation and commercial products based on it, Coletica is now considered as one of the leading companies in this field.

37.3 Limits of Current Technologies The term encapsulation covers a wide variety of technologies. Distinctions within this broad class of technology can be made depending upon the industrial area of application involved.[16] In the cosmetic field, many techniques are available and this makes the choice of an optimal approach for the formulators quite difficult. In order to narrow the choices of technique to the most appropriate ones, there are two questions that are important to consider when selecting the most appropriate encapsulation technology. What is the purpose of encapsulating a particular active compound? For example, is the purpose to modulate the rate of penetration, to address

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the actives potential for instability, or to obviate reactivity issues, and so forth? By what means, and at what time will the active compound be released? With answers to these fundamental questions in hand, it is then possible to easily classify available encapsulation technologies in order to select the optimal method for use during the development of a cosmetic formulation.

37.4 Overview of Trigger Release Mechanisms The most important question to answer before selection of the appropriate encapsulation method is, “How will the release of the encapsulated active compound be triggered?” Most of the encapsulation technologies employed in the pharmaceutical, food, or glue industries are not appropriate for use in the cosmetic field. Very acidic pH such as in the stomach, which is a pH of 2, very high temperature such as the 80°C reached during cooking for release of flavor, or strong mechanical strength, are not relevant for cosmetic purposes. For this reason, a variety of specialized technologies have been employed to trigger the release, for cosmetic applications of useful active compounds.

37.4.1

Release with Change in Pressure

It is possible to produce a release of the encapsulated active compounds under finger pressure, right after application on the skin surface. Active release may also be provided just inside the pump mechanism, as a result of pumping the formulation out of the packaging and just prior to skin application. Microspheres and microcapsules that have a diameter above 200 µm are typically employed for products that require a release with application of pressure. These have an outer membrane that is crosslinked and, at this particle size, the microcapsules and microspheres are sensitive to finger pressure. As a result, the outer barrier of the microcapsule/sphere will be ruptured as the application or dispensing force is applied. The larger the sphere, or capsule, the more sensitive it will be to

the pressure applied. This phenomenon can present a potential processing difficulty because the pressure sensitivity makes it difficult to use the microspheres or microcapsules in the industrial processing equipment used for pumping or stirring during manufacture. Spheres as large as 5 mm can be used for this type of release. Such spheres are called “beads” or “millispheres,” since their size is typically in the millimeter range. In these cases, a high degree of crosslinking of the outer encapsulating barrier is required. The resulting increase in strength makes the membrane barrier less soluble and less shear sensitive. This increased strength avoids potential breakage during industrial handling. Sphere membranes are typically prepared by simple coacervation, complex coacervation, and interfacial polymerization. Each of these methods is described in Sec. 37.5.

37.4.2

Release with Change in Temperature

Another technique that may be used to trigger the release of an active compound is temperature. In this approach, the idea is to obtain the release of the encapsulated material at a temperature corresponding to a specific temperature reached during the use of the capsules. For example, a substance that can undergo a sol/gel transition at a specified temperature change can be successfully employed when used below the melting temperature. If the melting point of the gel material is close to the temperature used during the release process, the gel will convert to its liquid (sol) form and thereby release the active. Many applications for this type of microcapsules are found in the food industry. During cooking or baking, the temperature will reach a level that allows melting of the synthetic or mineral waxes. It can also be used with hydrogenated vegetable oils and olefins as well. This technique is highly useful to induce the release of encapsulated active ingredients such as aromas. Cosmetic applications for products that employ a sol-gel transition are difficult to develop because the triggering temperature of the skin (32°C–37°C) is within the range generally used for stability studies (-10°C to 50°C). Thus, microcapsules must be stable in the latter range and demonstrate no tendency toward disruption of the membranes. This

PERRIER, HART: SMART VECTORIZATION same temperature range is also typical of what is observed during the manufacturing of cosmetic formulations. This too is undesirable since it would allow the release of the encapsulated ingredient during the manufacturing of cosmetic formulations. This specific technology has been developed for the encapsulation of ascorbic acid in a synthetic wax and has been proposed for use in the cosmetic field. Since such products are usually produced using a technique called simple coacervation, or simple gellification. With this technique, a substance that has the ability to gellify is mixed with the active substance to encapsulate, the resulting mixture is dropped into a gellifying agent, which produces an insoluble barrier around the encapsulated material.

37.4.3

Release with pH Change

Variations in pH may also be employed as a useful trigger for the release of encapsulated active compounds. The concept here is to design the release of the entrapped material at a pH corresponding to a pH value reached during the use of the active compound. For example, producing microcapsules or microspheres that are degraded at acidic pH will allow the release of the encapsulated active compound in the stomach, which is very acidic. This approach is widely used for encapsulating certain pharmaceutical active compounds[18] that must be released in the stomach for instance. Examples include oral intake and delayed delivery in the stomach. These approaches typically improve the drug bioavailability in the body. Triggering actives release by means of pH variation is very difficult to achieve in cosmetic applications. The pH of cosmetic formulations is normally between 5.0 and 7.0, while the pH of skin is about 5.5. This difference in pH does not allow a variation wide enough to induce significant active release and take full advantage of this concept. Microcapsules with a membrane based on pH sensitive polymers, such as polylactic or polyglycolic acids, have been proposed in the pharmaceutical field. In these cases, the microcapsules are usually produced using a technique called “solvent evaporation.” With this method, the polymer is first solubilized in a low boiling point solvent that is water im-

801 miscible. The active compound to encapsulate is then dissolved in the resulting solvent. The resulting solution is then poured into water, under agitation, in order to emulsify it and produce an emulsion. Finally, the solvent is removed by heating under vacuum. The resulting particles are then intensively washed and dried. The dried product is sometimes pressed into tablets for use in pharmaceutical products.

37.4.4

Release by Osmotic Pressure

Another approach to trigger the release of entrapped active compounds makes use of variations in osmotic pressure. The concept in this case is to obtain the release of the active material, which is generally adsorbed onto the highly porous surface of synthetic particles, and then released over time by a desorption process. These materials are known as micro- or nanosponges. Micro- or nanoencapsulation technology differs from this entrapment process because the membrane of a microencapsulate sphere is formed around particles or droplets of active compounds while, in the entrapment process, the active is “soaked” into a porous polymeric particle. For cosmetic applications, the “loaded” microor nanoparticles will release their entrapped active compounds after contact with skin. This release is a result of the need for the active compound to equilibrate its concentration in this new environment. While this is an appealing idea for release on the skin’s surface, the phenomenon is also at work within the formulations themselves. Thus, equilibrium forces are at work in the formulation relative to adsorbtion/ desorbtion of active compounds at oil/water interfaces. The approach is generally unsatisfying because of the low-use level of actives in formulations containing sponges. However, by careful selection of formulation components, this type of delivery system can be commercially feasible. In fact, this method is, in some cases, the only way to obtain delayed release effects in inexpensive formulations. This is so because the microsponge/nanosponge technology is generally less expensive than classical microencapsulation processes. Even if triggering active release through osmotic variation is not widely used in cosmetic applications, some ingredient labels report loaded nanosponges or microsponges for formulations containing entrapped retinol, for instance.

802 37.4.5

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Molecular Encapsulation and Release

The technology of release by osmotic pressure has been employed with “molecular” encapsulation of active compounds in alpha-, beta- or gammacyclodextrins. In this case, one molecule of active compound is encapsulated, or more precisely actively entrapped, in the hydrophobic cavity of one molecule of cyclodextrin. This approach provides yet another way to obtain release by osmotic pressure. Such applications have also been described in the literature. In particularly, it has been cited in anhydrous cosmetic formulations, where the encapsulated active compound is poorly exchanged among other ingredients of the formulation during the fabrication process or the storage period of the cosmetic formulations themselves. Applications are found for triggered release by osmotic pressure changes in the pharmaceutical industry. This is especially true when cyclodextrin powders are used in a dry form. In this case, the osmotic pressure release mechanism is invoked just after contact with moisture in the mouth or stomach. This approach is simply to demonstrate. Calculations can be made to model and simulate such a release.

37.4.6

Release by Enzymatic Digestion

Biodegradable polymers can be employed as constituents of the microsphere or microcapsule membranes. These polymers can be used to trigger the release of encapsulated active compounds. The goal, in this case, is to obtain release of the entrapped material after application of the particles onto the skin surface. Active release is directly linked to enzymatic digestion of the polymers. In this approach, the triggering mechanism is very specific because the encapsulated active compound is only released when the microsphere or microcapsule is in contact with some enzymatic activity on the skin’s surface. With the exception of cosmetic formulations purposely containing enzymatic hydrolytic activities, microspheres or microcapsules are able to release their encapsulated active compounds when they are in contact with skin only. This concept is the basis of a patented delivery system, also called “Bio-DS” (for

“biodegradable delivery system”). This technology has been developed and promoted by Coletica since 1988.

37.4.7

Enzymatic Release: An Exact Approach

Protease enzymes are naturally present on the skin surface, examples include stratum corneum trypsic enzyme (SCTE) and stratum corneum chymotrypsic enzyme (SCCE). Both of these enzymes have been widely described in the literature.[1][2][4]–[7][12][14][15] Other enzymes present on the skin’s surface are proteases that are secreted by microorganisms. Additionally, amylasic activity is present on the skin’s surface in areas such as on or around the lips, where saliva is regularly present. Some microorganisms are known to be present on the skin’s surface under very specific conditions.[3][8][10][13][17] These microorganisms provide enzymatic activity in the area where they are concentrated and this activity is sometimes due to pathologic situations. One example is pityrosporum ovale, which is mainly responsible for the microbial constituent of dandruff. Another example is the existence of staphylococcus aureus, staphylococcus epidermidis, and propionibacterium acnes that are primarily responsible for the microbial constituent of acne lesions. The selection of polymers that can be easily degraded by one of these specific enzymes, or microorganisms is a “smart” way to target the delivery of an active compound to the required site of action. This released mechanism is coming into wider use now because delivery can be achieved by using an exact approach. For pharmaceutical applications, this enzymatic release method is known as “second-generation DDS,” where the acronym DDS stands for drug delivery system. The ability to target the release to a specific cell, or zone on the skin, can be achieved using these delivery systems. In the pharmaceutical field this is referred to as “third-generation DDS.” Magnesium ascorbyl phosphate was encapsulated into microspheres based on wheat protein and acacia gum. Three formulations containing free magnesium ascorbyl phosphate, or one of those two cap-

PERRIER, HART: SMART VECTORIZATION sules were applied on human skin. After 1, 2, and 4 hours, D-squame® were taken from the skin and the vitamin content was analyzed by HPLC. It is demonstrated that the wheat based microspheres liberate their content very rapidly without inducing any storage of the vitamin in the skin, acacia-based microspheres were able to allow an increased bioavailability of the vitamin. (See Fig. 37.1.)

37.5 Encapsulation Technologies Applicable to Enzymatic Release Micro- and nanocapsules, or spheres, can be produced using a number of techniques to create encapsulation barriers by means of biodegradable polymers. These techniques are explained in the following sections.

37.5.1

Formaldehyde- or Glutaraldehyde-Based Techniques

Complex coacervation. This technique employs two natural biodegradable polymers of opposite charge. One commonly used pair of such polymers is alginate and gelatin. Using this example, gelatin is first dissolved into water at an acidic pH, normally below 6, in order to obtain visible positive charges along its chemical structure. Then, in a separate water solution, alginate is dissolved at a basic pH, normally above 8, in order to obtain negative

803 charges along its chemical structure. The active compound that has to be encapsulated is then mixed intensively with this solution. After good homogenization, the alginate phase is poured into the gelatin phase under intensive mixing, and the temperature is raised until reaction between alginate and gelatin has occurred. The polyanionic-polycationic insoluble polymer that is formed around the active compound induces an encapsulation of the materials. Because this polymer is made with ionic bonds and not covalent bonds, a further reticulation step needs to be performed to fully insolublize the membranes. With this process formaldehyde or glutaraldehyde reticulation is always used to avoid the swelling and loss of capsules when they are used in water-based formulations. Simple coacervation. This technique, for example, can employ calcium alginate beads reticulated with formaldehyde or glutaraldehyde. In this case, sodium alginate is solublized in water and the active compound that will be encapsulated, usually an oil, is emulsified into the gel that is produced. This emulsion is then released, drop by drop, into a gellifing media based on calcium chloride (CaCl2). When in contact with calcium, sodium alginate reacts and forms insoluble polymers based on calcium alginate. The resulting capsules are unstable in water-based media due to calcium diffusion outside the membrane. To completely insolubilize the membrane, a further reticulation step is necessary. It is usually performed again using glutaraldehyde or formaledehyde as a reticulation agent.

37.5.2 Non-Formaldehyde- or NonGlutaraldehyde-Based Techniques Interfacial polymerization. This process uses two sets of reactive monomers. These sets will react with each other, but must be soluble in opposite solvent polarity to create the capsule.

Figure 37.1 Drug release effect of wheat- and acacia-based spheres (∗: statistically significant, Student test, p < 0.05).

The interfacial polymerization reaction is shown in Fig. 37.2. The two monomers X and Y react at the interface to form a polymer (XY)n. The monomers could be included in the same or on the opposite phase.

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monomer couples that were used are diamine/ dicarboxylic acid and dialcohol/dicarboxylic acid, respectively. Diamine compounds, the most reactive monomers, are not acceptable for use in cosmetic formulations by international cosmetic regulations. Therefore, in order to develop Coletica’s microencapsulation technology using an interfacial polymerization process, other more acceptable compounds such as di- or polyamines were evaluated. One approach employed the use of natural polyamines such as proteins, or peptides in the form of amino-based monomers. Another approach employed using natural polyols such as oligosaccharides, polysacFigure 37.2 Interfacial and in situ polymerization reactions charides, and cyclo-oligosaccharides as alcoholic used to form microcapsules. Reactants: X, Y; polymerization function-based monomers. These ingredients product: —( X—Y )— or —( X )—. n n were selected from the family of biodegradable natural substances and this allowed for the formaInterfacial polymerization is widely used by tion of a range of biodegradable microcapsules deColetica as a new and smarter encapsulation propending on the monomer selected. Each membrane cess. The method allows the formation of covalent created in this manner can be designed to have a bonds between different molecules during the endifferent sensitivity to different protease enzymes capsulation process. In all other techniques of enand, therefore, opening the door for many powerful capsulation besides interfacial polymerization, a possibilities. cross-linking reaction needs to occur. The first step is designed to create ionic or hydrophobic bonds. Transacylation. Using trans-reaction of acaOnce these bonds are created, the second chemical cia and propylene glycol alginate macromolecules, cross-linking reaction produces covalent bonds this technology is inducing the formation of polymeric around microsphere or microcapsule structures. membranes in a very gentle way without any temperature or pH variations. When using this system, By contrast, with the prior art encapsulation techthere are no cross-linking agents involved, creating nologies described above, interfacial polymerization a perfect technique for the encapsulation of highly differs significantly on this approach. An emulsion sensitive active compounds or substances such as is formed from the two phases. Each of the phases enzymes or living cells. contains a reacting monomer. Thus, one reactive monomer is solublized in the oil phase and the other Transacylation reaction. The amine functions reacting monomer is solublized in the water phase. of acacia could react with the carboxylic acid of In this process, the oil phase is emulsified in the wapropylene glycol alginate to form acacia alginate with ter phase using constant stirring. During the emulsithe release of propylene glycol. This reaction ocfication process, a polymer is formed at the intercurs under very mild conditions. (See Fig. 37.3.) face and this polymer forms a membrane around the encapsulated active compound. Depending upon the solubility of the active compound, it can be placed in either the water or oil phase of the emulsion. The oldest application of interfacial polymerization processes is believed to be for the fabrication of textile fibers such as Nylon ® or Polyester®. In these two cases, the

Figure 37.3 Transacylation reaction.

PERRIER, HART: SMART VECTORIZATION The newest interfacial polymerization technology is known as transacylation. This encapsulation technique is very useful to encapsulate active ingredients that may be sensitive to oxidation or other types of degradation. It can be successfully used for the encapsulation of living cells and enzymes. In this approach, the wall of the microcapsule is formed by trans-polymerization of acacia gum and propylene glycol alginate macromolecules. Acacia is the result of air-dried gummy exudates, from the stems and branches of Acacia Senegal L. Willdenow, or from other related African species of Acacia. This complex polysaccharide is widely used in cosmetic, pharmaceutical, and food industries for its binding and emulsifying properties. The other compound used, propylene glycol alginate, is the result of the esterification of alginate using propylene glycol. The alginates that are usefully employed in this process are polysaccharides that have been extracted from brown algae. This algae has been known for centuries by the Chinese and Romans, and was widely used for both medical treatments and cosmetics. Most of the brown algae today are found on the rocky coasts of the North Atlantic, and mainly in the USA, Great Britain, France, and Norway. The reaction of the amino groups of the acacia macromolecules with an ester group of the propylene glycol alginate results in the formation of a strong covalent amide bond (also referred to as a “peptide” bond). The reaction mechanism involves the migration of acyl groups in an alkaline medium. The amino group present induces a nucleophilic substitution of ester functions with the release of propylene glycol. The resulting propylene glycol is then easily removed by a simple water rinse.

37.6 Micro- and Macrosized Particles for Enzymatically Activated Technologies Many applications have been developed for microcapsules and microspheres in cosmetic applications. Some of Coletica’s tradenames for these micro delivery systems are known as Thalasphere®, Phytosphere®, and Cylasphere®. Using these technologies, it is possible to topically target and delay the delivery of active compounds such as vitamins,

805 bactericides, collagen boosters, fragrances, anti-oxidants, and UV filters. Examples of targeted delivery include cosmetic treatment of oily skin, dandruff treatment, and bactericidal activity targeted on the microorganisms involved in anti-perspirant and deodorants. Other examples include anti-aging formulations and delayed release of fragrances. Some of the components of the membranes that have been used to create Coletica’s micro-delivery systems are marine collagen, wheat protein, soy protein, lupine protein, pea protein, locust bean gum, acacia, cyclodextrins, oligosaccharides, guar, and cellulose derivatives.

37.6.1 Marine Collagen Historically, the first biodegradable polyaminopolymer that was used in Coletica’s fabrication process of a microsphere or capsule delivery system was collagen. This polymer is now extracted from the white side of flat fish and demonstrates extraordinary film-forming properties. This capability makes this polyamino-polymer an excellent candidate for membrane formation during encapsulation process. Marine collagen has a very high quality in terms of its mechanical resistance, and also provides mildness during skin application. These unique properties are very difficult to mimic with any other polymer, and the material is widely used in the cosmetic field. The first step in the encapsulation process of a hydrophilic or lipophilic active compound using marine collagen is to solubilize it in a water-based gel of marine atelocollagen. The resulting solution is then poured into a low-viscosity fatty ester. In some cases, this emulsification process may be enhanced by the addition of a surfactant, under controlled stirring. Once the initial emulsion droplets are obtained, the interfacial polymerization is then initiated at the oil/ water interface by adding a dicarboxylic acid, such as azelaic acid or sebacic acid, in their reactive forms of dianhydrides or dihalides. The carboxylic acids then react with the lateral amino groups of the collagen and form covalent amide groups. This reaction forms a membrane around each droplet. Thus, once the interfacial polymerization is complete, these droplets are transformed into individualized microspheres or microcapsules that contain the

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active ingredient. The microparticles are then separated from the fatty ester media by centrifugation and washed intensively using fatty esters. Therefore, they are washed with water until all the impurities are removed and a concentrated suspension is obtained. The resulting microparticles are then suspended in a selected media that is compatible with the intended cosmetic formulation. Using the technology described above, the resulting products are known as Thalasphere®. Thousands of different active compounds have been encapsulated with this method, and the resulting products are widely used in various cosmetic formulations. Examples of these include oil- in-water or water-in-oil emulsions, water-based or oil-based gels, and anhydrous preparations as well. Examples of the latter include lipsticks, mascara, foundations, and various creams and gels. Thalaspheres are sensitive to degradation by specific proteases, such as trypsin and chymotrypsin. These proteases are naturally present on the skin’s surface. Thalasphere technology is often selected when a formulator wants to provide the controlled release delivery of an active material in a skin care product.

37.6.2 Plant Proteins Applying the same technical principals used to create the Thalasphere, Coletica created the Phytosphere® technology using plant proteins for the formation of the microsphere barrier. Various plant proteins have been used for this technology and they include high molecular weight wheat protein, pea protein, lupine protein, soy protein, and corn protein. In these cases, as previously described, the amino groups of the proteins are reacted with reactive forms of the dicarboxylic acids, in order to form amide linkages. The microspheres and microcapsules thus obtained using different membranes have a different sensitivity to proteases that are present on skin’s surface. For example, when the membrane of the Phytosphere is formed with wheat protein, it is more sensitive to the enzymes released from the bacteria typically found under the arms. This property could be useful when developing a product for anti-perspirants or deodorants. Different membranes

could then be selected depending on the expected properties of the final formulated product.

37.6.3 Polysaccharide-Based Encapsulation The Phytosphere technology has been extended to include the use of natural biodegradable polymers containing hydroxyl groups. Examples include plantbased polysaccharides or oligosaccharides. Various molecules used for this approach include locust bean gum, guar gum, acacia gum, cellulose derivatives, alginate derivatives, and cyclodextrins themselves. These latter materials typically used as molecular encapsulates can also be used as polymers in the Phytosphere interfacial polymerization process. This approach provides a double encapsulation system that is particularly efficient for the slow release of low molecular weight and partially hydrophobic active compounds. In this case, as described previously, the hydroxyl groups of the proteins are reacted with reactive forms of dicarboxylic acids and form ester bonds. By means of this approach, it is possible to design membranes that have a specific sensitivity to different proteases found on the skin’s surface. For example, when the membrane of the Phytosphere is formed with locus bean gum, it is more sensitive to the amylase enzyme. Amylase is present in our saliva; therefore this type of Phytosphere could be useful in a product developed for the lip area.

37.6.4 Nanoencapsulation When the technologies presented above have been adapted for the production of particles that have sizes below one micrometer, the resulting products are called nanoparticles. The main difference between the above mentioned process conditions and the ones required to produce nanosized particles is the process used to produce the nanoemulsion. High shear rate or homogenization equipment is commonly used in this process in order to produce particles below 1 µm. In view of their small size, the nanoparticles are quite difficult to separate and wash from their suspension media. The final nano-Thalasphere and nano-Phytosphere suspensions are commonly

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used in cosmetic applications when penetration into the hair follicle or long-lasting release properties are desired since their ultra small size makes them valuable in this regard.

37.7 Properties and Performance of Micro- and Nanospheres and Capsules The time-dependent release mechanism of the active compound is potentially useful for a wide variety of applications.

37.7.1

(a)

Enzymatic Digestion In Vitro

It is possible to quantify the sensitivity of a micro- or nanosphere membrane with respect to different enzymes and characterize the time-dependent degradation in vitro. Using microscopic evaluation, different enzymes are combined, one at a time, with different microspheres. This technique enables an evaluation of the sensitivity of each microsphere to different enzymatic degradation. The time dependant enzymatic digestibility of biodegradable microspheres, using in vitro enzymatic digestion, may be followed using light microscopy.

(b)

Enzymatic sphere digestion. When microspheres are incubated in the presence of different enzymes such as proteases, these microspheres are digested and their active compound is released. This phenomenon is observed in Fig. 37.4a–c using light microscopy under mid-range enlargement (×20) at T = 3 and T = 24 hours after incubation. Ex vivo experiments may also be performed to follow the enzymatic digestion process using the Franz cell diffusion technique. The Franz cell diffusion device has two compartments, the donor compartment and the receptor compartment, separated using a human skin biopsy. The penetration versus time of active compounds, free or encapsulated, can be followed using standard analytical techniques on the samples taken on receptor media (see Fig. 37.5).

(c) Figure 37.4 Enzymatic sphere digestion at (a) T = 0, (b) T = 3 h, and (c) T = 24 h.

808

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS example of such a target site is the melanocyte cells and the situation where a degree of pigmentation modulation is desired. Another example is the targeting of the fibroblast cells involved in connective tissue formation through cell multiplication, or collagen synthesis.

Figure 37.5 Franz cell diffusion device.

Using this technique, the microspheres are applied on the surface of a human skin biopsy. This experiment can be conducted with or without enzymes that are able to degrade the membranes of the microspheres.[19] After twenty-four hours, the amount of active compound that is able to diffuse through the skin is then quantified by means of the most appropriate analytical technique. Most often, high performance liquid chromatography (HPLC) is used to measure the quantity of an active compound that has either penetrated through the skin or has been stored by the skin.

37.7.2

Using a Franz cell diffusion device quantification of the degree of penetration by encapsulated active compounds can be evaluated. With this method, the active compound is usually tested “free vs encapsulated.” Typically, the active compound is applied in the donor compartment on the surface of a human skin biopsy. Thereafter, the concentration of actives is measured in the receptor compartment by an appropriate analytical technique. Penetration is followed for twenty-four hours, and, the concentration of the “free” active is compared to the encapsulated active. Improvement in penetration is often due to the nature and quality of formulations used to transport active compounds across the skin’s barrier. Significant improvements in penetration can be obtained by using vectors of penetration that are based on deformable lipidic or amphiphilic structures such as liposomes, second-generation liposomes, nanoemulsions and inverted liposomes. Figure 37.6 demonstrates the enhanced penetration of an active compound that is specific for tyrosinase inhibition. Looking at the tyrosinase inhibition in the in vivo model, it has been possible to demonstrate that 0.3% of an active compound able to whiten the skin is four times more effective for this activity when used encapsulated than when used free.

Penetration vs Storage

One of the main capabilities of Coletica’s encapsulation technology is to modify and control the degree of skin penetration by the encapsulated active compound. In this regard, two main properties may be evaluated: improvement of penetration and sustained delivery effectiveness. Penetration improvement. There is often a need to improve skin penetration of an active compound when it is lipophilic or insoluble. Usually, such materials are either unable to cross the barrier function of the epidermis or they are unable to reach the target site deeper in the dermis. One

Figure 37.6 Percent tyrosinase inhibition comparing free vs encapsulated vitamin C-PMg.

PERRIER, HART: SMART VECTORIZATION In this figure (Fig. 37.6), a comparison has been made between the diffusion of an active by itself, compared to the diffusion through skin, of the same active compound that has been incorporated into a biodegradable protein-based liposome. As seen from the figure, a 40% improvement was detected using the Franz cell diffusion device. Biodegradable protein-based liposomes, also known as second-generation liposomes, may be observed using transmission electronic microscopy. (See Fig. 37.7.) Sustained delivery. In personal skin-care formulations when the active compound penetrates the skin too rapidly and in this process induces skin intolerance and irritation, there is a need to slow and control the rate of penetration. Such systems are called sustained delivery systems. They are primarily used in the pharmaceutical field to delay the rapid and deep diffusion of an active compound, some-

809 times called “burst effect” when such behavior produces severe and undesirable side effects. Quantifying sustained delivery profiles. Measurement of sustained delivery behavior for an encapsulated active compound can be performed in vitro using a Franz cell diffusion technique, or in vivo using tape stripping. These techniques are able to quantify the amount of active compound stored in the upper part of the epidermis. As we have stated previously, such studies are normally conducted to compare the concentration of free active compound to the concentration of encapsulated active compounds ability to penetrate, to be stored and to be slowly released. The first step is to measure penetration. This is measured by the amount of active compound that can pass through the skin biopsy into the receptor compartment in the first 24 hours. In the second step, the skin biopsies are then rinsed, and the amount of active compound able to pass across the biopsies is collected in the receptor compartment for the next 24 hours. The amount of active released after rinsing is called “release.” The release is a measurement of the amount of active compound stored in the skin after the twenty-four hour contact and the rinse period. During the third step, the Franz cells are dismounted again and the skin biopsies are extracted with a solvent that is able to remove any trace amount of active compounds stored in the skin. The amount of active compound that can be extracted with the solvent is called “stored.” Figures 37.8 and 37.9 demonstrate diffusion, release, and storage of the active compound in the skin biopsy, when comparing free versus encapsulated concentration of active compound. Figure 37.8 shows that, using a Franz cell diffusion device, it is possible to follow the penetration of vitamin A into the skin versus the time. In this figure, it is possible to see that encapsulation reduces the penetration of this active compound providing a reservoir effect and a drug release property of this molecule into the skin.

Figure 37.7 Transmission electronic microscopy of second-generation liposomes.

Figure 37.9 is a comparison of the release and storage of free and encapsulated retinol. After twenty-four hours of diffusion using a Franz cell diffusion device (see Fig. 37.5), the human skin biopsy is dismounted and the quantity of retinol able to release by the skin during the next twenty-four hours

810

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS The release and storage improvements observed in Fig. 37.9 are due to the nature and quality of formulations based on microcapsules used to transport the active compounds. For a given formulation, significant improvements can be obtained using delivery systems that are based on non-deformable micro-/nanospheres or micro-/nanocapsules. These non-deformable structures stay on the surface of skin, thereby providing long-term storage on the top of the skin’s structure.

Figure 37.8 Diffusion of free vs encapsulated retinol.

Figure 37.9 Comparison of release and storage of free and encapsulate retinol.

is measured (release). After this time, an ethanolic extraction is performed on the biopsy and the quantity of retinol is evaluated (storage). This experiment demonstrates the increase of retinol content into the skin for those two parameters when retinol is used encapsulated compared to the free form. Figures 37.8 and 37.9 demonstrate the excellent ability of the right delivery system to slow down the diffusion of a very irritating well-known active ingredient used for its efficacy in the personal care field. Retinol, when applied directly to the skin is too harsh and will cause irritation. Using the Franz cell diffusion device, it is possible to demonstrate the ability of the delivery system to slow down the diffusion of the active for a progressive and mild delivery of the retinol through the skin. The storage and release parameters are both strongly improved allowing the retinol to become available to the skin over a long period of time for greatest efficacy.

The size of the particles is very important in controlling the increased storage capacity of the skin. Using microcapsules, with a median size of 50 µm, the storage capacity of the encapsulated active compound in the skin is approximately several hours. Longer storage times can be obtained for as much as a twenty-four hour period using nanocapsules with a size of about 500 nm. Nanoencapsulation made with non-deformable structures is different from liposomes, which are deformable structures with regard to their penetration effectiveness. Nanocapsules do not have the ability to enhance the penetration of active compounds but they are able to enhance the long-term delivery of the active compound, as well as the storage capacity of the skin for an active compound. This distinction is based on the ultra small size of the nanocapsule and hence their ability to migrate deeper into the stratum corneum than the larger microspheres or microcapsules. Hair follicle penetration. The hair follicle represents a powerful route of penetration through the skin. This pathway is interesting and useful for the delivery of active compounds designed for hair follicle treatment. Modified encapsulates can be used to store actives in the hair follicle. Keratolytic or anti-microbial active compounds are often used; examples include salicylic acid, a known active compound for acne treatment; Farnesol, for its anti-microbial activity; and azelaic acid, for its ability to reduce sebum production. Of course, special compounds for hair growth or hair removal treatments can be very beneficial for this type of targeted and enzymatically activated delivery. Certain active compounds can also be encapsulated in such delivery systems in order to enhance their penetration through the skin using the hair follicle as a pathway. One example would be an active compound that should penetrate into the deep part of the skin in

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order to modulate fibroblast activities or related enzymes. Such an active material could stimulate the production of collagen, or inhibit specific matrix metallo proteinase from damaging the connective tissue. To demonstrate the hair follicle penetration, a protocol developed by Coletica uses human skin or animal (rat or pig) biopsies, and grafts a fluorescent probe or dying agent onto an active compound. Biopsies are sliced and observed using fluorescent microscopy. By this means, it is possible to visually follow the penetration of the active compound inside the hair follicle. Quantification is done by computer image analyzing software. Figure 37.10a–d are examples of salicylic acid encapsulated in a biodegradable protein-based second-generation liposome and applied on skin biopsies. Skin biopsies are sliced perpendicular to the surface and observed under fluorescence microscopy. Three hours after application (Fig. 37.10b), the intense fluorescence is concentrated into the upper layer of the epidermis. After five hours (Fig. 37.10c), the fluorescence is on the epidermis and in the upper part of the hair follicle. After twenty-four hours (Fig. 37.10d), the fluorescence is maximized all along the hair follicle and a strong fluorescence is observable in the dermis. The figures demonstrate that this useful technique is able to measure hair follicle storage of cosmetic active compounds. Significant improvements of active compound storage in the hair follicles can be obtained using vectors that are nanospheres and/or nanocapsules that have non-deformable structures. As stated previously, these non-deformable structures are able to be stored in the hair follicles, thereby providing longterm storage or penetration through hair follicles. Results achieved are dependent upon the solubility properties of the encapsulated active material and this variable is important to be aware of during product development.

37.7.3

Pharmacokinetic

It is also possible to follow the biodelivery system effect of the different microencapsulate technologies when comparing the effectiveness of a concentration of encapsulated active compounds versus a concentration of free active compounds by

(a)

(b)

(c)

(d) Figure 37.10 Fluorescent salicylic acid in hair follicle: (a) control; (b) after 3 hours; (c) after 5 hours; (d) after 24 hours.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

means of in vivo experiments. The highest performing, and most relevant, tests are kinetic studies and these are usually performed in the pharmaceutical field. Using pharmacokinetics, the distribution in the body of a radio-labeled active compound, and the clearance of a selected radio-labeled active compound, both encapsulated and free, are followed over time in an animal. Figure 37.11 shows an experiment that has been done using this methodology. Three formulations (oil-in-water emulsion) containing free or micro- or nanoencapsulated paba was applied once on animal skin. The pharmocokinetic of this radioactive compound versus time was followed in the urine of animals (Fig. 37.11a). Used free, the major amount of the active is secreted within the first two days, which indicates a massive penetration and elimination of this compound sometimes called a burst effect. The encapsulation of this active com-

pound into micro- and nanocapsules allows a strong reduction of this release and a slow delivery. The bioavailability of the active into the skin was also measured (Fig. 37.11b). Seventeen days after the single application, human skin biopsies were analyzed for their active compound content. This figure demonstrates that a stronger content of active compound could be detected in the skin when nanocapsules have been used compared to the quantity that is able to be detected using microencapsulated active compounds or free ones. The results demonstrate that not only the release effect of the radio-labeled compound is stronger with micro- or nanocapsules, but that the incorporation of this compound inside the tissue is greater. This study demonstrates there is an increase in the bioavailability of the active compound in the area of the skin where the active compound has been applied.

37.7.4 In Vivo Results

(a)

(b) Figure 37.11 Pharmocokinetic results of an encapsulated compound (radioactive paraminobenzoic acid) used free and in micro- and nanosize particles. Radioactivity recuperated into the (a) urine and (b) skin.

Some other tests can also be performed to show efficacy upon release of the active compound. One example is the whitening effect obtained from an active delivery system using an induced pigmentation model. Other tests can be performed such as HPLC analysis of tape stripping materials removed versus time. Such tests are typically conducted after application to the skin’s surface of both the encapsulated and free active compound. Figure 37.6 shows the sustained delivery of magnesium ascorbyl phosphate. This active compound is a vitamin C derivative and is commonly used in cosmetic formulations. However, because of its poor bioavailability to the skin, it is typically not useful unless it is incorporated into an appropriate delivery system. Coletica commonly used the Phytosphere and

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Thalasphere technology to successfully achieve the delivery of this active.

37.7.5

Membrane Selection

Membrane design for the microencapsulation of active compounds into microencapsules or rigid nanoencapsules can be powerfully tailored. This approach is based on knowledge of microorganisms or enzymes present at the site where the encapsulated active compound is to be applied and released when the encapsulate encounters the microorganism enzymes that will digest the encapsulate. Figure 37.12 demonstrates the sensitivity of five different membranes to degradation by the enzyme trypsin. This enzyme is naturally present on the skin’s surface. Different microspheres were prepared using different polymers such as acacia, locust bean gum, cyclodextrins, marine collagen, or wheat protein. After incubation with trypsin, active compound release was evaluated and the polymers could be ranked from the susceptibility of enzymatic hydrolysis. It is clear from this study, that a microsphere membrane based on wheat protein is far more sensitive to degradation by trypsin than one based on locust bean gum, cylclodextrin, collagen, or acacia gum based spheres. Thus, by tailoring the delivery system to the enzymes typically present at the targeted delivery site, a whole new technology has emerged that provides formulators with a novel approach and a range of new product distinctions.

(DDS) in the pharmaceutical field. Cosmetic chemists and biologists regularly follow the development and evolution of these new drug delivery systems. There is now a significant interest, and enhanced understanding in the use of such delivery systems because stronger and stronger active compounds are now being used. Some of these may present some undesirable side effects. Cosmetic delivery systems based on enzyme-triggered technology are now available as tools that should be present in formulator’s minds when vectorization, penetration, slow delivery, and better tolerance of active compounds are desired. Many companies are now using Coletica’s “Smartvectors®,” that are able to bind onto hair, skin keratins, eyelashes, or oily areas of the face. These Smartvectors are able to release actives under very specific conditions. Enzymatically activated encapsulation is an emerging technology that suggests the possibility of many novel applications in the personal care field. The future holds great promise for the development and commercialization of new “smart-technologies” by finished goods companies. This calls to action a whole new line of thinking: product performance and distinction will be based on active release generated by a host of new triggers resulting from skin changes that occur from chemical and physical stressors, and UV stressors such as solar light irradiation, etc.

37.8 Perspectives and Conclusions Today, cosmetic chemists cannot use encapsulated active compounds without first thinking about how to trigger their release, and then thinking about how to target the release. Triggering and vectorizing represent the second and third generation of drug delivery systems

Figure 37.12 Enzymatic hydrolysis of different types of microspheres by trypsin (3.32 MU/g of wet spheres).

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37.9 Formulations Two example formulations containing “Bio-DS” microcapsules are presented here. These delivery

systems are usually very stable, and should be introduced at the end of the formulation process, after the emulsification step, at a temperature below 50°C, generally 30°C.

Formulation 37.1: Anti-Aging Serum

Phase

Trade Name

Ingredient Function

Eumulgin B 2

Solubilizing agent

Ceteareth-20

2.00

Cognis Care Chemicals

Aramol E

Skin conditioning agent

PPG-15 Stearyl Ether

1.20

Uniqema Americas

Brij 92

Emulsifying agent

Oleth-2

2.00

Uniqema Americas

Dow Corning 344 Fluid

Skin conditioning agent

Cyclomethicone

2.80

Dow Corning

A

Water B

C

D

E

INCI

Weight/ Weight%

Water

q.s. 100

Supplier

Carbomer 934

Thickener

Carbomer

10.00

Noveon

Atlas G-2330

Humectant

Sorbeth-30

5.00

Uniqema Americas

Coletica Microbiocide

Preservative

Phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben

0.50

Coletica

Butylene Glycol

Humectant

Butylene glycol

0.50

Universal PreservA-Chem, Inc.

Hyasol

Mositurizer

Sodium hyaluronate

1.00

Pentapharm/ Centerchem

Retinol Cylasphere

Encapsulated retinol for antiaging benefits and time release delivery

Water, butylene glycol, glycine soja (soybean) oil, retinol, carbomer, tocopherol, acacia senegal, propylene glycol alginate.

1.00

Coletica

Manufacturing Procedure: Prepare the A Phase by stirring the ingredients at 80°C, under vigorous stirring, and then allow to cool down under moderate stirring. When Phase A/B is at 40°C, add Phases C, D, and E while stirring. Continue stirring until the emulsion is perfectly homogeneous. At room temperature, adjust pH at 6.0–6.5

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815

Formulation 37.2: Anti-Age Day Cream

Phase

A

Trade Name

Function

Supplier

Opacifing agent

Myristyl alcohol

5.00

Cognis Care Chemicals

Crodacol CS-50

Opacifing agent

Cetearyl alcohol

3.00

Croda Inc.

Cetiol J600

Emolient

Oleyl erucate

3.00

Cognis Care Chemicals

Miglyol 812 Neutral Oil

Emolient

Caprylic/Capric triglyceride

2.00

Sasol Germany GMBH-Witten

Cropure wheatgerm

Skin conditioning agent

Wheat germ oil

4.00

Croda Inc.

Dow Corning 344 Fluid

Skin conditioning agent

Cylcomethicone

3.00

Dow Corning

Span 60

Emulsifying agent

Sorbitan stearate

2.17

Uniqema Americas

Tween 60

Emulsifying agent

Polysorbate 60

2.83

Uniqema Americas

Water

q.s 100

Urea

Humectant

Urea

0.50

EM Industries

Sorbitol

Humectant

Sorbitol

1.00

Merck KGaA

Preservative

Phenoxyethanol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben,

0.75

Butylene glycol

0.75

Pentapharm/ Centerchem

Water, butylene glycol, magnesium ascorbyl phosphate, xanthan gum, ceratonia silica gum

3.00

Coletica

Phenonip

Skin Butylene glycol Conditioning Agent

C

wt./wt.%

Lanette 14

Water

B

INCI Name

Vitamin CPMg Phytosphere

Anti-aging encapsulation system for Vitamin CPMg

Manufacturing Procedure: Heat Phase A and Phase B to 80°C Add Phase B into Phase A while stirring When phase A/B is at 30°C, add Phase C while stirring. Continue stirring until the emulsion is perfectly homogeneous.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References 1. Burleigh, M. C., Barett, A. J., and Lazarus, G. S., Cathepsine B1; A lysosomal enzyme that degrades native collagen, Biochem. J., 137:387–398 (1974) 2. Ekholm, E., Brattsand, M., and Egelrud, T., Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process, J. Invest. Dermatol., 114:56–63 (2000) 3. Feagermann, J., Seborrhic dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory cells and mediators in the skin by immunochemistry, Br. J. Dermatol., 144:549–556 (2001) 4. Horikoshi, T., Arany, I., Rajaraman, S., Chen, S. H., Brysk, H., Lei, G., Tyring, S. K., and Brysk, M. M., Isoforms of cathepsin D and human epidermal differentiation, Biochimie, 80:605–612 (1998) 5. Horikoshi, T., Igarashi, S., Uchiwa, H., Brysk, H., and Brysk, M. M., Role of endogenous cathepsin D-like and chymotrypsin-like proteolysis in epidermal desquamation, Br. J. Dermatol., 141:453–459 (1999) 6. Joronen, I., and Hopsu-Havu, V., Separation and partial characterization of four cysteine proteinases from a human epidermal cell line, Arch. Dermatol. Res., 279:524–529 (1987) 7. Lundstrom, A., and Egelrud, T., Immunolocalization of SCCE in human skin and oral epithelium with monoclonal antibodies: evidence of a proteinase specifically expressed in Stratum using squamous epithelia, J. Histoch. Cytochem., 42:459–465 (1994) 8. Mackiowiak, P., The normal microbial flora, N. Engl. J. Med., 307:83–93 (1982) 9. Mast, B., Cohen, K., Diegelmann, R., and Lindblad, W., The skin, Biochem. Clinic. Asp., pp. 344–355 (1992) 10. Nishijima, S., Kurokawa, I., Katoh, N., and Watanabe, K., The bacteriology of acne vulgaris and antimicrobial susceptibility of Pro-

pionibacterium acnes and Staphylococcus epidermidis isolated from acne lesions, J. Dermatol., 27:318–323 (2000) 11. Peyreffite, G., Biologie de la peau, Cahier d’esthétique cosmétique, Ed., SIMEP, p. 98 (1993) 12. Redoules, D., Tarroux, R., Assalit, M. F., and Perie, J. J., Characterization and assay of five enzymatic activities in the stratum corneum using tape-strippings, Skin Pharmacol. Appl. Skin Physiol., 12:182–192 (1999) 13. Reverdy, M. E., Fleurette, J., Surgot, M., and Martra, A., Etude de flore cutanée normale des mains, du pli du coude et de l’avant-bras, Pathol. Biol., 30:92–96 (1982) 14. Susuki, Y., Normura, J., Hori, J., Koyama, J., Takahashi, M., and Hori, I., Detection and characterization of endogenous protease associated with desquamation of stratum corneum, Arch. Dermatol. Res., 285:372–377 (1993) 15. Susuki, Y., Koyama, J., Moro, O., Hori, J., Kikuchi, K, Tanida, M., and Tagami, H., The role of two endogenous proteases oh the stratum corneum in degradation of desmogelin-1 and their reduced activity in the skin of ichthyotic patients, Br. J. Dermatol., 134:460– 464 (1996) 16. Thies, C., Micoencapsulation, Encyclopedia of Polymer Science and Engineering, Vol. 9, John Wiley & Sons, Inc. (1987) 17. Till, A. E., Goulden, V., Cunliffe, W. J., and Holland, K. T., The cutaneous microflora of adolescent, persistent and late-onset acne patients does not differ, Br. J. Dermatol., 142:885–892 (2000) 18. Wells, J. I., and Rubinstein, M. H., Pharmaceutical technology: controlled drug release, Vols. 1 and 2, Ellis Horwood, Ltd. (1991) 19. White, J. S., and White, D. C., Source book of enzymes, White Technical Research, GROUP 1, pp. 407–423 (1997)

38 “Thinking Outside the Jars and Bottles” Delivery Systems for Unit-Dose Topical Delivery of Complementary and/or Incompatible Actives James A. Smith and Betty Jagoda Murphy ReGenesis LLC Montclair, New Jersey

38.1 Simultaneous Delivery Systems .................................................. 818 38.1.1 Why Two Different Actives At The Same Time? ............. 818 38.1.2 Eureka! Keep Active Separate Until Time of Use ............ 818 38.1.3 Packaging Descriptions and Functional Characteristics .... 818 38.1.4 Stability: Effective Solutions for Incompatibility ................ 822 38.1.5 Heightened Effectiveness Due to In Situ Mixing on Skin . 822 38.1.6 Marketing Benefits ........................................................... 822 38.1.7 Patchless Patch—Sustained Release of Actives ........... 823 38.1.8 Formulation Combinations that Fulfill Consumer Needs .... 823 38.1.9 TanDerm™ and SnapPack Manufacturing ...................... 824 38.1.10 Summary ......................................................................... 825 38.2 Sequential Delivery Systems ........................................................ 825 38.2.1 A Systems Approach to Skin Care .................................. 825 38.2.2 Eureka! Two Separate Products in a Back-to-Back Wipe .. 825 38.2.3 Advantages of Two Formulations Delivered in Sequence from a Single System .................................... 825 38.2.4 TwinDerm™ Packette: Description and Function ........... 825 38.2.5 Marketing Benefits ........................................................... 826 38.2.6 Sequential Combinations that Fulfill Consumer Needs ... 826 38.2.7 Packette Manufacturing ................................................... 827 38.2.8 Summary ......................................................................... 827

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 817–830 © 2005 William Andrew, Inc.

818

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 38.3 Simultaneous Delivery Formulations ............................................ 828 Patents ........................................................................................ 830 References ........................................................................................ 830

38.1 Simultaneous Delivery Systems 38.1.1 Why Two Different Actives At The Same Time? The consistently busy schedules of today’s women, particularly the majority of those who have careers both outside the home and in raising a family, have imposed great constraints on the time available for personal care. Additionally, the so-called “Baby Boomers” are a very active generation, with the desire and commitment to maintaining as vital and youthful an appearance as possible. In short, women of all ages and demographics are creating a market pull on our industry for products that combat and even reverse the uninvited signs of aging skin and hair. Moreover, these discriminating consumers want products that are multi-functional since they will shorten the time spent on achieving the desired effects of those treatments. While the men’s market currently lags behind those products now aimed at women, there are a growing number of men paying attention to what they use on their skin and hair in order to preserve a healthy, masculine appearance. They, like their feminine counterparts, want products that can provide the most effect with the least effort and “mess.” Marketing indicators point to the fact that skinand hair-care products with the greatest consumer appeal are those that offer multiple effects, have superior activity, are provided in the most convenient form, and can achieve all this without compromising effectiveness or sophistication. Consumers are even willing to pay a premium for multiple effect products. Unfortunately, combining two treatments into one formulation can present major obstacles to the formulator. Although there are well-researched active ingredients that are proven to have beneficial effects, when they are applied in combination, many of the key ingredients tend to react with each other.

Such materials may typically become unstable when combined and contained in a single formulation, thus making it difficult to combine two of them together in one formulation. Thus, while it is accepted that consumers would like single products to provide multiple benefits, current skin-care treatment technology requires their formulation as separate preparations with the recommendation that they be used in concert.

38.1.2 Eureka! Keep Active Separate Until Time of Use Since consumers are already creatively applying combinations of products and dermatologists are often suggesting skin-care regimens comprising first one skin treatment, immediately followed by a second or third one, it is apparent that a “two-in-one” single product would be highly desirable as a delivery system. In turning this concept into useful personal-care products, our objective was to ignore the dilemma of developing single products with stable combination formulations. Instead, our approach was to design and develop cost effective, convenient to use, single delivery systems that would completely segregate diverse formulations until the actual time of use. Upon “opening,” these systems would simultaneously deliver their active formulations for in situ interaction and effect.

38.1.3 Packaging Descriptions and Functional Characteristics Recognizing the desirability and advantages of offering consumers a convenient way to apply multiple topical dermatological preparations at the same time, and working under the premise that we would keep those preparations separate until the time of use, ReGenesis developed several unit-dose packaging systems which addressed this need.

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES TanDerm™ pack double action wipe. The TanDerm™ packette concept relies on the simple idea of utilizing two peelable, heat-sealable films to form a slim pouch. Two individual impregnated applicator plagettes are attached side-by-side to the bottom, inside surface of this “peel apart” pouch. After the plagettes have been appropriately impregnated with their specific formulation, the top layer of the pouch is heat-sealed to the bottom layer around each plagette. The heat-seal configuration provides an impenetrable barrier and compartmentalizes the plagettes. (See Figs. 38.1–38.4) In this system, the user peels away and discards the top layer of the pouch to expose the two impregnated plagettes affixed to the bottom layer. Holding on to the outside of this supporting bottom layer, the plagette side is placed against the skin and wiped over the desired area in a circular motion. The circular movement integrates the two different formulations and provides a simultaneous effect on the skin. While the TanDerm packette can be almost any size, the preferred size for most facial and small area skin-care applications is approximately 2" × 2" with the plagettes cut to ¾" × 1½". These plagettes are comprised of absorbent material stock, such as nonwoven, plastic foam, or even paper with a suitable heat-sealable backing that is used to affix the plagettes to the film. The TanDerm design enables the simultaneous delivery of a wide range of totally diverse, but complementary, skin-care treatments in a unit-dose, portable, and highly convenient packette.

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SnapPack multiple chamber applicator. The simultaneous delivery of a combination of assorted liquids, flowable gels, and powder formulations can also be achieved via a thermoformed multi-chambered system ReGenesis calls the “SnapPack.” Basically, the SnapPack design is composed of two or more plastic reservoirs that are filled with their respective formulations. Each of these is then heat-sealed to a flat cardboard/plastic board, which has a scored line whose purpose is to break open the chambers. (See. Fig. 38.5.) Like the TanDerm delivery design, the SnapPack can be produced in a range of sizes. The preferred size is one that conveniently fits in one hand, and is, therefore, approximately 4" long and 2" wide prior to use but becomes 2" × 2" during use. In use, the user holds both ends of the SnapPack board and “snaps” it in half, along the scored line. This bending action also breaks open each individual plastic reservoir. When the board is snapped, it folds in half against itself so that the two opposing ends of the SnapPack board come together. This action results in positioning the two thermoformed compartments in a back-to-back configuration. (See Fig. 38.6.) Holding the folded SnapPack in one hand, the user then applies pressure to both compartments with opposing thumb and fingers. This action squeezes the contents and causes them to flow out of their respective compartments, thereby mixing them together for a dual treatment delivery. (See. Fig. 38.7.)

10 - Dispensing applicator device 12 - Cover sheet 14 - Backing sheet 20 - Applicator pad A 22 - Applicator pad B 30 - Peripheral edges 32 - Peripheral edges 34 - Center heat seal 37 - Peripheral seal line 60 - Cover flange 62 - Backing sheet flange

Figure 38.1 TanDerm™ packette unopened and opened.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 38.2 To use TanDerm packette, peel apart front and back covers.

Figure 38.3 TanDerm applicator pads are kept separate until time of use.

Figure 38.4 Discard front cover. Applicator is ready for use.

Figure 38.5 To use SnapPak, break along score lines to create a dispensing comb.

Figure 38.6 SnapPak with both sides in a back-toback configuration.

Figure 38.7 To dispense formulations, press against the SnapPak compartments.

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES Depending upon the end use, several different designs of SnapPack are possible. In skin-care applications, where the ideal technique is a wipe on or dab on application method, a reticulated sponge pad may be attached over the score line between the two compartments to function as a static mixer as the two compartments release their contents into, and through, the sponge. (See Fig. 38.8.)

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In situations where the SnapPack will deliver ingredients to the scalp, the score lines on the board and thermoformed compartments are configured to resemble interlocking fingers. (See. Fig. 38.9.)

Figure 38.9 SnapPack as a comb-like device.

10 12 21 22 36 50 51 80 81 97 310

-

SnapPack dispensing device First surface portion Receptacle unit Receptacle Unit Exterior surface of chamber Proximal end of backboard Proximal end of backboard Interior chamber 1 Interior chamber 2 Attached applicator sponge structure SnapPack dual receptacle one sided dispensing device 312 - First surface portion 314 - Backing sheet 315 - Proximal End 320 - First receptacle unit 324 - Opening member 347 - Distal End 351 - Proximal End 364a-d - Extension members 365a-d - Opposite extension members 380 - Interior Chamber 384a-b - Possible subdivision of Interior Chamber 386 - Possible dividing wall 390a-d - Openings in extension members

Figure 38.8 SnapPack with static mixer sponge cover and as a comb-like device.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

When the pack is “snapped,” the score lines form comb-like hollow teeth capable of dispensing the formulations directly to the scalp through the “teeth” without wetting the hair. This design could be particularly useful in hot-oil and conditioning treatments where the ingredients are desired on the scalp but not on the hair.

38.1.4 Stability: Effective Solutions for Incompatibility Obviously, keeping incompatible formulations segregated until they are used effectively solves one aspect of the product stability issue. Of course, each formulation must be stable on its own. Preservation requirements are often simplified in these systems since the number of potential interactions is considerably reduced when one has to deal with stabilizing each individual formulation itself.

38.1.5

Heightened Effectiveness Due to In Situ Mixing on Skin

With the concern over incompatibility alleviated via the TanDerm and SnapPack approaches, the formulator can turn his/her attention to the outcome of the interaction once the treatments are incorporated on the skin. Novel benefits that would be difficult or impossible to achieve from a single formulation now become more easily attained by means of employing the interaction of two formulations. A whole new area of possibility opens to formulators with these simultaneous delivery systems. For example, combining a solution and a gel at the time of use can result in both a unique skin feel and, if desired, increased substantivity. Natural and organic-certified materials may readily be contained and delivered. Another benefit of these delivery technologies is a way out of dealing with typical stability issues associated with lotion development. In traditional skincare product R&D, current practice requires that the formulator must select the appropriate surfactant system to emulsify oils and other water-insoluble ingredients. Thereafter, stability testing has to be undertaken and it is often the case that acceleration methods may not reliably predict stability on room temperature aging. However, by using

TanDerm and SnapPack systems, and mixing at the time of use, the emulsification steps and stability issues are completely eliminated. Working with TanDerm or SnapPack systems, polymers and lotions containing active ingredients can be dispensed together. In effect, providing “patchless” patches that can deliver multiple treatment ingredients to the skin over time, and providing a time-release action. As previously stated, compartmentalizing skincare formulations allows the formulator to develop systems that are designed to react together upon mixing and, therefore, would simply not be possible in a single system. For example, employing the SnapPack concept, an effervescent foamy cleanser can be delivered when Formula A (which is separated from Formula B) contains a granulated sodium bicarbonate anhydrous system and Formula B contains an acidic solution.

38.1.6

Marketing Benefits

It is a well accepted practice for marketing companies to endeavor to differentiate their products from their competitors. TanDerm and SnapPack systems offer the clear advantage of providing consumers with a demonstrably different-looking line of products. The marketing company that launches TanDerm and SnapPack simultaneous delivery systems can promote a myriad of “first time” combination products that can fulfill unmet consumer needs. In addition, these unique premiere products can be closely aligned with dermatologists’ directives by virtue of their ability to incorporate and deliver combinations of cosmeceutical, OTC, natural, and even prescription drug, ingredients. For example, instead of an advertisement promoting another “new” ingredient for anti-aging, these simultaneous delivery system designs will demonstrate the term “new” by their innovative and logical delivery method. There will be increased confidence in the “newness” by the application method of those new ingredients. The packettes will be “fresh” for each use. Their convenience will encourage compliance so that skin care will be more easily and efficiently accomplished. Time to market can also be shortened since stability issues, even for novel combinations of ingredients, will be more readily achieved.

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES 38.1.7 Patchless Patch—Sustained Release of Actives An enduring objective for skin-care companies has been the development of longer-lasting action and consumer perceivable, effective products and treatments. The objectives are eminently met by the TanDerm and SnapPack approaches. For example, they can deliver a film-forming polymer from one compartment and a plasticizing formulation from the other. When mixed together on the skin these two formulations form a flexible long-wearing patch. Each formulation can also be loaded with particular treatment ingredients. Upon application, the combination of the polymer and the plasticizer results in a cosmetically acceptable film patch that will maintain the treatment ingredients on the skin via a comfortable to wear, virtually invisible “patchless” patch. (See Sec 38.3, Formulation 38.1; see also Fig. 38.10.) The simultaneous delivery systems creatively overcome the major disadvantage of traditional patches in that there is no bulky physical or visible patch to wear! Such systems, applied by means of the wipe-on application technique, form their own substrates. These substrates then deliver benefits ranging from anti-aging, “demonstrable” skin firming, and sunscreen protection to pain relief from muscle soreness, anti-itch, and athlete’s foot counteraction. Prescription drug remedies are also deliverable from these invisible film patches.

38.1.8

Formulation Combinations that Fulfill Consumer Needs

There are innumerable combination products that can be envisioned for these simultaneous delivery

Figure 38.10 Discard front cover. Applicator is ready for use.

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systems. A few examples are described in the following sections. Anti-aging and moisturization. A large segment of the skin-care market is driven by the needs of women over 45 who are buying products that promise the reduction of wrinkles, smoother skin with firmer tone, and brighter looking skin. In short, they want and need products that make their skin look young and cared for. Younger women, who do not want to end up looking old, will purchase such products with the hopes of mitigating signs of the aging process. Simultaneous delivery system approaches such as TanDerm and SnapPack offer the personal care chemist an entirely new realm of possibilities for developing products that can promote younger-looking skin. For example, a formulation with treatment ingredients such as alpha hydroxy-acids can be impregnated into one side of the packette while a formulation containing moisturizing ingredients such as liquid hydrocarbons, animal fats and oils, alkyl fatty acid esters, and silicones, etc., in the second side can be envisioned. (See Sec 38.3, Formulation 38.2.) Blemish control and moisturizing. Currently, most of the OTC and cosmeceutical products targeted to the teenage and adult acne sufferer utilize astringent forms of salicylic acid solutions, gels or lotions; or percentages of benzoyl peroxide within the OTC monograph.[1] These products are often described as unpleasant to use since they are prone to leaving the treated skin feeling irritated and dry. Currently marketed, solution saturated, anti-acne pads like Stridex® do not contain benzoyl peroxide. Teenagers frequently describe these pads as “drippy,” hard to remove one at a time, cold, and inconvenient. On the other hand, TanDerm packettes are completely portable and offer neat, usable-anywhere capabilities. A myriad of companion anti-acne and skin treatment formulations (with or without film forming polymers) can be impregnated into the plagettes. This technology enables the marketing introduction of a first time anti-acne benzoyl peroxide product that can also simultaneously deliver a skinsoothing, moisturizing, or substantive oil-absorptive formulation. (See Sec 38.3, Formulation 38.3.) Natural and organic ingredients. The evolving trend of “natural” and “organic” is gaining a wide audience of consumers who believe that products that are called natural are superior for their skin than those that are chiefly comprised of synthetic ingre-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

dients. Formulating with these natural ingredients brings new challenges when combined in traditional lotion formats but the ReGenesis compartmentalized systems alleviate many of these challenges. For example, polyhydroxy acids (gluconol lactones) can be formulated in a skin care base on Side A and vitamins, such as C or E, in a properly stabilized pH base can be put into Side B. Keeping these relatively unstable naturals separate in their own specific formulation until they are used allows the application of active naturals that compliment each other on the skin. Sunscreens and moisturizing. With the heightened awareness of the deleterious effects of sun exposure on the skin’s appearance and its links to skin cancer, consumers are insisting on products that will protect from the sun’s harmful rays while still imparting elegant cosmetic attributes. Simultaneous delivery systems are perfect for the dual application of sunscreen and moisturizing ingredients. TanDerm’s protective film backing keeps the hands clean while applying these materials and the nonwoven pads aid in delivering uniform coverage to the skin. Anti-oxidants and moisturizing. Dermatological research is providing increasingly strong evidence that free-radicals are part of the cause of aging skin and that ingredients that act as anti-oxidants are effective in fighting the free-radical damage. The simultaneous delivery systems are perfectly suited for maintaining the activity of these anti-oxidants, including derivatives of green tea, grape seed, vitamin E and C, etc., until they are transferred to the skin with a complementary moisturizing formulation (see Fig. 38.11).

Color foundation and sunscreen. Another example of an attractive partnering of ingredients that are well suited to the simultaneous delivery systems technology is a color-foundation makeup that would be wiped on along with a sunscreen formula to protect the face as it applies skin color or tint. Since the dual compartment systems isolate the two formulations until time of use, the individual formulas can be selected and designed to impart a greater range of component flexibility. This approach allows the possibility of greater sun protection without impacting the elegance of the makeup foundation. Color foundation plus a range of complementary treatments including anti-wrinkling and skin firming entries are possible as well. Aromatherapy. An ever-growing segment of the body-care audience is purchasing products that are advertised as aromatically therapeutic. That is, the fragrance component of the product is chosen for its ability to encourage relaxation, relieve stress, stimulate creativity and sensuality, invite sleep, etc. It is often the case that such products have only a narrow selection of ingredients as a result of the natural elements of the fragrance oil or the need to “lift” the fragrance from the product in use. Further, there is typically an overwhelming marketing objective to offer “natural” products. SnapPack is an excellent delivery device for fragrance delivery products such as these since one side of the pack can hold granulated materials, (i.e., bubble bath powders) and the other side can contain natural fragrance oils that will “bloom” when added to the powders under the running water. Moreover, as the concept of aromatherapy products greatly relies on the user’s ability to perceive the effects of the fragrance over a period of time, skin-substantive polymers can be put into one compartment and fragrance oils in the other. In use, this combination will generate a highly desirable controlled release capability.

38.1.9

Figure 38.11 TanDerm is applied in a circular motion to combine complementary formulations in situ on the skin.

TanDerm™ and SnapPack Manufacturing

The TanDerm manufacturing is accomplished on horizontal form, fill, and seal equipment where the peelable packaging film stock web is brought together with the nonwoven pads 90° perpendicular to the film. The nonwoven pads are heat-sealed to

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES the interior side of the packette. A second “top” layer peelable film web is brought into contact with the bottom web and heat-sealed on three sides and through the center, dividing the packette into two compartments. The top of the packette is left unsealed to allow filling. At the next station, the two independent formulations are dispensed into their respective compartments and the top of the packette is heat-sealed leaving an unsealed strip to facilitate opening. The SnapPack construction is accomplished using thermoforming equipment in a flat-bed configuration (horizontal form, fill, and seal machinery) where plastic sheet stock is thermoformed into cavities. The formulations are filled into the plastic cavities and covered with a peelable backing board that is heat-sealed and scored to facilitate snapping the package open.

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tanning preparation or an anti-wrinkle composition containing a newly discovered ingredient are just a few examples of possible regimens. These routines require the application of a series of products that are delivered according to a scheduled time sequence in the hopes of achieving the desired end result.

38.2.2 Eureka! Two Separate Products in a Back-to-Back Wipe Since multiple products are being recommended and interviews with women consistently emphasize that personal time is always at a minimum, we created TwinDerm™, a “back-to-back” impregnated pad delivery system that keeps the individual steps of a skin-care regimen independent but ready-to-go in a unit-dose, peel apart packette. (See Fig. 38.12.)

38.1.10 Summary Simultaneous delivery systems for personal care can satisfy the consumers’ demand for effective, elegant products that are convenient to use and produce multiple benefits at the same time. These systems encourage personal care formulators and marketers alike to think “outside the jars and bottles.”

38.2 Sequential Delivery Systems 38.2.1

A Systems Approach to Skin Care

Dermatologists and cosmeticians are typically recommending skin-care regimens that depend upon sequentially applied products in order to achieve particular end results. Personal care companies, attuned to the advice that professional skincare experts are giving the public, are promoting product lines that fulfill the “product A followed by product B” protocol. While the typical routine of cleansing followed by moisturizing is an obvious one, modifications of the traditional soap, astringent, and face cream sequence are endless. Deep cleansing to rid the skin of blackheads followed by moisturizing, or gentle abrasion with ground fruit pits to slough off dead skin cells, followed by application of either a sunless

38.2.3 Advantages of Two Formulations Delivered in Sequence from a Single System TwinDerm packettes offer the consumer a neat and convenient way to apply a specific amount of product to her/his skin and complete a two-step program quickly and easily. When compared to normal routines like uncapping a jar of cleansing cream, applying it, then removing it from the face, followed by drying, and then finally applying a moisturizing treatment, the TwinDerm system allows the user much greater convenience for application any time, anywhere. The TwinDerm system is designed for the application of two products in sequence from a single neat portable packette. As with the simultaneous TanDerm system, the TwinDerm packette relies on impregnated pads that are attached to the packette’s peelable film backing but used one at a time. The user does not have to touch the formulations during use, making the process very neat and practical.

38.2.4

TwinDerm™ Packette: Description and Function

The TwinDerm packette is comprised of a 2" × 3" three-layer sandwich structure with impregnated pads attached to the outside (or front and back) lay-

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

10 12 13 14 16 18 20 22

-

Dispensing and applicator device First cover sheet Back cover sheet Inner support sheet side 1 Surface of the Inner support sheet Inner support sheet side 2 First cover applicator pad Back cover applicator pad

30 31 32 34 35 60 61 62

-

Peripheral edges of first cover sheet Peripheral edges of back cover sheet Peripheral edge of support sheet Sealing area of first cover sheet Sealing area of back cover sheet First cover sheet flange Back cover sheet flange Inner support sheet flange

Figure 38.12 TwinDerm packette unopened and opened.

ers of heat-sealable and peelable film stock. A barrier/dividing layer of peelable film stock is interposed between the front and back layers. The outer perimeters of the packette are completely heat sealed so that each pad is completely “compartmentalized.” To expose the first impregnated pad, the outer layer of one side of the packette (Side A) is peeled away, leaving the second impregnated pad still attached inside Side B and sandwiched between the dividing layer. To use the second impregnated pad (Side B), the user peels apart the second side of the remaining section of the packette. (See Figs. 38.13–38.15.)

38.2.5

Marketing Benefits

Portability is certainly one advantage of the TwinDerm packette. These packettes are small, neat and self contained and readily carried for convenient use away from home. TwinDerm packettes are disposable and, most importantly, can contain any number of different kinds of dual step companion formulations.

38.2.6

Sequential Combinations that Fulfill Consumer Needs

Any two-step skin-care regimen whose components are made up of lotions, gels, solutions or ointments can be contained within the TwinDerm system. The unit dose packettes can satisfy a myriad of dermatological treatments that are designed to work in sequential application. Cleansing followed by a secondary treatment are “made-to-order” TwinDerm candidates. The Step 1 compartment of the TwinDerm packette can be any one of a variety of sudsy or non-sudsy cleansing or pre-treatment formulations that are ready-to-use as soon as Side A is peeled away from the TwinDerm packette. Side B can then apply a variety of functional formulations, including a moisturizing formulation, or a toning astringent, a treatment incorporating an anti-aging ingredient such as AHA or a skin lightening composition, or simply a color cosmetic makeup foundation. In each case the user can quickly and efficiently clean and treat the skin with no need for water and towel drying.

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES

Figure 38.13 TwinDerm. Peel the cover sheet from the support sheet to reveal Pad A.

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Cleansing and blemish control. An excellent product entry for the TwinDerm system is a cleansing and blemish control packette. Staying within the OTC monograph, Side A can hold a cleansing formulation and Side B can be used to wipe on a formulation containing salicylic acid or benzoyl peroxide to control acne and oiliness. Additionally, the cleansing formulation can contain ingredients that moisturize or soothe skin, which may be red or irritated from the acne condition. The packettes are highly attractive to teenagers who understand that they need to treat blemish problems, even when they are away from home (after gym, in school, at camp, etc.) but dislike the hassle of conventional anti-acne products and the need to cleanse before using them. The convenient little packettes invite compliance because they may be used anywhere and unobtrusively without stickiness, drippy pads, washing the face first, etc. Natural and organic ingredients. The individualized sections of TwinDerm provide a delivery system that can dispense volatile and incompatible formulations without the concern of contamination. Natural ingredients can be safely contained, hence, the marketer gains an opportunity to supply the consumer with vitamins, plant extracts, and biopolymers in a two-step regimen.

38.2.7 Figure 38.14 Twin Derm. Peel the back sheet from the support sheet to reveal Pad B.

Packette Manufacturing

With specific modifications to allow for the backto-back design, the TwinDerm package is manufactured similarly to the TanDerm in that it is produced on horizontal form, fill and seal equipment.

38.2.8 Summary The TwinDerm technology, described in Sec. 38.2, like the TanDerm and SnapPack simultaneous delivery systems described in Secs. 38.1, offer marketers and consumers heightened convenience and rational skin care using a new technological approach to dual step regimens that makes the “package” an integral functional part of the “product.” Figure 38.15 Twin Derm. Both Pads A and B.

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38.3 Simultaneous Delivery Formulations Thinking outside the jars and bottles. Formulations 1 through 3 are presented as examples of formulations mentioned in the text of this chapter. Formulation 38.1 can be dispensed from either the

TanDerm or SnapPack device. Formulation 38.2 is an example of a complimentary moisturizing formula that would be dispensed from “side” 2 of either the TanDerm or SnapPack device to mix with a different skin care formulation in “side 1.” Formulation 38.3 is an example of an anti-acne formulation to be dispensed from one pad of the TanDerm packette.

Formulation 38.1: Skin Treatment Patchless Patch

Side A

Ingredients

Function

Weight Percent

ES-335 I

Film forming polymer

25.00

Isopropanol

Solvent

72.00

Actives (vitamin E, etc.)

Skin treatment

3.00 Total

100.00

Oil Phase

B

Cerasynt 945

Emulsifier

3.50

Crodacol C95-NF

Emulsifier

0.50

Lipowax D

Emulsifier

1.50

Mineral Oil Light

Moisturizer

4.00

Finsolv TN

Emollient

3.00

Generol 122E-16

Emollient

1.00

Propylene glycol

Solvent

5.00

Glycerin (96%)

Emollient

4.00

Standamox LAO-30

Surfactant

3.00

Citric acid (10%)

pH adjuster

2.00

Water

Diluent

PVP/VA E-535

Film former

5.00

Sandopan KST

Emulsifier

0.30

Sandopan LS-24

Emulsifier

0.20

Isopropyl alcohol (USP)

Solvent

5.00

Propyl paraben

Preservative

0.30

Buytl paraben

Preservative

0.05

Methyl paraben

Preservative

0.30

Aqueous Phase

B

61.35

Manufacturing Procedure Side B Lotion: Add oil phase at 70ºC into aqueous phase at 70ºC with rapid agitation. Cool down using water bath to 30ºC. Side A is a solution of polymer in IPA with appropriate actives.

SMITH, JAGODA MURPHY: THINKING OUTSIDE THE JARS AND BOTTLES

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Formulation 38.2: Moisturizing Composition

Phase

A

B

C

Ingredient

Function

Weight %

Cerasynt Q

Emulsifier

5.00

Crodacol C-95 NF

Emulsifier

0.50

Mineral oil

Moisturizer

5.00

Ceraphyl 375

Emollient

3.00

Proply paraben

Preservative

0.10

Butyl paraben

Preservative

0.05

Water (deionized)

Diluent

Methyl parabens

Preservative

0.60

Propylene glycol

Solvent

5.00

Glycerine (96%)

Emollient

5.00

Standamox LAO-30

Surfactant

3.00

Butyl paraben

Preservative

0.10

Water

Diluent

5.00

Texapon K-1296

Surfactant

0.50

Fragrance

(Optional)

0.30

66.80

Total

100.00

Manufacturing Procedure 1. Charge components of oil-phase (Phase A) in suitable mixing vessel; heat to 75°C–78°C, with slow agitation. 2. In the primary mixing vessel, charge components of the water-phase (Phase B) in order as listed; heat to 75°C, with slow agitation. 3. In separate container, charge the first two components of Phase C; water should be 25°C. Mix in Texapon K-1296 with slow agitation. 4. Add oil phase (Phase A) to water phase (Phase B) at 75°C–78°C, using subsurface addition technique and rapid agitation; take special care not to whip air into system. Addition rate should be between 0.43–0.55 lbs/minute. 5. After addition has been completed, continue to agitate for approximate 10 minutes; temperature of batch should be 75°C–78°C. 6. Continue agitation and add Phase C to mixture slowly using subsurface addition rate of 0.25–0.3 lbs/min. Upon completion of Phase C addition, batch should be approximately 65°C–71°C. Continue agitation. 7. Start very cautious water bath cool-down of approximately 4.0°C–4.5°C per hour temperature drop. Fragrance is added when batch is 40°C–45°C. Agitation is continued along with cool down procedure.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 38.3: Blemish Control

Ingredient

Function

Weight %

Water (distilled)

Diluent

63.73

Laponite XLS

Gelling agent

Isopropanol

Solvent

Cetiol HE

Emollient

1.45

Edenol 302

Emollient

0.43

Schercemol DISD

Emollient

0.65

Naturechem OHS

Emollient

0.95

Finsolv TN

Emollient

0.70

Cetiol

Emollient/surfactant

0.16

Lamapon S

Protein

0.05

Procetyl AWS

Surfactant

0.15

Lanexol AWS

Protein/emollient

0.15

Mineral oil light

Emollient

0.25

Schercamox C-AA

Surfactant

0.06

Benzoyl peroxide (35%)

Drug

1.97 15.00

14.30 Total

100.00

Manufacturing Procedure 1. Add the laponite to the water, with vigorous stirring. 2. In another vessel, the emollient oils and the amine oxide are added in the order listed, with stirring. 3. The mixture is heated gradually to 60°C and then cooled to 25°C. 4. The isopropanol is then added to the water-laponite, stirring with good agitation. 5. The resultant mixture is stirred into the emollient mixture, followed by the addition of benzoyl peroxide.

Patents Packaging System with In-Tandem Applicator Pads for Topical Drug Delivery: USPatent 5,242,433, US Patent 5,470,323. Method of Applying In-Tandem Applicator Pads for Transdermal Delivery of a Therapeutic Agent: US Patent 5,460,620. Separately Packaged Applicator Pads for Topical Delivery of Incompatible Drugs:US Patent 5,254,109, US Patent 5,417,674, US Patent 5,562,642. Package System for Flowable or Solid Substances: US Patent 5,316,400.

References 1. 21 CFR Part 201 (Docket No. 92N-0311) Topical Drug Products Containing Benzoyl Peroxide; Required Labeling.

Part XIII Substrate-Based Systems

Water-Soluble Adhesive Patch Delivery Systems for Personal Care Actives

SUBSTRATE-BASED SYSTEMS

Substrate Based, WaterActivated, Anhydrous Delivery Systems: "Dry & Deliver!"

39 Water-Soluble Adhesive Patch Delivery Systems for Personal Care Actives Steve Kantner 3M Company Saint Paul, Minnesota

39.1 Introduction ................................................................................... 834 39.2 Background .................................................................................. 834 39.2.1 The “Eureka!” Moment ...................................................... 835 39.3 Features and Benefits .................................................................. 835 39.4 Suggested Uses and Applications ................................................ 837 39.4.1 Skin Care .......................................................................... 837 39.4.2 Skin Decoration ................................................................ 837 39.4.3 Hair Treatment .................................................................. 837 39.4.4 Oral Care .......................................................................... 838 39.4.5 Nail Care ........................................................................... 838 39.5 Materials of Construction .............................................................. 838 39.5.1 The Carrier ........................................................................ 838 39.5.2 The Adhesive .................................................................... 840 39.5.3 Active Agents .................................................................... 841 39.5.4 Support Layer ................................................................... 842 39.6 Formulations ................................................................................. 842 39.6.1 Product and Safety Information ........................................ 842 39.6.2 Notice ................................................................................ 842 39.6.3 Warranty Information ........................................................ 842 References .......................................................................................... 848

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 833–848 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

39.1 Introduction This chapter provides details about 3M™ HydroElegance, a unique dissolvable adhesive patch system developed at 3M Company. Numerous applications for this patch system are suggested for personal care products. The system consists of water-soluble or dispersible films, fabrics, and tapes. These serve as carriers for coated, dissolved, suspended, or emulsified personal care active ingredients or decorative agents. The films, or fabrics, are placed on the skin or hair in order to provide localized delivery of the active ingredient or decorative agent. Actives can be placed in a water-soluble or water-dispersible pressure-sensitive adhesive and made available for immediate and continuous delivery. The actives may also be placed in a film or fabric and designed to produce a triggered release on exposure to aqueous solutions. During or following delivery of the active or agent, and achieving the desired benefit, water is applied to the film or fabric in order to quickly disintegrate it. This process allows the film or fabric to be washed away, or even rubbed into the substrate. The 3M™ HydroElegance technology is the subject of a recent patent application[1] and is available for licensing. Customized products can also be produced with your active ingredient through a partnership with 3M Company.

39.2 Background A variety of delivery vehicles are typically employed to topically treat the skin, nails, hair, or teeth with pharmaceutical, cosmetic, or decorative agents. Such vehicles include lotions, creams, ointments, foams, powders, plasters, emulsions, bandages, and adhesive patches. They may contain one or more pharmaceutical, cosmetic, or decorative agents and are employed to deliver the active to the body surface for which treatment is desired. Lotions, creams, ointments, foams, emulsions, and powders may be undesirable physical forms for delivery of active agents in certain circumstances. Many of these product types suffer from the deficiency that they can be removed too easily from a body surface such as the skin, and before the full

benefit of the intended treatment is delivered. Such delivery systems are also subject to an undesirable physical removal from the skin. For example, this may occur by foreseeable contact with clothing or another part of the body. Removal of the active by such normal day-to-day actions not only interferes with the intended treatment, but it also creates an undesirable residue on the clothing. Further, for applications in which metered dosing is important, reliably dispensing a properly measured dose of the active is often quite challenging. This process is made even more difficult when the composition delivering the treatment may be undesirably, or uncontrollably, removed before the treatment is complete. Such compositions may also be undesirable because they can leave the treated body surface feeling greasy, wet, sticky, or slippery. Bandages and adhesive patches have long been used to deliver active agents to body surfaces. This method delivers the actives in a manner that reduces premature removal of the actives. Further, it allows more reliable dosing, and reduces mess. Such treatment devices are often bulky, however, and may be quite uncomfortable for the user. Depending on the treatment location, bandages and adhesive patches may also be obvious and unsightly, thereby creating more appearance issues than they solve. Further, removal of the bandage or adhesive patch from the body surface after treatment is an often uncomfortable or even painful process. Film devices for delivery of pharmaceutical agents to mucosal surfaces may be water-soluble and, therefore, may dissolve after delivery of the pharmaceutical agents. For example, the composition of such delivery films includes a monolayer of a water-soluble polymer, an active agent and, optionally, one or more additional components that are muco-adhesive. As such, these films may be used for the rapid delivery of pharmaceutical or cosmetic agents to the mucosal lining of an oral cavity.[2] Such films are designed for rapid dissolution in the oral cavity, thereby minimizing any prolonged discomfort for the user. They are generally unsuited for use on dry body surfaces because they rely upon an interaction between the film and the moisture contained within the oral cavity. In this process, saliva provides the moisture and enables the device to be bioadhesive to the mucosal lining. Such devices are generally unsuited for any prolonged treatment since

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES they are specifically designed for rapid solvation and release of the active within the oral cavity. Besides the devices already described, other water-soluble delivery devices are known. These may be suited to varying degrees for the topical delivery of pharmaceutical or cosmetic agents. For example, films including polyoxazoline polymer compositions and an adhesive layer may be used for the delivery of certain antimicrobial agents.[3] However, it has been found that tackifier from the adhesive layer may undesirably diffuse into the film layer during prolonged storage of such films. In this process, a portion of the adhesive character of the device may be undesirably transferred from the adhesive layer into the film layer. As a result, the adhesive layer has less than optimal adhesion and the film layer then exhibits increased tack, thereby making the device more difficult to handle. A medicament may be delivered to a body surface by means of a film prepared from a suspension of the medicament, a film-forming polymer and, optionally, a release agent or filler.[4] However, such films generally do not adhere well to a dry body surface. Further, in the absence of a pre-wetting step, active agents are not easily delivered to a dry body surface. Another type of water-soluble delivery device is a bathing preparation that may be simultaneously delivered to a body surface and dissolved upon contact with the bath water. This method employs a patch that includes a water-soluble adhesive sheet containing the bathing preparation, and an optional water-soluble protective material.[5] However, since such patches will dissolve in the bath over time, their effectiveness for direct delivery of an active to a defined, specific area is quite limited.

39.2.1

The “Eureka!” Moment

We realized there existed a need for a device similar to an adhesive delivery patch, but one that would be thinner and easier to remove. To address this issue, we considered the concept of patch removal by the dissolving process itself. Initial prototypes with commercially available water-soluble films as carriers demonstrated the feasibility of the concept. However, early results gave patches that were unwieldy to apply due to their lack of rigidity. Further, these patches were not providing the ease

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of dissolution and rub-in we were seeking. The problem was solved by coating the water-soluble film carrier onto a second film. This resulted in a light, but minimal, degree of adhesion after drying of the water-soluble film. In this way, we were able to employ even thinner carrier films. This technique accelerated the speed of dissolution and yet provided a removable support layer for the back of the patch. It also provided necessary rigidity to the patch during its application.

39.3 Features and Benefits The 3M™ HydroElegance system is designed to be easy to apply and easy to remove. It provides a single device that is capable of delivering a wide variety and number of active agents. These include decorative, therapeutic, and cosmetically useful agents. It is most useful in delivering a pre-measured unit dose of an active agent to a limited, specific area. However, it may also be designed to provide treatment over a larger area, or to deliver systemic treatments. Certain variations of the device may be applied to dry skin, hair, or nails. Other variations may be applied to moistened surfaces such as teeth or mucosal tissue. This technology allows for prolonged treatments, which, in many cases, is essential to achieve efficacy. The 3M™ HydroElegance technology includes a water-soluble or water-dispersible carrier for the delivery of one or more active agents. The carrier can take the form of a film, fabric, or tape. It can be designed to slowly or rapidly dissolve in aqueous solvents at either room temperature, or only at elevated temperature. This degree of control enables effective use of the device for several hours and removal will occur only during the bathing or showering process. One variation of the delivery patch includes the use of a water-soluble or water-dispersible adhesive on one surface of the carrier film. The adhesive permits it to be attached to dry skin, although, due to the unique design, application on wet or pre-moistened skin is also possible. Adhesion of the patch to dry skin allows it to be used for various applications in which sustained actives delivery is desirable. For example, it may be used to apply an active agent for an overnight skin treatment.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

3M™ HydroElegance technology optionally includes one or more support layers releasably adhered to the carrier, the adhesive, or both adhesive and carrier. The support layer provides support and structure to the device, thereby making it easier to handle. The result is a useful film laminate that is both flexible and shape conformable. As a result, it is capable of providing comfortable attachment to various skin contours. In some applications, the device is applied to dry skin in order to provide prolonged treatment. Following treatment completion it is easily and quickly washed away. For other treatments, it may be desirable to completely dissolve or disperse the adhesive and carrier. This process provides immediate and complete delivery of the active agent to the target surface. Alternatively, for some treatments, it may be desirable to dissolve or disperse only a portion of the carrier, adhesive, or both. The remaining carrier or adhesive can then be rubbed into the skin along with the active agent. In this way, the carrier or adhesive thereby serves as a binder and provides some degree of substantivity and persistence for the active agent. Active agents that may be delivered to the skin in this manner include glittering pigments, fragrances such as aromatherapy agents and perfumes, sunscreen agents, insect repellants, and deodorants and antiperspirants. Still another example of this device includes its use as a wound dressing, first aid bandage, or athletic tape wrap. All of these may be desirably removed gently, and without pain to the user by soaking in water. These medical applications and products are capable of including actives such as antimicrobial agents, antibiotics, and wound healing agents. In another aspect of the use of this technology, the patches may be designed to act as wound dressings that may also include water-soluble absorbents. 3M’s device technology allows one to deliver an active agent in a substantially dry state to a specific area. It is superior to adhesive tapes, bandages, and patches that may be applied to substantially dry skin. Such devices are typically very noticeable once applied, uncomfortable to wear, and painful to remove. By contrast, the novel device technology includes a carrier film that is designed to be thin, flexible, substantially transparent, and water-soluble or water-dispersible. Thus, the patch can be designed

to be essentially unnoticeable. Further, it is thin and flexible enough to avoid causing discomfort while being worn, and may be removed easily and painlessly after use. Since the patch dissolves or disperses upon application of water, its use generates no solid waste that may contain residual active agent. Consequently, small children and pets will not unintentionally be exposed to such waste. The 3M™ HydroElegance device also may be designed to provide a delivery vehicle that will not stick to, or be absorbed by, clothing. When delivering active agents in which dosing is an important consideration, the patch may be designed to allow for delivery of pre-measured doses of the active agent. By contrast, with other watersoluble films, the device may be used for prolonged treatments. They may be applied to dry body surfaces without wetting, and are easy to handle. The adhesive and the carrier can be selected to limit chemical or mechanical skin irritation. This allows moisture to escape from the skin and prevents maceration. Such a construction allows for long-term wear of these patches, which is a desirable attribute for providing sustained release of actives. A wide variety of water-soluble and water-insoluble active ingredients can be incorporated into the delivery patch. These are then maintained in a dry state until activated during use. This feature provides greater product stability during storage than a pre-formulated lotion or cream. Useful active agents include one or more pharmaceutical, cosmetic, decorative, or other suitable type of agents. The active agent can be coated onto, dissolved into, suspended in, emulsified with, or otherwise applied to the carrier, the adhesive, or both. In another use of this technology, two incompatible actives, or co-reactive actives, can be combined into a single device by placing one active in the carrier and the other active in the adhesive. Delivery of the active component in the adhesive begins when the patch is placed on the skin or hair. Delivery of the active in the carrier begins only upon activation with an aqueous solution. In the case of co-reactive actives, such as two component hair dyes, they can be held separately in the two layers and mixed by applying water, or an aqueous solution only after the device is placed on the treatment site.

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES

39.4 Suggested Uses and Applications 3M’s novel HydroElegance delivery technology has broad utility. It can deliver treatments such as acne treatments; or corn, wart or callus removers. They can also act as hair conditioners, teeth whiteners, and other treatments for the skin, hair, nails, or teeth. The patch can also have decorative utility. For example, it can provide temporary tattoos, masks, or decorative appliques on the face, body, toenails, fingernails or teeth. It may also be used to deliver color to hair or skin. The technology can serve to cover blemishes, scars, or disfigurations, thereby providing a smoothed surface over which traditional powder or liquid make-ups can be applied. The patch may also have particular utility in delivering active agents such as antimicrobials, antibiotics, and growth factors. Such materials are useful for the treatment of topical wounds including burns, abrasions, and chronic wounds. It can be used to cushion sores, remove unwanted hair, or apply sunscreen or insect repellant. The technology can be used to provide a protective, abrasion-resistant, or solvent-resistant film for skin exposed to external stressors. It may also be useful for delivery of topical, or systemic pharmaceutically active agents being delivered through the stratum corneum into deeper layers of the skin. If desired, an active agent may be provided in a unit dose amount when the device is manufactured. The use of some of the nanoparticulate delivery technology discussed elsewhere in this book is forseen as being usefully incorporated into the device technology. Examples of several uses are presented in the following sections.

39.4.1 Skin Care The patch technology allows for targeted treatment delivery for skin conditions including: • Wrinkles: by incorporation, for example, of tretinoin, alpha hydroxy acids, vitamins A, C, or E; witch hazel; N-6-furfuryl adenine, copper tripeptide. • Psoriasis: by incorporation of corticosteriods, coal tar, calciprotriene, tazatorene, anthralin, or salicylic acid.

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• Dry skin: by incorporation of humectants such as urea, hyaluronic acid, lactic acid, or glycerin and emollients such as lanolin, triglycerides, or fatty acid esters. • Insect bites or poison ivy exposure: by incorporation of hydrocortisone, emu oil, almond oil, ammonia, bisabolol, papain or diphenhydramine, jewelweed extract or calamine. • Acne: by incorporation of benzoyl peroxide or salicylic acid.

39.4.2 Skin Decoration Incorporation of pigment or dyes into the device provides formulations with opportunities to develop skin cosmetics such as eye shadow, lip color, rouge, and foundation. Each of these can be applied as thin, dry films and “feathered in” with a small amount of aqueous solution. The carrier can also be printed to generate shade and color transitions, or designs and graphics.

39.4.3

Hair Treatment

Incorporation of hair growth-stimulating ingredients such as minoxidil, fenugreek, or saw palmetto into the adhesive portion of the device and use of a carrier soluble in warm water provides a patch that can be topically applied to bald spots and left invisibly in place thereby providing prolonged treatment and proper dosing without stimulating growth in unintended areas. Incorporation of hair growth inhibitors such as eflornithine HCl into the adhesive portion of the device along with a carrier soluble in warm water provides a patch that can be topically applied to areas with unwanted facial hair. These can be left invisibly in place and thereby provide prolonged treatment and proper dosing. Incorporation of depilatories such as thioglycolates into the adhesive provides a patch that removes hair but limits the odor of the process. In this approach, the carrier acts as a physical barrier for the sulfur-like odor. Once complete, the film is simply washed away.

838 39.4.4

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Oral Care

Use of a moisture activated, slow-to-dissolve carrier provides the capability of prolonged treatment in the mouth. Examples include: • Toothache pain: can be relieved by incorporating clove oil • Sensitive teeth: can be treated by incorporating strontium chloride or potassium nitrate. • Plaque and gingivitis: can be treated with triclosan. • Cavity prevention: can be provided by fluoride • Tartar: can be treated with pyrophosphate or zinc chloride • Prolonged teeth whitening: can be accomplished by placing baking soda in one layer of the patch and peroxide in another layer. This approach keeps the two separate and stable until the moisture of the mouth mixes and activates them.

39.4.5 Nail Care Pigmented hot-water–soluble carriers with adhesive can be cut to shape and applied to nails to provide a glossy, mar-resistant decorative coating. This type of coating is easily removed without the odor, mess, and dehydration associated with standard nail enamels and removers. Designs or decorations can also be printed on the carrier to give nail appliques. An antimicrobial, or antifungal agent, such as ciclopirox or tea tree oil, can be incorporated into the adhesive to prevent, or treat, fungal infections of the nail bed. Incorporation of lanolin into the adhesive provides a treatment that can be worn overnight to soften cuticles.

39.5 Materials of Construction 39.5.1

The Carrier

The material used to prepare the carrier may be any of the known natural or synthetic water-soluble

or water-dispersible film-forming polymers and oligomers. In certain applications, the carrier material is selected to be soluble in cold water. Suitable polymers and oligomers for cold water include vegetablederived natural polymers such as alginic acid, alginic acid derivatized polymers, and arabinogalactan. Other useful polymers for cold-water–soluble applications include cellulose derivatives such as hydroxyethyl and hydroxypropyl cellulose, starch and starch derivatives, microorganism-derived natural polymers such as polysaccharides, and polymers derived from animals including gelatin, collagen, and mucopolysaccharides. Still other examples of useful polymers for cold water-soluble applications include poly(ethylene oxide), polyethylene glycol, polymers and copolymers derived from ethylenically unsaturated monomers including vinylic monomers, acrylates, and methacrylates. Still other useful polymers include acrylamides, methacrylamides, and polyethyleneimines. Useful mixtures of polymers include one or more polymers such as polyvinyl alcohols, polyvinyl pyrrolidone, proteins such as gelatin and collagen and derivatives thereof, or carbohydrates such as arabinogalactan. Polymers of polyvinyl alcohols may be prepared from polyvinyl acetate and can be commercially obtained in a variety of molecular weights and degrees of hydrolysis. The degree of hydrolysis determines, in part, whether the polymer is cold water soluble or warm water soluble. Polyvinyl alcohol polymers with a degree of hydrolysis greater than about 87% result in a more crystalline structure. Such materials require higher temperatures to dissolve the polymer. The rate of polymer dissolution is a function of the molecular weight of the polymer, and the presence of additional additives such as plasticizers or crosslinking agents. One additional advantage of using polyvinyl alcohol polymers to prepare the carrier film is that, as a result of its low oxygen permeability, such films provides protection for oxygen sensitive materials such as vitamin C and its derivatives. In addition, certain plasticized polyvinyl alcohol and poly(ethylene oxide) resins are thermoplastic and may be melt extruded or cast into films. Plasticizers can be used to reduce the brittleness of the carrier film, thereby making it tougher, more conformable, and generally improving its handling properties. Certain plasticizers can also provide a degree of adhesiveness to the carrier, if de-

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES sired. Using water alone as the plasticizer yields a carrier that is undesirably prone to rapid loss of moisture. This loss in moisture produces a concomitant change of the material to a glassy or brittle structure. To overcome this phenomenon, suitable plasticizers are employed. These may include alcohols, mixtures of alcohols, and mixtures of water and alcohols. Useful plasticizers include polyhydric alcohols such as glycerin, polyglycerol, alkyl polyglycosides, diethylene glycol, triethylene glycol, polyethylene glycol, random copolymers of ethylene oxide and propylene oxide, and ethylene oxide/propylene oxide block copolymers. Examples of the latter type of polymer are available from BASF under the Pluronic™ trade name. Other useful plasticizers include propylene glycol, sorbitol, sorbitol esters, butanediol, and their alkoxylated derivatives. Still others include monohydric alcohols such as 3methoxy-3-methyl-1-butanol, alkyl ether ethoxylates, alkyl ester ethoxylates, aryl ether ethoxylates, aryl ester ethoxylates, aralkyl ether ethoxylates, and aralkyl ester ethoxylates. The plasticizer list continues with urea, pyrrolidone carboxylic acids, pyrrolidone carboxylate salts, triethanol amine, and acetamide MEA. Water and certain active agents may also serve as plasticizers. Non-polar active agents, such as vitamin E (α-tocopherol), as well as many common emollients; or any mixture of emollients, may be suspended, or emulsified in the carrier by including a non-ionic surfactant having an optimal hydrophilic-lipophilic balance (HLB)[6] value of about 8 or more as part, or all, of the plasticizer. Non-ionic surfactants having an HLB value of about 12 or more have been shown to have particular general utility in this regard. Representative non-ionic surfactants include, C8 to C22 alkyl ether ethoxylates, C8 to C22 alkyl ester ethoxylates, sorbitol C8 to C22 alkyl esters, sorbitol C8 to C22 alkyl ester ethoxylates, and mixtures including one or more of these. The amount of plasticizer present in the carrier may vary depending upon, among other things, the polymer used to form the carrier and the particular active agent or agents that may be contained within the carrier. However, the plasticizer is generally present in the range of 1 wt% to 50 wt% in order to provide good flexibility without compromising strength.

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The carrier film can be prepared by dissolving at least one polymer and at least one plasticizer in water, or another appropriate solvent. The solution thus prepared, is cast into a film and then dried. Water-soluble materials such as vitamin C, hydroquinone, and salicylic acid may be dissolved directly into the polymer solution. Water-insoluble materials such as vitamin E, benzoyl peroxide, and polydimethylsiloxane may be emulsified into the polymer solution with an added surfactant. Alternatively, the active agent may be applied to the carrier film after it is cast and dried. In this case, the active agent is coated onto the surface of the film. If certain characteristics are desired in the delivery device, additional additives may be combined with the polymer solution in order to impart the desired characteristics to the carrier film. For example, addition of low levels of polydimethylsiloxane or silicone copolyols provides carriers with a lubricious feel. Addition of a biocide prevents mold, or bacterial growth on the carrier during storage and addition of particulate materials, such as the flattening agents used in the paint industry, provides a non-glossy matte finish to the dried carrier. A water-insoluble film-forming polymer may be included in the carrier to improve its flexibility, strength, or barrier properties as well as to adjust its solubility properties (e.g., rate of dissolution). One method of introducing the water-insoluble polymer is by adding an aqueous dispersion of the waterinsoluble polymer to an aqueous solution of the water-soluble polymer. The film obtained on drying the resulting mixture may take the form of a phaseseparated blend of both polymers. If the watersoluble polymer is present in sufficient concentration, then the water-dispersibility of the resulting carrier is maintained. Thermoplastic carriers may be embossed with heat and/or pressure after drying to impart a texture or pattern to it. The carrier may also be cast and dried to produce a textured surface or a matte surface texture. Conversely, casting on a very smooth surface produces carriers with a high gloss appearance. Fabrics useful as the carrier of the device may be constructed by any known technique for making woven, nonwoven, knitted, or other types of fabrics as well as both open and closed cell foams. Nonwoven techniques for making the carrier include

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

spun bonding, melt blowing, wet laying, hydroentangling (such as with cold water, relatively high salt concentration, or both), thermal bonding, or any combination of the above. Polymeric fibers useful for the manufacture of the fabric are commercially available. Alternatively, the films or fabrics employed in the device can be melt processed with the appropriate polymer composition using known techniques. For example, certain plasticized polyvinyl alcohols may be melt processed. Heat-stable active agents such as pigments may be added directly to the polymer melt. Alternatively, active agents may be coated onto or absorbed into a water-soluble or water-dispersible film or fiber.[7] Water-insoluble thermoplastic polymers may be included in the melt to alter the solubility, flexibility, strength, barrier, or other properties of the resulting carrier. The particular form of the carrier and the materials used to prepare it may be selected to provide the carrier with appropriate characteristics. For example, a thin, transparent film carrier may be desired for treatments requiring that the device be substantially unnoticeable in use. A woven or nonwoven fabric carrier may be employed for treatments in which high porosity is required. A film, or higher basis weight nonwoven, may be useful for treatments in which a more substantial device is needed. Such treatments may include strips woven into hair for delivery of colorants, dyes, or bleach, or where printing is done on the carrier, such as for a mask or temporary tattoo.

39.5.2

The Adhesive

A wide variety of chemistries are known that provide water-soluble or water-dispersible adhesive compositions suitable for use in 3M’s novel adhesive-based delivery device. Generally, such adhesives may include a lightly crosslinked or uncrosslinked polar polymer and a plasticizer present in an amount sufficient to provide a degree of pressuresensitive tack. Suitable adhesives may or may not include water. The adhesive can consist of an uncrosslinked polar polymer and a compatible plasticizer in the absence of water. Such an adhesive provides good adhesion and rapid water-solubility without negatively affecting the carrier. Also useful

are adhesives that include a polymer of crosslinked polyvinyl pyrrolidone, a glycol plasticizer and, optionally, water.[8] Polymers suitable for use in the adhesive include homopolymers and copolymers containing ethylenically unsaturated hydrophilic monomers including acrylic acid and salts thereof, acrylamide, N-vinyl pyrrolidone, and acrylamidopropane sulfonic acid and its salts. Still others include polymers based on methyl vinyl ether, ethyl vinyl ether, and those having ammonium functionality derived from the reaction of amine containing monomers with alkylating agents or protic acids. Examples of related types include N,N’-dimethylaminoethyl (meth)acrylate and its derivatives, and vinyl pyridine. One useful adhesive contains a homopolymer or copolymer of acrylic acid, wherein the acidic groups may be neutralized from 0.5% to 95%.[9] Alkali hydroxides, such as sodium hydroxide or potassium hydroxide, may be used as a neutralizing agent for the acidic groups. Another useful adhesive uses a homopolymer or co-polymer of N-vinyl pyrrolidone as the polymer. Synthetic polymers that provide cohesive, conformable, non-ionic, hydrophilic adhesives are also useful.[10] Generally, the polymer represents about 10 wt% to about 60 wt% of the adhesive composition and is an uncrosslinked polymer, or mixture of polymers, with an overall number average molecular weight between 10,000 and 100,000 Daltons. Adhesive compositions containing this level and type of hydrophilic polymeric matrix have a desirable balance of tack, softness, adhesiveness, and cohesive strength. The adhesive composition may have a substantially homogeneous appearance, i.e., the aqueous, liquid phase is retained in the polymeric matrix and essentially no phase separation can be observed. A plasticizer is present in the adhesive formulation that includes from about 10 wt% to about 80 wt% polar organic compound and about 0 wt% to 60 wt% water. Suitable compounds for use in the plasticizer include, but are not limited to, monohydric alcohols and polyhydric alcohols such as lowmolecular–weight polyethylene glycols with an average molecular weight up to 600 Daltons (i.e., PEG 600), polypropylene glycols, glycerol, monomethoxypolyethylene glycols, and propylene glycol.

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES The plasticizer may also include a compatible anionic, cationic, non-ionic, or amphoteric surfactant. The use of such surfactants improves the adhesion of the adhesive to oily surfaces by providing the adhesive with lipophilic properties. [11] The compatibility between the adhesive and the oily surface is improved by incorporating low HLB surfactants into the adhesive. The surfactant may also serve to make hydrophobic active ingredients more compatible with the adhesive.

39.5.3

Active Agents

3M’s novel delivery patch is designed to deliver one or more active agents to a specific, limited body surface. The delivered active agent can remain localized at the site of delivery or can enter the bloodstream in order to provide a systemic treatment. A single device may deliver any number of active agents. More than one active agent may be mixed together so long as each active agent is compatible with each of the other active agents being co-delivered by the same device. Alternatively, an active agent that reacts with a second active agent may be used. This second active would be configured within the device and separated from the first active agent by the carrier, the adhesive, or both. It would be allowed to react with the first active agent only when the device is activated by moistening. For example, this may be particularly useful for in situ mixing of baking soda and hydrogen peroxide for oral care. Active agents that may be delivered to skin for personal care applications include emollients, humectants, conditioners, moisturizers, vitamins, herbal extracts, antioxidants, exfoliants such as alpha hydroxy-acids or beta hydroxy-acids, bleaching or coloring agents, antifungal or antimicrobial agents, and emulsifiers. Other actives include those employed as artificial tanning agents, tanning accelerants, and fragrances, including aromatherapy agents, perfumes, and sunscreen agents. Still others include insect repellants, deodorants and antiperspirants, skin soothing agents, skin tightening agents, antiwrinkle agents, skin repair agents, sebum inhibiting agents, and sebum stimulators. The actives list also includes protease inhibitors, anti-itch ingredients,

841

agents for inhibiting hair growth, agents for accelerating hair growth, skin sensates, anti-acne treatments, depilating agents, astringents, hair removers, or corn, callus, or wart removers. Ornamental or decorative designs, colorants, tattoos or glitters may also be applied in this manner. For example, the device may be used to fashion water-removable masks for decorating at least a portion of the skin, including the face. The delivery film may also be used to provide various treatments to the hair. Again, depending upon the particular application, treatments may be prolonged or immediate. Because the device is flexible and conformable, it may be used to deliver a wide variety of hair treatments. For example, it may be braided into the hair in order to provide prolonged delivery of hair colorants or bleach. Braiding of one or more colored strips of the device into the hair, followed by activation with water can create a “tiedyed” appearance. Other hair treatments that are possible include prolonged or immediate delivery of conditioners, moisturizers, humectants, anti-dandruff agents, vitamins, fragrances, perfumes, herbal extracts, hair colorants, bleaching agents, texturizers, and decorative agents including glitters. The device may also be used to provide treatment to fingernails or toenails including decorative colorings or appliques. Antifungal agents, antimicrobial agents, or other medicinal agents may also be delivered to the nails with the delivery device technology. Dissolvable adhesive patches can also deliver treatments to moistened surfaces such as teeth or mucosal tissue. Since such treatments occur in a naturally moist environment, it is desirable to design the device for such treatments so that it dissolves or disperses slowly. Examples of dental treatments include fluoridation, whitening, stain bleaching, stain removing, remineralizing to form fluorapatite, plaque removal, and tartar removal. Examples of suitable medicaments include hydrogen peroxide, carbamide peroxide, sodium fluoride, sodium monophosphate, pyrophosphate, chlorhexidine gluconate, polyphosphate, triclosan, enzymes, and combinations thereof. Other useful medicaments include anti-inflammatory agents, antimicrobial agents, emollients, flavorants, fresheners, antipruritics, and other agents for treating soft tissues.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

For all treatments, the active agents should be compatible with the carrier, adhesive and support layer. The active agents, adhesive, and carrier are selected so that each will remain stable during storage.

described in Table 39.2; Formulation 39.11 is represented in Table 39.3; Formulations 39.12 and 39.13 are in Table 39.4; and Formulations 39.14 through 39.17 are described in Table 39.5.

39.6.1

Product and Safety Information

39.5.4 Support Layer The dissolvable patch may include one or more support layers releasably adhered to the carrier, the adhesive, or both. The support layer is typically removed from the carrier and the adhesive at about the time a treatment is initiated. Because the carrier and the adhesive of the patch tend to be thin, flexible, and conformable, a support layer is used to provide structural support, thereby making the patch easier to handle. A support layer may also cover the adhesive until the user is prepared to apply the device. In this way, the support layer protects the adhesive layer from contact with surfaces other than the body surface selected for the desired treatment. This capability improves handling of the adhesive patch prior to treatment and reduces mess. A second support layer may be adhered to the carrier in order to provide rigidity to the patch after removal of the first support layer from the adhesive. This prevents the adhesive patch from wrinkling or curling up on itself, and allows for smooth, easy placement onto skin. Once the patch has been applied to the desired body surface, the second support layer may be removed. One method of producing such a supported device has been reported.[12] This method involves releasably attaching a support layer to the carrier with a heat seal bond. Suitable materials for use in the support layer include paper, foils, and polymeric films as well as multilayered laminates thereof. It should be easily releasable from the carrier or adhesive so that the device may be applied to the body surface receiving treatment. The material for the support layer also may be coated with one or more materials designed to make the support layer easily releasable.

39.6 Formulations Formulations 39.1 through 39.6 are described in Table 39.1; Formulations 39.7 through 39.10 are

User is solely responsible for determining the suitability of 3M samples and products for the intended use including any necessary safety or toxicity assessment.

39.6.2

Notice

Nothing contained herein shall be construed to imply the nonexistence of any relevant patents or to constitute a permission, inducement or recommendations to practice any invention covered by any patent, without authority from the owners of this patent.

39.6.3 Warranty Information All statements, technical information and recommendations herein are based on tests 3M believes to be reliable, but the accuracy or completeness thereof is not guaranteed. 3M warrants only that products will meet 3M’s specifications at the time of shipment to the customer. 3M does not offer any other warranty and does not warrant the performance, safety or such other characteristics of products in combination with other materials. 3M specifically DOES NOT warrant products for any intended or unintended uses (whether or not foreseeable); for compatibility or suitability with other components or compatibility with any methods of manufacture or conversion. The foregoing warranty is made in lieu of all other warranties, expressed or implied, including the implied warranties of merchantability, fitness for a particular purpose and freedom from infringement.

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES

843

Table 39.1. Incorporation of Active Agents into Water-Soluble Films

Function Formulation

Polymer

0.55 g

1

2 5g

3

5 5g

10% solids solution of salicylic acid in isopropanol

10% solids solution of sodium ascorbyl phosphate (BASF Poly(vinyl pyrrolidone) 0.55 g Corporation, Mount Olive, (PVP) 10,000 molecular NJ) in water weight (Sigma-Aldrich Fine Chemicals, St. mixture of 5 g tocopherol Louis, MO) acetate (Sigma-Aldrich Fine 0.30 g Chemicals) with 0.5 g of sorbitan laurate (Uniqema, New Castle, DE) 0.35 g

4

6

Active Agent

Poly(vinyl alcohol) (PVA) 9,000 molecular 0.35 g weight (80% hydrolyzed) (SigmaAldrich Fine Chemicals, St. Louis, MO) 0.05 g

Film Characteristics Clear, flexible Clear, flexible

Clear, flexible, mottled surface

10% solids solution of salicylic acid in isopropanol

Clear, inflexible

10% solids solution of sodium ascorbyl phosphate (BASF Corporation, Mount Olive, NJ) in water

Clear, inflexible

mixture of 5 g tocopherol acetate (Sigma-Aldrich Fine Chemicals) with 0.5 g of sorbitan laurate (Uniqema, New Castle, DE)

Clear, some dewets, inflexible

Manufacturing Procedures for Formulations 39.1 through 39.6: 1. Two types of polymer solutions were prepared. Unless otherwise indicated, all percentages are by weight. A 55% aqueous solution of 10,000 m.w. PVP was prepared by dissolving 55 g in 45 g deionized water. A 35% aqueous solution of 9,000–10,000 m.w. 80% hydrolyzed PVA was prepared by dissolving 35 g in 65 g deionized water. 2. The following solutions were prepared as active agents: 10% salicylic acid in isopropanol, 10% sodium ascorbyl phosphate in water, and a mixture of 5 g tocopherol acetate with 0.5 g of sorbitan laurate. 3. Table 39.1 shows the amount of active agent added to 5 g of polymer solution to form each of six blends used to form the water-soluble films. Each blend was coated onto polyester film, dried for 10 minutes at 65°C., and the visual appearance of the coating was assessed after cooling. 4. These results show that water-soluble, alcohol-soluble, and water-insoluble actives can be dissolved or dispersed in the carrier. Further they show that the carrier can be prepared conveniently from high solids solutions of two different polymers. Films made from PVP are flexible and easy to handle and process. Films made from PVA tend to be less flexible than films made from PVP.

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Table 39.2. Addition of Plasticizer to a Water-Soluble Film

Formulation 7 8 9 10

Function Polymer 9K PVA [80% hydrolyzed 9,000 molecular weight poly(vinyl alcohol) (PVA)] (Sigma-Aldrich Fine Chemicals, St. Louis, MO) 13K PVA [80% hydrolyzed 9,000 molecular weight poly(vinyl alcohol) (PVA)] (Sigma-Aldrich Fine Chemicals, St. Louis, MO)

Plasticizer

Film Characteristics

2% glycerin

Clear, moderately flexible

5% glycerin

Clear, soft and flexible

2% glycerin

Clear, moderately flexible

5% glycerin

Clear, soft, and flexible

Manufacturing Procedures for Formulations 39.7 through 39.10: 1. Two polymer blends were used to form plasticized water-soluble films, as shown in Table 2. A 35% solids aqueous solution of 9,000 m.w. PVA was prepared as for Formulation 5, above. Additionally, a 30% solids aqueous solution of 13,000 m.w. 87% hydrolyzed PVA was prepared by dissolving 30 g of 13K PVA in 70 g deionized water. 10 g of this solution was combined with 0.6 g of 10% salicylic acid in isopropanol. 2. A 25% aqueous solution of glycerin was prepared. 0.28 g of the glycerin solution was added to 10.7 g of 35% 9K PVA for Formulation 39.7 (final concentration, 2%), 0.70 g of the glycerin solution was added to 10.7 g of 35% 9K PVA for Formulation 39.8 (final concentration 5%). 0.24 g of the glycerin solution was added to 10.6 g of 30% 13K PVA for Formulation 39.9 (final concentration, 2%), 0.60 g of the glycerin solution was added to 30% 13K PVA for Formulation 39.10 (final concentration, 5%). 3. Coating and drying, as described for Formulations 39.1–39.6, gave clear films with Formulations 39.7 and 39.9 (with 2% glycerin) still a bit brittle and Formulations 39.8 and 39.10 (with 5% glycerin) providing softer, tougher, more flexible films. A drop or two of water allows one to disperse these films and rub them in without perceiving much tackiness during dry down. 4. These results demonstrate that the flexibility and strength of films made from PVA can be improved by adding low levels of plasticizer.

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES

845

Table 39.3. Preparation of a Water-Soluble Film With Two Actives

Ingredient

Function

Percentage in Coating Solution (%)

Percentage in Dried Film (%)

Polyvinyl alcohol (PVA)

Polymer

33.3

75.5

Glycerin

Plasticizer

1.7

3.8

Deionized water

Solvent

48.3

0

Arabinogalactan

Active

8.3

18.9

Isopropanol

Solvent

7.5

0

Salicylic acid

Active

0.8

1.9

Manufacturing Procedure for Formulation 39.11: 1. 40 g of 9,000 m.w. PVA was dissolved in a mixture of 2 g glycerin and 58 g deionized water with heating and stirring. 10 g of this solution was charged with 1 g of arabinogalactan (Larex Company, White Bear Lake Township, Minn.) and 1 g of 10% salicylic acid in isopropanol yielding a hazy solution. Coating and drying as above gave a hazy somewhat brittle film.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Table 39.4. Preparation of Water-Dispersible Tapes with Active in Carrier and Adhesive

Ingredient

Function

Percentage in Coating Solution (%)

Percentage in Dried Film (%)

Formulation

Carrier

12

13

12

13

37.0

27.9

93.4

93.5

1.9

1.4

4.7

4.7

Polyvinyl alcohol (PVA)

Polymer

Glycerin

Plasticizer

Deionized water

Solvent

53.7

65.1

0

0

Isopropanol

Solvent

6.7

5.0

0

0

Salicylic acid

Active

0.7

0.6

1.9

1.8

Adhesive

Both Formulations

Polyvinyl pyrrolidone (PVP)

Polymer

13.0

34.3

PEG 300

Plasticizer

24.1

63.7

Deionized water

Solvent

55.5

0

Isopropanol

Solvent

6.7

0

Salicylic acid

Active

0.7

2.0

Manufacturing procedures for Formulations 39.12 and 39.13: 1. 20 g of the 9K PVA/glycerin/water solution prepared in Formulation 39.11 was charged with 1.6 g of 10% salicylic acid in isopropanol. This was coated to a wet thickness of 75 microns onto siliconized polyester liner and dried 7 minutes at 65° C. to provide the carrier for Formulation 39.12. Similarly, the carrier for Formulation 39.13 was prepared from a solution of 20 g of the 13K PVA/water solution prepared in Formulations 39.9 and 39.10 mixed with 0.30 g glycerin and 1.2 g 10% salicylic acid in isopropanol. Adhesive[13] containing active was prepared with 14 g of polyvinyl pyrrolidone powder that had been crosslinked via gamma irradiation suspended in 26 g of 300 m.w. polyethylene glycol (PEG 300). 60 g of water was added while mixing with high shear with an Omni Macro Homogenizer (Omni International, Waterbury, Conn.). 20 g of the resulting 40% solution was mixed with 1.6 g of 10% salicylic acid in isopropanol and coated and dried as above. The carriers were then laminated to the adhesive to give tapes sandwiched between two polyester support layers. The laminates seemed to be quite stable with no migration of plasticizer between the two layers apparent.

KANTNER: WATER-SOLUBLE ADHESIVE PATCH DELIVERY SYSTEMS FOR PERSONAL CARE ACTIVES

847

Table 39.5. Preparation of Water-Dispersible Tapes with Active Only in the Adhesive

Ingredient

Percentage in Coating Solution (%)

Function

Percentage in Dired Film (%) Formulation

14

15

16

17

14

15

16

17

Polyvinyl pyrrolidone (PVP)

Polymer

13.0

49.0

32.9

46.5

34.3

70.0

56.6

65.4

PEG 300

Plasticizer

24.1

19.6

16.5

23.3

63.7

28.0

28.3

32.7

55.5

24.5

32.9

23.3

0

0

0

0

Deionized water Solvent Isopropanol

Solvent

6.7

5.5

8.9

5.6

0

0

0

0

Salicylic acid

Active

0.7

1.4

2.2

1.4

2.0

2.0

3.8

1.9

Brij 56

Plasticizer

0

0

6.6

0

0

0

11.3

0

Manufacturing procedures for Formulations 39.14 through 39.17: 1. The adhesive coating from Formulations 39.12 and 39.13 was laminated to a strip of plasticized polyvinyl alcohol film (Solublon SA-17 from Mitsui Plastics, White Plains, NY) for Formulation 39.14. Another tape (Formulation 39.15) was prepared with a low tack adhesive obtained from a solution of 20 g uncrosslinked PVP (PVP K30 from BASF, Mount Olive, N.Y.), 10 g deionized water, 8 g of 400 m.w. polyethylene glycol (PEG 400), and 2.8 g of 20% salicylic acid in isopropanol, coated and dried as above. Another tape (Formulation 39.16) was prepared with a skin temperature activated adhesive obtained from a solution of 10 g PVP K30, 10 g deionized water, 5 g PEG 400, 2 g Brij 56 (Uniqema, New Castle, Del.), and 3.4 g of 20% salicylic acid in isopropanol, coated and dried as above. Another tape (Formulation 39.17) also was prepared with an alternative high tack adhesive obtained from a solution of 20 g PVP K30, 10 g PEG 400, 10 g deionized water, and 3 g 20% salicylic acid in isopropanol, coated and dried as above. This adhesive was also laminated to a textured water-soluble plasticized polyvinyl alcohol film (Monosol E6030 from Chris Craft). The resulting tapes had good adhesion to skin and could be worn comfortably for several hours, then removed with water. Alternatively, after adhering to skin, the tape could be treated with a few drops of water and rubbed in to give a flexible, durable film that may be removed by rinsing with more water.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

References 1. US Patent Application 20020187181 (Dec. 12, 2002)

7. US Patent No. 5,688,523 (Nov. 18, 1997)

2. US Patent No. 6,177,096 (Jan. 23, 2001); US Patent No. 5,948,430 (Sep. 7, 1999)

8. US Patent No. 4,931,282 (Jun. 5, 1990); US Patent No. 5,225,473 (Jul. 6, 1993); and US Patent No. 5,276,079 (Jan. 4, 1994)

3. US Patent No. 4,990,339 (Feb. 5, 1991)

9. US Patent No. 4,848,353 (Jul. 18, 1989)

4. US Patent No. 4,136,162 (Jan. 23, 1979) 5. US Patent No. 5,780,047 (Jul. 14, 1998) 6. Schlossman, M. L., ed., The Chemistry and Manufacture of Cosmetics, Vol. I, 3rd Ed., Allured Publishing Corp., Carol Stream, Ill. (2000)

10. US Patent No. 4,273,135 (Jun. 16, 1981); US Patent No. 4,352,359 (Oct. 5, 1982) 11. US Patent No. 6,121,508 (Sep. 19, 2000) 12. US Patent No. 6,169,224 (Jan. 2, 2001) 13. US Patent No. 5,276,079 (Jan. 4, 1994); US Patent No. 5,438,988 (Aug. 8, 1995)

40 “Dry & Deliver!” Substrate-Based, Water-Activated, Anhydrous Delivery Systems James A. Smith and Betty Jagoda Murphy ReGenesis LLC Montclair, NJ 40.1 Anhydrous Delivery Systems: An Overview ................................. 850 40.2 Eureka! Solid Lotion Coatings for Drying and Treating Wetted Skin . 850 40.3 Functional Characteristics of Solid Anhydrous Formulations ....... 850 40.3.1 Advantages of Solid Anhydrous Formulations .................. 851 40.3.2 Limitations ......................................................................... 851 40.3.3 Stability Issues .................................................................. 851 40.4 Single or Multiple Active Coatings ................................................. 852 40.5 Selection of Substrate Carrier ...................................................... 852 40.5.1 Paper Substrates .............................................................. 852 40.5.2 Nonwoven Substrates ...................................................... 853 40.5.3 Urethane Foams ............................................................... 853 40.6 Marketing Benefits ........................................................................ 853 40.7 Skin Care Products ...................................................................... 853 40.7.1 Cleansing .......................................................................... 853 40.7.2 Treatment .......................................................................... 854 40.7.3 Blemish Control ................................................................ 854 40.7.4 Organic Actives and Natural Ingredients .......................... 854 40.7.5 Make-Up Application ......................................................... 854 40.7.6 Dermabrasion ................................................................... 855 40.7.7 Skin Lightening .................................................................. 855 40.8 Packaging ..................................................................................... 855 40.9 Manufacturing Methods ................................................................. 855 40.10 Summary ...................................................................................... 855 40.11 Formulations ................................................................................. 856 Reference .......................................................................................... 858 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 849–858 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

40.1 Anhydrous Delivery Systems: An Overview Examination of the ingredients on the back of any skin-care product package typically lists water as the first ingredient. It is inexpensive, natural, readily available, and a practical environment for a multitude of formulations. However, in certain instances, it is preferable to develop skin treatment products without water. This may be particularly relevant to technologies where the ingredients are designed to be “water activated” and, specifically, when the skin is wetted during a cleansing step preceding a treatment delivered via a water-activated wipe. As versatile as water can be for the formulating chemist, there are certain especially efficacious active ingredients that, at high levels, are insoluble in a water-based formulation. Further, the presence of desirable oils and esters in such formulations require precise methods to maintain product stability. Still other types of ingredients that are incompatible in a water-based system are interesting vitamin complexes, antioxidants, and other lipophilic or natural ingredients.

40.2 Eureka! Solid Lotion Coatings for Drying and Treating Wetted Skin Anhydrous cosmetic formulations are not extraordinary. Examples of some common anhydrous formulations are lipsticks, facial foundations, and antiperspirants. During a brainstorming session to examine different ways to introduce innovation to skin care, ReGenesis developed the concept of a lotion that did not contain water as part of the formulation. We asked “If dryer fabric softener sheets can be water-activated by wet laundry to release softening and anti-static ingredients, then why not coat paper or nonwoven substrates with a ‘solid,’ anhydrous formulation?” This type of formulation would release skin treatments onto wet skin at the time of use. In other words, if water was not in the formulation until it was needed to solubilize and transfer the ingredients, then a major formulating hurdle would be bypassed. Further exploration of this concept led

ReGenesis to the idea of developing a product that would physically absorb water from wetted skin at the same time that the “treatment” is transferred to it. While preliminary anhydrous formulations could actually be molded into an independent solid, like a stick deodorant, the preferred system evolved into one in which the formulation can be print-coated in a pattern of dots, stripes, or other design; or it could be applied as an overall coating onto the carrier substrate. The coating techniques we developed permit single or multiple anhydrous formulations to be applied to the same substrate and, thereafter, absorb water from wetted skin.

40.3 Functional Characteristics of Solid Anhydrous Formulations The ReGenesis solid anhydrous formulations are based on the premise of a “hot-melt–like” system. The basic formulating concept depends on a cosmetic waxy base capable of incorporating and holding a wide variety of skin-care ingredients. Using a precise manufacturing method, the molten waxy formulation is readily deposited as a uniform film onto a dispensing applicator or carrier substrate such as nonwoven paper, dauber, or foam. The resulting anhydrous film coating is a solid at room temperature, yet is water soluble upon contact with any residual water left on the skin. If preferred, the applicator/ substrate itself may be moistened with water prior to its use on dry skin. The cosmetic base for these solid formulations, which usually comprises about 40% to 60% of the formulation, is best described as a combination of low, medium, and high melting cosmetic waxes such as ethoxylated fatty alcohols, fatty esters, etc. The waxes are combined in a ratio such that the mixture results in a formulation that becomes solid at about 45°F. Since each of the base ingredients can have varying degrees of water solubility, this variability needs to be carefully assessed to balance the combined melt point and the desired rate of dissolution in water during use. Upon contact with water during use, the anhydrous formulation transforms into the typically white, creamy consistency and appearance

SMITH, JAGODA MURPHY: “DRY & DELIVER!” of a cosmetic lotion oil-in-water emulsion. This is not surprising since, after all, many of these solid ingredients are currently used to form the traditional lotions presently on the market. As long as the solid ingredients employed are free of water, a wide variety of personal care adjuvants can be added to the base mixture. These include a combination of one or more surfactants and emollient oils. Other ingredients include solid components such as starches, sugars, hydrophilic or hydrophobic polymers, and specialty actives such as silicones, antioxidants, bleaching agents, etc. Still other ingredients include color dyes or pigment dispersions, sunless tanning ingredients, organic or inorganic ingredients, abrasive materials, fragrance oils, pH buffering agents, and preservatives. Of course, each added ingredient will impact both the set point and melt temperature of the finished formula. With this in mind, the formulator must measure the set/ melt points constantly to determine which ingredient and level of that ingredient is affecting these important functional physical characteristics. The finished formulation, in the molten state, should have a smooth, homogeneous consistency with a viscosity high enough to facilitate a uniform coating on the applicator/carrier substrate stock.

40.3.1 Advantages of Solid Anhydrous Formulations The advantages of ReGenesis’s anhydrous formulation coatings revolve around two key facts: they do not contain water, and they are solids at room temperature. Therefore, the creative chemist can incorporate all manner of hydrophobic ingredients into the coatings (e.g., emollients, esters, or oils) without the need for added emulsifying surfactants or specialized mixing and addition equipment. This capability minimizes any irritation effects that might have come from the presence of these materials. Further, solid active components can be suspended or dispersed in these systems more easily than in systems that are liquids at room temperature, thus improving product stability by limiting the potential for the development of sediment or layering. Hydrophilic solids, like sugars and other polysaccharides, can be readily included in the coating for-

851 mulations to adjust water sensitivity as well as the rate of aqueous dissolution. Since there is no water component, these types of formulations can be considered essentially 100% active. That is, every part of the formulation’s ingredients is transferred to the skin and can be considered 100% active. Conversely, traditional lotion emulsions are usually only 10% to 20% actives dispersed in water. Thus, on a “gram-for-gram” basis they simply cannot deliver the same level of actives as the anhydrous systems. This point alone gives the marketer of anhydrous-coated products a significant novelty and capability of generating product distinctions. Another major advantage of these systems is the ability to separately print-coat multiple formulations on the same dispensing substrate, thereby, allowing the user to conveniently obtain more than one benefit from the same product. An added value offered by these systems is that the carrier substrate can also absorb the water from the skin as it releases the formulation. This results in the ability to dry the skin as it is being treated.

40.3.2

Limitations

Interestingly, the solid form of these coatings can be viewed both as an advantage and as a disadvantage depending on the desired set/melt point of the final product. As a result, the formulator creating these anhydrous systems must work within the constraints of the restricted amount of liquid ingredients that can be incorporated in such formulations. In other words, if too many liquid components are added to the formulation, it tends to become “mushy” and separate into solid and liquid phases. This tendency can be overcome using certain packaging and dispensing means, however, under the correct formulary conditions, the use of the described water-activated stable anhydrous solid does not require such special packaging and dispensing machinations.

40.3.3

Stability Issues

Cosmetic applicators coated with solid anhydrous cosmetic formulations present different stability issues than those associated with the usual separation

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

concerns of lotion or gel compositions. The formulator working with these anhydrous coatings faces two major stability issues: • The potential for the coated formula to crack or flake off the wipe itself. • Blooming of low molecular weight or too high a level of liquid ingredients in the formula being forced to the surface of the solid coating. This flaking/cracking problem can be caused by several conditions including the overall hardness of the individual base materials, the chemical nature of the waxy base, or overly high percentages of dispersed solids and their respective particle size.

40.4 Single or Multiple Active Coatings Although single skin-care formulations are an appealing utilization of the anhydrous coating delivery system, the more ReGenesis worked and evaluated the possible coating technique alternatives, the more evident it became that multiple individual anhydrous formulations could be independently applied to, and then delivered from, the same carrier substrate. Multiple coatings invite the opportunity to deliver innovative and complimentary skin treatments at the same time. The challenge was to develop “companion” formulations that would have similar solubility and rate of dissolution characteristics when exposed to water. This coordinated solubilization is a principal factor required in order to facilitate the following:

the product will be used and then rinsed, or will generate a lotion that does not need a drying step, the coating can be applied to virtually the entire delivery substrate.

40.5 Selection of Substrate Carrier As with the coating method, the marketing intent plays a large role in selecting the substrate. While paper is perfectly acceptable for the delivery of some ingredients, a nonwoven could be preferable for a formulation that contains abrasives and will be used to exfoliate the skin. Factors such as absorbency, loft, texture, wet-strength, durability, and, of course, cost are all important considerations in choosing the delivery substrate.

40.5.1

Paper Substrates

Technical advances in manufacturing have greatly enhanced the physical properties of paper products. Historically, paper processing involved chemical residues from bleaching agents (sulfites). These have now been virtually eliminated, thereby making them much more acceptable as substrate carriers for cosmetic skin-care products. Current manufacturing processes allow for paper made without binders to hold the cellulosic fibers. Binderless papers can now consist of blends of fibers, including non-cellulousic fibers and absorbent polymers that add strength, cleanliness, and coating ability.

• The integration of the two formulas as they are activated. • Achieving the optimum transfer of the resulting mixture to the skin as the wipe is used. The subject of coating methods is of great interest in these systems because the coating can be printed in selected patterns on the wipe, (see Fig. 40.1) or laid down as an overall coverage. For the most part, the coating method is determined by the marketing intent. Products envisioned as treatments applied as the wipe dries the skin, demand that the coating pattern expose sufficient uncoated substrate material to absorb the water on the skin. If, on the other hand,

Figure 40.1 Nonwoven sheets with water-activated “dot” printed anhydrous formulation for skin care.

SMITH, JAGODA MURPHY: “DRY & DELIVER!” 40.5.2 Nonwoven Substrates Nonwovens of many styles and compositions can serve as excellent delivery carriers for these anhydrous coatings. Recent advances in nonwoven production technology include the hydro-entangled process that produces materials without chemical binders of any type. Moreover, there is a growing selection of varying lofts, densities, and blends (rayon/ polyester, nylon/rayon, etc.) that can be employed in this process. The preferred nonwoven substrate for the ReGenesis coated systems, depending upon the end use, would be one having an optimal balance of water absorbency and the ability to efficiently dispense the anhydrous ingredients on contact with wetted skin.

40.5.3

Urethane Foams

Hydrophilic polyurethanes, as well as traditional urethane foams, are also possible candidates for the delivery of anhydrous formulations to wet skin. These can be more expensive than paper or nonwoven substrates, but are usually perceived as more luxurious and “up-scale” by the consumer. They also have the added benefit of providing a cushiony feel during use. The formulator must be cognizant of the potential interaction of the coating formulation with the urethane cell structure in that certain emollients or solvents could weaken the cell structure or dissolve the urethane.

40.6 Marketing Benefits The goal of any marketer, especially in personal care categories, is to make the new product more desirable and noticeably different from its competition. The anhydrous delivery systems readily satisfy this objective. One of the most obvious benefits is the convenient dual action of drying the skin as treatment/ingredients are transferred. Compared to traditional lotions, creams, or pre-moistened wipes, the anhydrous systems deliver a richer, warmer feeling product to the skin. Conversely, the marketer has an opportunity to choose stimulating, more abrasive particles as part of the moisturizing formulation benefit. Additionally, the ability to deliver more than one

853 skin-care formulation at the same time is a highly acclaimed benefit for today’s busy consumer. Moreover, water-activated formulas delivered via carrier substrates, such as wipes or pads, are not only convenient to use at home, but also portable for use away from home.

40.7 Skin Care Products The initial products developed within this anhydrous delivery technology were OTC and prescription drug, anti-acne treatments. The ReGenesis R&D program initially focused on OTC systems formulated to deliver a single anti-acne active via a cosmetically acceptable formulation that also contained skin soothing and moisturizing ingredients. The prescription products incorporated two coordinating formulation coatings, each containing their own antiacne drugs. During the development program, it became clear that, as long as it was logical to apply a treatment to wetted skin, an entire range of skin cleansing, cosmetic, and treatment products could be delivered via water-activated anhydrous-coated delivery wipes.

40.7.1 Cleansing In the past few years, a variety of consumer product companies have introduced skin-care products in “dry,” water-activated wipe/towelette form. Facial cleansing was the original target for this approach. ReGenesis’ anhydrous technology adds a new dimension to this market in view of its ability to deliver a broad range of nutraceutical and botanical ingredients from the anhydrous base coating. Compared to competitive cleansing wipes that are detergent dipped and dried, or pads filled with water-activated dry surfactants, the ReGenesis anhydrous system utilizes a base, which is moisturizing in and of itself. This anhydrous moisturizing base can more readily incorporate hydrophobic emollient actives than is feasible for aqueous systems. Hence, the ReGenesis system can achieve the significant advantage of a creamier feeling product with greater moisturizing effect. (See Formulation 40.1 in Sec 40.11.)

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40.7.2 Treatment The anhydrous-coated delivery systems are an attractive method for the application of skin treatments following cleansing because they also concurrently dry the skin as the treatment is transferred. Additionally, because the manufacturing process does not require an “oven-drying” stage, suitable heat sensitive treatment ingredients, like botanical preparations, can be included in the formulations. Such systems can be formulated to include antifungals, antibacterials, anti-acne drugs, steroids, vitamins, natural emollients, AHAs, chitins, dermal abrasives, retinoids, pigments and color cosmetics, etc.

40.7.3 Blemish Control Some of the most popular currently marketed OTC products used to combat acne are solutionsaturated pads packaged in jars, and, the more recently introduced, impregnated wipes. These pads are saturated with liquids that usually contain salicylic acid. Teenagers often describe them as cold, drippy, and tending to cause the skin to be “tingly” and redden. While benzoyl peroxide is the preferred anti-acne OTC medication, it is relatively difficult to put it into stacked saturated pads. This is because the fibrous makeup of the pads tends to act like a filter paper inhibiting the homogeneous impregnation of the benzoyl peroxide particulates within the liquid composition throughout the stack of pads in the jar. (See Formulation 40.2 in Sec 40.11.) ReGenesis undertook an intensive consumer market research study to determine the appeal of a water-activated benzoyl peroxide treatment product delivered through the process of drying wetted skin. Separate studies with teenage boys and girls who have acne confirmed the attractiveness of a blemish control product that is as easy to use as simply drying one’s face. Additionally, the dry towelette form itself was very appealing to the teenagers, especially the boys since there are no cold drippy pads that are difficult to remove, one-by-one, from the jar. Separate interviews with women who have “adult acne” also confirmed the consumer appeal of

a medicated dry wipe that was portable and convenient to use. Additionally, since the written market research concept described the product as “kind to the skin,” respondents were quite positive about trying an anti-acne product that might actually have a soothing effect, and be less irritating than the usual anti-acne products.

40.7.4 Organic Actives and Natural Ingredients Part of the appeal of these anhydrous delivery systems is that without the water and solvent components commonly utilized in skin-care preparations, they can accommodate the incorporation of lipophilic actives like neem oil, jojoba, vitamin extracts, naturals, and botanicals. Even solid naturals like bamboo, oatmeal, and loofah are readily incorporated into the anhydrous systems.

40.7.5

Makeup Application

One area where the anhydrous-coated wipes could provide outstanding innovative opportunities is in unit-dose, portable color cosmetic applications. Dispersions of organic or inorganic particulates, which comprise the bulk of color cosmetic formulations, are easily incorporated. Many cosmeticians are currently recommending that their clients apply facial color foundation on damp skin to take advantage of the surface water for added hydration and ease of application. Rather than use a separate dampened sponge applicator, the coated wipes can be used directly on just cleansed and rinsed skin. By this means, the water can be incorporated as the color foundation is dissolved and transferred to the skin. For enhanced skin treatment, the color foundation wipe could also be printed with oil-free moisturizing, sunscreen, or other ingredients that would be incorporated into the foundation and delivered at the time of use. In the area of eye shadow, the anhydrous formulations could be coated onto a Q-tip®-like dauber enabling the marketer to provide a myriad of colors in an attractive and unique presentation.

SMITH, JAGODA MURPHY: “DRY & DELIVER!” 40.7.6 Dermabrasion The use of aggressive, gentle particles to “renew” and “brighten” the skin’s surface has become a common practice in dermatologists’ offices, skincare salons, and even at home. The anhydrouscoated wipes offer a viable, appealing, and convenient method for the consumer to give herself a dermabrasion treatment at home. The waxy base of such compositions allows for the incorporation of a myriad of types of particles that can be included in a moisturizing, creamy cleanser. Depending on the final envisioned product, the formulating chemist can create a base with a controlled degree of aggressiveness that can be activated by water left on justcleansed skin. (See Formulation 40.3 in Sec 40.11.)

40.7.7 Skin Lightening The ReGenesis anhydrous systems provide an efficient foundation for skin lightening products. One OTC skin-lightening ingredient, hydroquinone, is a white powder that can be successfully dispersed and/ or solubilized in a cosmetically acceptable anhydrous base, coated onto a carrier substrate and then applied to wet skin for activation. A unique approach would be to combine the lightening effects of hydroquinone with another powder consisting of polyamide-12-triazaminostilbenedisulfonate and polyoxymethylene urea. This ingredient, called LipoLight™ OAP/C, emits and diffuses visible light and has the effect of dramatically reducing the appearance of skin imperfections such as wrinkles, enlarged pores, and uneven skin tone/color. Other possibilities include combinations of plant extracts from Sederma that are also designed for skin lightening.

40.8 Packaging Depending on the nature of the formulation, packaging requirements for the anhydrous delivery systems may not be as demanding as aqueous or solvent-based systems. The coated substrates can be individually wrapped or packaged in stacks of multiples, with or without slip-sheets, depending upon the formulation and the selected carrier substrate. For example, a smooth, dense substrate with a coat-

855 ing on top could have a tendency to stick together while a rougher, more porous applicator with the coating penetrated into the matrix could be more easily stacked and separated from each other.

40.9 Manufacturing Methods The formulation “melt” is produced in temperature-controlled equipment (jacketed stainless steel or glass lined) with adequate stirring to maintain a uniform mixture and then transferred to the coating dashpot. Currently available traditional heated coating equipment, such as those used for producing anhydrous-coated fabric softener sheets, could also be used to produce these anhydrous-coated products, i.e., knife-over-roller, slot die coating or gravure printing. The appropriate coating method would be selected depending on whether the end product is a total over-coated substrate or a patterned design. The trick is to find OTC GMP (Good Manufacturing Practices) manufacturing facilities with this type of dedicated equipment. After the carrier substrate is coated, it would move along the conveyor, or rewind station, to be allowed to cool to room temperature. Alternatively, it could be put through a chiller and either rolled for future processing or cut and immediately packaged.[1]

40.10 Summary Employing anhydrous delivery substrates that use surface water on the skin as an in situ trigger for the formation of oil-in-water lotions opens the door to new and innovative products that can enhance skin-care regimens in unexpected ways. Working within the technology of anhydrous systems, the creative chemist and marketer can design novel systems with a wider range and higher levels of ingredients than are possible in more traditional aqueousbased systems. When coated onto absorbent carrier substrates, these solid systems can also deliver results usually obtained from multiple products, uniquely tranfser ingredients to wet skin, and, at the same time, dry the skin as well.

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40.11 Formulations Formulation 40.1: Cleansing

Ingredient

Function

Weight %

Calamide C

Foam booster

7.07

Cetiol HE

Emollient

3.00

Procetyl AWS

Surfactant

13.93

Lipacol C-10

Plasticizer

10.00

Crodacol CS-50

Wax

10.84

Liponate SS

Wax

10.27

Liponate PS-4

Wax

14.49

Tauranol WS-HP

Surfactant

30.00

Robertet TZ-37

Fragrance

0.40 100.00

Manufacturing Procedure: 1. Weigh and add the Calamide, Cetiol, Procetyl, Lipocol C-10, Crodacol, and Liponates to a suitable water bath flask with vigorous stirring. 2. The mixture is heated gradually to 55°C–60°C until all the ingredients are melted, with continued stirring. 3. The Tauranol is then added slowly to the mixture, stirring with good agitation. 4. Finally the fragrance is added. 5. The composition is maintained at 57°C–60°C and is applied to a porous nonwoven fabric or proper base sheet.

SMITH, JAGODA MURPHY: “DRY & DELIVER!”

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Formulation 40.2: Anti-Acne

Ingredient

Function

Weight %

Myritol 318

Emollient/moisturizer

7.89

Procetyl AWS

Surfactant

7.08

Lipocol C-2

Surfactant/emollient

4.24

Crodacol CS-50

Wax base

11.94

Liponate SS

Wax base

11.13

Liponate PS-4

Wax base

19.80

Vulca 90 starch

Gelling agent

23.62

Benzoyl peroxide (35%) (stabilized with dicalcium phosphate)

Anti-acne

14.30 100.00

Manufacturing Procedure: 1. Weigh and add the Myritol, Procetyl, Lipocol C-2, Crodacol, and Liponates to a suitable water bath flask with vigorous stirring. 2. The mixture is heated gradually to 55°C–58°C until all the ingredients are melted, with continued stirring. 3. The starch is then added slowly to the mixture, stirring with good agitation. 4. Once the starch is efficiently mixed in, the benzoyl peroxide is added slowly with continued stirring until it is dispersed uniformly. 5. The composition is maintained at 57°C–58°C and is applied to a porous nonwoven fabric or proper base sheet.

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Formulation 40.3: Dermabrasion

Ingredient

Function

Weight %

Myritol 318

Emollient

5.10

Procetyl AWS

Surfactant

4.56

Lipocol S-2

Plasticizer

2.72

Crodacol CS-50

Wax

7.69

Liponate SS

Wax

7.17

Liponate PS-4

Wax

12.76

Acuscrub 52

Dispersant

20.00

EuroPeel crystals

Dermabrasive

40.00 100.00

Manufacturing Procedure: 1. Weigh and add the Myritol, Procetyl, Lipocol S-2, Crodacol, and Liponates to a suitable water bath flask with vigorous stirring. 2. The mixture is heated gradually to 55°C–60°C until all the ingredients are melted, with continued stirring. 3. The Acuscrub is then added slowly to the mixture, stirring with good agitation. 4. Finally, the EuroPeel crystals are added. 5. The composition is maintained at 57°C–60°C until uniform and is applied to a porous nonwoven fabric or proper base sheet.

Reference 1. US Patent 5,538,732; US Patent 6,001,380

Part XIV Specific Ingredient Delivery

Retistar™ for Cosmetic Formulations: Stabilized Retinol

SPECIFIC INGREDIENT DELIVERY

Controlled Delivery of Hydroxy Acids

Controlled Delivery and Enhancement of Topical Activity of Salicylic Acid

41 RetiSTAR™ for Cosmetic Formulations Stabilized Retinol Axel Jentzsch BASF Aktiengesellschaft Ludwigshafen, Germany Patricia Aikens BASF Corporation Ledgewood, New Jersey 41.1 41.2 41.3 41.4

Introduction ................................................................................... 861 Retinol: An Anti-Aging Skin Care Ingredient .................................. 863 Formulating Skin Treatment Products with Retinol ...................... 863 Advantages Over Prior Art Systems............................................. 865 41.4.1 Use of Antioxidant Vitamins to Deliver Stabilized Retinol . 865 41.4.2 Technical and Economic Advantages of RetiSTAR™ ...... 866 41.5 Formulations ................................................................................. 867 References .......................................................................................... 871

41.1 Introduction Retinol (vitamin A) is a highly potent, active cosmetic ingredient for skin care. In particular, the material is quite useful as an anti-aging treatment. Retinol is a member of the class of skin care actives known as retinoids. Its chemical structure is shown in Fig. 41.1. Retinol is highly susceptible to oxidative degradation. It is intrinsically unstable when exposed to light, oxygen, heat, and acids. Therefore, it requires stabilization in personal care formulations. In a cosmetic emulsion, for example, retinol is usually stabilized by manufacturing the formulated product at low

temperatures and at a pH between 6 and 8 under an inert atmosphere such as nitrogen or argon. Subsequent packaging in oxygen and light impermeable containers is also common practice.

OH

Figure 41.1 The chemical structure of retinol (vitamin A).

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 861–872 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

RetiSTAR™ is a unique combination of retinol and an antioxidant system that effectively addresses these issues. The product prevents the degradation of the active ingredient retinol during storage of personal care emulsions. This preventative reaction occurs without the need for use of an inert atmosphere during emulsion preparation and packaging processes. It has long been known that vitamin E (tocopherol) and vitamin C (ascorbic acid) are potent antioxidants. The combination of these two vitamins is well-known to function in a redox cycle and to scavenge organic free radical species as first described by Packer.[1][3] Tocopherol is an oil-soluble (lipophilic) material. As a result, in the physiological environment, this vitamin easily partitions into the lipid membrane of cells. Free radicals, particularly peroxide species, react with and oxidize a variety of biological molecules such as unsaturated lipids. Tocopherol reacts with these oxygen-based free radicals and converts them back to their respective carboxylic acid or alcohol form, thereby forming a tocopheroxyl radical.[1] Since tocopherol has an aromatic ring, this radical is not as reactive as the oxygen radical. (See Fig. 41.2.)

functions as the primary antioxidant that reacts with an organic free radical. Thereafter, ascorbic acid reacts with the free radical tocopheroxyl to regenerate tocopherol. In physiological conditions, the ascorbyl radical formed by regenerating tocopherol is then converted back to ascorbate by the thiol cycle. Figure 41.4 shows part of this cycle where an organic free radical is reduced by tocopherol and then ascorbate reduces the tocopheroxyl radical that is generated. The antioxidant package designed for use in RetiSTAR™ is highly useful for protecting retinol against oxidative degradation in skin care formulations and during their preparation. This action is, in part, based on the thiol cycle of tocopherol and ascorbate described in Fig. 41.4. In fact, under some conditions, ascorbate and tocopherol can sometimes act as pro-oxidants and research has shown that the ratio of the two antioxidants as well as their absolute concentration is critical to their performance. Not all combinations of ascorbate and tocopherol are optimal. In fact, when one vitamin is present in an

HO O

O

O

HO HO

HO Figure 41.2 Chemical structure of tocopherol (vitamin E).

Ascorbic acid and it’s salt sodium ascorbate are water soluble and, therefore, able to dissolve into the aqueous phase of a personal care emulsion. This vitamin is known to be a reducing agent in biological systems. In such situations, it reacts with and reduces both oxygen- and nitrogen-based free radicals.[4] (See Fig. 41.3.) Like tocopherol, the ascorbyl free radical formed is less reactive than the original free radical species. Another property of ascorbic acid is its ability to act as a co-antioxidant with the tocopheroxyl radical to regenerate tocopherol.[1][2] In this reaction, the two vitamins act synergistically. Tocopherol first

OH

Figure 41.3 Chemical structure of ascorbic acid (vitamin C).

R-O-H

R-O free radical

tocopheroxyl radical

tocopherol

ascorbate

ascorbyl radical

Figure 41.4 Tocopherol reacts with the free radical to form tocopheroxyl radical. Tocopherol is then regenerated by ascorbate in an antioxidant network cycle.[1]

JENTZSCH, AIKENS: RETISTAR™ FOR COSMETIC FORMULATIONS: STABILIZED RETINOL insufficient amount or in too high of an amount, the effect can be the opposite of what is desired. In such cases, the decomposition of retinol is actually accelerated rather than prevented. In a personal care oil-in-water emulsion, the tocopherol partitions into the oil phase while the sodium ascorbate partitions into the water phase. Together, this combination of vitamins acts in a synergistic fashion and prevents oxidative degradation of the retinol. Both vitamins can act to neutralize free radical species and furthermore, the ascorbate can regenerate the tocopherol from the tocopheroxyl radical. This phenomenon allows for the preparation and packaging of a retinol-containing emulsion to be carried out in open environments without the need for an inert atmosphere. Significant cost benefits and increased stability can be achieved by using RetiSTAR™.

41.2 Retinol: An Anti-Aging Skin Care Ingredient The active ingredient of RetiSTAR™ is retinol (vitamin A). This vitamin is in a class of skin-care active ingredients known as retinoids. Such retinoids are all derivatives of vitamin A which is an alcohol (as seen in Fig. 41.1); examples include the esters retinol acetate, retinol propionate, and retinyl palmitate; other examples include the aldehyde form, retinal, and the carboxylic acid form, tretinoin, also known as all trans retinoic acid. The most effective retinoid is the carboxylic acid tretinoin. This material is regulated as a drug and cannot be used as a cosmetic ingredient. It can be harsh on the skin and cause excessive reddening, photosensitivity, and irritation. Tretinoin was first introduced as a prescription acne drug and later its anti-aging properties were recognized.[5][6] Retinol, retinal, and associated esters are all used for cosmetic purposes. Generally, the skin tolerates them better than retinoic acid.[7][8] The main effect of the class of retinoid compounds is to reduce the visual appearance of skin aging and to treat fine lines, wrinkles, and the rough skin surface caused by photodamage. Retinol works by being converted to all trans retinoic acid within the skin. This material is the biologically active retinoid in skin normalization. The mechanism for this

863

transition is achieved by a two-step process in which retinol is first oxidized to retinal, and then further [8][9] oxidized to the carboxylic acid. When the esters of retinol are used, they must first be hydrolyzed to release retinol. Thereafter, the retinol is oxidized to retinoic acid. Retinol acts to increase the levels of two types of receptors within the skin. These are known as cellular retinol binding proteins and cellular retinoic acid binding proteins.[8][10] One biochemical mode of action of the retinoids is to normalize keratinization of the skin and increase epidermal thickness. Keratinization, also known as cornification is the final differentiation of the keratinocytes leading to the stratum corneum in the end. These powerful compounds regulate epithelial cell growth (increase in size and number of keratinocytes) and cell differentiation. The process leads to an improved barrier function of the skin and helps retain moisture. These phenomena provide enhanced elasticity and anti-wrinkling benefits. Besides improving barrier function, reduction of fine lines and wrinkles, retinol also has a normalizing effect on skin pigmentation thus helping to fight age spots. Exposure of the skin to UV radiation, particularly the longer wavelength UV-A radiation which penetrates deeper into the skin than UV-B, generates reactive oxygen species (ROS). These can break down lipids and proteins of the skin cells as well as the extracellular matrix of the skin. Processes triggered by the ROS can give rise to an overexpression of matrix metallo-proteinases. These degrade the extracellular matrix proteins collagen and elastin,[11] important matrix proteins that give the skin its mechanical strength and elasticity. Retinoids have been shown to down-regulate this overexpression and, therefore, normalize the cellular function acting directly on UV-induced cellular processes, thus guarding the skin against premature aging.[12][13]

41.3 Formulating Skin Treatment Products with Retinol Retinol is highly reactive and unstable. It will degrade over time in the presence of heavy metal

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 41.5 shows a typical set of data comparing of retinol levels over time, in finished skin care formulation at 40°C, when these precautions are not taken. After 12 weeks, the retinol level is approximately 40% lower than its original concentration, if no inert atmosphere is used during manufacture and packaging. If the formulation were packaged in air and light-impermeable aluminum tubes, there would be some improvement in retinol recovery achieved. If an argon atmosphere is used during preparation, less

than of retinol is lost and this stabilizes after about six weeks. Effects of encapsulating retinol. One method of attempting to stabilize retinol in personal care formulations is to encapsulate it. Examination of several types of encapsulated retinol showed that if an inert atmosphere is not used, generally 30% of the original retinol is lost to degradation after 12 weeks at 40°C, as seen in Fig. 41.6.

80

70

60

No Argon or aluminum packaging Aluminum packaging, no Argon

50

Aluminum packaging with Argon 40 0

2

4

6

8

10

12

Storage time in weeks (cosmetic emulsion at 40°C)

Figure 41.5 Retinol requires stabilization when used in cosmetic formulations.

100.0

90.0

% Retinol recovery

As a result of the inherent instability of retinoids, formulators of personal care products have been required to provide an inert atmosphere of nitrogen or argon gas during preparation and packaging of their retinol-containing products in order to exclude oxygen and, thereby, minimize degradation of the active ingredient. Retinol should be added in the final step of the process at a temperature below 30 oC in order to avoid thermal decomposition. UV filters and chelating agents are typically incorporated into such formulations in order to provide long-term stability. The final formulation must be packaged (under an inert atmosphere) in airtight and light-impermeable aluminumlined tubes in order to maintain the activity of retinol over a reasonable shelf life.

% Retinol recovery

catalysts (iron in particular), heat, UV light, and oxygen. Pure retinol is a crystalline material and is virtually impossible to use by itself in personal care formulations since it decomposes so rapidly. While use of retinyl esters helps to prevent this decomposition, the esters themselves are less active than retinol, since they require an extra hydrolysis step in the skin. Typically, retinol is supplied as a 10%–50% solution in oil, or in a solubilizer such as polysorbate 20 in order to slow the rate of degradation. To further decrease degradation, antioxidants such as BHT (butylated hydroxytoluene) are usually incorporated, and the product 100 is typically stored at low temperatures (6°C–8°C) in aluminum cans in order to 90 prevent exposure to light and oxygen.

80.0

70.0

60.0

50.0

40.0 0

#1

#2

#4

#5

2

4

6

8

10

12

Storage time in weeks Figure 41.6 Levels of retinol recovery from a formulation using encapsulated retinol and no inert atmosphere after 12 weeks at 40°C.

JENTZSCH, AIKENS: RETISTAR™ FOR COSMETIC FORMULATIONS: STABILIZED RETINOL

41.4 Advantages Over Prior Art Systems RetiSTAR™ consists of 5% retinol in an oilbased dispersion of caprylic/capric triglycerides. This dispersion contains the antioxidants tocopherol and sodium ascorbate in an optimally balanced ratio and concentration. This combination of vitamins, in the proper ratio to each other, provides for superior protection against retinol degradation in personal care formulations as compared to the systems described previously. A rheology modifier is incorporated to enhance the physical stability of the dispersion against sedimentation of the insoluble ascorbate. A photomicrograph of the dispersion is shown in Fig. 41.7. RetiSTAR™ can be used in cosmetic formulations without the need for an inert atmosphere during preparation and packaging and, therefore, offers significant new flexibility unavailable previously. To achieve this stabilization effect it is absolutely mandatory to use air- and light-impermeable packaging for the cosmetic products. RetiSTAR™ is an easily pourable dispersion with over one year storage stability at 5°C–10°C. Once opened, containers can be stored closed at 5°C–10°C without the need for an inert gas blanket over a period of several weeks without significant losses of retinol (<10%). For longer storage times, air in the container vapor space should be replaced by a blanket of inert gas (preferably argon). It is advisable to check the retinol concentration before use. RetiSTAR™ can be readily incorporated into both water-in-oil and oil-in-water emulsions and can be used over a pH range of 5.5–8. The method of incorporation is simply to add the oily dispersion dur-

50 µm

Figure 41.7 Photomicrograph of RetiSTAR™ dispersion.

865

ing the final stage of emulsion preparation below 30°C. Higher temperatures up to 50 oC can be tolerated if the exposure time does not exceed 30 minutes. The recommended use level for RetiSTAR™ is between 1 wt% and 2 wt%. This level provides typical retinol concentrations in the finished formulation of 0.05 wt% to 0.1 wt%. The use of additional technical antioxidants (e.g., ascorbyl palmitate, additional sodium ascorbate, or tocopherol) with RetiSTAR™ can lead to a decreased stability of retinol and is, therefore, not recommended. By contrast, physiologically active antioxidants, such as tocopheryl acetate and sodium ascorbyl phosphate (SAP), do not have an impact on the stability of retinol in RetiSTAR™ and will further enhance the performance of such formulations. Incompatibilities have been observed with ascorbyl palmitate and titanium dioxide, and formulations such as sunscreens and others, which employ these ingredients, should be checked carefully for retinol stability.

41.4.1

Use of Antioxidant Vitamins to Deliver Stabilized Retinol

The RetiSTAR™ system for protection of retinol is based on the tocopherol–ascorbate antioxidant synergism. The most important factor in achieving retinol stabilization is the proper concentration and ratio of tocopherol to sodium ascorbate. Surprisingly, either of the two antioxidants alone, or in combination at improper ratios, appear to destabilize rather than stabilize retinol in an emulsion. This phenomenon is seen in Fig. 41.8. Figure 41.9 shows that stabilization of retinol occurs only in a narrow concentration range where over 90 % of the vitamin is recovered after 12 weeks at 40 oC. The data shown in Fig. 41.9 is for a personal care formulation made with a tocopherol–sodium ascorbate system containing an optimal amount of tocopherol. The concentration of sodium ascorbate is varied in Fig. 41.9. Analysis of the data clearly shows that too much or too little sodium ascorbate causes significant destabilization of the retinol. RetiSTAR™ is designed to be in the region where greater than 90% recovery of retinol occurs. As such, it represents a breakthrough in retinol stabilization over the more cumbersome and expensive prior art approach.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

100.0

% Retinol recovery

80.0

60.0

40.0

unstabilised Retinol adequate combination

20.0

inadequate Vitamin E inadequate Vitamin C

0.0 0

3

6

9

12

Storage time [weeks]

Figure 41.8 Cosmetic o/w formulation at 40°C without inert gas in aluminum-lined tubes. Inadequate amounts of tocopherol (vitamin E) or sodium ascorbate (vitamin C) can cause decomposition or retinol.

100.0

% Retinol recovery

80.0

60.0

40.0

20.0

optimized concentration of tocopherol 0.0

Increasing concentration sodium ascorbate

Figure 41.9 Retinol recovery from a skin care formulation stored at 40°C with optimized tocopherol levels and varying levels of sodium ascorbate.

41.4.2

Technical and Economic Advantages of RetiSTAR™

RetiSTAR™ provides a significant reduction in manufacturing and packaging cost of retinol-containing personal care formulations because no specialized equipment is required for maintaining an inert atmosphere during the process. This advantage re-

duces the formulation preparation time since the emulsions can be prepared in a manner similar to systems that do not contain sensitive ingredients. RetiSTAR™ should be added at temperatures below 30°C, and the emulsion should be packaged in light- and air-impermeable aluminium-lined tubes for long-term storage stability.

JENTZSCH, AIKENS: RETISTAR™ FOR COSMETIC FORMULATIONS: STABILIZED RETINOL

867

41.5 Formulations The following are concept cosmetic formulations using RetiSTAR™ stabilized retinol. Formulation 41.1: Retinol Water-in-Silicone Emulsion With RetiSTAR™

Phase

Ingredient

Function

Weight%

Octyl palmitate

Emollient

Cyclomethicone

Skin conditioner

5.00

Cetyl dimethicone copolyol

Emulsifier

3.00

Cetyl methicone

Skin conditioner

2.00

Hydrogenated castor oil

Thickener/emollient

2.00

Phenyl trimethicone

Skin conditioner

3.00

Tocopheryl acetate

Antioxidant

1.00

Bisabolol

Anti-inflammatory agent

0.20

Deionized water

Aqueous phase

Sodium chloride

Electrolyte

1.00

Glycerin

Humectant

2.00

Xanthan gum

Internal phase thickener

0.10

D

Preservative

Preservative

qs

E

Fragrance

Fragrance

qs

F

RetiSTARTM (stabilized retinol)

Anti-aging ingredient

A

B

C

10.00

qs

1.00

Manufacturing Procedure: 1. Combine Phase A and Phase B separately. 2. Heat Phases A and B to 75°C–80°C. Add combined Phase C to Phase B under propeller mixing. Mix well. 3. Using homogenizer, add Phases BC to Phase A very slowly and homogenize for 4–5 minutes. Transfer to slow mixing. 4. At 40°C, add Phases D and E one at a time and mix well. 5. Add Phase F to batch and mix well. 6. Cool to room temperature and package in aluminum tubes. Important: While the information and data contained in this bulletin are presented in good faith and believed to be reliable, they do not constitute a part of our terms and conditions of sales unless specifically incorporated in our Order Acknowledgement. NOTHING HEREIN SHALL BE DEEMED TO CONSTITUTE A WARRANTY, EXPRESS OR IMPLIED, THAT SAID INFORMATl0N OR DATA ARE CORRECT OR THAT THE PRODUCTS DESCRIBED ARE MERCHANTABLE OR FIT FOR A Particular PURPOSE, OR THAT SAID INFORMATl0N, DATA OR PRODUCTS CAN BE USED WITHOUT INFRINGING PATENTS OF THIRD Parties. All trademarks are owned by BASF AG or BASF Corporation. © 2003 BASF Corp.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 41.2: Retinol Moisturizing Lotion With RetiSTAR™

Phase

Ingredient

Function

Weight%

Deionized water

Aqueous phase

qs

Butylene glycol

Skin conditioner

3.00

Polyglyceryl-3 distearate

Emulsifier

2.00

Ceteareth-25

Emulsifier

2.00

Behenyl alcohol

Emulsion stabilizer

2.00

Cetyl alcohol

Emulsion stabilizer

2.00

C12-15 Alkyl benzoate

Emollient

6.00

Caprylic/capric triglyceride

Emollient

12.00

Cyclomethicone

Skin conditioner

2.00

Dimethicone

Skin conditioner

0.50

Tocopheryl acetate

Antioxidant

1.00

Bisabolol

Anti-inflammatory agent

0.20

C

Preservative

Preservative

qs

D

Fragrance

Fragrance

qs

E

RetiSTAR™ (stabilized retinol)

Anti-aging ingredient

A

B

1.00

Manufacturing Procedure: 1. Combine Phase A and Phase B separately. 2. Heat Phases A and B to 75°C–80°C. 3. Using homogenizer, add Phase B to Phase A and homogenize for 4–5 minutes. Transfer to sweep mixing. 4. At 40°C, add Phases C and D one at a time and mix well. 5. Add Phase E to batch and mix well. 6. Cool to room temperature and package in aluminum tubes. Important: While the information and data contained in this bulletin are presented in good faith and believed to be reliable, they do not constitute a part of our terms and conditions of sales unless specifically incorporated in our Order Acknowledgement. NOTHING HEREIN SHALL BE DEEMED TO CONSTITUTE A WARRANTY, EXPRESS OR IMPLIED, THAT SAID INFORMATl0N OR DATA ARE CORRECT OR THAT THE PRODUCTS DESCRIBED ARE MERCHANTABLE OR FIT FOR A Particular PURPOSE, OR THAT SAID INFORMATl0N, DATA OR PRODUCTS CAN BE USED WITHOUT INFRINGING PATENTS OF THIRD Parties. All trademarks are owned by BASF AG or BASF Corporation. © 2003 BASF Corp.

JENTZSCH, AIKENS: RETISTAR™ FOR COSMETIC FORMULATIONS: STABILIZED RETINOL

869

Formulation 41.3: Retinol Daily Wear Facial Lotion With RetiSTAR™

Phase

Ingredient

Function

Weight%

Deionized water

Aqueous phase

Propylene glycol

Humectant

5.00

D-Panthenol (75% in water)

Skin conditioning agent

1.00

Ceteareth-6 (and) stearyl alcohol

Emulsifier

2.00

Ceteareth-25

Emulsifier

1.00

Cetearyl alcohol

Emulsion stabilizer

3.00

Glyceryl stearate

Emulsion stabilizer

2.00

Cetearyl cctanoate

Emollient

Petrolatum

Skin protectant

3.00

Octyl methoxycinnamate

UV absorber

3.00

Bisabolol

Anti-inflammatory agent

0.20

Tocopheryl acetate

Antioxidant

1.00

C

Preservative

Preservative

qs

D

Fragrance

Fragrance

qs

E

RetiSTAR™ (stabilized retinol)

Anti-aging ingredient

A

B

qs

10.00

1.00

Manufacturing Procedure: 1. Combine Phase A and Phase B separately. 2. Heat Phase A and Phase B to 75°C–80°C. 3. Using homogenizer, add Phase B to Phase A and homogenize for 4–5 minutes. Transfer to slow mixing. 4. At 40°C, add Phase C and D one at a time and mix well. 5. Add Phase E to batch and mix well. 6. Cool to room temperature. And package in aluminum tubes. Important: While the information and data contained in this bulletin are presented in good faith and believed to be reliable, they do not constitute a part of our terms and conditions of sales unless specifically incorporated in our Order Acknowledgement. NOTHING HEREIN SHALL BE DEEMED TO CONSTITUTE A WARRANTY, EXPRESS OR IMPLIED, THAT SAID INFORMATl0N OR DATA ARE CORRECT OR THAT THE PRODUCTS DESCRIBED ARE MERCHANTABLE OR FIT FOR A Particular PURPOSE, OR THAT SAID INFORMATl0N, DATA OR PRODUCTS CAN BE USED WITHOUT INFRINGING PATENTS OF THIRD Parties. All trademarks are owned by BASF AG or BASF Corporation. © 2003 BASF Corp.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 41.4: Anti-ageing Retinol Cream With RetiSTAR™

Phase

A

B

C

D

Ingredient

Function

Weight %

Deionized water

Aqueous phase

71.1

Glyceryl

Humectant

2.00

1,2 Propylene glycol

Humectant

3.00

D-Panthenol 75W (Panthenol)

Skin-conditioning agent

1.00

Carbomer

Thickener

0.30

Ceteareth-6 (and) stearyl alcohol

Emulsifier

2.00

Ceteareth-25

Emulsifier

2.00

Grape seed oil

Anti-aging ingredient

6.00

Glyceryl stearate SE

Emulsifier

3.00

Cetearyl octanoate

Emollient

8.00

Deionized water

0.30

Triethanolamine

Neutralizer

0.30

E

Preservative

Preservative

qs

F

Fragrance

Fragrance

qs

G

RetiSTAR™ (stabilized retinol)

Anti-aging ingredient

1.00

Manufacturing Procedure: 1. Combine Phase A and sprinkle Phase B under propeller mixing. Mix well. 2. Combine Phase C. 3. Heat Phases AB and C to 80°C–85°C. 4. Using homogenizer, add Phase C to Phase AB and homogenize for 4–5 minutes. 5. Add Phase D to batch and mix for 2–3 minutes. Transfer to sweep mixing. 6. At 40°C, add Phases E and F one at a time and mix well. 7. Add Phase G to batch and mix well. Cool to room temperature. While the information and data contained in this bulletin are presented in good faith and believed to be reliable, they do not constitute a part of our terms and conditions of sales unless specifically incorporated in our Order Acknowledgement. NOTHING HEREIN SHALL BE DEEMED TO CONSTITUTE A WARRANTY, EXPRESS OR IMPLIED, THAT SAID INFORMATl0N OR DATA ARE CORRECT OR THAT THE PRODUCTS DESCRIBED ARE MERCHANTABLE OR FIT FOR A Particular PURPOSE, OR THAT SAID INFORMATl0N, DATA OR PRODUCTS CAN BE USED WITHOUT INFRINGING PATENTS OF THIRD Parties. All trademarks are owned by BASF AG or BASF Corporation. © 2003 BASF Corp.

JENTZSCH, AIKENS: RETISTAR™ FOR COSMETIC FORMULATIONS: STABILIZED RETINOL

871

References 1. Packer, J. E., Slater, T. F., and Willson, R. L., Nature, 278:737–738 (1979)

8. Lipo, M. P., Clinics in Dermatology, 19(4):467-473 (2001)

2. Buettner, G., Arch. Biochem. Biophys., 300920535–543 (1993)

9. Boerman, M., and Napoli, J., J. Biol. Chem., 271:5610 (1996)

3. Packer, L., and Obermuller-Jevic, U. C., The Antioxidant Vitamins C and E, pp. 133–151, AOCS Press (2002)

10. Kang, S., Duell, E. A., Fisher, G. J., Datta, S. C., Wang, Z. Q., Reddy, A. P., Tavakkol, A., Yi, J. Y., Griffiths, G. E., and Elder, J. T., J. Invest. Dermatol., 105(4):549–555 (1995)

4. Higdon, J. V., and Frei, B., The Antioxidant Vitamins C and E, pp. 1–16, AOCS Press (2002) 5. Kligman, A. M., US patent 4,603,146 (1986) 6. Weiss, J. S., Ellis, C. N., Headington, J. T., Tincoff, T., Hamaliton, T. A., and Voorhees, J. J., JAMA, 259(4):527–532 7. Toma, S., and Sacchi, N., Retinoids LipidSoluble, Vitam. Clin. Pra., 17:4 98–102 (2001)

11. Malak, A. N., and Perrier, E., 20th IFSCC Congress Proceedings, 1:79–89, Cannes (1998) 12. Varani, J., Warner, R. L., Gharaee-Kermani, M., Phan, S. H. , Kang, W., Chung, J.H., Wang, Z. Q., Datta, S. C., Fisher, G. J., and Voorhees, J. J., J. Invest. Dermatol., 114:480–486 (2000) 13. Voorhees, J. J., Clin. Exp. Dermatol., 25:161– 162 (2000)

42 Controlled Delivery and Enhancement of Topical Activity of Salicylic Acid Paul Thau PaCar Tech Berkeley Heights, New Jersey 42.1 Introduction ................................................................................... 873 42.2 Contemporary Technologies and Vehicles to Modify Delivery and Activity of Salicylic Acid .......................................................... 874 42.2.1 Polymeric Complexation ................................................... 874 42.2.2 Liposome Delivery System ............................................... 875 42.2.3 Polymeric Entrapment and/or Encapsulation ................... 875 42.2.4 Acid pH Emulsion Systems .............................................. 877 42.2.5 Gel Delivery Vehicles ........................................................ 878 42.2.6 Anti-Irritant Compositions ................................................. 878 42.3 Conclusions .................................................................................. 878 References .......................................................................................... 879

42.1 Introduction During the past fifteen years, a variety of sophisticated topical delivery systems have been developed to enhance the properties of functional ingredients. Examples of these include salicylic acid, benzoyl peroxide, retinol, and ascorbic acid. These delivery systems have enabled formulators to realize the full potential of these distinctive ingredients by providing a wide range of novel features such as substantivity, improved stability, targeted delivery, reduced skin irritation, better ingredient compatibility, and enhanced functionality. This review surveys innovative delivery systems that have been developed to control and enhance

the delivery of salicylic acid. A review of over-thecounter (OTC) ingredient labeling shows that salicylic acid, a “classical” ingredient, is one of the most frequently employed OTC active ingredients employed for the treatment of conditions such as acne, dandruff, and psoriasis. Salicylic acid (SA) (2-hydroxybenzoic acid) was originally derived from willow bark, wintergreen leaves, and sweet birch bark. Today, this material is commonly produced synthetically by the KolbeSchmidt process in which CO2 is reacted with sodium phenolate. This process is carried out under pressure at about 130°C to form sodium salicylate. Treatment of sodium salicylate with a mineral acid then provides the final product. One gram is soluble

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 873–880 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

in 460 ml of water, 3 ml of ethyl alcohol, or about 15 ml of boiling water.[1] Salicylic acid has keratolytic properties and is applied topically in the treatment of hyperkeratotic and scaling skin conditions such as dandruff, seborrheic dermatitis, ichthyosis, psoriasis, and acne. This acid has a long history of use in OTC and Rx dermatological products; however, the approved use concentration for salicylic acid in OTC products is from 0.5% to 2%. For some Rx uses, such as the removal of plantar warts, use levels can be as high as 60%.[2] During the 1990s, the outstanding success of alpha hydroxy acids (AHAs) in personal care products employed to increase cell turnover and enhance skin moisturization has fostered additional in-depth investigations of the action of salicylic acid on the skin. The recent commercial designation of salicylic acid as a beta hydroxy acid is a reflection of the marketplace success of AHA-based products. An important distinction of salicylic acid from the alpha hydroxy acids, such as glycolic acid, is that salicylic acid is lipophilic. This feature enables it to penetrate sebaceous material in the hair follicle and to exfoliate pores.[3]

42.2 Contemporary Technologies and Vehicles to Modify Delivery and Activity of Salicylic Acid A persistent flow of new and innovative delivery systems for salicylic acid have become available in the past fifteen years to target, enhance, and reduce the irritation potential of salicylic acid for OTC product applications. This variety of contemporary delivery systems offers formulators a range of tools to prepare products with improved functionality. The primary goal of delivery systems for salicylic acid has been to diminish its rapid penetration into the stratum corneum. By this approach, irritation potential of the acid is greatly reduced, and a reservoir of the material is created for sustained topical activity. One conclusion that emerges from a review of such systems is that the topical bioavail-

abilty of salicylic acid in the stratum corneum varies substantially among formulations employing different delivery systems. These delivery technologies can be categorized as follows: • Polymeric complexation and molecular film technology • Liposome systems • Polymeric entrapment and/or encapsulation • Acid pH emulsion systems • Gel delivery • Anti-irritant systems

42.2.1 Polymeric Complexation Polymers such as Polyolprepolymers and Cyclodextrins are examples of polymers that have the capacity to complex salicylic acid.[4] Polyolprepolymers (polyurethane type polymers). These are a mixture of oligomers ranging in molecular weight from about 525 to 5,000 Daltons. When applied to the skin, a gradient of such oligomers is formed within the stratum corneum. It is well-known that higher-molecular–weight materials tend to stay on the surface of the skin, while lowerweight materials tend to penetrate into the stratum corneum. Polyolprepolymers form a liquid matrix of oligomers that associate with the stratum corneum.[4] In a study conducted by Penedederm, Inc., delivery of radio-labeled salicylic acid into human skin was measured from a 1% salicylic acid ethanol/water mixture containing 1% polyolprepolymer-15 (PP-15) [polyethylene glycol-8/SMDI copolymer (SMDI represents saturated methylene diphenyldiisocyanate)] and a control system which did not contain the polymer. A tape strip study showed that a greater amount of salicylic acid was present in the upper layers of the skin from the formulation containing 1% PP-15, as compared to the formulation without the PP-15. The increased deposition of salicylic acid in the upper layers of the stratum corneum provides the potential for increased keratolytic activity.[4] Further substantiation of this PP-15 controlled delivery technology is presented in a paper published in the Journal of Cosmetic Science.[5] The researchers demonstrated that PP-15 decreased the permeation of salicylic acid through pigskin and

THAU: CONTROLLED DELIVERY AND ENHANCEMENT OF TOPICAL ACTIVITY OF SALICYLIC ACID increased its deposition within the stratum corneum. Their data suggests that the binding of salicylic acid to PP-15 is the critical phenomenon responsible for alteration by the polymer and salicylic acid permeation kinetics.[5] In another study,[6] the penetration of salicylic acid into various layers of skin, (i.e., epidermis, dermis, and receptor fluid) was measured using a modified Franz cell in vitro diffusion method after various exposures for periods up to 24 hours. PP-15 was found to be an effective agent in regulating the delivery of salicylic acid. In a dose-dependent fashion, the prepolymer targeted the delivery of relatively more salicylic acid to the epidermis as compared to through the skin into the receptor fluid. The prepolymer also reduced the rapid permeation of a large dose of SA through skin. Cumulative irritation studies showed that targeting delivery of salicylic acid to the epidermis and eliminating the rapid, early penetration of a large dose of the drug through the skin resulted in reduced irritation potential. This result was achieved while still maintaining the same total delivery of salicylic acid to the skin as standard commercial acne products. See Fig. 42.1.

of slightly soluble active molecules has been observed to increase when incorporated in a cyclodextrin complex.[6][7] While the solubility of salicylic acid in aqueous solution is low because of its lipophilicity, its complex with a cyclodextrin molecule makes this acid significantly more water soluble. Thus, some potentially irritating reactions that result from use of the free acid form can be prevented because of better homogeneity provided by the cyclodextrin. It is claimed that cyclodextrin complexes enhance the disinfectant, bacteriostatic, and keratolytic properties of salicylic acid.[8] Cyclodextrin complexes of salicylic acid are commercially available from both Collaborative Laboratories and Lipo Chemicals, Inc. They have been used in products like Bioclin Sebo Care Impure Skin Cream® (Ganassini).

42.2.2 Liposome Delivery System A liposome delivery system for salicylic acid has been developed by Collaborative Laboratories and is described as follows in US Patent 5,585,109. “A cosmetic composition and salicylic acid delivery system includes membrane lipid bilayers formed as liposomes and un-neutralized salicylic acid localized within the lipidic bilayers of the liposomes. Other cosmetic ingredients may be located either within the membrane compartment or in either the external or internal aqueous compartments, relative to the liposomal bilayers. The composition also includes an organic, water-soluble membrane-impermeable base, and water.”[9]

Figure 42.1 In vitro skin permeation study.

Cyclodextrins. Cyclodextrins are a class of “molecular cavity-containing” cyclic compounds (oligosaccharides), sometimes described as being donut-shaped. These possess the ability to form special types of complexes known as molecular inclusion complexes. These complexes form with a variety of chemicals, including salicylic acid. The physical and chemical properties of the “guest” molecules, such as salicylic acid, change due to complex formation with the cyclodextrin “host.” The solubility

875

Clinique has employed this delivery system described as “Salisomes” in some of its commercial products.

42.2.3

Polymeric Entrapment and/or Encapsulation

Several commercial products have been developed using polymeric entrapment and/or encapsulation of salicylic acid.

876

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Liponyl™ N30SA (Lipo Chemicals, Inc.) is a new, patented ingredient that has been designed to minimize the adverse effects of salicylic acid. This raw material is a fine, white-to-off-white powder containing approximately 15% salicylic acid that has been impregnated into a polyamide copolymer matrix. The product has a silky after-feel and has been designed as a time-release product that delivers salicylic in a stable, easy-to-use form. This delivery system is not suitable for formulations containing high levels of ethyl alcohol. Release of salicylic acid to aqueous vehicles is controlled by the limited solubility of salicylic acid in water.[10] The INCI name of Liponyl™ is nylon 6/12, salicylic acid, and butylene glycol. Benefits for the use of this type of entrapment of salicylic acid are claimed to include elimination of the need for solubilizers, such as ethanol, a prolonged release profile of salicylic acid into the skin, reduced irritation, and reduced interaction with pigments and metal containers. The supplier of this material has conducted in vitro skin permeation studies as well as relative cumulative irritation studies. These studies demonstrate that entrapped salicylic acid is a delivery system that can offer a targeted, prolonged release delivery of salicylic acid to the skin for topical treatment. The material provides higher safety levels by reducing irritation caused by salicylic acid that has not been entrapped or encapsulated. Two formulations containing Liponyl™ N30SA (Lipo Chemicals, Inc.) were studied to compare the

relative cumulative irritancy of the complexed salicylic acid with the free salicylic acid control. These formulations are described in Table 42.1. • % of salicylic acid permeating the skin was 30% higher in the lotion containing free salicylic acid. • After 27 hours, 37% more salicylic acid remained in the epidermis after the application of Liponyl™ N30SA. • This demonstrates that Liponyl™ N30SA the activity of salicylic acid within the skin persists, even after the lotion is washed off. Application of Liponyl™ N30SA was shown to significantly reduce salicylic acid irritation. (See Fig. 42.2.) Poly-Pore™ 150SA, Salicylic acid delivery system (Amcol Health and Beauty Solutions, Inc.). The composition of this material is described as follows: INCI Name: Allyl methacrylates crosspolymer and 2-hydroxy-benzoic acid. PP 150SA contains a 50% loading of salicylic acid inside the matrix of the Poly-Pore polymer and is supplied as a free-flowing powder. This type of polymer is highly adsorptive because of its high surface area and intruded volume. In view of the multifunctional characteristics of this system, the use of the PP 150SA dispersion of salicylic acid requires only mixing rather than the

Table 42.1: Formulations Tested for Relative Cumulative Irritancy Formulations Studied

A

B

85.50

79.83

Liponic EG-1 (Glycereth-26)

5.00

—

P-23 (preservative)

0.50

0.50

Salicylic acid

1.00

—

Liponate™ 2-DH (PEG-4- diheptanoate)

3.00

3.00

2.00

2.00

2.50

2.50

0.50

0.50

—

6.67

1.0% Xanthan gum soln.

Liponate™ GC (caprylic/capric triglyceride) Lipomulse™ 165 (glyceryl stearate and PEG-100 stearate) Lipocol™ C (cetyl alcohol) Liponyl™ N30SA

THAU: CONTROLLED DELIVERY AND ENHANCEMENT OF TOPICAL ACTIVITY OF SALICYLIC ACID

877

uct containing salicylic acid does not destroy carbopol’s thickening properties. It has been theorized that the acid functionality of the salicylic acid is hidden from the carbopol because it is entrapped within the Poly-Pore.[12][13] Chronosphere® SAL (Arch Personal Care Products). These controlled time-release delivery vehicles are heat Figure 42.2 Relative cumulative irritancy study of Liponyl™ N30SA and pressure stable and compatible with vs free salicylic acid. a variety of actives and bases. They are supplied as a powder containing 20% saliuse of alcohols or other solvents as typically required cylic acid. The INCI names are acrylate/carbamate for solutions. This allows the formulator a range of copolymer and salicylic acid. The recommended alternatives to use as the vehicle, without concerns applications are treatment lotion, toner, facial moisover buffering the system.[11] turizer, makeup, and lipstick.[12][13] The matrix of the Poly-Pore delivery system provides a “reservoir” for active ingredients. Release of the salicylic acid occurs through a combination of friction upon application to skin and controlled diffusion of salicylic acid from the Poly-Pore matrix into the skin, providing a substantial decrease in release of the salicylic acid. Slowing the release of salicylic acid helps to minimize expected irritation effectiveness.[11] Results of Franz diffusion cell studies below show that PP 150SA reduces the diffusion of salicylic acid through the membrane. (See Fig. 42.3.) The PP 150SA powder can be suspended in an aqueous system thickened with a rheology modifier such as carbopol. Suspension of the Poly-Pore prod-

42.2.4 Acid pH Emulsion Systems A unilever patent discloses low pH, high fatty acid, vanishing cream compositions that have a pH in the range of 1–5. These are based upon a relatively high concentration of fatty acid, especially stearic acid, an acid pH stable emulsifier, (such as methyl glucose sesquistearate), and acidic skin treatment agents. Particularly preferred as the acidic skin treatment agents are a combination of alpha and beta hydroxy acids. An example disclosed in the patent contains 1% lactic acid and 1% salicylic acid.[14]

Figure 42.3 Release of salicylic acid from Poly-Pore® E200 in a Franz diffusion cell.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

42.2.5

Gel Delivery Vehicles

Ingredients:

ISP’s Stabileze® PVM/MA decadiene crosspolymer can be used to prepare elegant salicylic acid gels for acne and skin care products. Because salicylic acid is insoluble in water, processing these formulations require special care and attention. ISP technical literature states that either a cold or hot process can be used.[15] Formulations that employ this material are buffered to pH 4.0–4.5, preferably with sodium hydroxide, 10% aqueous solution.

The active ingredient for Neutrogena’s product is salicylic acid, 2%.

Neutrogena Clear Pore® Gel utilizes this gel delivery technology commercially in their product. The label claims read as:

A common problem with formulations containing salicylic acid is that some individuals experience a stinging sensation and even redness on the skin after applying these products to their face. Two US patents that have come to the author’s attention describe the use of anti-irritant agents to ameliorate these undesirable side effects. US patent 5,482,710 describes and substantiates the use of glycyrrhizinic acid and salts thereof, especially the dipotassium and ammonium salts, as the preferred water-soluble, antiirritancy agents. Alpha bisabolol and azulene are described as the preferred water-insoluble, anti-irritancy agents in this patent.

Salicylic acid acne treatment: • Oil-free • Alcohol-free • Won’t clog pores • Sloughs off dead skin cells • Light gel formula leaves no greasy afterfeel • Can be used with moisturizers Neutrogena Clear Pore® product literature states that this product has been clinically proven to effectively control acne and improve the appearance of skin as shown in Table 42.2.

Table 42.2. Neutrogena Clear Pore® Results of Three Week Efficacy Study

Appearance

Week 1

2

3

Smoother skin

*

*

*

Improved skin clarity

o

*

*

Improved skin texture

o

*

*

Fewer blocked pores

o

o

*

Fewer blemishes

o

o

*

Improved overall complexion

o

*

*

o—Some improvement. *—Distinct improvement.

Inactive ingredients include water, PEG-32, PVM/MA decadiene crosspolymer, sodium hydroxide, and fragrance (pH 4.0 to 4.5).

42.2.6 Anti-Irritant Compositions

US patent 6,168,798 claims that the unique presence of the glycerophosphate ester or salt, particularly sodium or calcium glycerophosphate, serves to significantly reduce the irritation of the astringent compositions of the present invention, as well as playing a role in reducing sebum production on the skin. An illustrative formulation for this patent is shown in Table 42.3.

42.3 Conclusions A survey of modalities described to control the delivery of salicylic acid to skin has been presented. Most of these delivery systems have been developed with the objective to both enhance efficacy and diminish potential skin irritation of the acid. These systems differ significantly in composition, mechanism of action, and performance. The choice of an appropriate delivery system for salicylic acid by a formulator will depend upon factors such as esthetics desired, physical and chemical stability of the vehicle, required release characteristics, effectiveness, and cost constraints.

THAU: CONTROLLED DELIVERY AND ENHANCEMENT OF TOPICAL ACTIVITY OF SALICYLIC ACID

879

Table 42.3. Non-Irritating Cosmetic Astringent Composition

Ingredient

Weight%

Denatured alcohol (95%)

30.00

Deionized water

66.14

Salicylic acid

0.52

Calcium glycerophosphate

0.50

Sodium hydroxide (10% aqueous solution)

0.05

Glycerin

1.00

Menthol

0.08

PEG-40 Hydrogenated castor oil

1.00

Fragrance

0.30

Hydroglycolic plant extract

0.30

Colorant

0.11 Total

References

100.00%

7. US Patent 5,942,501.

1. Remington’s Practice of Pharmacy, 65:1212

8. Buschmann, H. J., and Schollmeyer, E., J. Cosmet. Sci., 53:185–191 (May/Jun. 2002)

2. Martindale, 32nd Ed., pp. 90

9. US Patent 5,585,109.

3. Kligman, A., Cosmet. Dermatol., Supplement (Sep. 11, 1997)

10. Liponyl™ N30SA Company Literature, Lipo Chemical, Inc.

4. Barnet Products Polyprepolymers.

11. Amcol Poly-Pore 150 SA Technical Data.

Literature

for

5. Fares, H. M., and Zatz, J. L., Mechanism of Polyethylene Glycol-8/SMDI Copolymer in Delivery of Topically Applied Drugs, J. Cosmet. Sci., 50:133–146 (May/Jun. 1999) 6. Rhein, L. D., Chaudhuri, B., Jivani, N., Fares, and Davis, A., Targeted Delivery of Salicylic Acid from Acne Treatments: Relationship to Irritation.

12. Rosen, M., GCI, Special Deliver, p. 38 (Sep. 2001) 13. Arch Technical Literature, Chronosphere® SAL. 14. WO 01 70, 187, Unilever PLC , Unilever NV, Hindustan Lever Ltd., UK. 15. ISP Stabileze Technical Literature.

43 Controlled Delivery of Hydroxyacids Barbara Green and David Milora NeoStrata Company, Inc. Princeton, New Jersey

43.1 Topical Use of AHAs ..................................................................... 881 43.1.1 An AHA has to be Absorbed to Work ................................ 882 43.1.2 Why Stinging is Important, but Not Essential .................... 882 43.1.3 The Case for Controlled-Delivery of AHAs........................ 882 43.2 Amphoteric Controlled-Release Systems .................................... 883 43.2.1 Evidence of Amphoteric AHA Complexes ......................... 884 43.2.2 Commercialization of Amphoteric AHAs........................... 887 43.3 Molecular Complexing Agents ...................................................... 888 43.3.1 Selection of Molecular Complexing Agents....................... 888 43.3.2 Applications of AHA Molecular Complexing Agents .......... 889 43.4 Summary ...................................................................................... 889 43.5 Formulations ................................................................................. 890 References .......................................................................................... 907

43.1 Topical Use of AHAs The alpha-hydroxyacids (AHAs), such as glycolic acid and lactic acid, exhibit profound normalizing effects on skin keratinization. This capability led to their use for various skin conditions including ichthyosis, acne, age spots, and warts.[1]–[4] Alpha-hydroxyacids also provide significant anti-aging benefits including increased biosynthesis of glycosaminoglycans (GAGs) and collagen fibers, improved quality of elastic fibers, normalized epidermal thickness and differentiation, and enhanced cell turnover

of the stratum corneum.[5]–[10] To the consumer’s eye, these effects are apparent as firmer, smoother, and brighter skin with a diminished appearance of fine lines and wrinkles. The overall effect is one of younger-looking skin. The alpha-hydroxyacids have helped to build a billon dollar skin care industry. In fact, skin care products were expected to produce 2.3 billion dollars in sales in the year 2003 and enjoy a seven percent annual growth rate.[11] As one of relatively few major ingredient technologies with clinically supported

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

anti-aging claims, the AHAs have been utilized in countless cosmetic formulations ranging from creams and gels to tonics. The most common complaint related to AHA use is a sensation of stinging and burning immediately upon application.[12] While usually transient in nature, these undesirable sensations occur when the AHA ingredient penetrates the skin in a rapid, uncontrolled manner.[13][14] Some hydroxyacids can penetrate the skin so rapidly that they stimulate superficial nerve endings and cause stinging and burning, along with the resultant perception of irritation.[15]

43.1.1 An AHA has to be Absorbed to Work The single, most important factor that influences AHA bioavailability to the stratum corneum is formulation pH. The pH of aqueous-based products determines the amount of AHA that will be present in the undissociated, free acid form. Based on the Henderson-Hasselbalch equation[16] (see Table 43.1) and, knowing the pH of the formulation and the pKa of the acid (glycolic acid is 3.83 and lactic acid is 3.86), one can determine the relative molar concentration of AHA present in the acid form versus the ionized, anion form. Only the free acid, non-salt form is immediately bioavailable for penetration into skin.[17]

43.1.2 Why Stinging is Important, but Not Essential A stinging sensation typically confirms penetration of the AHA ingredient into the skin. To many users, this is perceived as a positive effect—if it stings, it works. To many other people, perhaps those with more sensitive skin, this sensation is viewed negatively and causes a concern that the skin is being harmed. Stinging is important because it proves that the AHA can penetrate skin. Having proved this, it is no longer essential to cause these negative sensations. Controlled-release delivery of AHAs is a solution for reducing undesirable sensations and irritation caused by AHAs.

43.1.3

The Case for ControlledDelivery of AHAs

Irritation studies of AHA formulations utilizing conventional neutralizing agents (i.e., not controlreleased) indicate that the potential for irritation from lactic and glycolic acid increases significantly when the pH of a formulation falls below 3.5.[18] To counter this effect, many formulators have taken the approach of reducing the amount of bioavailable acid. This can be accomplished by either increasing pH or by reducing the concentration of the acid to such an extent that it is less effective than desirable. Recognizing that a sufficient concentration of bioavailable acid is needed to provide significant, consumer-perceivable benefits to skin, these formulation options are not preferred.

Understanding that pH is a logarithmic relationship of the hydrogen ion concentration, as the pH is adjusted above the pKa value of the AHA, the calculated amount of free acid quickly falls below 50%. Accordingly, a 10% glycolic acid product formulated at pH 4.8 contains less than 1% calcuTable 43.1. Calculated Bioavailability of a 10% Glycolic lated bioavailable acid. Conversely, when the Acid Formulation as a Function of pH* pH is reduced to a value below the acid’s pKa, there is a large increase in calculated free acid. The same 10% glycolic acid-containing product formulated at pH 2.8 contains mostly bioavailable acid, over 9%. When the pH is adjusted to the same number as the pKa of the acid, the amount of free acid in the formulation is calculated to be approximately half of the concentration of the AHA; a 10% glycolic acid formulation at pH 3.8 contains 5% free glycolic acid in the bioavailable form, and 5% in the ionized salt form.[17] (See Table 43.1.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS Controlled-release mechanisms were sought for use specifically with hydroxyacids in order to facilitate their use at sufficiently high concentration and low pH to provide undissociated free acid at sufficient levels to produce anti-aging skin benefits. These mechanisms would, ideally, reduce irritation, stinging, or burning from hydroxyacids as well. The concept of temporarily interacting with the free acid portion of the AHA in order to slow down the usual, immediate penetration of free acid into the stratum corneum led to the development of patented, controlled-release technology. The approach for controlled-release AHA formulations involves two types of molecular interactions. These include: • Use of amphoteric amino acids.[19][20] • Use of molecular complexing agents such as amino acid esters.[21]

43.2 Amphoteric ControlledRelease Systems The controlled-release mechanism in an amphoteric formulation is based upon the intermolecular attractions that occur between a hydroxyacid and an amphoteric substance. Amphoteric substances are compounds that can function as either an acid

883

or a base, depending on pH. In order to penetrate skin, the molecular weight of the chosen amphoteric agent should not exceed about 600 Daltons. Amino acids are optimal candidates for this technique since they are safe, nutritionally useful for skin, and relatively small in molecular size. Such acids are amphoteric since they contain a carboxylic acid group in conjunction with at least one alkali group such as an amino, imino, or guanido. The preferred amphoteric amino acids include arginine, lysine, and ornithine.[14] There are three major types of attracting forces between a hydroxyacid and an amphoteric substance: (1) ionic/ionic, (2) dipolar/ionic, and (3) dipolar/dipolar.[14] (See Table 43.2.) Amphoteric amino acids contribute to pH adjustment by forming ionic bonds with a portion of the alpha-hydroxyacid in the formulation, thereby raising product pH. The remaining undissociated AHA molecules are attracted to, for example, the AHA amino acid complex via temporary hydrogen bonds and dipole-dipole interactions.[14] The extent of these interactions depends upon pH and temperature. The potential structures and stoichiometries of these amphoteric complexes are likely to change continuously due to the transient nature of the attractive forces at play.[22] (See Fig. 43.1.)

Table 43.2. Major Attractive Forces between AHAs and Amphoteric Amino Acids

884

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS tration of ionic species in solution. Equivalent aqueous glycolic acid (50%) solutions were adjusted to the desired pH using the following: • The amphoteric agent, arginine. • The commonly used, non-amphoteric neutralizing agent, ammonium hydroxide.

Figure 43.1 Glycolic acid/arginine complex.

43.2.1 Evidence of Amphoteric AHA Complexes The existence of amphoteric complexes has been demonstrated by the following: • Physical-chemical means. • Isolation of amphoteric AHA salts. • Their clinical effects on human skin. Physical-chemical evaluation of amphoteric AHA complexes. It is well known that electrical resistance is inversely proportional to ionic strength of a solution. Therefore, the fewer the number of ions present in the solution, the greater its resistance to carrying an electrical current. Electrical resistance is typically measured using commercially available conductivity meters, recognizing that conductance is the inverse of resistance. Based on the premise that amphoteric systems will result in fewer free ionic species due to complex formation, electrical resistance is expected to be higher in amphoteric formulations as compared with non-amphoteric formulations. To substantiate the presence of amphoteric complexes, laboratory investigations of amphoteric and non-amphoteric AHA solutions were conducted utilizing an Accumet pH/ Conductivity meter (model 20, Fisher Scientific) equipped with a two-cell conductivity glass probe. This apparatus measures electrical resistance (ohms) values, which are employed as a quantitative measure of the concen-

Results indicate that glycolic acid solutions containing arginine are more resistive to the passage of electrical current, in a concentration-dependent manner, than equivalent solutions containing ammonium hydroxide. Therefore, this data substantiates reduced free ion content (due to complex formation) in the amphoteric system compared to the non-amphoteric system, at equivalent pH. (See Fig. 43.2.) With increasing concentration of the amino acid (greater than a 10:1 molar ratio of glycolic acid:arginine), viscosity increases substantially. (See Fig. 43.3.) Viscosity measurements were made at 25°C after one minute using a Brookfield Viscometer LVT (Brookfield Engineering) equipped with Spindle #2, set at 30 revolutions per minute. This effect presumably diminishes flow properties of the solution and reduces the accuracy of the resistance measurement. Indeed, there is a significant increase in electrical resistance above the 10:1 molar ratio concentration that is assumed to be due, in part, to the compromised flow properties of the solution. (See Fig. 43.2.) Nevertheless, the data indicate that fewer ions are present in the solutions containing arginine in comparison to identical solutions containing ammonium hydroxide, thus indicating the presence of

Figure 43.2 Reduced ion content in amphoteric AHA solutions vs non-amphoteric AHA solutions due to amphoteric-AHA complex formation.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

885 complexes compared to non-amphoteric AHA formulations. The lactic acid sting test is commonly used to identify a sting-prone population. Screening is conducted using unneutralized lactic acid solutions, usually at a 5%–10% weight concentration. The lactic acid solution is applied to the nasolabial fold and inner cheek using a cotton swab and is compared with a control vehicle. Individuals that can reliably discern the stinging sensation of a lactic acid solution versus the control are empanelled.[27]

Figure 43.3 Increased viscosity of amphoteric AHA solutions at high molar ratios.

an arginine-glycolic acid molecular complex in the amphoteric solutions. Creation of AHA-amino acid salts. Physical evidence for the formation of amphoteric complexes was provided when AHA-amino acid salts were collected and characterized. Aqueous solutions containing various mole ratios of lactic acid:arginine were dried to yield solid salts.[24] Fourier transform infrared (FTIR) analysis of the salt forms revealed the presence of arginine lactate, arginine dilactate, and arginine trilactate. A 1:1 ratio produces nearly complete conversion to the lactate salt form; the 1:2 ratio mostly presents as the lactate salt; and, at the 1:3 ratio, approximately 20% of the lactic acid remains in the acid form.[25] Further evaluation of the arginine lactate salts via X-ray diffraction revealed clear evidence of salt formation in the 1:1 ratio with no evidence of remaining crystalline arginine. The 1:2 and 1:3 ratios clearly demonstrated salt formation of varying stoichiometries.[25] Clinical effects: amphoteric AHA complexes reduce stinging. Many AHA product users experience stinging and burning following topical application of lactic acid and glycolic acid. To overcome these negative sensory responses and continue to provide the benefits of AHAs, many formulation approaches have been attempted with varying degrees of success.[26] The following data demonstrate diminished stinging with amphoteric AHA

Amphoteric AHA formulations were tested on 21 females previously identified as “stingers.” Test formulations required partial neutralization in order to assess the effects of the amphoteric system. Therefore, test material evaluations were made using 20% solutions of lactic acid adjusted to pH 3.5, instead of the conventional 10% concentration with no pH adjustment. At the selected concentration and pH, approximately 13.6% freely bioavailable lactic acid was present. Lactic acid solutions were partially neutralized to pH 3.5 using the following: • Arginine (representing a 2.5:1 molar ratio of lactic acid:arginine). • Ammonium hydroxide. • Sodium hydroxide (alkali). Water (vehicle) served as a negative control. Subjects rated the intensity of sting sensations using a four-point scale (none, mild, moderate, severe) at 10 seconds after application, and 2, 5, and 8 minutes later. Sting testing results demonstrated that the lactic acid solutions which contained arginine induced significantly less stinging (p<0.05) than those containing the non-amphoteric neutralizers ammonium hydroxide and sodium hydroxide. (See Fig. 43.4.) In fact, the arginine-containing solutions were statistically equivalent to the negative control solution (water). (See Fig. 43.5.) Sting reductions were also noted for lactic acid solutions that were formulated at a weaker amphoteric concentration (20:1 molar ratio of lactic

886

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS A panel of 24 healthy volunteers was enrolled. Products were applied under full occlusion for 14 consecutive days, including weekends. Irritation was graded by a trained visual assessor using a four-point scale. Patches were loaded with identical amounts of test materials for comparative purposes. Aqueous solutions of 20% glycolic acid were partially neutralized to pH 3.5 using the following:

*20% lactic acid solution adjusted ot pH 3.5 using ammonium hydroxide (NH4OH, non-amphoteric) caused statistically more stinging than an equivalent solution containing the amphoteric, pH adjusting agent arginine, p<0.05.

Figure 43.4 Stinging effect of amphoteric vs non-amphoteric lactic acid solutions.

• Arginine (representing a 2.5:1 mole ratio of glycolic acid:arginine). • Ammonium hydroxide. • Sodium hydroxide (alkali). Controls included normal saline (0.9% sodium chloride aqueous solution), as a negative control, and 0.1% sodium lauryl sulfate (SLS) aqueous solution, as a mild-irritant positive control.

*20% lactic acid solution adjusted ot pH 3.5 using arginine (amphoteric) was equivalent to the water control.

The results of the tests described above are shown in Figs. 43.6 and 43.7. The glycolic acid-arginine solution is significantly less irritating than the glycolic acid solutions partially neutralized with either sodium hydroxide or ammonium hydroxide (p<0.05). (See Fig. 43.6.)

As seen in Fig. 43.7, moderate levels of irritation (grade 2) occurred after four days of patching in the ammonium hydroxide treatment group as compared to nearly 11 days in the arginine treatment group.

Figure 43.5 Stinging effect of amphoteric lactic acid solution vs water control.

acid:arginine).[22] In addition, a sting test was conducted with glycolic acid using the molar ratio 2.5:1 of glycolic acid:arginine and revealed significantly reduced stinging of the amphoteric solution as compared to the non-amphoteric glycolic acid solution.[22] Clinical effects: amphoteric AHA complexes reduce irritation. Topical formulations are routinely evaluated for irritation potential, using patch test models that are exaggerated beyond normal use, in order to approximate long-term safety in a short period of time. To demonstrate the improved safety profile of amphoteric AHA formulations, a 14-day cumulative irritation patch test was conducted in comparison to non-amphoteric AHA solutions.

Equivalent levels of irritation were eventually achieved toward the end of the study between the amphoteric and non-amphoteric AHA solutions. This demonstrates that the glycolic acid penetrates into the skin, and is, therefore, bioavailable in both the amphoteric and non-amphoteric solutions. However, the amphoteric system reduces irritation under occlusion through much of the two-week study. This study provides documentation of reduced irritation potential as well as maintenance of overall bioavailability of amphoteric AHA technology.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

887 assessor equipped with a fluorescent Wood’s lamp.[23]

*20% glycolic acid solution adjusted ot pH 3.5 using ammonium hydroxide (NH4OH) or sodium hydroxide (NaOH), the non-amphoteric AHA solutions, caused statistically more irritation than arginine-containing, amphoteric AHA solution, p<0.05. (NH4OH vs arginine: days 2-11 and overall; NaOH vs arginine: days 2-6, 6-10, and overall.)

Figure 43.6 Cumulative irritation of amphoteric vs non-amphoteric glycolic acid solutions.

*20% glycolic acid solution adjusted ot pH 3.5 using ammonium hydroxide (NH4OH), the non-amphoteric AHA solution, caused significantly more irritation than arginine-containing, amphoteric AHA solution on days 2-11 and overall, p<0.05.

Figure 43.7 Amphoteric AHA solution slows onset to moderate irritation in cumulative irritation test vs non-amphoteric AHA solution.

Clinical effects: amphoteric AHA complexes maintain cell turnover benefits. AHA product benefits extend well beyond their effects on the stratum corneum and mere exfoliation. However, exfoliation is a useful biological indicator to quickly screen AHA activity. Exfoliation can be measured with a dansyl chloride cell turnover model, which measures the disappearance of a fluorescing stain (dansyl chloride) from a pre-stained stratum corneum. The strength and confluence of the stained skin are evaluated using a 0–3 scale by a trained

An amphoteric AHA prototype cream (oil-in-water emulsion) was compared to an untreated control in order to evaluate its effects on cell turnover and exfoliation. Twenty-six healthy volunteers participated. Test sites on the volar forearm were pre-stained with dansyl chloride, and product application was initiated twice daily. Test materials included an amphoteric AHA cream containing 6.3% glycolic acid with arginine (molar ratio 15:1, glycolic acid:arginine, pH 3.5), in comparison to an untreated control. The amphoteric AHA cream significantly reduced the mean value of stratum corneum turnover time by 15.7% as compared to the untreated control, p < 0.01. Mean total fluorescence scores were statistically reduced by 18.4% as compared to the untreated control, p < 0.01. (See Fig. 43.8.) Therefore, amphoteric AHA technology does not hinder AHA activity, as measured by this exfoliation model. These results are in agreement with other cell turnover studies that compared amphoteric lactic acid formulations to non-amphoteric lactic acid.[22]

43.2.2 Commercialization of Amphoteric AHAs

A significant body of data has been collected to support the existence and benefits of amphoteric AHA formulations. Through incorporation of amphoteric amino acids into standard AHA formulations, the irritating effects of AHAs are diminished and the formulations using AHAs are more gentle and less stinging, all while maintaining the desirable and expected anti-aging benefits. Amphoteric AHA technology has been commercialized in many NeoStrata Company products. Certain amphoteric AHA complexes are also made available as raw

888

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS sis of dermal components, photo-aged skin, pigmented skin, and others.[21]

43.3.1Selection of Molecular Complexing Agents Optimal complexing agents range in size between 100 and 600 Daltons in order to be small enough to penetrate the skin. In addition, these complexing agents contain multiple molecular functional groups with unshared electrons and include at least one amino group. When raising the pH of a formulation, the amino group of the complexing agent converts to an ammonium catFigure 43.8 Exfoliation effect of amphoteric AHA formulation. ion forming an ionic bond with the carboxylate group of the AHA-anion. Additional temporary interactions also occur between materials by Cognis Corporation. (Refer to Tables the free-acid AHA molecules and the complexing 43.11 and 43.12 for examples.) Cognis markets amagent as a result of hydrogen-bonding phenomena. photeric AHA blends that include a pass-through For example, the hydroxyl group of the AHA interlicense for the use of NeoStrata’s patented anti-agacts with one of the functional groups on the ing claims. complexing agent. In this way, the undissociated AHA is immediately available for penetration into skin, but is controlled by the temporary hydrogen bonds that exist in the molecular complex-AHA 43.3 Molecular Complexing moiety.

Agents

An emerging formulation technology incorporates the use of molecular complexing ingredients to temporarily bind the bioavailable AHA. This approach diminishes the immediate penetration of AHAs, reducing the perception of stinging and burning. Use of chemically basic molecular complexing agents offers two advantages: • The ability to employ a higher formulation pH. • The ability to control the release of the AHA into target sites such as skin, nails, or hair. This formulation approach is recommended for AHA products that may be used on various dermatological conditions, some of which may be partly characterized by the existence of heightened skin sensitivity. Examples of these include conditions involving abnormal keratinization, defective synthe-

The molar ratio of the alpha-hydroxyacid to the complexing agent is usually in the 1 to 20 range. This results in the presence of the following: • Undissociated, bioavailable AHA. • The dissociated anion of the AHA (which is not readily available for skin penetration). • The complexing agent cation.[21] Possible candidates for molecular complexing agents fall into several categories including amino acid esters (e.g., glycine ethyl ester), non-amphoteric amino acid amides (e.g., glycinamide), aminosaccharides (e.g., glucosamine), aminoalditols (e.g., aminoxylitol), and aminocyclitols (e.g., aminoinositol). Of these, some amino acid esters, amino acid amides, and aminosaccharides are the current focus of AHA-molecular complex delivery systems due to their commercial availability. In order to function in an AHA-molecular complex controlled-release capacity, molecular complexing

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS agents that are commercially available as hydrochlorides, or other salt forms, must first be converted to the free base form. This can be achieved by various chemical means and includes reacting the salt form of the molecular complexing agent with an equimolar amount of sodium hydroxide or potassium hydroxide.[21]

43.3.2

Applications of AHA Molecular Complexing Agents

The following example demonstrates the utility of molecular complex AHA technology. When glycolic acid is reacted with glucosamine base (an aminosaccharide complexing agent) at a mole ratio of 11:1, the pH of the solution is approximately 2.6. The resulting molecular species include the following: • Undissociated free glycolic acid. • Glycolate anion. • Glucosammonium cation. At pH 2.6, there are 10 moles of free glycolic acid for each mole of neutralized glycolic acid (i.e., glucosammonium glycolate). If more glucosamine base is added to the formulation, the pH of the formulation will increase, and there will be less free glycolic acid to absorb into the skin.

Figure 43.9 Molecular complex interaction between glycolic acid and glucosamine.

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Conventional AHA formulations allow the free glycolic acid to rapidly penetrate skin, potentially causing stinging and burning. In the above example, which utilizes glucosamine as the neutralizing agent, temporary molecular complexes are readily formed between the remaining free glycolic acid and the glucosammonium cation. The hydroxyl groups of the undissociated glycolic acid can interact with one of four hydroxyl groups found on the glucosammonium cation. (See Fig. 43.9.) Although temporary and weak in nature, these hydrogen bonds appear to be strong enough to temporarily impede the permeation of the free AHA into skin, a key factor in reducing the stinging potential of an AHA formulation. When some of the undissociated glycolic acid absorbs into the skin, there is an equilibrium shift that occurs and this results in the disruption of additional hydrogen bonds and the availability of more, undissociated AHA for absorption into skin. In this way, the AHA is bioavailable, but controlled-released to enhance product gentleness. Examples demonstrating the use of molecular complex AHA technology can be found in Tables 43.9 and 43.10 of this chapter.

43.4 Summary Alpha-hydroxyacids provide important therapeutic and cosmetic benefits to the skin. These materials are used extensively in anti-aging skin care, and are increasingly being used in topical pharmaceutical preparations in order to enhance therapeutic effects, as well as provide consumer-perceivable cosmetic benefits. As a result, there is a growing need for well-tolerated AHA delivery technologies. The previously described amphoteric AHA and molecular complex AHA technologies offer the promise of improved tolerance and controlled-release of AHAs, while maintaining AHA effectiveness and formulation aesthetics. Now, formulating in the acidic pH range to optimize skin benefits of AHAs does not have to result in increased skin irritation or sensitivity, as it has in the past. This technology opens the door for the use of AHAs, alone or in combination, with topical pharmaceutical agents for use on various skin conditions, including those with increased skin sensitivity.

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43.5 Formulations NeoStrata Company, Inc., is providing the following formulations (see Formulations 43.1–43.10) to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered

by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

Formulation 43.1: Daytime AHA Cream with Sunscreens

Phase

A

Ingredient

C

Trade Name Manufacturer

Weight %

Purified water USP

Solvent

Purified water

Magnesium aluminum silicate

Viscosity increasing agent

Veegum Ultra

R. T. Vanderbilt

1.00

Glycerin 99% USP

Skin conditioning agent

Glycerin USP

Dow, Cognis, Ruger

3.00

Xanthan gum

Viscosity increasing agent

Keltrol or Vanzan NF

Kelco, R. T. Vanderbilt

0.30

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.20

Triethanolamine 99% NF pH adjuster

Trolamine 99 Dow, Ruger

1.50

Purified water USP

Solvent

Purified water

8.00

Glycolic acid 70%

pH adjuster

Glypure 70

DuPont

11.50

Ammonium hydroxide 28% (to pH 3.8 or desired pH)

pH adjuster

Ammonium hydroxide solution

Generic

1.5–2.0

L-Arginine

Skin conditioning agent

L-Arginine

Ajinomoto

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

3.75

Cetyl alcohol

Emulsion stabilizer

Lanette 16 NF

1.50

Glyceryl stearate/PEG100 stearate

Emulsifying agents

Arlacel 165V Uniqema

4.00

Octylmethoxycinnamate (Octinoxate)

Sunscreen active ingredient

Escalol 557, NeoHeliopan ISP, Symrise AV

7.50

Disodium EDTA

B

Function

30.00

Cognis

1.00

(cont’d.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

891

Formulation 43.1: (cont’d.)

Phase

C

D

Ingredient

Function

Trade Name Manufacturer Weight %

Propylene glycol dicaprylate/dicaprate

Skin conditioning agent

Captex 200

Abitec

1.00

Tocopherol acetate (Vitamin E acet.)

Antioxidant

Tocopherol acetate USP

Roche

0.50

Isocetyl alcohol

Skin conditioning agent

Eutanol G-16 Cognis

4.00

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

2.00

C12-15 Alkyl benzoate

Solvent

Finsolv TN

Finetex

3.00

Octyldodecyl neopentanoate

Skin conditioning agent

Elefac I-205

Bernel/Alzo

5.00

TiO2/isononyl isononanoate/stearic acid/ aluminum hydroxide

Sunscreen enhancer

IN 60 S4

Kobo

4.00

Phenoxyethanol/methyl paraben/ethylparaben/ propylparaben

Preservative blend

Phenonip

Nipa/Clariant

1.00

Butylparaben/isobutylparaben Fragrance Purified water USP

As desired Solvent

Purified water

qs to 100%

Manufacturing Procedure: 1. Prepare Phases A, B, and C, separately. 2. When preparing Phase C, homogenize for 30 minutes after addition of the TiO2 dispersion. 3. Heat Phases A & C to 70°C–75°C. 4. Blend Phases A & C with stirring and homogenizing for a minimum of 10 minutes. 5. Cool to 65°C. 6. Add Phase B and stir with homogenizing for a minimum of 10 minutes. 7. Cool and add preservative, fragrance, and purified water below 40°C. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.2: AHA + Pro-Vitamin A Cream

Phase

Ingredient

Function

B

Purified water USP

Solvent

Purified water

Glycolic acid 70%

pH adjuster

Glypure 70

DuPont

6.70

L-Arginine

Skin conditioning agent

L-Arginine

Ajinomoto

2.00

Lysine hydrate

Skin conditioning agent

Lysine hydrate

Spectrum

0.30

Glycine

Skin conditioning agent

Glycine

Ajinomoto

0.50

Propylene glycol USP

Skin conditioning agent/solvent

Propylene glycol USP

Dow, Spectrum

2.00

Phenoxyethanol

Preservative

Phenoxetol

Nipa/Clariant

0.30

Methylparaben

Preservative

Methyl parasept

Nipa/Clariant

0.30

Chlorphenesin

Preservative

Lab. Elestab CPN Serobiolgiques /Cognis

0.30

Purified water USP

Solvent

Purified water

25.00

Hydroxyethylcellulose

Emulsion stabilizer

Natrosol 99250HHX

Aqualon

0.20

Propylene glycol USP

Skin conditioning agent/solvent

Propylene glycol USP

Dow, Spectrum

3.00

Xanthan gum NF

Viscosity increasing agent

Keltrol CG-T Kelco

0.40

Ethoxydiglycol

Solvent

Transcutol

Gattefosse

2.00

Disodium EDTA

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.10

White petrolatum

Skin conditioning agent/solvent

Protopet 1S

Crompton

4.00

Meadowfoam seed oil

Skin conditioning agent

Meadowfoam Fancor seed oil

4.00

White beeswax NF

Skin conditioning agent

White beeswax NF

0.50

C

D

E

F

Weight %

Deionized water

Deionized water

A

Trade Name Manufacturer

20.00

Strahl & Pitsch

(cont’d.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

893

Formulation 43.2: (cont’d.)

Phase

F

Ingredient

Function

Trade Name Manufacturer

Weight %

Isopropyl palmitate

Skin conditioning agent

Dermol IPP

Alzo

3.50

Sorbitan stearate

Emulsifying agent

Span 60K

Uniqema

1.50

Glyceryl stearate/PEG100 stearate

Emulsifying agents

Arlacel 165V Uniqema

3.50

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

2.00

Octyl hydroxystearate

Skin conditioning agent

Dermol OO

Alzo

3.50

Tocopherol acetate USP

Antioxidant

Vitamin E acetate

Roche

1.00

BHT

Antioxidant

BHT

Roche

0.01

Cetearyl alcohol

Emulsion stabilizer

Lanette O

Cognis

1.50

Propylparaben

Preservative

Nipasol M

Nipa/Clariant

0.10

Vitamin A acetate

Skin conditioning agent

Vitamin A acetate in peanut oil

Roche

0.50

Fragrance Purified water USP

As desired Solvent

Purified water

qs to 100%

Manufacturing Procedure: 1. Prepare Phase A and mix for a minimum of 2 hours before use. 2. In separate containers, prepare Phases B, D, & E. 3. Prepare Phase C in the main blending vessel and mix at high speed until polymer is fully hydrated. 4. Add Phases B, D, & E to Phase C separately with continued mixing. This is the main water phase. 5. To a separate vessel, add the ingredients of the oil phase (Phase F) and begin heating to 70°–75°C. 6. Heat the water phase to 70°C–75°C. 7. Add the oil phase to the water phase and stir while homogenizing for 15 minutes. 8. Cool to 65°C and add Phase B with continued mixing. 9. Continue mixing and cooling to 45°C and add Vitamin A acetate. 10. Continue mixing and cooling to 35°C and add fragrance and make-up water. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.3: Face Cream

Phase

A

Ingredient

C

Trade Name Manufacturer

Weight %

Purified water USP

Solvent

Purified water

Glycerin 99% USP

Skin conditioning agent/solvent

Glycerin USP

1,3-Butylene glycol

Skin conditioning agent/solvent

1,3-Butylene Ruger glycol

4.00

Methylparaben

Preservative

Methyl parasept

0.30

Xanthan gum NF

Viscosity increasing agent

Keltrol CG-T Kelco

0.35

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.10

Chlorphenesin

Preservative

Lab. SeroElestab CPN biolgiques/ Cognis

0.30

Magnesium aluminum silicate

Viscosity increasing agent

Veegum Ultra

R.T. Vanderbilt

0.75

Steareth-2

Emulsifying agent

Brij 72

Uniqema

0.50

Glyceryl stearate/PEG100 stearate

Emulsifying agents

Arlacel 165V Uniqema

5.00

Isocetyl stearate

Skin conditioning agent

Ceraphyl 494 ISP

4.00

C12-15 alkyl benzoate

Solvent

Finsolv TN

Finetex

1.00

Diisostearyl malate

Skin conditioning agent

Bernel Ester DISM

Bernel/Alzo

1.00

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

2.50

Cetearyl alcohol

Emulsion stabilizer

Lanette O

1.00

Cetyl ricinoleate

Skin conditioning agent

Nature Chem CasChem CR

1.00

Tocopherol acetate (Vitamin E acet.)

Antioxidant

Tocopherol acetate USP

Roche

0.50

Propylparaben

Preservative

Nipasol M

Nipa/Clariant

0.20

Purified water USP

Solvent

Purified water

Disodium EDTA

B

Function

30.00 Dow, Cognis, Ruger

Nipa/Clariant

Cognis

1.00

25.00 (cont’d.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

895

Formulation 43.3: (cont’d.)

Phase

Ingredient Glycolic acid 70%

C

D

Function pH adjuster

Trade Name Manufacturer Glypure 70

DuPont

Weight % 5.70

Triethanolamine 99% NF pH adjuster

Trolamine 99 Dow, Ruger

2.00

L-Arginine (amphoteric agent)

Skin conditioning agent

L-Arginine

1.00

Cyclomethicone

Skin conditioning agent/solvent

DC Fluid 345 Dow Corning

2.00

Isododecane

Skin conditioning agent/solvent

Permethyl 99A

Presperse

2.00

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

1.00

Fragrance Purified water USP

Ajinomoto

As desired Solvent

Purified water

qs to 100%

Manufacturing Procedure: 1. Prepare Phase C and mix for a minimum of 2 hours before use. 2. Prepare Phase A by adding water to the main vessel and dispersing the Veegum with high speed mixing. 3. Mix for 30 minutes. 4. Add the disodium EDTA, and methylparaben with mixing. 5. Dissolve the xanthan gum in the glycerin and butylene glycol and add to Phase A. 6. Add the chlorphenesin to Phase A and begin heating to 70°C–75°C. 7. To a separate vessel, add ingredients of Phase B in order and heat to 70°C–75°C. 8. When Phases A & B are at temperature, add Phase B to Phase A. Stir and homogenize for 15 minutes. 9. Cool to 50°C–55°C and add Phase C to Phase AB. Continue cooling to 40°C. 10. In a side kettle, mix ingredients of Phase D and add to Phase ABC when temperature is 40°C–45°C. 11. Homogenize for 15 minutes. 12. Continue cooling and add fragrance and make-up water. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

896

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.4: Lactic Acid Hand Cream

Phase

Ingredient

Trade Name Manufacturer

Weight %

Purified water USP

Solvent

Purified water

Magnesium aluminum silicate

Viscosity increasing agent

Veegum Ultra

R.T. Vanderbilt

0.50

Glycerin 99% USP

Skin conditioning agent/solvent

Glycerin USP

Dow, Cognis, Ruger

5.00

Propylene glycol NF

Skin conditioning agent/solvent

Propylene glycol NF

Ruger

3.00

Xanthan gum NF

Viscosity increasing agent

Keltrol CG-T Kelco

0.15

Chelating agent

Hampene NA2X, Dissolvine NA2S

0.05

Chlorphenesin

Preservative

Lab. Elestab CPN Serobiolgiques /Cognis

0.20

Cetyl alcohol

Emulsion stabilizer

Lanette 16 NF

Cognis

3.00

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

2.00

Octyl stearate

Skin conditioning agent

Cetiol 868

Cognis

2.00

Mineral oil

Skin conditioning agent

Carnation

Crompton

0.75

Octyldodecanol

Skin conditioning agent

Eutanol G

Cognis

3.00

Dicaprylyl Ether

Skin conditioning agent

Cetiol OE

Cognis

1.00

Glyceryl stearate/ ceteareth-20/ceteareth12/cetearyl alcohol/cetyl palmitate

Emulsifier blend/stabilizer

Emulgade SE Cognis

1.20

Ceteareth-20

Emulsifying agent

Eumulgin B2 Cognis

1.50

Dimethicone

Skin conditioning agent

DC 200/100 cst

0.75

Cetearyl glucoside/ cetearyl alcohol

Emulsifier blend/stabilizer

Emulgade PL Cognis 68/50

A

Disodium EDTA

B

Function

45.00

Dow, Akzo

Dow Corning

2.00 (cont’d.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

897

Formulation 43.4: (cont’d.)

Phase

B

C

Ingredient

Function

Trade Name Manufacturer

Weight %

Octylmethoxycinnamate (Octinoxate)

Sunscreen active ingredient

Escalol 557, NeoHeliopan ISP, Symrise AV

7.50

TiO2/octyldodecanol/ cyclomethicone

Sunscreen enhancer

Tioveil GCM Uniqema

2.50

88% Lactic acid

pH adjuster

Purac HP 88

Purac America

11.25

L-Arginine

Skin conditioning agent

L-Arginine

Ajinomoto

1.20

Triethanolamine 99% NF pH adjuster D

Fragrance

E

Purified water USP

Trolamine 99 Dow, Ruger

1.30

As desired Purified water

qs to 100%

Manufacturing Procedure: 1. Prepare Phase A by adding water to the main vessel and dispersing the Veegum with high speed mixing. 2. Mix for 30 minutes. 3. Dissolve the xanthan gum in the glycerin and propylene glycol and add to Phase A. 4. Add the disodium EDTA, and chlorphenesin with mixing. Begin heating to 70° C–75°C. 5. To a separate vessel, add ingredients of Phase B in order and heat to 70°C–75°C. Homogenize 15 minutes. 6. To a separate vessel, prepare Phase C with continuous mixing. 7. When Phases A & B are at temperature, add Phase B to Phase A. Stir and homogenize for 15 minutes. 8. Cool to 60°C–65°C and add Phase C to Phase AB. Homgenize for 10 minutes. 9. Begin cooling to 40°C. 10. When temperature is <40°C, add fragrance and make-up water. 11. Cool to 25°C–30°C with sweep mixing. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

898

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.5: Night Cream

Phase

A

B

C

Ingredient

Function

Trade Name Manufacturer Weight %

Purified water USP

Solvent

Purified water

Glycerin 99% USP

Skin conditioning agent/solvent

Glycerin USP

Dow, Cognis, Ruger

2.00

Propylene glycol NF

Skin conditioning agent/solvent

Propylene glycol NF

Ruger

3.00

Ethoxydiglycol

Solvent

Transcutol CG

Gattefosse

2.00

Hydroxyethylcellulose

Emulsion stabilizer

Natrosol 99250HHX

Aqualon

0.20

Xanthan gum NF

Viscosity increasing agent

Keltrol CG-T Kelco

0.20

Disodium EDTA

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.05

Algae extract/propylene glycol/water

Skin conditioning agent

Actiphyte of algae

Active Organics

2.00

Purified water USP

Solvent

Purified water

Glycolic acid 70%

pH adjuster

Glypure 70

DuPont

6.50

L-Arginine (amphoteric agent)

Skin conditioning agent

L-Arginine

Ajinomoto

2.00

13.00

18.00

Triethanolamine 99% NF pH adjuster (to pH 3.7–4.0)

Trolamine 99 Dow, Ruger

2.50

Glyceryl stearate/PEG100 stearate

Emulsifying agents

Arlacel 165V Uniqema

3.00

PEG-100 stearate

Emulsifying agent

Myrj 59P

0.50

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

1.00

Octyldodecyl myristate

Skin conditioning agent

ODM 100

Barnet

2.00

Stearyl alcohol

Emulsion stabilizer

Lanette 18

Cognis

2.00

Hydrogenated lecithin

Skin conditioning agent

Lecinol S-10 Barnet

1.00

C12-15 Alkyl ethylhexanoate benzoate

Skin conditioning agent/solvent

Hetester FAO Bernel

2.00

Steareth-2

Emulsifying agent

Brij 72

Uniqema

0.70

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

1.00

Uniqema

(cont’d.)

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

899

Formulation 43.5: (cont’d.)

Phase

C

Ingredient

Function

Trade Name Manufacturer Weight %

Glycol distearate

Skin conditioning agent

Lexemul EGDS

Inolex

2.00

Capric/capric/stearic triglycerides

Skin conditioning agent

Softisan 370

Degussa-Huls

0.50

Octyl hydroxystearate

Skin conditioning agent

Dermol OO

Alzo

3.20

White petrolatum

Skin conditioning agent

Protopet 1S

Crompton

1.00

Meadowfoam seed oil

Skin conditioning agent

Meadowfoam Fancor seed oil

2.00

Cyclomethicone

Skin conditioning agent

DC Fluid 345 Dow Corning

9.00

Sodium hyaluronate 1% solution

Skin conditioning agent

Sodium Hyaluronate 1% solution

Tri-K

2.00

Elestab FL-15

Lab. Serobiolgiques/ Cognis

2.50

Butylene glycol/glycerin/ chlorphenesin/methylPreservative blend paraben Dye, fragrance, and additives Purified water USP

As desired Solvent

Purified water

qs to 100%

Manufacturing Procedure: 1. Prepare Phase A by adding water to the main vessel. 2. Pre-wet the polymers in the propylene glycol and transcutol. Add to the water and homogenize. 3. Add the remaining ingredients with mixing. 4. In a separate vessel, prepare Phase B and mix for a minimum of 2 hours. Add Phase B to Phase A. 5. In a separate vessel, add ingredients of Phase C and begin heating to 70°C–75°C. 6. When both Phase AB and Phase C are at 70°C–75°C, add Phase C to Phase A. Homogenize 15 minutes. 7. Cool to 60°C–65°C and add cyclomethicone to Phases ABC. Homogenize for 10 minutes. 8. Begin cooling to 40°C. Add sodium hyaluronate and preservative blend. 9. When temperature is <40°C, add fragrance and make-up water. 10. Cool to 25°C–30°C with sweep mixing. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

900

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.6: Revitalizing Peel

Phase

Ingredient

Function

Trade Name Manufacturer Weight %

Purified water USP

Solvent

Purified water

Glycolic acid (70% solution) (AHA)

pH adjuster

Glypure 70

DuPont

42.90

L-Arginine

Skin conditioning agent

L-Arginine

Ajinomoto

4.00

SD alcohol 40B, 190 proof

Dow

10.00

SD alcohol 40B, 190 Solvent proof A

35.00

Propylene glycol NF

Skin conditioning agent/solvent

Propylene glycol NF

Ruger

5.00

Nonoxynol-11

Emulsifying agent

Alkasurf CO-710

Rhodia

0.50

Ammonium hydroxide 28%

pH adjuster

Ammonium hydroxide 28%

0.50–1.25

Purified water USP

Solvent

Purified water

qs to 100%

Manufacturing Procedure: 1. To a suitable stainless steel kettle equipped with a propeller mixer, add the glycolic acid to the water with mixing. 2. Add the arginine to the mixture with moderate agitation and mix for 30 minutes. 3. Add the SD alcohol and the nonoxynol-11. 4. Add ammonium hydroxide to pH 3.0 and qs with water. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

901

Formulation 43.7: Glycinamide/Glycolic Acid Complex Skin Smoothing Cream

Phase

Ingredient

Function Solvent

Purified water

25.00

Glycinamide hydrochloride

Molecular complex agent

Glycinamide hydrochloride Acros 98%

6.04

Sodium hydroxide NF

pH adjuster

Sodium Spectrum hydroxide NF

2.14

Purified water USP

Solvent

Purified Water

34.02

Glycolic acid 70% (AHA) pH adjuster

Glypure 70

DuPont

11.43

Magnesium aluminum silicate

Viscosity increasing agent

Veegum Ultra

R.T. Vanderbilt

1.00

Disodium EDTA

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.20

Propylene glycol NF

Skin conditioning agent/solvent

Propylene Glycol NF

Ruger

2.00

Hydroxyethylcellulose

Emulsion stabilizer

Natrosol 99250HHX

Aqualon

0.20

B

Deionized water

Deionized water

D

Weight %

Purified water USP

A

C

Trade Name Manufacturer

Stearamidopropyl dimethylamine

Skin conditioning agent

Lexamine S-13

Inolex

0.20

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

1.00

Butylated hydroxy toluene (BHT)

Antioxidant

Embanox 2

Rhodia

0.02

Sorbitan stearate

Emulsifying agent

Span 60K

Uniqema

0.50

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

3.00

Glyceryl stearate/PEG100 stearate

Emulsifying agents

Arlacel 165V Uniqema

3.50

Capric/caprylic triglycerides

Skin conditioning agent

Myritol 318

Cognis

4.00

Isopropyl palmitate

Skin conditioning agent

Lexol IPP NF Inolex

2.75 (cont’d.)

902

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.7: (cont’d.)

Phase

Ingredient

Function

Trade Name Manufacturer

Weight %

Phenoxyethanol

Preservative

Emeressence Cognis 1160 Rose

0.50

Cetyl alcohol

Emulsion stabilizer

Lanette 16 NF

2.50

D

Cognis

Manufacturing Procedure: 1. Prepare Phase A amino acid amide in free base form. 2. Add 1st portion of water and glycinamide hydrochloride; stir until dissolved. 3. Cool solution externally in ice water and add the sodium hydroxide, mixing until dissolved. 4. Dilute with 2nd portion of water and slowly add glycolic acid. 5. With stirring, add the ingredients of Phase B individually and mix for a minimum of 30 minutes. 6. Prepare Phase C separately by dispersing the hydroxyethycellulose in the propylene glycol; add to Phases AB. 7. In a separate vessel, prepare Phase D by adding ingredients in order. 8. Heat Phases ABC and Phase D to 70°C–75°C. Add Phase D to Phases ABC with homogenization. 9. Begin cooling with homogenization and mixing to 40°C. 10. At 40°C, stop homogenization and sweep mix to ambient temperature. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

903

Formulation 43.8: Glycine Ethyl Ester/Glycolic Acid Complex Skin Smoothing Cream

Phase

Ingredient

Function

Weight %

Purified water USP

Solvent

Purified water

25.00

Glycine ethyl ester hydrochloride

Molecular complex agent

Glycine ethyl ester hydro- Sigma chloride 99%

7.46

Sodium hydroxide NF

pH adjuster

Sodium Spectrum hydroxide NF

2.14

Purified water USP

Solvent

Purified water

32.60

Glycolic acid 70%

pH adjuster

Glypure 70

DuPont

11.43

Magnesium aluminum silicate

Viscosity increasing agent

Veegum Ultra

R.T. Vanderbilt

1.00

Disodium EDTA

Chelating agent

Hampene NA2X, Dissolvine NA2S

Dow, Akzo

0.20

Propylene glycol NF

Skin conditioning agent/solvent

Propylene glycol NF

Ruger

2.00

Hydroxyethylcellulose

Emulsion stabilizer

Natrosol 99250HHX

Aqualon

0.20

Stearamidopropyl dimethylamine

Skin conditioning agent

Lexamine S-13

Inolex

0.20

Dimethicone

Skin conditioning agent

DC 200/100 cst

Dow Corning

1.00

Butylated hydroxy toluene (BHT)

Antioxidant

Embanox 2

Rhodia

0.02

Sorbitan stearate

Emulsifying agent

Span 60K

Uniqema

0.50

Stearic acid

Emulsion stabilizer

Emersol 7036 Cognis

3.00

Glyceryl stearate/ PEG-100 stearate

Emulsifying agents

Arlacel 165V Uniqema

3.50

Capric/caprylic triglycerides

Skin conditioning agent

Myritol 318

Cognis

4.00

Isopropyl palmitate

Skin conditioning agent

Lexol IPP NF Inolex

2.75

A

B

C

D

Trade Name Manufacturer

(cont’d.)

904

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.8: (cont’d.)

Phase

Ingredient

Function

Trade Name Manufacturer

Weight %

Phenoxyethanol

Preservative

Emeressence Cognis 1160 Rose

0.50

Cetyl Alcohol

Emulsion stabilizer

Lanette 16 NF

2.50

D

Cognis

Manufacturing Procedure: 1. Prepare Phase A amino acid ester in free base form. 2. Add 1st portion of water and glycine ethyl ester hydrochloride; stir until dissolved. 3. Cool solution externally in ice water and add the sodium hydroxide, mixing until dissolved. 4. Dilute with 2nd portion of water and slowly add glycolic acid. 5. With stirring, add the ingredients of Phase B individually to Phase A and mix for a minimum of 30 minutes. 6. Prepare Phase C by dispersing the hydroxyethylcellulose in the propylene glycol; add to Phases AB. 7. Prepare Phase D by adding ingredients in order to a side kettle. 8. Heat Phases ABC and Phase D to 70°C–75°C. Add Phase D to Phases ABC with homogenization. 9. Begin cooling with homogenization and mixing to 40°C. 10. At 40°C, stop homogenization and sweep mix to ambient temperature. NeoStrata Company, Inc., is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

905

Formulation 43.9: Alcohol-Free AHCare Toner

Phase

Ingredient

Function

Trade Name

Manufacturer Weight %

A

Purified water USP

Solvent

B

1,3-Butylene glycol USP

Skin conditioning 1,3-Butylene agent/solvent glycol USP

Ruger

3.00

C

1% Sodium hyaluronate solution

1% Sodium Skin conditioning hyaluronate agent solution

Tri-K

1.00

D

PEG-40 hydrogenated castor oil/polysorbate 20/octoxynol 11

Emulsifier blend

Gattefosse

3.00

E

Algae extract

Skin conditioning Sea plasmatic agent complex

Phytochem Inc.

1.00

F

Butylene glycol/glycerin/ chlorophenesin/methylparaben

Preservative blend

Lab. Serobiologiques/Cognis

2.00

G

Dimethicone copolyol

Skin conditioning DC 190 Fluid agent

Dow Corning

1.00

H

Propylene glycol/water/ glycerin/polysorbate 20/ chamomile extract/rosemary extract/althea officianalis extract/cucumber extract/aloe extract/chlorophenesin

Botannical extract blend

I

Glycolic acid/arginine blend

AHA complex

J

Ammonium hydroxide 28% pH adjuster USP (adjust pH to 4.5 - 4.9)

Ammonium hyGeneric droxide 28% USP

K

Purified water USP

Purified water USP

Solvent

Purified water

Solubilisant gamma 2428

Elestab FL-15

73.00

Blend B-1725

Bell Flavors & (new designation Fragrances blend # 6810717)

1.00

AHCare G-60

3.00

Cognis

1.20 q.s to 100

Manufacturing Procedure: 1. To a suitable vessel equipped with a cover and propeller mixer, add the water and begin stirring. 2. Slowly add each ingredient individually in the order listed. Be sure each ingredient is dissolved before adding the next. Cover mixing vessel between additions. 3. Continue mixing for 30 minutes after the last ingredient is added. pH Range: 4.5–4.9 NeoStrata Company, Inc. is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

906

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 43.10: AHCare Facial Toner with Alcohol

Phase

Ingredient

Function

Trade Name

Manufacturer Weight %

A

Purified water USP

Solvent

Purified water USP

73.00

B

1,3-Butylene glycol USP

Skin conditioning agent/solvent

1,3-Butylene glycol USP

Ruger

3.00

C

1% Sodium hyaluronate Skin conditioning solution agent

1% Sodium hyaluronate solution

Tri-K

1.00

D

PEG-40 hydrogenated castor oil/polysorbate 20/octoxynol 11

Emulsifier blend

Solubilisant gamma 2428

Gattefosse

1.00

E

SD alcohol 40-B

Solvent

SD alcohol 40-B

Dow

10.00

F

Algae extract

Skin conditioning agent

Sea plasmatic complex

Phytochem Inc.

1.00

G

Butylene glycol/ Preservative glycerin/chlorophenesin/ blend/skin methylparaben conditioning agent

Elestab FL-15

Lab. Serobiologiques/ Cognis

2.00

H

Propylene glycol/water/ glycerin/chamomile extract/cucumber extract/ althea extract/rosemary extract/aloe extract/ methylparaben/propylparaben/diazolidinyl urea

Botannical extract blend

Blend B-1725

Bell Flavors & Fragrances

1.00

I

Glycolic acid/arginine blend

AHA complex

AHCare G-60

Cognis

3.00

J

Ammonium hydroxide 28% USP (adjust pH to 4.5–4.9)

pH adjuster

Ammonium hydroxide 28% USP

Generic

1.20

K

Purified water USP

Solvent

Purified water USP

qs to 100%

Manufacturing Procedure: 1. In a suitable vessel equipped with a cover and propeller mixer, add the water and begin stirring. 2. Slowly add each ingredient individually in the order listed. Be sure each ingredient is dissolved before adding the next. Cover mixing vessel between additions. 3. Continue mixing for 30 minutes after the last ingredient is added. pH Range: 4.5–4.9 NeoStrata Company, Inc. is providing these examples to demonstrate the amphoteric and/or molecular complex technologies. These technologies are covered by NeoStrata patents.[19]–[21] In addition, many of these compositions and product claims are also covered by patents.

GREEN, MILORA: CONTROLLED DELIVERY OF HYDROXYACIDS

907

References 1. Van Scott, E. J., Yu, R. J., Control of Keratinization with the Alpha Hydroxy Acids and Related Compounds, Arch. Dermatol., 110:586–590 (1974) 2. Van Scott, E. J., Yu, R. J., Substances that Modify the Stratum Corneum by Modulating its Formation, Principles of Cosmetics for the Dermatologist, (P. Frost, and S. N. Horwitz, eds.), pp. 70–74, C.V. Mosby, St. Louis (1982) 3. Van Scott, E. J., Yu, R. J., Hyperkeratinization, Corneocyte Cohesion, and Hydroxy Acids, J. Am. Acad. Dermatol., 111:867–879 (1984) 4. Van Scott, E. J., Yu, R. J., Actions of Alpha Hydroxy Acids on Skin Compartments, J. Ger. Dermatol., 3(3):19A–25A (1995) 5. Ditre, C. M., Griffin, T. D., Murphy, G. F., Sueki, H., Telegan, B., Johnson, W. C., Yu, R. J., and Van Scott, E. J., Effects of Alpha-Hydroxy Acids on Photoaged Skin; A Pilot Clinical, Histologic, and Ultrastructural Study, J. Am. Acad. Dermatol., 34:187–195 (1996) 6. Van Scott, E. J., Ditre, C. M., and Yu, R. J., Alpha-hydroxyacids in the Treatment of Signs of Photoaging, Clinics in Dermatol., 14:217– 226 (1996) 7. Yu, R. J., and Van Scott, E. J., Alphahydroxyacids and carboxylic acid, J. Cosmet. Dermatol., 3:76–87 (2004) 8. Bernstein, E. F., Dermal Effects of Alpha Hydroxy Acids, Glycolic Acid Peels, pp. 71–113, (R. Moy, D. Luftman, L. Kakita, eds.), Marcel Dekker, New York (2002) 9. Bernstein, E. F., Lee, J., and Brown, D. B., Glycolic Acid Treatment Increases Type I Collagen mRNA and Hyaluronic Acid Content of Human Skin, Dermatol. Surg., 27:429–433 (2001) 10. Bernstein, E. F., Underhill, C. B., Lakkakorpi, J., et al., Citric Acid Increases Viable Epidermal Thickness and Glycosaminoglycan Content of Sun-damaged Skin, Dermatol. Surg., 23:689–694 (1997)

11. Cosmeceuticals Market Expected to Surpass $4 Billion in 2003, Chemical Market Reporter, 256(15):24 (1999) 12. Wickett, R. R., Effects of Alpha Hydroxy Acids on Skin, KRA Corp., Silver Spring, Maryland (written for FDA) (Feb. 22, 1996) 13. Yu, R. J., and Van Scott, E. J., Bioavailable Alpha Hydroxy Acid in Topical Formulations, Glycolic Acid Peels, pp. 15–28, (R. Moy, D. Luftman, and L. Kakita, eds.), Marcel Dekker, New York (2002) 14. Yu, R. J., and Van Scott, E. J., A Discussion of Control-release Formulations of AHAs, Cosmet. Dermatol., 10:15–18 (2001) 15. Green, B. G., and Bluth, J., Measuring the Chemosensory Irritability of Human Skin, J. Toxicol.– Cutan. & Ocular Toxicol., 14(1):23–48 (1995) 16. Niebergall, P. J., Ionic Solutions and Electrolytic Equilibria, Remington’s Pharmaceutical Sciences, (A. R. Gennaro, G. D. Chase, M. R. Gibson, C. B. Granberg, S. C. Harvey, eds.), 17:244, Mack Publishing Company, Easton (1985) 17. Yu, R. J., and Van Scott, E. J., Bioavailability of Alpha-hydroxy Acids in Topical Formulations, Cosmet Dermatol., 9:954–962 (1996) 18. Johnson, A. W., Nole, G. E., Rozen, M. G., and DiNardo, J. C., Skin Tolerance of AHAs: A Comparison of Lactic and Glycolic Acids and the Role of pH, Cosmet. Dermatol., 10(2):38–45 (1997) 19. Yu, R. J., and Van Scott, E. J., Amphoteric Composition and Polymeric Forms of Alpha Hydroxy Acids and their Therapeutic Use, US Pat 5,091,171 (1992) 20. Yu, R. J., and Van Scott, E. J., Amphoteric Composition and Polymeric Forms of Alpha Hydroxy Acids and their Therapeutic Use, US Patent 5,702,688 (1997) 21. Yu, R. J., and Van Scott, E. J., Molecular Complex and Control-release of Alpha Hydroxy Acids, US Patent 5,877,212 (1999)

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22. Kraechter, H. U., McCaulley, J. A., Edison, B., Green, B., and Milora, D. J., Amphoteric Hydroxy Complexes: AHAs with Reduced Stinging and Irritation, Cosmetics & Toiletries, 116(1):47–52 (2001) 23. Green, B. A., Wildnauer, R. H., Hwu, R. C., Milora, D. J., and Edison, B. L., Amphoteric Complexes Offer Unique Benefits to Alpha Hydroxyacid (AHA) Skin Care Formulations, Amer. Acad. of Derm. Poster Exhibit, Washington, DC (Mar. 2001) 24. Process on file, NeoStrata Company, Inc.

25. Data on file, Cognis Corporation. 26. Kligman, D. E., Pagnoni, A., Stoudemayer, T., and Kligman, A. M., Strontium Nitrate Decreases the Efficacy of Glycolic Acid Peels, Amer. Acad. of Derm. Poster Exhibit, San Francisco (Mar. 2000) 27. Basketter, D. A., Griffiths, H. A., A Study of the Relationship Between Susceptibility to Skin Stinging and Skin Irritation, Contact Dermatitis, 29:185–188 (1993)

Part XV Efficacy and Safety

EFFICACY & SAFETY

Evaluating Safety & Efficacy of Delivery Systems and Their Active Ingredients

44 New and Emerging Testing Technology for Efficacy and Safety Evaluation of Personal Care Delivery Systems David Tonucci Interactive Consulting, Inc. East Norwich, New York

44.1 Introduction ................................................................................... 912 44.2 History of Clinical Testing .............................................................. 912 44.3 Regulatory Oversight .................................................................... 913 44.3.1 United States Food and Drug Administration (FDA) ......... 913 44.3.2 European Union ................................................................ 914 44.4 Developing a Clinical Safety Plan ................................................. 915 44.4.1 Identifying the Target Population ....................................... 915 44.4.2 Defining the Product Claims ............................................. 916 44.5 Preclinical Safety Data ................................................................. 918 44.5.1 Preclinical Animal Data ..................................................... 918 44.5.2 In Vitro Data ...................................................................... 918 44.5.3 Comparative Analysis ....................................................... 919 44.6 Safety Testing Protocols ............................................................... 919 44.6.1 Irritation Testing ................................................................. 920 44.6.2 Sensitization Testing ......................................................... 921 44.6.3 Phototoxicity Testing ......................................................... 922 44.6.4 Photoallergenicity (Photosensitization) Testing ................ 922 44.6.5 Safety-in-Use Testing ........................................................ 923 44.6.6 Systemic Exposure .......................................................... 923 44.7 Product Testing Programs ............................................................ 924 44.7.1 Example 1: Evaluation of a New Delivery System ............ 924 44.7.2 Example 2: Clinical Testing of a New Delivery System .... 924 44.7.3 Example 3: Safety Testing for a New Delivery System ..... 926

Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 911–930 © 2005 William Andrew, Inc.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS 44.8 Post-Market Surveillance .............................................................. 926 44.9 Conclusion .................................................................................... 927 References .......................................................................................... 928

44.1 Introduction

44.2 History of Clinical Testing

Unlike the serendipitous discovery of penicillin, the successful development and marketing of most consumer products and pharmaceuticals frequently has a long and often arduous history. Examination of the 19th and early 20th century American and European press shows numerous examples of ill effects from the use of such products. During this time period, expansion of technology and increased understanding in the areas of chemistry, food science, and manufacturing led to the manufacture of tainted or dangerous chemical-containing products. Examples of these included chemicals used to reprocess rancid butter, manufacture pharmaceuticals and preservatives, and material used to improve meat texture.[1]

In the United States, there was little organized clinical research during the 19th century. What little research existed focused on treating life-threatening diseases and developing new surgical procedures. Clinical testing for consumer products (including cosmetics, household products, and pharmaceuticals) has its foundations in defending the safety of the general public. Early clinical testing for these products, however, was limited to small investigations by astute and curious dermatologists that noticed relationships between a patient’s skin disorder and exposure to a particular chemical or product. These limited types of “case study” investigations eventually led to the development of protocols for diagnostic and predictive determination of clinical safety in personal care products. In the area of dermatology, clinical research has progressed considerably since these early days.

The resulting misuse of technology and widespread threat to public health and safety forced the US Congress to pass the Food and Drug Act of 1906 as amended through 1997. This Act was the first to provide meaningful national regulation intended to protect the public health from adulterated foods and medicines. However, due to lack of enforcement and inadequate government resources, instances of widespread injury to the public from such products continued through the early part of the 20th century.[2] These incidents led to increased government oversight, resulting in the early development of regulated clinical trials in the United States. In Europe, the thalidomide disaster of the early 1960s resulted in thousands of infants being born with serious limb defects.[3] This disaster led to the creation of the first European regulation on the marketing of pharmaceuticals (65/65/EEC). Since clinical testing encompasses a vast area of interests, this chapter is focused on clinical safety testing as it relates to personal care products that come into direct contact with the skin. With the significant market growth of cosmetic and personal care products around the world, there is an understanding that this area is of vital importance to both the formulator and product developer.

It wasn’t until the last forty to fifty years that predictive clinical testing was used to support the safety of consumer products. Initial safety testing focused upon the effects of chemicals on skin barrier function, wound healing, and irritation.[4] Today, clinical studies are far more sophisticated and are now designed to determine the impact of products on intracellular endpoints such as cytokine production, mRNA regulation, and protein synthesis. In addition, the instrumentation used today is much more sophisticated than in the early years. For example, investigators are exploring the use of electrochemical, ultraviolet (UV) imaging, Doppler imaging, and spectrophotometric methods to quantify changes in the skin and relate them to product performance.[5]–[9] Today the clinical scientist has available a vast array of tools to support both the formulator and the marketer in developing efficacy claims and demonstrating the safety of new product technology. This chapter focuses on the strategies used to determine what clinical testing is required to demon-

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY strate safety of a new ingredient, delivery system, or fully formulated product, as well as tools available for assessing product safety. The formulation of appropriate testing strategies forms a complex and interesting foundation one builds upon in order to provide sound clinical testing and reliable claims substantiation whether material is legally classified as a drug or cosmetic.

44.3 Regulatory Oversight Regulatory oversight exists for both pharmaceuticals and cosmetics. However, it is far more stringent for materials or products whose claims fall into the pharmaceutical or “drug” class. At its core, clinical testing is designed to demonstrate that new products will not cause harm to patients and consumers. In addition, for pharmaceuticals, clinical testing will produce data to demonstrate efficacy when a product is used as designed. This definition of clinical testing is one that has broad implications for many different types of personal care products. Safety testing, in some form, is conducted on almost all products intended for human use or that have the potential for human contact. However, the approach to clinical testing varies greatly among products. Clinical safety testing requirements are generally based upon route of exposure, product type, proposed ingredients, and intended use. For example, a new chemical or delivery system designed as a pharmaceutical requires the final formulation be approved for sale by a national regulatory agency. It must undergo significant preclinical and clinical safety and efficacy testing prior to being marketed. This testing establishes that the benefits of using a new drug far out ways the perceived potential risks. Such clinical studies are designed to establish limitations as to which individuals can use the drug, under what conditions use is permitted, and establish an appropriate risk-to-benefit ratio. By contrast with pharmaceuticals, a cosmetic does not require clinical testing at all! It is possible to sell a cosmetic product based solely upon a scientific review of the ingredients contained in the product in conjunction with a determination, by a qualified individual, that the product is not expected to cause serious harm when used as designed.

913 44.3.1

United States Food and Drug Administration (FDA)

The United States Federal government regulates the manufacture and sale of foods, cosmetics, pharmaceuticals, and medical devices through the Federal Food and Drug Act as amended through 1997.[2] As the covered entities in this act are varied, the FDA has developed different procedures and processes to regulate foods, cosmetics, and drugs. For a compound or delivery system to be used in a cosmetic product, there is no requirement to conduct clinical tests prior to marketing the product or any of its individual components. As defined by the FDA, the term cosmetic means (1) “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance,” and (2) “articles intended for use as a component of any such articles; except that such term shall not include soap” [FD&C Act, Sec. 201(i)]. The basic safety standard for cosmetics is that no product can be marketed if it contains “a poisonous or deleterious substance which may render it injurious to health” [FD&C Act §601(a)]. This requirement has been further defined to prohibit the sale of cosmetics that “cause more than transitory harm when used as directed.” This legal definition is appropriate for cosmetics because the continuing sales of such products that cause harm are assumed to be self limiting. There is a built-in expectation that as consumers stop using such products, sales will decrease and the manufacturer will no longer profit from their production. Once the application for a personal care product is determined and the regulatory status of the intended use is identified, the toxicologist in charge of the testing programs is able to determine the appropriate guidelines for the testing protocols. Manufacturers need to demonstrate “due diligence” if ever confronted with a claim against their product, and depending upon the nature of the product, or delivery system, this may range from a cursory review of the components, or it may involve a complex battery of in vitro and clinical studies. For materials used in drugs, the FDA requires pre-market approval of the finished product as out-

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lined in the Food, Drug, and Cosmetic Act and amended in 1997 under the Federal Modernization Act. Under this Act, the FDA requires that manufacturers demonstrate that a new drug is both safe and efficacious for the indication it is designed to treat. This process requires submission of an Investigational New Drug (IND) application to the FDA by the sponsor. An IND outlines the clinical plan that will be used to demonstrate safety. It includes preclinical data that is expected to show the product does not produce significant toxicity in humans. After successfully completing clinical trials to show safety and efficacy, the sponsor will submit a New Drug Application (NDA) to the FDA. The NDA will support the product claims, demonstrate safety, and provide an understanding of the pharmacokinetics and pharmacodynamics of the product and provide recommended labeling. In addition to the IND/NDA approval process described above, the FDA has also established an intermediate class of products that are classified as drugs, but do not require pre-market approval prior to sale. This type of product is called an “over-thecounter” (OTC) drug. OTC drugs are regulated by the FDA through a monograph system. This system establishes product specifications and testing requirements for new formulations, as well as specifying required labeling. Once a specific monograph has been finalized, a manufacturer must comply with all aspects of the monograph (including ingredients, labeling, required testing, etc.). If additional claims are desired by a manufacturer, an NDA to support the marketing of the product must be submitted to the FDA. More detailed information on FDA prescription and OTC pharmaceuticals and cosmetic regulations is available on the FDA website (www.fda.gov).

44.3.2 European Union As in the United States, the European Union (EU) has created binding regulations for cosmetics and drugs intended to safeguard public health. In 1976, the EU Council adopted the European Cosmetic Directive 76/768. This Directive outlines the roles and responsibilities of manufacturers and government agencies to ensure public safety for the manufacture and distribution of cosmetic products.

Since its inception, this Directive has been amended six times in order to deal with issues such as international trade conflicts, labeling, excluded/banned ingredients, animal testing, as well as several administrative changes. According to the EU Directive, a cosmetic is defined as any substance or preparation intended to be placed in contact with the various external parts of the human body (epidermis, hair system, nails, lips, and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, and/or correcting body odors and/or protecting them or keeping them in good condition.

The intent of the EU Directive is to ensure that a cosmetic product put on the market within the (European) Community must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use, taking account, in particular, of the product’s presentation, its labeling, any instructions for its use and disposal, as well as any other indication or information provided by the manufacturer or his authorized agent, or by any other person responsible for placing the product on the Community market.

In addition to the primary EU Council Directives, there are additional European Commission Directives that add details to the general Council Directives. This stratification of guidelines is a similar system to the United States Congressional Food, Drug, and Cosmetic Act that is supplemented by FDA regulations concerning cosmetics. Unlike the US system, the EU system puts the focus on testing individual cosmetic ingredients instead of complete formulations. The EU Directive asserts that it is more logical to test ingredients versus formulations because there are a limited number of ingredients used to create an innumerable number of potential finished products. The EU Directives also outline the types of safety data required for an ingredient to be approved by the Council. Further information on the EU Directives can be found on European Union web sites (www.emea.gov and europa.eu.net). The manufacture and distribution of pharmaceutical products is regulated in a similar fashion to that used in the United States. The European Union has

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY adopted a harmonized approach for market approval of new pharmaceuticals that requires submission of a dossier containing safety and efficacy data similar to an NDA prior to marketing of the product. More information on the EU pharmaceutical regulations can be found on the EU web site “pharmacos. eudra.gov.”

44.4 Developing a Clinical Safety Plan In constructing a clinical safety testing program for ingredients or products that are used on the skin, it is necessary to define product-specific testing parameters. The skin often serves as the first line of defense against exposure to both natural and synthetic materials. When chemicals reach the skin most will be absorbed and will interact with the viable tissue below, or be absorbed into the bloodstream due to the anatomical characteristics of the stratum corneum and epidermis.[10] On the other hand, certain materials, such as proteins and polymers that have a high molecular weight (i.e., above approximately 500 Daltons), or a polarity incompatible with the skin, will be poorly absorbed, if at all, and will remain mostly on the surface of the stratum corneum or possibly the epidermis. Many compounds that come in contact with the skin elicit little or no physiological response at all. However, all chemicals have the potential for causing some kind of injury and this depends upon the amount, frequency, and inherent characteristics of the chemical(s).[11] In view of these complexities, the primary role of a toxicologist is to understand the disposition of a chemical, a delivery system, or a full formulation after it comes in contact with the skin. In addition to knowing the disposition of the chemical or delivery system on the skin, the toxicologist must also focus on the proposed use and potential exposure to the consumer during reasonable foreseeable use and misuse. Prior to developing a clinical testing plan to demonstrate the safety of any new product, the developer and marketer must first determine the market for their product, what claims are desired for their product, and how their product compares to the competition.

915 44.4.1

Identifying the Target Population

Identifying the target population and product use conditions are usually an integral part of the product development process. As such, this information is typically defined during the product conceptualization process. It is important to determine target consumers in order to identify candidates who will be used to evaluate product safety. An understanding of the intended market and use conditions are essential to development of an appropriate clinical safety plan. In order to address this issue, the following questions are typically asked and answered. What is the target age group for a product? In determining the target age group for a product there are typically two general populations chosen: adults (e.g., those over 18 yrs of age) and children (e.g., those under 18 yrs of age). If the product will be used preferentially by small children (typically under 12), further considerations in the safety testing plan may need to be considered. A small child has a significantly smaller potential volume of distribution than an adult. These differences may significantly affect the safety of a product applied to the skin at doses designed for adults. A skin care product applied at concentrations anticipated for adults may increase the concentration of product absorbed to toxic levels.[12] Likewise, if the product will be used in a generally aged population, the clinical safety program will be constructed to use people in the appropriate cohort, wherever possible. The reason this age stratification is used is due to differences in the protective and barrier functions of the skin. Typically, older skin is thinner, more fragile and provides a weaker barrier to penetration of chemicals.[13]–[15] It is also more likely to develop irritation and less likely to develop sensitization than younger skin following exposure to products. However, a more important consideration for very young children is systemic exposure to a product. Will the product be used preferentially by a specific ethnic group? The expansion of focus continues for products developed for global markets. This is becoming a major driver of developing a safety testing program. Evidence suggests that Asian and African skin responds differently than European skin to cosmetic and skin care products.[16]–[18] This is especially true for native Asian populations that

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maintain traditional dietary customs. Products developed for African or South American populations also need to be specifically tested in those populations as there are differences in the sensitivity of these populations to certain product types as well as different rates of occurrences for such skin pathologies (such as “eczema”). If a potential exists for use of the products in markedly different populations (i.e., Europeans and Asians), then separate clinical tests may need to be conducted. This is especially true in the area of sensitization and phototoxicity testing. Will the product be used by consumers with specific health conditions? The existence of conditions or testing of varying health is certainly important for drug products is often overlooked, however, for cosmetic testing. When testing drug products that will be registered with a national health authority, the initial safety tests are always conducted on normal, healthy volunteers. This works because the product will eventually be tested more extensively, in the target population, and safety will be extensively monitored. However, safety testing for cosmetic products, or other OTC products, is much less regulated, and there is significant potential to overlook the need to test in a certain population. For example, if a product will be used by people with “atopic” dermatitis, then a significant portion of the safety tests should be conducted in subjects with this condition. Another common example is testing products designed to be used in those with especially dry skin. Although these examples are focused on skin care products, the same principles hold true for any cosmetic or drug product. How many customers are likely to use the product? The answer to this question will assist in determining the size of the studies that are conducted. If one is developing a product for a very well defined population that is easy to quantify, one can modify the size of the studies accordingly. However, it is always safe to assume that the product will find its way into the hands of unintended consumers. As a consequence of this, it is always better to significantly overestimate the size of the target population. Underestimating the size of the target market often causes conscious product developers to reduce the size of the testing program. This often leads to undesirable product liability issues.

Are there certain geographic considerations that will impact product safety? This too is often overlooked in designing a clinical safety testing plan. One must be careful to determine if the product will be used preferentially in a climate that impacts the condition of the skin (i.e., very humid or very dry) and, therefore, impacts the ability of the product to penetrate or damage the skin. Even if the product will be used in different climates, one must look at the impact of these climate effects on product safety. It is often prudent to consider testing the product under multiple conditions if the product will be used in a wide range of environments. This is typically accomplished by seeking out a testing facility in the environment that is desired to ensure the subjects will be acclimated and truly representative of the target consumer population. The important message here is to test the product in the population that will use the product under anticipated environmental conditions. If a product will truly be used in a global market place, then it should be tested in a diverse population.

44.4.2

Defining the Product Claims

During the course of designing an appropriate clinical testing program, product use conditions and claims are also defined in addition to identifying the target population. It is critically important to determine the extent of product exposure in order to assess the depth and extent of the clinical testing program required. How often will the consumer use the product? Products that are used daily, for prolonged periods of time, require extensive evaluation in order to evaluate chronic exposure effects. By contrast, products that are used for a short duration (i.e., only occasionally, or a few times to treat a specific condition), generally require less testing for periods of time that are consistent with the anticipated use duration. For products used on skin, cumulative irritation data (typically 14 to 21 days) is generally required in order to demonstrate that repeated application of the product will not damage the skin. These studies are conducted with positive and negative controls and are typically designed to exaggerate exposure (see Sec. 44.6.1).[19]

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY Following a cumulative irritation study, a Repeat Insult Patch Test (RIPT) (see Sec. 44.6.2) is typically conducted to determine if the product causes sensitization followed by a “safety-in-use” study (see Sec. 44.6.5). The latter study is used to demonstrate safety under unsupervised, anticipated use conditions. Products that are used infrequently, or repetitively for short periods, often require modified cumulative irritation studies (that reduce the frequency or length of time of application/exposure) and a RIPT. However, a “safety-in-use” study is not always required if the exposure is infrequent and non-repetitive. The use of “primary irritation” studies (see Sec. 44.6.1) is only used to screen products in order to make sure they are not inherently toxic upon acute exposure. They should not be used as a definitive assessment of safety for finished goods nor a means to assess chronic, long term effects. Will the product be left on or rinsed off after application? Products that are rinsed off have a relatively short contact period with the skin. These do not require extensive cumulative irritation data to demonstrate safety. In such cases, a short term, primary irritation study is often conducted to show that under conditions of misuse the product is not inherently dangerous. The primary irritation study is also used to identify an appropriate test concentration for a subsequent RIPT study. An RIPT is also performed on new or modified formulations, or formulation components, to ensure that sensitization will not occur in a large segment of the population. A safety-in-use study is often conducted to demonstrate safety under anticipated use conditions. Frequently, market research studies are modified to allow for the collection of safety data if a separate safety-in-use study is not performed. Other studies are conducted based on specific product characteristics. Products that are of the “leave-on” type and may be used chronically do require cumulative irritation data under appropriate application conditions. The purpose of such testing is to demonstrate that prolonged skin contact will not induce irritation, inflammation, or other undesirable effects. These products may also require an RIPT as well as a safety-in-use study to ensure that under anticipated use conditions the product will not elicit unexpected adverse events. Still other studies may also be necessary as determined by product specific characteristics.

917 What is the anticipated exposure/use concentration? In general, products or delivery systems should be tested at, or slightly above, their anticipated use concentration. The reason for this is obvious. If the studies are designed to predict safety in a large population of consumers, the exposures encountered in the limited safety test must exaggerate the expected exposure concentration in order to heighten the sensitivity of the study design. This approach allows the toxicologist to pick up responses in the small percentage of the population, which may be more sensitive to a given product than the bulk of the population. How will the body be exposed to the product? This is an obvious question that will determine if oral, dermal, or inhalation safety testing is required. Oral and inhalation exposure, or use of a product or chemical, often requires that oral or inhalation safety data be generated. The same principle is true for dermally applied compounds or formulated products. A consideration that is often missed in determining the appropriate exposure conditions is secondary routes of exposure. For many years, manufacturers only tested their products for the primary route of exposure. Today, however, toxicologists realize that a significant number of adverse events may arise from secondary routes of exposure. For example, a product that is applied to the skin may be inhaled during application or as the product evaporates from the skin. For these types of products, inhalation safety must be considered to adequately model the product’s safety. Recent developments in volatile delivery system fluids would fall into this category requiring a review of the potential inhalation risks. Does the ingredient absorb UV radiation? For products used externally, absorption of UV radiation is a critical endpoint. With increased awareness of the damaging effects of UV radiation on the skin and the body as a whole, more and more products are being evaluated for their propensity to produce photo irritation.[20] Photo irritation is composed of two distinct types and each type must be evaluated independently. The following definitions are presented for understanding the concepts in this presentation because, in the literature, the naming schemes are confusing regarding irritant responses enhanced by UV radiation and sensitization reactions involving the immune system that are enhanced or caused by UV exposure. The first component of

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photo irritation is phototoxicity. Phototoxicity is an immediate toxic response of the skin to a product that forms toxic chemicals upon exposure to sunlight that damage the skin. One common example of such a chemical is lime juice. When lime juice comes in contact with the skin and is exposed to direct sunlight, an immediate skin reaction resulting in erythema, edema, and burning is observed. The second type of photo irritation is photoallergenicity, or photosensitization. This type of reaction is very similar to the typical sensitization response (e.g., erythema, edema, and often itching), but only occurs after the person using the product is exposed to UV radiation. As in sensitization reactions, photosensitization occurs after the person is exposed multiple times and the body has time to develop an immune response.[21]

44.5 Preclinical Safety Data Prior to testing any product on humans, each material must be carefully evaluated to determine that it will not produce severe toxicity. Such reaction would far outweigh the benefit of using the product. When a material under review is a pharmaceutical, a formal risk/benefit analysis is conducted.[22] In this analysis, the toxicity, as well as expected adverse events, is identified. The toxicity is then weighed against the benefit that the drug will provide the patient. An example of a class of pharmaceuticals that have a significant toxicity profile, due to the potential benefit they produce, are anti-cancer agents and those used to treat infections such as HIV. Obviously, if the potential prognosis is poor without treatment, regulatory agencies and patients are much more likely to tolerate serious adverse events. However, for drugs that treat far less severe conditions, especially those particularly sensitive populations, for example, children using anti-acne medications, adverse events due to toxicity must be mild and rare in occurrence. This principle holds true even more so for cosmetics. Since cosmetics are only intended to improve one’s appearance, the anticipated adverse effects must be very mild and infrequent. Although there is no pre-approval process for cosmetics, the ingredients used and the claims that can be made are regulated. Preclinical safety data

for such materials can come from many sources. These sources include animal toxicology data, in vitro data, and by comparative analysis of the new product versus an existing similar product. In all circumstances, these evaluations must be conducted or supervised by an experienced toxicologist.

44.5.1 Preclinical Animal Data Traditionally, products have been tested in animals prior to being tested for safety in humans. While this is still true for pharmaceuticals, it is becoming increasingly rare for other types of products in response to lobbying interests in animal protection. At this time, most cosmetics companies have completely abandoned the use of animal testing. Many other manufacturers of consumer products use such testing only when required by a regulatory authority when there is a lack of validated alternative methods. A full discourse on preclinical toxicology is beyond the scope of this chapter, so it is important to realize that translating animal data into meaningful support for a human clinical trial can only be conducted by toxicologists and physicians that are very familiar with animal models, as well as human physiology and pathology.

44.5.2 In Vitro Data In vitro data is becoming more widely accepted for use in determining the suitability of a compound or product for use in clinical studies.[23] There are many models under development to predict human systemic and target organ toxicity. Currently, there are accepted in vitro models for dermal and ocular toxicity.[24]–[27] The most important concept to remember when using in vitro assays is that the test chosen should be based on a physiologically meaningful endpoint and it should be relevant to the toxicity anticipated in the clinical trials. One of the most complex areas of safety evaluation and regulatory oversight concerns dermal absorption. If one can demonstrate that very little, or none, of the chemical in question is absorbed into the skin, determining the safety of a chemical or system becomes far simpler. If, however, there is absorption into the skin, the toxicologist has to determine

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY the impact of this absorption. This impact must be determined on the skin itself as well as on the body as a whole. There are several ways to determine if a chemical penetrates the skin. The most common method is in vitro percutaneous absorption.[28] A method currently used involves placing an excised piece of cadaver skin (stratum corneum and epidermis) in the middle of a dual chamber apparatus, called a “Franz” cell, containing the test material in cell test solution on one side and a receiving chamber on the other. Skin permeability is determined by sampling the receiving chamber media over a period of time. This method has been modified and improved with time so that kinetics of the rate of penetration through the skin can be determined.[29] If one can demonstrate that no product penetrates the skin in this test, under appropriate conditions, the need to do systemic exposure and safety work is greatly reduced and may be eliminated. There are a number of other non-clinical methods to predict dermal safety; they include dermal irritation, dermal penetration, and dermal sensitization. There are many excellent references in this area; two are listed (Refs. 30 and 31) since a full discussion is beyond the scope of this chapter.

44.5.3

Comparative Analysis

With the ever increasing availability of computer databases, the ability of a toxicologist to compare new products (either formulations or ingredients) to existing materials has become significant. StructureActivity Relationship (SAR) analysis of chemicals to other chemicals of a related class became a useful methodology as soon as computers became available. By this method, computer programs are created to compare and contrast the molecular structure of a known chemical, with a known toxicity profile, to a new chemical with an unknown toxicity profile.[32] One of the most important considerations in making such comparisons is to accurately determine the appropriate toxicological endpoint. Most SAR models use a well defined toxicity level as a standard for comparison. For example, if a class of compounds is known to be a potent sensitizer, then

919 data from sensitization assays for a given class of compounds can be used to predict the potential sensitization in humans of a related, untested compound based on chemical structure similarities.[33] This type of analysis can be conducted for any well defined toxicological endpoint such as teratogenicity, mutagenicity, or carcinogenicity. Another less sophisticated, yet just as useful, technique is a direct comparison of the components of a new product with those in an existing product having a known safety profile in humans. In this approach, comparison can be made to existing clinical data, market experience, and adverse event reports. Often, new products are very similar to existing, well characterized products. If there are only modest changes to the formulation of composition, it is often the case that all that is needed for a toxicologist assessment is a side-by-side comparison of the two products by a qualified toxicologist. This eliminates the need for chemical testing completely.

44.6 Safety Testing Protocols There are literally dozens of standard protocols employed to determine the clinical safety of products. These protocols cover everything from inhalation to oral and dermal exposure under a wide range of exposure scenarios. The focus of this chapter is on dermal exposure protocols most relevant to assess the toxicity of developing systems and formulations containing them. In order to limit the size, cost, and duration of clinical studies, study designs typically overestimate, or exaggerate, the anticipated exposure. This is because it would be logistically difficult, if not impossible, to conduct studies under typical use conditions in a large enough population to elicit enough adverse events to conduct an appropriate safety assessment. Further, safety studies are often conducted to demonstrate what could happen with anticipated misuse of the product. As average consumers will not consistently comply with labeling instructions, it is important to understand what could happen to a consumer when there is “foreseeable” misuse of the product. This approach will ensure that the product would not cause serious harm under such circumstances.

920 44.6.1

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Irritation Testing

Cumulative irritation. Irritation is defined as damage to the skin, following single or repeat exposure to a product. It can range from complete destruction of the skin (i.e., as would be seen after exposure to a corrosive chemical) to mild erythema following repetitive exposure to a cosmetic.[34] Cumulative irritation refers to skin damage following multiple exposures to a product or chemical. Tests for cumulative irritation vary in design and refer to any protocol where a test material is repetitively patched to the same location for more than three days. Typically, cumulative irritation studies are conducted for a period of 7, 14, or 21 days. Such cumulative irritation studies are valuable for several reasons. Human skin has been shown to be more resistant to acute damage following a single application of a weak irritant. Thus, repetitive application of a test material is more likely to predict relevant skin damage from these test materials than a single application protocol. Second, depending on the patch system used (see Glossary), such tests have been shown to be highly useful in discriminating toxicity effects between products having only slight changes in ingredient concentrations. In addition, when high and low irritation controls are added, one is able to extrapolate the results and predict levels of irritation to actual use situations when a comparison to previously tested and marketed products is possible.[35] The industry “gold” standard cumulative irritation test requires 21 days of continuous application. This study design is used for products that require long term use, or are continuously used for prolonged periods of time. The 21-day cumulative irritation design is the most sensitive design when discriminating between very mild to mild products of a similar nature. In this protocol, typically, 20 to 30 subjects are patched 21 times continuously for a three week period. Patches are worn for 24 hours and patch sites are evaluated between removal and reapplication. If excessive irritation is observed, patching is discontinued for that site and a maximum score is carried for the remainder of test days. As with the primary irritation study design, selection of the grading scale for these tests is critical. It is important that the chosen scale can adequately discriminate between the test materials. Typically, the scale will have a numerical score that ranks the erythema and edema response as well as an “alpha score” for

the characterization of superficial effects. The alpha scores are converted to a numerical grade and combined with the erythema score for a combined irritation score for that site on a given day. Combined scores for a given test material over the 21day period are classified according to a derived categorization system developed for that scoring system and test design. The 21-day cumulative irritation test design can discriminate mild materials (no irritation): very mild, mild, mild-to-moderate, and primary irritants.[36][37] The 14-day and 7-day cumulative irritation tests are a modification of the 21-day cumulative irritation test design. The 14-day cumulative irritation test is run in a manner similar to the 21-day test and has been shown to be as discriminatory as the 21-day cumulative irritation test for all but the mildest of irritants. Similar grading scales and classification scales have been validated for this type of study design for a number of product categories.[19][37] The 7-day cumulative irritation test is a study designed to give a “top line” read on irritation potential and is typically used for products that only come in contact with the skin on an infrequent or transient basis. It can be used to demonstrate safety for rinseoff products, raw materials used in low concentrations in final products, or for other non-repetitive use products. This type of test is not advised for products used on a continuous basis unless there is a significant amount of prior safety history available for the product. Primary irritation. The purpose of the primary irritation test is to evaluate the potential for a test material to produce irritation following limited dermal exposure modeled after animal testing methods.[38] Typically, 10 to 15 subjects are exposed to small quantities of test material (typically 0.5 ml or less). Test materials may be liquids, solids, or other mixtures. They may be applied under occlusive, semiocclusive, or open application. The test materials are applied once for 24 hours or repetitively from 24 to 72 hours. In each case, they are removed following a set time period. The resulting test sites are then evaluated for several days after exposure. Observation is made to determine the presence of erythema, blistering, cracking, or other damaging skin effects. One issue to consider when evaluating results from this study design is the selection of the skin-grading scale. There are a number of scales

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY that are better suited for one type of product than another. The most important considerations when selecting a grading scale are familiarity with the scale and its ability to discriminate sufficiently among test materials. Primary irritation tests are usually performed on new ingredients that have little or no prior human irritation data, and have the potential for causing significant skin damage. Primary irritation tests may also be used as dose range finding tests for cumulative irritation studies.

44.6.2 Sensitization Testing Sensitization is an immune response resulting from exposure to a foreign substance. Sensitization reactions can be due to inhalation, systemic, or dermal exposure to chemicals. Inhalation exposure that results in sensitization is typically manifested as an asthmatic response but can result in serious anaphylactic responses. Systemic sensitization reactions can also result in rashes, hives, asthma, gastrointestinal upset, and severe anaphylaxis. Dermal exposure typically results in rashes and hives, but has also produced serious anaphylactic reactions.[39] Typically, systemic and inhalation reactions are observed in regulated clinical trials or after a product is distributed to the general consumer. It is uncommon that a study would be designed specifically to test for systemic or inhalation sensitization in humans. Most products are tested for their ability to produce dermal sensitization. Such dermal sensitization can be due to immediate hypersensitivity or delayed hypersensitivity.[39] Most sensitization studies determine the potential to develop delayed hypersensitivity since the vast majority of such products, or chemicals, produce this type of reaction. There have been a number of study designs created to adequately predict the potential for a product to produce dermal sensitization. Currently, there are several study designs used frequently to predict sensitization in humans. However, the Modified Draize protocol and the JordanKing Modified Draize protocol are the two most common protocols in use today.[40]–[43] Both of these industry standard designs are conducted in 100 or 200 subjects over a seven week period. The study is broken down into three distinct phases. The induction phase lasts for three weeks and requires nine applications of the test material. The rest phase lasts

921 approximately 14 days. During the rest phase, subjects are not exposed to test material. This is followed by a challenge phase, where subjects receive only one application of test material. Typically, small patches with test material are applied to the backs of subjects three times per week for a three week period during induction. Patches are worn for a period of 24 or 48/72 hours during this three week period. The time of patch application is the basic difference between the two protocols. The Draize protocol requires three 24-hour patches typically applied on a Monday, Wednesday, Friday schedule. The patches are removed the following day with Sunday being a non-treatment day. By contrast, the JordanKing design requires continuous application of the test material applied three times per week. This results in 48-, 48-, and 72-hour wear times during induction. After induction, subjects are given a period of rest to allow for the possible development of an immune response. After the two week rest period, subjects are then exposed to a single application of the test material in order to determine if it will elicit a sensitization reaction. Sensitization is usually defined as a reaction that is equal to, or greater than, a response seen during induction. This reaction typically increases in severity from 48 to 72 hours after patch removal. For both protocol designs, for reactions that are equivocal or unclear, a subject may be re-challenged after a prolonged rest period (i.e., typically four weeks or more). There are other protocols that are still used in industry today that include steps to damage the stratum corneum and the protective barrier of the skin prior to administration of the test article. These protocols have merit only if a sufficient number of subjects are included in the study. Attempting to decrease the required panel size by increasing exposure does not always produce desirable effects. The US FDA requires panels of 200 subjects for any pharmaceutical product.[44] However, the cosmetic industry has adopted a standard of 100 subjects. The reason for such large panels is that if a product is negative in a 200-subject JordanKing RIPT, historical data indicates that the anticipated sensitization rate in the general population will be approximately 1%. This has been deemed acceptable as a tolerable rate of sensitization in the general population. However, for a 25-subject RIPT, a negative response indicates that the potential incidence rate in the general population is approximately 3%, meaning that 30,000 consumers of ev-

922

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

ery 1,000,000 may become sensitized to the product, an unacceptable level of risk even for cosmetics. Even if exposure is increased in the 25-subject study, there is no way to demonstrate that the study is more sensitive.[45] As with irritation testing, the type of patch used (i.e., open, semi-occlusive, or occlusive) is chosen based upon the product itself, and the anticipated use conditions. If the product is not held in contact with the skin for long periods of time, or it is highly volatile, then an open or semi-occlusive patch is appropriate. However, if the product is applied continually to the skin, or is covered after application in order to retard evaporation and increase exposure, then occlusive patches should be used. For sensitization protocols, the approach should be to maximize exposure and, thereby, increase penetration in order to ensure adequate exposure to the test material without increasing the observed irritation. For this reason, it is often prudent to conduct a rangefinding primary irritation or short cumulative irritation study (e.g., 7-day) for use in selecting the dosing levels of the sensitization study.

44.6.3

Phototoxicity Testing

Phototoxicity is observed when a compound or product is applied to the skin and forms toxic decomposition products following exposure to sunlight or UV radiation. Several modifications of the method initially developed by Kaidbey and Kligman[46] are still widely in use today to determine photoxicity. Briefly, prior to product application, a subject’s minimal erythemal dose is determined, then a product or compound is applied to the skin in duplicate. This is typically done under a patch for a period of 24 or 48 hours. After patches are removed, one site is irradiated with UV radiation (UVA and UVB) to an extent that causes only a very minimal erythemal response (referred to as the minimal erythemal dose). Both sites (irradiated and non-irradiated) are then evaluated 24 hours after patch removal to determine if the UV exposure increased the skin’s response to the test material as compared to the control. This study is usually carried out in a small number of subjects (25–50) as most truly phototoxic compounds will be positive in a large percentage of the population. This is a proven method for identifying prob-

able reactive products. However, the investigator must also be aware that there is still a strong possibility that, upon widespread use, phototoxicity will occur in a small subset of the population who are individuals hypersensitive to UV radiation. If one wants to determine if the phototoxicity is specifically caused by UVA or UVB radiation, the test may be conducted using UVA and UVB specific light sources.

44.6.4

Photoallergenicity (Photosensitization) Testing

The photoallergic potential of a compound, or product, is predicted using a similar method to the sensitization protocol previously described. Since this response is also classified as a delayed hypersensitivity response, it is essential that the immune system be given appropriate time to develop a response or the photoallergic reaction may be missed completely. In a manner similar to the sensitization study designs, subjects are exposed to the test material and UV radiation during a three-week induction period. This is followed by a two-week rest period, and a single challenge application of test material and UV radiation.[47] The significant differences between the two methods are: 1. The test material is only applied six times during induction in the photosensitization protocol versus nine applications in the sensitization protocol. 2. The subjects wear duplicate patches during induction and challenge. 3. One of the duplicate patches is exposed to UV radiation after patch removal and one is not. Typically, this photosensitization testing schedule is followed: duplicate patches are applied on Monday and removed on Tuesday. After patch removal, one of the duplicate patches is irradiated on Tuesday and subjects return on Wednesday for evaluation. Both sites are evaluated prior to patch application on Thursday, with patches removed on Friday when the irradiated site is exposed to UV radiation. Subjects return on Saturday for evaluation. This process is repeated for a total of three weeks. After a two week rest period, subjects return for application of two more duplicate patches.

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY These are then worn for 24 or 48 hours. At this time, they are removed and one site is exposed to UV radiation. Subjects then return after 48 and 72 hours, respectively, in order to determine if the UV exposure has increased the potential of the test material to induce contact sensitization.

923 examination and daily diaries are reviewed for product-related safety observations. In addition to collecting valuable safety data, this often gives the toxicologist valuable information regarding unanticipated-use safety information.

44.6.6 Systemic Exposure 44.6.5 Safety-in-Use Testing In many ways, safety-in-use data is very important, but often the most overlooked component of the clinical safety package. Since the irritation, sensitization, and phototoxicity studies will generally identify potential problems with a product, one must be very careful to apply an appropriate frame of reference for interpreting the data. Typically, these studies exaggerate product exposure and it is important to be able to predict how the product will really act in the hands of the consumer. This analysis, conducted in the context of a valid data interpretation, is the strength and advantage of the safety-in-use study. Since safety-in-use studies must mimic real-life use conditions, these studies are generally several weeks to several months in duration. They may also require the use of several unique populations. Further, a large enough population must be used to adequately cover the intended consumer base and to identify unexpected adverse events. For these reasons, safety-in-use studies are often conducted on 100 subjects or more. Typically, safety-in-use studies are limited control studies where subjects are given a product and asked to use the product at home according to label instructions for a given period of time. Subjects are generally screened in order to make sure they meet demographic as well as prior product use criteria. For example, if the test material is a mouthwash that must be used twice a day for optimal effectiveness, it is important to pre-qualify subjects who actually use a mouthwash at least twice a day. Once qualified subjects are given the product, they are often asked to maintain a diary to record their comments and answers to questions about which the product sponsor is interested. Further, the subjects are often asked to return to the test facility during the study to allow the opportunity for additional questions. At these times, interim subject safety evaluations can also be conducted. At the end of such studies, the subjects return for a final safety

Typically, products that are used on the skin are meant to stay on the stratum corneum and not penetrate into the dermis. This is to eliminate the possibility of systemic absorption and distribution. However, with the increasing prevalence of cosmeceutical products containing biologically active compounds, it is increasingly likely that a product may contain an ingredient that penetrates the skin. As previously described, there are in vitro methods to determine if skin penetration occurs. If penetration does occur, a systemic exposure/safety study should also be conducted. These studies are designed to replicate typical exposure scenarios, and are as unique as the products themselves. However, all systemic exposure and safety study designs share some similarities. As for other clinical studies, identifying the appropriate subject population and anticipated-use conditions is essential to producing meaningful data. Once this scenario is established, a relevant biological marker must be identified, along with an appropriate sampling schedule. For example, exposure to a skin care product containing a new botanical extract that is used twice daily in women for six months could be determined as follows: 1. Select women with appropriate demographics. 2. Determine that the extract can be quantified in serum. 3. Decide that women will use the product for one week prior to sampling in order to establish a steady state for the extract in the serum. 4. Sample women every 24 hours for four days as they continue to use the product. 5. Monitor safety during the entire length of the use period. 6. Obtain a final serum sample following a 96 hour washout period to determine

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS how long the extract remains in the system.

Data from this type of study would show if the product, or ingredient of concern, was absorbed, what levels were reached during steady state, if there were any associated toxicity observed, and how long the product or ingredient took to clear from the system.

44.7 Product Testing Programs Since it is often easier to understand basic principles by following specific examples, the following case studies are provided in order to give examples of how safety experts design and construct effective clinical testing programs. These examples are meant to describe the “thought process” involved, and are not intended to be viewed as “cookbook” programs for specific product types.

44.7.1 Example 1: Evaluation of a New Delivery System The clinical evaluation of a new delivery system or ingredient represents a typical situation that is faced by developers and toxicologists. Often there is likely to be little prior information that can be used to support the clinical safety of the new system or ingredient. The toxicologist would have a physical and chemical characterization, references to other similar products or technologies, and possibly some preclinical safety information. For this example, assume a new delivery system that contains no “new” chemicals is being evaluated; it will be used in a facial toner that is used by both adult men and women. It is anticipated that this toner would be used in the general population on a regular basis for prolonged periods of time. Table 44.1 shows what issues drive the decision-making process for determining the appropriate clinical safety plan. The following clinical testing program is recommended based on the evaluation of the product in relationship to the questions in Table 44.1: • A seven-day cumulative irritation test in men and women between the ages of 18 and 60.

• A repeat application patch test (Draize RIPT) for sensitization in 100 subjects in men and women between the ages of 18 and 60. • A two-week safety-in-use test with facial application in approximately 30–50 men and women (20%/80% based on typical reported product use) that typically use facial toners. The reduced cumulative irritation test (i.e., seven-day) is used because the ingredient and formula are assumed to have historical use data that supports the general safety when used in this type of skin care product.

44.7.2 Example 2: Clinical Testing of a New Delivery System For a product with less information and a slightly different anticipated use, a toxicologist is again asked to determine the clinical testing needs of a new delivery system that will be used to encapsulate active ingredients for delivery to the skin in a cosmetic. This product is a body wash that can be used on the entire body, contains an ingredient known to absorb UV light, and is used to reduce dry skin. For this product, Table 44.2 shows the decision-making process for determining the appropriate clinical safety plan. The following clinical testing program is recommended based on the evaluation of the product in relationship to the questions in Table 44.2: • A three-day primary irritation study in men and women (18–60 years). • A RIPT study in 200 subjects with 50% of subjects to be identified as dry skin individuals based on visual assessment of skin by a trained dry skin evaluator. • A two-week safety-in-use test with facial application in approximately 30–50 men and women (20%/80% based on typical reported product use) with dry skin, that are regular body wash users. • A photo-irritation study to include both phototoxicity and photosensitization in normal, healthy volunteers.

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY

925

Table 44.1. Evaluation of a New Delivery System

Product Characteristic Leave on

Yes

No

Comments

X X

Possible, but unlikely due to cost of product and size of product container.

Use in children

X

Possible, but not in small children under age 12 years.

UV absorber

X

Use on whole body Use on face

X

Daily use

X

Chronic use

X

Potential eye exposure

X

Highly anticipated in this product type.

Percutaneous absorption

X

Special population

X

There are no ingredients anticipated to be absorbed.

Table 44.2. Clinical Testing of a New Delivery System

Product Characteristic

Yes

Leave on

No

Comments

X

Use on whole body

X

Use on face

X

Daily use

X

Chronic use

X

Use in children

X

Not to an extent that identifies children to be at risk.

Potential eye exposure

X

Not highly anticipated in this product type.

Percutaneous absorption

X

There are no ingredients anticipated to be absorbed.

UV absorber

Special population

X

X

Clinically demonstrated dry skin individuals.

926

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS • Photo-irritation study with phototoxicity and photosensitization endpoints with a placebo patch in normal healthy volunteers.

There is no cumulative irritation test recommended because the product is “wash off” and in this case, some irritation data can be obtained from the RIPT. However, one must be careful to overestimate the value of irritation data from a RIPT. This is only applicable if there is a significant amount of knowledge available regarding the product type, prior formulations, and ingredients used.

44.7.3

• A pharmacokinetic (PK) study to determine systemic exposure (to determine safety and adequate exposure) with the active patch system in normal, healthy volunteers. All of these studies should include assessment of changes from base line in clinical endpoints including serum and urine analysis.

Example 3: Safety Testing for a New Delivery System

A toxicologist is asked to determine the clinical safety testing requirements for a new delivery system that will be used in a pharmaceutical transdermal patch. The component is a new adhesive that also serves as a reservoir for the active ingredient. The transdermal patch is anticipated to be used for chronic pain management in cancer patients. Table 44.3 shows the decision-making process for determining the appropriate clinical safety plan.

44.8 Post-Market Surveillance Post-marketing safety data is often the most overlooked resource one has to defend the safety of a product. As the number of product liability litigation actions increase, product developers have to use every means available to protect themselves from legal action by consumers. By law,[2] pharmaceutical companies that market regulated drugs must actively maintain adverse event databases for their products. Further, they must regularly report types of adverse events and incident rates to national health agencies. Unfortunately, there is no requirement for this type of system for cosmetics and other types of consumer products. However, it is not difficult to set up systems to monitor and record the types of adverse events that are being reported for a given

For this pharmaceutical product, the recommended clinical testing plan should include: • A 21-day cumulative irritation study with adhesion assessment in 30 normal, healthy volunteers with a placebo patch. • A Modified Draize RIPT study in 200 normal, healthy volunteers with a placebo patch.

Table 44.3. Safety Testing for a New Delivery System

Product Characteristic Leave on

Yes

No

Comments

X

Use on whole body

X

Use on face

X

Daily use

X

Chronic use

X

Use in children

X

UV absorber

Not to an extent that identifies children to be at risk. Unknown.

Potential eye exposure

X

Not highly anticipated in this product type.

Percutaneous absorption

X

There are potential ingredients that may be absorbed.

Special population

X

Used preferentially on patients with chronic pain.

TONUCCI: NEW & EMERGING TESTING TECHNOLOGY product. These systems can later be used to demonstrate due diligence on the part of the manufacturer, and to generate alerts as to any developing safety issues or trends for a given product. Often, the easiest way to establish a surveillance system is to modify the customer service system that is likely to be already in place. Frequently, the customer service department is already receiving customer complaints that relate to product safety. In such cases, the only components missing are education of the customer representative and a system that adequately allows for capturing the necessary information.

927 On the other hand, if a product is causing even a small percentage of adverse events (i.e., even 2% for a broadly marketed product), it provides valuable information to determine if there is real concern that the product is unsafe. Further, this data can be used to identify if the product is being used in an unforeseen manner that increases the incidence of adverse events, or if labeling instructions/warnings need to be modified to reduce specific use habits. There are several good references available on how to establish a safety monitoring program that can be used to supplement and enhance the recommendations made within this chapter.

Important data points to capture from a customer that has a safety-related complaint include: 1. The exact product name including product identification of serial/lot/batch numbers, if available. 2. Signs and symptoms of the adverse event including start and stop dates, intensity, and treatments used. 3. Exact product-use conditions that preceded adverse event (i.e., amount used, frequency of use, how used, where on body used). 4. Frequency of product use prior to event. 5. Prior occurrence of specific adverse event(s) assumed to be caused by product. 6. Physician or other health care provider involvement. Additional questions that might be relevant for the specific product should be identified by an appropriate safety expert. Once all of the necessary data categories are identified, responses should be identified and categorized in order to allow the database to be readily searched and queried for the incidence of product-specific safety complaints. As such a database grows in size, it can be used to calculate the number of adverse events reported versus the number of units sold, in order to provide an indication of incident rates. If the manufacturer can show that under expected use conditions, the product has not caused any reported adverse events for every X million units sold. This goes a long way to support the safety claims and documentation for a product.

44.9 Conclusion Clinical testing of products is an essential component of establishing the safety of all consumer products. Supporting this need, most, if not all governments, have established rules and guidelines for marketing consumer products that ensure safety and, in many cases, efficacy of products. As the use of animals in safety testing continues to decrease, the need for more appropriate and comprehensive in vitro and clinical test methods is expected to increase. In spite of this, there is still valid concern for testing products in humans without any prior safety data being generated. For this reason, the US FDA and th EU EMEA have established comprehensive in vitro alternatives programs to establish non-animal models to ensure that no dangerous products are tested or used by humans. As these methods develop, it may be possible to reduce the amount of clinical testing required to market a product. However, at this time, there are few true replacements for human testing due to complex and unique human physiology and biochemistry. Once it is determined that a product may be tested in humans, there is a defined approach to identifying the clinical testing that needs to be conducted. These tests need to be conducted and interpreted under the guidance of an experienced safety specialist in order to ensure that it is safe for its intended use or foreseeable misuse. Although there are standard protocols for most clinical tests conducted for consumer and pharmaceutical products, it should not be assumed that there is a “one-sizefits-all” approach to clinical testing.

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References 1. Kurian, G., ed., A Historical Guide to the U.S. Government, Oxford University Press, New York (1998) 2. http://www.fda.gov/oc/history/default.htm 3. Smithells, R. W., Thalidomide and Malformations in Liverpool, Lancet, 1:1270–1273 (Jun. 16, 1962) 4. Maibach, H. I., Cutaneous Pharmacology and Toxicology, Ann. Rev. Pharm. and Tox., 16:401–411 (1976) 5. Barardesca, E., and Maibach, H. I., Bioengineering and The Patch Test, Contact Dermatitis, 18(1):3–9 (1988) 6. Wielhelm, and Maibach, H. I., Skin Color Reflectance Measurements for Objective Quantification of Erythema in Human Beings, J. Am. Acad. Dermatol., 21(6):1306–1308 (Dec. 1989) 7. Kawasaki, et al., Analysis of Structural Changes in Intracellular Lipids of Human Stratum Corneum Induced by Surfactants: Electron Paramagnetic Resonance (EPR) Study, Dermatotoxicology, 6 th Ed., (Zhai and Maibach, eds.) CRC Press (2004) 8. Barel, A. O., and Clarys, P., Study of Stratum Corneum Barrier Function by Transepidermal Water Loss Measurements: Comparison Between Two Commercial Instruments: Evaporimeter and TEWAmeter, Skin Pharmacol., 8:186–195 (1995) 9. Ho, D. Q., Bello, Y. M., Grove, G. L., Manzoor, J., Lopez, A. P., Zerweck, C. R., Pierce, E. A., Werkheiser, J. L., and Phillips, T. J., A Pilot Study of Noninvasive Methods to Assess Healed Acute and Chronic Wounds, Dermatol. Surg., 26(1):42–49 (Jan. 2000) 10. Monteiro-Riviere, N. A., Anatomical Factors Effecting Barrier Function, th Dermatotoxicology, 6 Ed., (Zhai, and Maibach, eds.) CRC Press (2004) 11. York, M., Griffiths, H. A., Whittle, E., and Basketter, D. A., Evaluation of A Human Patch Test for the Identification and Classification of Skin Irritation Potential, Contact Dermatitis, 34(3):204–212 (Mar. 1996)

12. FAD Pediatric Subcommittee of the Medical Policy Coordinating Committee (MPCC) and the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research (CDER), and by the Center for Biologics Evaluation and Research (CBER); Guidance for Industry General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products, DRAFT GUIDANCE 13. Roskos, K. V., Maibach, H. I., and Guy, R. H., The Effect of Aging on Percutaneous Absorption in Man, J. Pharmacokinet. Biopharm., 17(6):617–630 (Dec. 1989) 14. Elsner, J. P., Wilhelm, D., and Maibach, H. I., Effect of Low-concentration Sodium Lauryl Sulfate on Human Vulvar and Forearm Skin; Age-related Differences, J. Reprod. Med., 36(1):77–81 (Jan. 1991) 15. Schwindt, D. A., Wilhelm, K. P., Miller, D. L., and Maibach, H. I., Cumulative Irritation in Older and Younger Skin: A Comparison, Acta Derm. Venereol., 78(4):279–283 (Jul. 1998) 16. Berardesca, E., de Rigal, J., Leveque, J. L., and Maibach, H. I., In vivo Biophysical Characterization of Skin Physiological Differences in Races, Dermatologica., 182(2):89–93 (1991) 17. Berardesca, E., and Maibach, H. I., Sensitive and Ethnic Skin; A Need for Special Skin-care Agents? Dermatol. Clin., 9(1):89–92 (Jan. 1991) 18. Lotte, C., Wester, R. C., Rougier, A., and Maibach, H. I., Racial Differences in The In vivo Percutaneous Absorption of Some Organic Compounds: A Comparison Between Black, Caucasian and Asian Subjects, Arch Dermatol. Res., 284(8):456–459 (1993) 19. Bowman, J. P., Berger, R. S., Mills, O. H., Kligman, A. M., and Stoudemayer, T., The 21day Human Cumulative Irritation Test Can Be Reduced to 14 Days Without Loss of Sensitivity, J. Cosmet. Sci., 54(5):443–449 (Sep.Oct. 2003) 20. Kaidbey, K. H., and Kligman, A. M., Photomaximization Test for Identifying Photoallergic Contact Sensitizers, Contact Dermatitis, 6(3):161–169 (Apr. 1980)

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21. Kligman, A. M., and Kaidbey, K. H., Human Models for Identification of Photosensitizing Chemicals, J. Natl. Cancer Inst., 69(1):269– 272 (Jul. 1982)

29. Bronaugh, R. L., and Stewart, R. F., Methods for In vitro Percutaneous Absorption Studies IV: The Flow-through Diffusion Cell, J. Pharm. Sci., 74(1):64–67 (Jan. 1985)

22. Farley, D., Benefit Vs. Risk: How FDA Approves New Drugs, FDA Consumer Special Report on New Drug Development in the US (Jan. 1995)

30. Basketter, D. A., and Cadby, P., Reproducible Prediction of Contact Allergenic Potency Using the Local Lymph Node Assay, Contact Dermatitis, 50(1):15–17 (Jan. 2004)

23. Stokes, W. S., Schechtman, L. M., and Hill, R. N., The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM): A Review of the ICCVAM Test Method Evaluation Process and Current International Collaborations With the European Centre For the Validation of Alternative Methods (ECVAM), Altern. Lab. Anim., Suppl. 2:23–32 (Dec. 30, 2002)

31. Welss, T., Basketter, D. A., and Schroder, K. R., In Vitro Skin Irritation: Facts and Future; State-of-the-art Review of Mechanisms and Models, Toxicol. In Vitro, 18(3):231–243 (Jun. 2004)

24. Basketter, D. A., Smith Pease, C. K., and Patlewicz, G. Y., Contact Allergy: The Local Lymph Node Assay for The Prediction of Hazard and Risk, Clin. Exp. Dermatol., 28(2):218–221 (Mar. 2003)

33. Patlewicz, G. Y., Basketter, D. A., Pease, C. K., Wilson, K., Wright, Z. M., Roberts, D. W., Bernard, G., Arnau, E. G., and Lepoittevin, J. P., Further Evaluation of Quantitative Structure-Activity Relationship Models for The Prediction of The Skin Sensitization Potency of Selected Fragrance Allergens, Contact Dermatitis, 50(2):91–97 (Feb. 2004)

25. Fentem, J. H., Briggs, D., Chesne, C., Elliott, G. R., Harbell, J. W., Heylings, J. R., Portes, P., Roguet, R., van de Sandt, J. J., and Botham, P. A., A Prevalidation Study on In Vitro Tests for Acute Skin Irritation; Results and Evaluation By The Management Team, Toxicol. In Vitro, 15(1):57–93 (Feb. 2001) 26. Cooper, K. J., Earl, L. K., Harbell, J., and Raabe, H., Prediction of Ocular Irritancy of Prototype Shampoo Formulations by the Isolated Rabbit Eye (IRE) Test and Bovine Corneal Opacity and Permeability (BCOP) Assay, Toxicology In Vitro, 15(2):95–103 (Apr. 2001) 27. Harbell, J. W., Koontz, S. W., Lewis, R. W., Lovell, D., and Acosta, D., IRAG Working Group 4, Cell Cytotoxicity Assays; Interagency Regulatory Alternatives Group, Food Chem. Toxicol., 35(1):79-126 (Jan. 1997) 28. Bronaugh, R. L., In Vitro Percutaneous Absorption Models, Ann. NY Acad. Sci., 919:188–191 (2000)

32. Barratt, M. D., Prediction of Skin Corrosivity Using Quantitative Structure-activity Relationships, Toxicology of Skin, (H. Maibach, ed.) Taylor & Francis (2001)

34. Weltfriend, S., et al., Irritant Dermatitis (Irritation), Dermatotoxicology, 6th Ed., (Zhai and Maibach, eds.) CRC Press (2004) 35. Bagley, D. M., Boisits, E. K., Spriggs, T. L., and Schwartz, S., Effect of Patch Type on the Cumulative Irritation Potential of 4 Test Materials, Am. J. Contact Dermat., 12(1):25–27 (Mar. 2001) 36. Lanman, B. M., Elvers, E. B., and Howard, C. J., The Role of Human Patch Testing in a Product Development Program, Joint Conference on Cosmetic Sciences, The Toilet Goods Association (currently, the Cosmetic, Toiletry and Fragrance Association), Washington, D.C. (Apr. 21–23, 1968)

Part XVI Marketing by Design and Advertising Analysis

Marketing by Design

GraphiSenses: A New Methodology for Identifying Personal Care Opportunities

45 GraphiSenses A New Methodology for Identifying Personal Care Opportunities Myriam Delvaux Dow Corning Corp., Brussels, Belgium 45.1 Introduction ................................................................................... 934 45.1.1 How Does the GraphiSenses Approach Lead to New Products? ................................................................. 934 45.2 Idea Generation ............................................................................ 935 45.3 First Step: Database of Print Advertisements .............................. 935 45.3.1 Database .......................................................................... 935 45.3.2 Advertisement Analysis .................................................... 936 45.3.3 Synthesis of Verbatim Responses: Definition of Key Words 936 45.3.4 Definition of the Axes of Communication .......................... 936 45.3.5 Product Mapping ............................................................... 937 45.3.6 Product Clustering ............................................................ 937 45.3.7 Driver Definition ................................................................ 937 45.4 Second Step: Sensory Evaluation of the Drivers ......................... 938 45.4.1 Procedure ......................................................................... 938 45.4.2 Results ............................................................................. 939 45.4.3 The Sensory Analysis Leads to A Kind of “Identity Card” That Qualifies Each Driver................................................ 940 45.5 Formulations ................................................................................. 941 45.5.1 Formulation Philosophy .................................................... 941 45.5.2 Formulation Details ........................................................... 941 45.6 Validation ....................................................................................... 949 45.6.1 Validation by Sensory Evaluation ...................................... 949 45.6.2 Validation by Consumer Testing ........................................ 952 45.7 Conclusions .................................................................................. 952 Definitions and Methodology ................................................................... 954 Details on Sensory Analysis and Definitions ................................ 954 Methodology of Evaluation ............................................................ 955 References .......................................................................................... 956 Meyer R. Rosen (ed.), Delivery System Handbook for Personal Care and Cosmetic Products, 933–956 © 2005 William Andrew, Inc.

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45.1 Introduction A new technique, called GraphiSenses, helps developers of personal care products examine the marketplace from several different perspectives at the same time. This novel approach provides an alternative viewpoint for identifying new product opportunities. By analyzing the print advertising of leading personal care products (in this case, with a focus on skin moisturizers) and personal care delivery systems, the method defines the latest trends motivating consumers to purchase these products. As such, this approach provides a powerful new viewpoint from which to understand the marketplace and provide fresh insight into the latest trends. The GraphiSenses method is particularly useful since it goes well beyond traditional measurement of objective sensory benefits that can be induced by specific raw materials. The method provides access to the more subtle, subjective parameters which motivate consumers and combines this information with objective data. This dual approach of using subjective and objective data is illustrated in this chapter with silicones as an example of useful actives for personal care products. However, the same methodology can be applied to assess the value of any active raw material and it specifically allows for differentiation in a system in which an active is incorporated into a delivery/carrier system. Since a wide range of delivery systems are available, a lack of these may provide different features and benefits on the finished product. The GraphiSenses approach offers a unique methodology for comparing different delivery systems, especially those containing the same active ingredient.

45.1.1 How Does the GraphiSenses Approach Lead to New Products? The GraphiSenses process involves four steps: • Assemble a database and identify drivers. A database of print advertisements for leading skin moisturizers is assembled. A panel of skin care professionals is asked to register their immediate reactions as each advertisement is

flashed upon a screen. The reactions are sorted and grouped, and the four most prevalent communication dimensions are identified. These dimensions are used to define graphical axes on which all relevant flash response reactions are then plotted. Natural data clusters are formed as a result of the process, and the most extreme of these are used to define the market trendsetters, or “drivers.” • Sensory profile analysis. The drivers identified in the first step are subjected to objective sensory profile analysis in order to identify the ideal group of properties that define each subjective quadrant of the graph. The result is an objective graphical description that corresponds with the subjective analysis. • Develop new formulations. The third step of the GraphiSenses process is to develop new formulations that specifically reflect the identified trends and respond to consumer expectations from each of the four communication areas. This step can be done using detailed documentation for substantiated benefits of specific actives or delivery systems. In this chapter, we have chosen Dow Corning® brand silicones as the exemplar actives. Of course, similar data from any other strategic raw materials, such as specific actives or fragrances, and delivery systems for these actives can be evaluated in the same way. This approach can also be used to help differentiate the perception/sensory parameters from clinical claim substantiation, and to determine if those two aspects of the formulation are consistent. Ultimately, it is possible to target specific active ingredients and delivery systems for them to formulate new products and make optimal comparisons. • Validation. Using the GraphiSenses methodology, Dow Corning developed four siliconebased skin care products to match requirements of each of the four quadrants. In-depth sensory evaluations demonstrated a clear fit between sensory performance and product positioning, thereby substantiating the authenticity of the method and its potential value for evaluating other types of actives and their delivery systems.

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935

45.2 Idea Generation The usual approach used by suppliers to develop new raw materials is based on matching customers’ expectations with internal capabilities. This is then followed by a development phase in which new molecules are developed that respond either to a specific customer need or to general market trends. Promotion of the new raw material by the supplier is then based on evidenced benefits that are rarely used in final consumer communication. The latter is usually handled by a marketing team associated with the cosmetic product company and may be at a distance from the original benefits determined. Unlike the traditional method, the GraphiSenses technique offers a novel approach that starts with the final consumer communication (see Fig. 45.1). It then turns these communication criteria into a comprehensive tool that enhances the link between the raw material suppliers and the cosmetic product companies.

RAW MATERIALS SUPPLIER

. . . . .

45.3 First Step: Database of Print Advertisements 45.3.1 Database The best way to create a database related to communications by cosmetic product suppliers is by collecting their advertisements and promotional brochures. A wide selection is available including television advertisements, magazine or newspaper advertisements, and internet advertisements. We selected trade magazine advertisements since this medium is widely used by cosmetic product suppliers. Different types of magazines were purchased[2] from countries in Europe (France, Italy, Spain, Germany, the United Kingdom, Belgium, and Portugal) and the United States. These countries represent the best-in-class offerings of cosmetic products. Clearly, we could not consider this first step exhaustive. Therefore, because the United States and France can be considered as having the most advanced skin care products, as a second source of

NEW RAW MATERIALS DEVELOPMENT EVALUATION OF BENEFITS APPLICATION TO SKIN CARE SEGMENT PROMOTE BENEFITS SALE TO CUSTOMERS

Promotion

COSMETIC PRODUCTS COMPANY

.

IN ACCORDANCE WITH TRENDS

? BUY RAW MATERIALS FROM SUPPLIERS ? INSERT RAW MATERIAL IN FORMULATION .

GRAPHISENSES TECHNIQUE

NOT IN ACCORDANCE

? DO NOT BUY RAW MATERIALS

Communication

CONSUMERS Figure 45.1 GraphiSenses approach provides key lijnk between raw material suppliers and consumers.

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advertisements we used some software called USA Cosmetic Research® and fiches France Cosmetic Research®. Each of these sources contain a long list of new cosmetic products. For each of these products, the description sheet showed the following: • The name and brand of the product • Its date of launch • Its price • The segment where the product is found • Its positioning: mass market, drugstore, or selective store • The formulation ingredients We added to our advertisement database with the help of this software and, finally, for broader coverage, we visited websites where all advertisements published in magazines can be found. As a result, the final database covered advertisements of new product introductions for the period January 1999 to April 2000.

45.3.2 Advertisement Analysis Analysis of the advertisement pool of the GraphiSenses protocol consisted of collecting spontaneous statements provided by four European specialists in a series of professionally organized interviews. These specialists were requested to describe the advertisements in a substantive manner, using adjectives, verbs, and short sentences; their verbatim responses were recorded.

45.3.3

Synthesis of Verbatim Responses: Definition of Key Words

The pool of verbatim responses was then sorted and grouped. Four prevalent “dimensions” of communication were then identified. These led to a graphical representation containing: • Four areas, or quadrants • Two main axes of communication (see Fig. 45.2) These four prevalent “dimensions” led to the selection of certain “criteria” and the selection of these criteria was based on repeated key words made in flash responses by the industry experts.

45.3.4

Definition of the Axes of Communication

Each product was mapped in the area that best represents its profile as defined by the spontaneous verbatim responses. We identified two main axes of communication: • The first axis is expressed based on texture: – Sense minus texture (shown on the graph as “Sense – Texture”), with light, airy, and transparent features. – Sense plus texture, (shown on the graph as “Sense + Texture”), with rich, creamy, and nourishing features.

The four industry experts included: • A marketing strategic manager in the skin care segment • A market communications specialist • A technical service adviser • A skin care and cosmetic R&D expert Each industry expert was interviewed for a maximum of one hour for each session. It was found that people would begin to loose their objectivity and spontaneity after longer sessions. For each advertisement, we collected approximately 10 to 15 verbatim responses that describe spontaneous perceptions.

Figure 45.2 Advertisement analysis. Selection of criteria based on repeated key words used in flash responses by industry experts.

DELVAUX: GRAPHISENSES

937

• The second axis is expressed based on the sophistication and complexity of the product: – The far right of the graphical representation shown in Fig. 45. 3 represents communication based on products with a highly sophisticated, technical and scientific dimension. Products mapped in this zone contain active ingredients for which it is useful to understand the impact of the delivery system. This zone is especially important when comparing different delivery systems for the same active. – The far left of the graphical representation shown in Fig. 45.3 represents a communication based on natural, freshness, and water-like images.

Figure 45.3 Advertisement analysis. Axes definition.

45.3.5 Product Mapping For each finished product, the analysis of its respective print advertisements (based on the flashed responses of industry experts) allowed it to be plotted somewhere within the four quadrants in the graphical represenation described. (See Fig. 45.4.)

45.3.6 Product Clustering It was observed that closely positioned groups of products could be pulled together into clusters in order to better define certain “classes” of product behavior. Natural clusters were formed because of the relative similarity of their messages leading to this clustering exercise (see Fig. 45.5).

Figure 45.4 Advertisement analysis. Leading skin care product advertising mapped out individually.

To make certain that the advertisement reflected the correct profile for a product, we also conducted a store check. Analysis of active ingredients, and their related delivery system, helped us to map the most relevant ones into the “Sophistication” zone.

45.3.7 Driver Definition The most extreme clusters (i.e., the ones farthest from the center) of the four quadrants of the GraphiSenses representation can be considered typical of each quadrant and very segmenting. These

Figure 45.5 Advertisement analysis. Leading skin care product advertising clustered.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

clusters were chosen to represent the four prevalent market trends. In each of these clusters (see Fig.45.6), a “Driver” (see Fig. 45.7) was defined to be the product that best fits with the product’s positioning both in terms of: • Advertisement correlation with market positioning in terms of active content • A sensory profile that corresponds to customer expectation in each quadrant

45.4 Second Step: Sensory Evaluation of the Drivers The drivers were submitted to an objective sensory profile analysis leading to the identification of an “ideal group” of properties. This is the result of introducing objective parameters (i.e., sensory analysis) that corresponds with the subjective analysis of flashed responses given by the industry experts.

45.4.1

Procedure

To obtain the sensory profile of the drivers, the four creams we selected as examples to demonstrate the GraphiSenses method were analyzed with the help of a complete sensory evaluation developed specially for this study. This sensory test was based on software called SigmaStat 2.0. See “Appendix 45.I” for more details on the methodology.

ning the test. Using a skin pencil, three rectangles (5 cm × 4 cm) were drawn on one forearm for each of the panelists. The panelists were allowed to choose the forearm he or she preferred. The formulated product was rubbed on the skin making rotations with a different finger for each rectangle (index, middle, and ring fingers, one for each test site). The test took place in a quiet room with stable temperature and humidity. Room lighting consisted of both daylight and spotlight. The jars. Jars without brand connotations were used and driver creams were transferred into transparent jars in order to conduct the test under blind conditions. Sensory analysis and definitions. The sensory parameters were predefined and well known in the literature. Many are typically used for sensory tests.[1] Other sensory parameters were selected from the trends found in the mapping. For example, panelists were asked to judge the criterion “waterlike perception” in the “appearance in the jar” category. The following categories were investigated: • Appearance in the jar (mainly based on texture and gloss) • Creaminess at pickup (feel at pickup) • Perception of skin feel when the cream was applied • Perception of skin feel when the cream was absorbed

The principle. The principle of this test was based on a comparison of the four drivers using sets of three creams and a statistical design method known as incomplete block design with randomization (refer to: Sensory Evaluation Techniques, 2 nd Edition, Meilgaard/Civille/Carr, pp. 107–122). The panel. The test was conducted with a group of 28 volunteer panelists. These panelists were asked to wash their hands and forearms with a basic soap, dry them with a clean towel, and wait for five minutes before begin-

Figure 45.6 Advertisement analysis. These key products are chosen for objective sensory profile analysis.

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939

Figure 45.7 CTFA designation of drivers.

45.4.2 Results

• Having a soft and slippery texture

For each section of the sensory test, a spider diagram was made that showed the mean value for each parameter. Based on a statistical analysis for each parameter, we identified the “strengths” and “weaknesses” for each tested cream. These results, coupled with the graphical analysis, led to the following conclusions:

In criteria related to the absorption profile, Driver A exhibited these characteristics:

Driver A was found in visual appearance and pickup in the jar as follows:

Most of these characteristics were expected for Driver A and fit with its positioning of a moisturizing cream placed in the “natural/sense minus texture” quadrant. The same analysis was done for Drivers B, C and D. The relevant criteria evidenced after statistical analysis are summarized in Fig. 45.8.

• Having the appearance of a nonshiny cream • Having water-like perception • Being light in appearance

• A cooling effect • A low presence after absorption • Easy spreading during absorption • An aqueous feel during absorption

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45.4.3 The Sensory Analysis Leads to A Kind of “Identity Card” That Qualifies Each Driver Key findings from the statistical analysis were summarized and presented in a spider diagram (as in Fig. 45.8) showing the significant criteria typical for each driver. This approach corresponds to what may be viewed as an “identity card,” which reflects the unique sensory profile for each driver. The four creams evaluated had very different profiles, and ranged from very simple to more complex types. However, the four creams were found to be very representative of their market positioning, and corresponded to the advertisement analysis for each relevant quadrant. As seen in Fig. 45.8, Driver A had a very complex profile. The “natural” criteria are associated with no shine, a water-like appearance, slipperiness, ease of spreading, wetness, and a cooling effect. The fact that there is no film can be considered natural as well. The Sense – Texture criteria are associated with transparency, lightness, and flat peaking on pickup.

Figure 45.8 Sensory profile of drivers.

For Driver B, the profile is simple. The appearance is linked to transparency and lightness, and advertisements related to this driver correspond to Sense – Texture. The non-stickiness and non-greasiness criteria require sophistication in the formulation to create a product that is perceived as a moisturizing cream. For Driver C, the profile is also simple. Stiff peak and slipperiness are very important because they express the richness and creaminess of the products texture. The cream tends to have a heavy, nourishing texture with a slippery feel. The slippery characteristic is positively combined with the other sensory criteria to support a sense of sophistication. Driver D is the second example of a complex profile. Heaviness, creaminess, firmness, thickness, and low absorbency show complete advertisement correlation with the Sense + Texture feature. In this case, the natural side is not really present in the profile but is present in the advertisement. The work reported above demonstrates that we succeeded in showing that communication advertisements and sensory profiles are correlated:

DELVAUX: GRAPHISENSES • The sensory profile is the logical consequence of the formulation. • Communication and product positioning are the logical consequences of sensory profiles.

45.5 Formulations These GraphiSenses sensory profiles (Fig. 45.8) can be useful by considering them indicators of the work needed to develop and design products that answer identified consumer trends in the cosmetic market. New formulations that specifically reflect these trends and respond to customer expectations from each of the GraphiSenses quadrants were developed and are described in Sec 45.5.2, “Formulation Details.” The approach used detailed documentation and enabled the substantiation of claimed benefits of active strategic raw materials, specific silicones, and adapted fragrances.

45.5.1 Formulation Philosophy The formulation philosophy for development of new products which addressed market trends were based on three main features: • Trendy actives in the cosmetic industry were chosen to support the positioning of products in a certain segment of the GraphiSenses visualization approach. • Specialty silicones from Dow Corning offering unique consumer-perceivable benefits. These were chosen to be in line with market positioning and deliver claimed and expected benefits. • Specific fragrances to seduce the senses, but also employed to complement the product positioning. This approach was done in consultation with Mane, one of the world’s leading independent fragrance creators (V. Mane Fils s.a., http://www.vmf-mane.com/).

941 45.5.2

Formulation Details

Cream A (called “Fresh Wave”). For cream A referring to Natural and Sense – Texture, we chose to make a cream gel (see Formulation 1). It conveys a sense of water, freshness and lightness, and airy and transparent texture. The ingredients are as follows: 1. Silicones, with their demonstrated functionalities and specific benefits: • Dow Corning 246 ® Fluid gives a light, nongreasy feel. • Dow Corning 1501® Fluid provides emolliency and enhances spreading of the cream. • Dow Corning 2501® Cosmetic Wax provides a smooth and silky feel as well as the perception of moisturization. 2. Active ingredients: • Carbopol EDT 2020, a gelling agent. • Glycerin, a humectant. • Jojoba oil, a vegetable oil, to enhance spreading and moisturization. • Ormagel SHE, an algae extract from red and brown seaweeds, which moisturizes and immunostimulates. • Citrus Medica Limonium Fruit Water and Citrus Grandis Fruit Water that replace water in the formulation. The product is extracted from fruits and composed of volatile ingredients, oligo-elements and mineral salts. • Alcohol; to give a cooling effect. • Blue colorant to convey the perception of water. 3. Perfume: • Specially designed fragrances to create an olfactive universe enhancing each formulation and product profile have been created by Mane. Cream A employed Fresh Wave Perfume. • Fresh Wave perfume evokes a fresh and natural sensation. This perfume has strong accents of green citrus elements stimulated by a watery and marine nuance. It has floral, musky, fruity, woody, green, and marine dimensions.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 45.1: Cream A – Fresh Wave

Oil-in-Water Skin Cream: Improved Spreading, Light Feel Skin Moisturizers: Formulation 00016 Attributes: Emolliency, reduced greasiness, silky feel, improved spreading, light feel.

Ingredient

Weight %

Trade Name and Supplier

Phase A 1. Cyclopentasiloxane (and) Dimethiconol

10.0

Dow Corning® 1501 Fluid

2. Cyclomethicone

10.0

Dow Corning® 246 Fluid

3. Acrylate, C 10-30 Alkyl Acrylate Crosspolymer

0.6

CarbopolÆ ETD 2020, BF Goodrich Chemical S.A.

4. Simmondsia Chinensis (Jojoba) Seed Oil

2.0

Jojoba Oil, Alban Muller International

5. BHT

0.1

BHT, Merck KGaA

6. Dimethicone Copolyol

3.0

Dow Corning® 2501 Cosmetic Wax

7. Glycerin

2.0

8. Citrus Medica Limonum (Lemon) Fruit Water

10.0

Lemon Fruit Water, Gattefosse S.A.

9. Citrus Grandis (Grapefruit) Fruit Water

10.0

Grapefruit Fruit Water, Gattefosse S.A.

10. Water (and) Propylene Glycol (and) Hypnea Musciformis Extract (and) Gellidiela Acerosa Extract (and) Sargassum Filipendula Extract

1.0

Ormagel SHE, Assessa - Industria

11. Blue 1

0.1

FD and C Blue No. 1 W 092, LCW Les colorants, Wackherr S.A.

12. Alcohol Denatured

5.0

Ethyl Alcohol Absolute, No Supplier Specified

13. Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and) Propylparaben (and) Butylparaben

0.5

SepicideÆ HB, Seppic S.A.

14. Distilled Water

16.3

15. Fragrance

0.3

16. Sodium Hydroxide

q.s.

Phase B

Fresh Wave Fragrance, V. Mane Fils S.A.

Phase C 17. Distilled Water

29.4 (Cont’d.)

DELVAUX: GRAPHISENSES

943

Formulation 1: (Cont’d.) Cream A – Fresh Wave

Procedure 1. Prepare a 0.1% solution of Ingredient 11 in distilled water. 2. Mix Ingredients 1, 2, 4, and 5 3. Disperse Ingredient 3 in Phase C. Add to the previous mix. 4. Mix Ingredients 6, 7, 8, 9, 10, and 14 at 45°C. Cool to 25°C. 5. Add 0.125% of Blue 1 solution. 6. Add Ingredient 13 solubilized in ingredient 12. 7. Add Fragrance. 8. Add slowly Phase B to Phase A with moderate stirring. 9. Adjust viscosity and pH with a solution of Ingredient 16. Variations Alternative Dow Corning® Products have not been tested as of this printing. Stability Stable for 6 months at room temperature and 3 months at 40°C. External Reference Material GraphiSenses presentation given at In Cosmetics Dusseldorf 2001. Samples available at the booth. Dow Corning hopes that this suggested formulation will be of interest to you, but you should be cautioned that this is only a representative formulation and is not a commercialized product. Dow Corning believes that the information and data on which this formulation is based are reliable, but it has not been subjected to extensive testing for performance, efficacy or safety. In addition, Dow Corning has not undertaken a comprehensive patent search on the formulation. BEFORE COMMERCIALIZATION, YOU SHOULD THOROUGHLY TEST THE FORMULATION OR ANY VARIATION OF IT TO DETERMINE ITS PERFORMANCE, EFFICACY AND SAFETY. IT IS YOUR RESPONSIBILITY TO OBTAIN ANY NECESSARY GOVERNMENT CLEARANCE, LICENSE OR REGISTRATION. Suggestions of uses should not be taken as inducements to infringe any particular patent. SAFE HANDLING INFORMATION: PRODUCT SAFETY INFORMATION REQUIRED FOR SAFE USE IS NOT INCLUDED. BEFORE HANDLING, READ PRODUCT AND MATERIAL SAFETY DATA SHEETS AND CONTAINER LABELS FOR SAFE USE, PHYSICAL AND HEALTH HAZARD INFORMATION.

Cream B (called “Tender Delight”). The ingredients in Formulation 2 are as follows:

• Jojoba oil, a vegetal oil, to enhance spreading and moisturization.

1. Silicones, with their known functionalities and specific benefits:

• Vitamin E acetate; an antioxidant agent.

•

Dow Corning® 246 Fluid provides a light, non greasy feel.

• Dow Corning® 9040 Silicone Elastomer Blend gives a unique silky and smooth touch. 2. Active ingredients: • Emilium Delta, an emulsifier that gives a smooth feel at the beginning of rubbing. • Keltrol, a viscosity builder. • Myritol 312, a vehicle emollient. • Glycerin, a humectant.

• Calcium D pantothenate (vitamin B5), bringing emolliency and softness. • Hydrasens® (chitosan derivative); a highly moisturizing active. 3. Perfume: • The perfume of Tender Delight evokes playful and lively sensations. • It is a brilliant floral harmony bouquet with a touch of fruity accent having additional watery and musky dimensions.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 45.2: Cream B – Tender Delight

Oil-in-Water Skin Cream: Light Feel, Silky Feel, Smooth Feel Skin Moisturizers: Formulation 00018 Attributes: Light feel, silky feel, smooth feel

Ingredient

Weight %

Trade Name and Supplier

Phase A 1. Cyclomethicone

15.0

Dow Corning® 246 Fluid

2. Cyclomethicone (and) Dimethicone Crosspolymer

10.0

Dow Corning® 9040 Silicone Elastomer Blend

3. Simmondsia Chinensis (Jojoba) Seed Oil

2.0

Jojoba Oil, Alban Muller International

4. Caprilic/Capric Triglyceride

2.0

Myritol® 312, Cognis Corporation

5. Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and) Propylparaben (and) Butylparaben

0.5

Sepicide® HB, Seppic S.A.

6. Cetyl Alcohol (and) Glyceryl stearate (and) PEG-75 Stearate (and) Ceteth-20 (and) Steareth-20

4.0

Emulium® Delta, Gattefosse S.A.

7. Glycerin

2.0

8. Xanthan Gum

0.2

9. Distilled Water

up to 100

Phase B

Keltrol®, Kelco Biopolymers

Phase C 10. Tocopheryl Acetate

1.0

Vitamin E Acetate, Roche Vitamins

11. Calcium Pantothenate

0.5

Calcium D Pantothenate, Roche Vitamins

12. Chitosan Succinamide

1.0

Hydrasens®, Laboratoire Bomann

13. Red 40

0.1

FD and C Red No. 40 W 093, LCW Les colorants Wackherr S.A.

14. Yellow 5

0.1

FD and C Yellow No. 5 W 081, LCW Les colorants Wackherr S.A.

15. Fragrance

0.3

Tender Delight Fragrance, V. Mane Fils S.A.

Phase D

(Cont’d.)

DELVAUX: GRAPHISENSES

945

Formulation 2: (Cont’d.) Cream B – Tender Delight

Procedure 1. Prepare a 0.1% solution of Ingredient 13 in distilled water. 2. Prepare a 0.1% solution of Ingredient 14 in distilled water. 3. Heat Phase A ingredients to 60°C while gently mixing. 4. Add Ingredient 6. 5. Disperse Ingredient 8 in the Phase B at 60°C with moderate stirring. 6. Add Phase B to Phase A with gentle mixing. 7. Cool to 35°C. 8. Add Phase C ingredients. 9. Add 0.14% of Red 40 solution. 10. Add 0.055% of Yellow 5 solution. 11. Add fragrance. 12. Mix until uniform. Variations Alternative Dow Corning® Products have not been tested as of this printing. Stability Stable for 6 months at room temperature and 3 months at 40°C. Dow Corning hopes that this suggested formulation will be of interest to you, but you should be cautioned that this is only a representative formulation and is not a commercialized product. Dow Corning believes that the information and data on which this formulation is based are reliable, but it has not been subjected to extensive testing for performance, efficacy or safety. In addition, Dow Corning has not undertaken a comprehensive patent search on the formulation. BEFORE COMMERCIALIZATION, YOU SHOULD THOROUGHLY TEST THE FORMULATION OR ANY VARIATION OF IT TO DETERMINE ITS PERFORMANCE, EFFICACY AND SAFETY. IT IS YOUR RESPONSIBILITY TO OBTAIN ANY NECESSARY GOVERNMENT CLEARANCE, LICENSE OR REGISTRATION. Suggestions of uses should not be taken as inducements to infringe any particular patent. SAFE HANDLING INFORMATION: PRODUCT SAFETY INFORMATION REQUIRED FOR SAFE USE IS NOT INCLUDED. BEFORE HANDLING, READ PRODUCT AND MATERIAL SAFETY DATA SHEETS AND CONTAINER LABELS FOR SAFE USE, PHYSICAL AND HEALTH HAZARD INFORMATION.

Cream C (called “Tender Radiant Beauty”). The ingredients are as follows (see Formulation 3): 1. Silicones: with their known functionalities and specific benefits: •

Dow Corning® 245 Fluid; to reduce tackiness

• Dow Corning® 9040 Silicone Elastomer Blend; providing a silky and smooth touch Corning ®

2503 Cosmetic Wax; for • Dow moisturization, perception of nourishment and its specific ability to act as an SPF enhancer. 2. Active ingredients: • Sepigel 305, an emulsifier that provides good emulsion stability.

• Glycerin, a humectant • Jojoba oil, a vegetal oil, to enhance spreading and moisturization • Parsol MCX and Parsol 1789, sunscreens, giving protection toward sun (UVA and UVB) • Hyaluronic Acid, an active moisturizer 3. Perfume: • The perfume of Radiant Beauty conveys comforting and warm sensations with the contrast between the vigorous tones of black currant and the radiant presence of ylang-ylang and rose.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 45.3: Cream C – Radiant Beauty

Water-in-Oil Skin Cream: High Consistency, Perception of Nourishment Skin Moisturizers: Formulation 00020 Attributes: Rheology modifier, high consistency, perception of nourishment

Ingredient

Weight %

Trade Name and Supplier

Phase A 1. Ethylhexyl Methoxycinnamate

3.0

Parsol® MCX, Roche

2. Butyl Methoxydibenzoylmethane

1.5

Parsol® 1789, Roche

3. Glyceryl Stearate (and) PEG 100 Stearate

4.0

Arlacel® 165, ICI

4. Butyrospermum Parkii (Shea butter)

1.0

Cetiol® SB 45, Cognis Corporation

5. Stearyl Dimethicone

3.0

Dow Corning® 2503 Cosmetic Wax

6. Cetyl Alcohol

1.0

7. Simmondsia Chinensis (Jojoba) Seed Oil

4.0

Jojoba Oil, Alban Muller International

8. Isononyl isononanoate

3.0

Isononyl Isononanoate, Stearinerie Dubois Fils

9. Cyclomethicone

8.0

Dow Corning® 245 Fluid

10. Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and) Propylparaben (and) Butylparaben

0.5

Sepicide® HB, Seppic S.A.

11. Cyclomethicone (and) Dimethicone Crosspolymer

5.0

Dow Corning® 9040 Silicone Elastomer Blend

Phase B 12. Glycerin

2.0

13. Distilled Water

59.0

14. Hyaluronic Acid

1.0

Hyaluronic Acid, Seporga

0.5

Radiant Beauty Fragrance, V. Mane Fils S.A.

4.0

Sepigel® 305, Seppic S.A.

Phase C 15. Fragrance Phase D 16. Polyacrylamide (and) C13-14 Isoparaffin (and) Laureth-7

(Cont’d.)

DELVAUX: GRAPHISENSES

947

Formulation 3: (Cont’d.) Cream C – Radiant Beauty

Procedure 1. Melt Ingredients 1 and 2 at 60°C. 2. Add Ingredients 3, 4, 5, and 6 in order at 60°C, ensuring that each ingredient is melted before incorporating the next. 3. Add Ingredients 7, 8, 9, and 10. 4. Add Ingredient 11 to form phase A. 5. Mix Phase B ingredients together. 6. Add Phase B to phase A at 1500 RPM. 7. Cool to room temperature. 8. Add Phase C with mixing. 9. Add Phase D quickly (one shot) while stirring at maximum speed. 10. Cease agitation immediately once viscosity increases. Variations Alternative Dow Corning® Products have not been tested as of this printing. Stability Stable for 3 months at room temperature and for 1 month at 40°C. External Reference Material Graphisenses presentation given at In Cosmetics Dusseldorf 2001. Samples available at the booth. Dow Corning hopes that this suggested formulation will be of interest to you, but you should be cautioned that this is only a representative formulation and is not a commercialized product. Dow Corning believes that the information and data on which this formulation is based are reliable, but it has not been subjected to extensive testing for performance, efficacy or safety. In addition, Dow Corning has not undertaken a comprehensive patent search on the formulation. BEFORE COMMERCIALIZATION, YOU SHOULD THOROUGHLY TEST THE FORMULATION OR ANY VARIATION OF IT TO DETERMINE ITS PERFORMANCE, EFFICACY AND SAFETY. IT IS YOUR RESPONSIBILITY TO OBTAIN ANY NECESSARY GOVERNMENT CLEARANCE, LICENSE OR REGISTRATION. Suggestions of uses should not be taken as inducements to infringe any particular patent. SAFE HANDLING INFORMATION: PRODUCT SAFETY INFORMATION REQUIRED FOR SAFE USE IS NOT INCLUDED. BEFORE HANDLING, READ PRODUCT AND MATERIAL SAFETY DATA SHEETS AND CONTAINER LABELS FOR SAFE USE, PHYSICAL AND HEALTH HAZARD INFORMATION.

Cream D (called “Velvet Peace”). The ingredients (see Formulation 4) are as follows: 1. Silicones: with their known functionalities and specific benefits: • Dow Corning® 5200 Formulation Aid, for its unique water-in-oil emulsification properties combined with a pleasant feel. • Dow Corning® AMS C30 Wax, to provide body and consistency to the cream without the drag of organic waxes. • Dow Corning® 200 fluid 350 cst, to enhance spreading properties.

2. Active ingredients: • Sodium chloride, to aid the cream stability. • Glycerin, a humectant. • Huile de Bourrache, an oil composed of linoleic acid, which brings moisturization and nourishment. • Glutange, wheat protein that increases the moisture content of the skin. 3. Perfume: • The Velvet Peace perfume provides opulence and sensuality based on a floral bouquet complemented by fresh top notes of peach and violet leaves.

948

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Formulation 45.4: Cream D – Velvet Peace

Water-in-Oil Skin Cream: High Consistency, Rich Feel Skin Moisturizers: Formulation 00021 Attributes: High consistency, rich feel

Ingredient

Weight %

Trade Name, Supplier

1. Laurylmethicone Copolyol

2.0

Dow Corning® 5200 Formulation Aid

2. C30-45 Alkyl Methicone

2.0

Dow Corning® AMS-C30 Wax

3. Dimethicone

1.0

Dow Corning® 200, Fluid 350 CS

4. Cyclomethicone

4.0

Dow Corning® 245 Fluid

5. Prunus Armeniaca (Apricot) Kernel Oil

4.0

Prunus Armeniaca, Alban Muller International

6. C12-15 Alkyl Benzoate

6.0

Crodamol® AB, Croda, Inc.

7. Borago Officinalis Seed Oil

2.0

Borage Seed Oil, Alban Muller International

8. BHT

0.1

BHT, Merck KGaA

9. Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and) Propylparaben (and) Butylparaben

0.5

Sepicide® HB, Seppic S.A.

10. Triticum Vulgare

1.0

Glutange, L'Angelica

11. Glycerin

2.0

12. Sodium Chloride

1.0

Phase A

Phase B

13. Distilled Water

to 100

Phase C 14. Fragrance

0.5

Velvet Peace Fragrance, V. Mane Fils S.A.

Procedure 1. Mix Phase A ingredients at 80°C at 1000 t/min. 2. Dissolve Ingredients 10, 11, and 12 in distilled water at 80°C. 3. Add slowly Phase B to Phase A at 1000 t/min. 4. Mix until cool. 5. Add fragrance. Variations Alternative Dow Corning® Products have not been tested as of this printing.

(Cont’d.)

DELVAUX: GRAPHISENSES

949

Formulation 4: (Cont’d.)

Stability Stable for 3 months at room temperature and for 1 month at 40°C. Dow Corning hopes that this suggested formulation will be of interest to you, but you should be cautioned that this is only a representative formulation and is not a commercialized product. Dow Corning believes that the information and data on which this formulation is based are reliable, but it has not been subjected to extensive testing for performance, efficacy or safety. In addition, Dow Corning has not undertaken a comprehensive patent search on the formulation. BEFORE COMMERCIALIZATION, YOU SHOULD THOROUGHLY TEST THE FORMULATION OR ANY VARIATION OF IT TO DETERMINE ITS PERFORMANCE, EFFICACY AND SAFETY. IT IS YOUR RESPONSIBILITY TO OBTAIN ANY NECESSARY GOVERNMENT CLEARANCE, LICENSE OR REGISTRATION. Suggestions of uses should not be taken as inducements to infringe any particular patent. SAFE HANDLING INFORMATION: PRODUCT SAFETY INFORMATION REQUIRED FOR SAFE USE IS NOT INCLUDED. BEFORE HANDLING, READ PRODUCT AND MATERIAL SAFETY DATA SHEETS AND CONTAINER LABELS FOR SAFE USE, PHYSICAL AND HEALTH HAZARD INFORMATION.

45.6 Validation 45.6.1

Validation by Sensory Evaluation

Creams A, B, C, and D are new formulations developed by Dow Corning’s experts. These were validated via the GraphiSenses sensory profile methodology in a manner similar to that described in Sec. 45.4.1 (visual appearance in the jar, the feel at pickup in the jar; skin feel perception during cream absorption, and skin feel perceptions after absorption of the cream). Validation via sensory profile analysis confirmed a performance profile that fit with the positioning of each cream in its chosen, respective quadrant. For example, regarding visual appearance in the jar (see Fig. 45.9), the Fresh Wave formulation showed high transparency and a water-like perception, while the Velvet Peace formulation was visually perceived as nonlight (i.e., rich) and nontransparent (i.e., opaque). The feel at pickup (see Fig. 45.10) in the jar showed low stickiness for both Fresh Wave and Tender Delight, but a strong dimension of firmness and peaking for Radiant Beauty. The skin feel during application of Fresh Wave (see Fig. 45.11) showed a strong perception of wetness and cooling. By contrast, the Velvet Peace cream had the strongest connotation of thickness and rich feel.

These comparisons confirmed step-by-step that each cream has a performance profile in sensory evaluation that is in perfect conjunction with its market positioning. Skin feel, after cream absorption (see Fig. 45.12), showed a strong silkiness feature: • Tender Delight; provided by the presence of Dow Corning® 9040 Silicone Elastomer Blend. • Fresh Wave; provided by the effect of Dow Corning® 2501 Cosmetic Wax. The gloss feature was also very segmenting: • A high gloss for Fresh Wave (which supports the wetness dimension). • A low gloss for Tender Delight. An overview of the significant characteristics that make each cream different from the others is presented and summarized in Fig. 45.13. The GraphiSenses approach allows formulators to introduce the concept of an identity card for each formulation. Fresh Wave, the cooling and silky-feeling hydrogel, has a strong transparent appearance, a perceived cooling effect, and provides a shiny and radiant appearance to skin after absorption. In addition, Fresh Wave cream: • has a shiny and water-like appearance in the jar, • has a soft and nonsticky texture in pickup, • is easy and light in spreading, • provides a silky feel after absorption.

950

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Figure 45.9 Sensory validation. Visual appearance in the jar.

Figure 45.10 Sensory validation. Feel in the jar.

Figure 45.11 Sensory validation. Skin feel during absorption.

DELVAUX: GRAPHISENSES

Figure 45.12 Sensory validation. Skin feel after absorption.

Figure 45.13 Sensory profile of leading candidates.

951

952

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Tender Delight cream, the light, silky, and vitamin-enriched cream, performs the best of the four in having a slippery texture in pickup as well as a nonshiny, nontacky, and silky feel after absorption. To a lesser extent, Tender Delight cream has a nonsticky and tender texture and is light and easy to spread. Radiant Beauty cream, the firm, nourishing, and protective cream offers a firm and opaque texture and a rich appearance, while providing a non-aqueous and rich feel. Velvet Peace cream, the ultra rich cream with natural ingredients, has a shiny, rich, and opaque appearance in the jar. During and after absorption, it provides a unique rich feel with a rich texture and a nonslippery characteristic.

· In Fig. 45.14c, 80% of the panelists perceived the cream as “neutral to very light.” · In Fig. 45.14h, 95% of panelists perceived the product as “easy and very easy to spread.” Besides the match between cream A and the driver A profile, 75% of the consumer panelists described their skin as being silky or very silky after absorption. These results demonstrate the creams addressed the predefined market needs and showed that the selected silicones, with their known functionalities and specific benefits, produced creams with the desired dimensions. The analysis also uncovered a new parameter which indicated that the silkiness of the cream was enhanced by the use of silicones. The consumer validation fully supported the credibility of this survey and the effectiveness of the GraphiSenses approach.

45.6.2 Validation by Consumer Testing An in-house consumer test was conducted at Dow Corning Corp. with the formulated Cream A as described in Sec. 45.5.2. A questionnaire was provided to panelists and collected after seven days of home use of the formulation. Panelists were asked to give their evaluation on prompted parameters and their spontaneous comments were also recorded. Procedure for cream application. Each panelist was directed to apply the cream to the face each morning or each evening. The test was conducted for seven days without interruption (except if the panelist developed an allergy to the product). Good Laboratory Practices (GLPs) were observed during manufacture of the 20 samples. Results and interpretations. As observed in the pie diagram representations of their perceptions (Figs. 45.14, a through k), the consumers’ answers confirmed the expected profile of cream A: · In Fig. 45.14b for example, 80% of the consumer panelists perceived cream A as gel-like and 20% as a cream “full of water.” This result is completely in accordance with the results of the sensory test regarding waterlike perception.

45.7 Conclusions The GraphiSenses technique is a new method for developing products (in this case, for skin care) that reflect the latest consumer trends. However, because new product development briefs typically use subjective and emotional terms, GraphiSenses can also be used to generate other aspects of a new product introduction such as product name, fragrance creation, the packaging brief, and advertising strategy. With GraphiSenses, Dow Corning provides a different perspective and approach for assisting formulators in the product development process. Indepth sensory evaluation demonstrated a clear match between sensory performance and product positioning, thereby substantiating the authenticity of the GraphiSenses methodology. This new methodology can be applied to study the effects of any active raw material. It specifically allows for differentiation in a system in which actives are placed into a delivery system and there is a choice of delivery system to be used. The approach offers a powerful way to assess the effect of various delivery systems on final formulation properties and dimensions.

DELVAUX: GRAPHISENSES

953

When you look at the product in the jar, do you think the product is:

When you look at the cream in the jar, the product is:

very shiny 20%

very opaque 10% very transparent 5%

opaque 50%

shiny 75%

transparent 15%

neutral 5%

neutral 20%

(a)

(d)

When you put the cream on your face, is the texture ...

When you look at the cream in the jar, the cream evocates for you:

easy to apply 45%

a cream full of water 20%

a gel cream 80%

normally 15%

(b)

Other 85%

(e)

When you put the cream on your face, is the texture ...

When you look at the cream in the jar, the texture is:

slippery 30%

neutral 25% heavy 20%

Other 80%

very heavy 0%

very easy to apply 40%

light 35%

neutral 25%

Other 75%

very light 20%

(c) Figure 45.14 (a)–(k) Consumer test results.

(f)

very slippery 45%

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

When you rub the cream on your face, does the cream give wetness?

After absorption of the cream, do you feel a film on your face?

no film is felt 20%

normally 25% a little 25%

Other 75%

a lot 15% well 35%

no film at all 5%

Other 90%

thicker film 5%

(g)

easily 45% Other 95% very easily 50%

badly 5%

thinner film 45%

(j)

When you rub the cream on your face, how does the cream spread?

neutral 0%

neutral 25%

After absorption of the cream, does your face feel silky?

neutral 20%

Other 75%

very silky 30%

rough 5%

(h)

silky 45%

(k) Figure 45.14 (Cont,d.)

Is the cream perceived as cool or give the impression of freshness when applied on your face?

neutral 15%

Other 80%

not cool 5%

Details on Sensory Analysis and Definitions Appearance in the jar.

very cool 15%

(i)

Figure 45.14 (Cont,d.)

cool 65%

Definitions and Methodology

• Gloss: the degree of light reflected by the product (in the jar); 1 is attributed for a nonshiny product and 10 for a shiny product. • Water-like perception: the perception of high moisture, water content; 1 is attributed for a greasy perception and 10 for a watery perception.

DELVAUX: GRAPHISENSES • Transparency: the relative ease with which light passes through the cream; 1 is attributed for opaque and 10 for clear, transparent. • Appearance: the visible characteristic of the cream: lightness; 1 is attributed to heavy and 10 to light. Pickup. • Firmness: the force required to fully compress the product slowly between index finger and thumb (one time); 1 is attributed for no force and 10 for a high force. • Stickiness: the force required to separate the fingertips slowly between index finger and thumb; 1 is attributed to not sticky and 10 to sticky. • Peaking: the degree to which the product makes stiff peaks on the fingertips. The panelist compresses the product slowly between the index finger and thumb, then separates the fingers; 1 is attributed for a flat peak and 10 is attributed for a stiff peak. • Slipperiness: the easiness with which the index finger and thumb move against each other when the product is applied between them; 1 is attributed to a non-slippery product and 10 to a slippery product. Before absorption. • Spreadability: the ease with which the product is spread over the skin. The panelist makes three rotations to evaluate spreadability; 1 is attributed for difficult spreadability and 10 for easy spreadability. • Wetness: the amount of wetness perceived during three rotations with the respective fingers on each site; 1 is attributed for a product giving low wetness and 10 for one showing high wetness. • Greasiness: the feel of greasiness while making three rotations with the respective fingers on each site; 1 is attributed for a non-greasy feel and 10 for a greasy feel. • Thickness: the amount of product felt between the fingertip and skin while making three rotations with the respective finger on each site; 1 is attributed for a thin film of product and 10 for a thick film.

955 • Absorbency: an evaluation of the speed of absorbency; determined by rubbing the product on the skin until total penetration is achieved; 1 is attributed to slow and 10 to quick absorption. • Powdery: an evaluattion of the powdery feel of the product on the skin; 1 is attributed for a non-powdery feel and 10 for a powdery feel. • Type of sensation: the perception of coolness of the product when the panelist applies it to the skin; 1 is attributed for a non-cool feel and 10 for a perception of coolness. After absorption. • Gloss: the degree of light reflected off the skin; 1 is attributed for non-shiny skin and 10 for shiny skin. • Stickiness: adherence of the skin when the panelist presses on a particular area; 1 is attributed if the fingers do not adhere and 10 if the fingers adhere. • Greasiness: the feel of greasiness by making three rotations with the respective finger on each site; 1 is attributed for a non-greasy feel and 10 for a greasy feel. • Film residue: an evaluation of the quantity of product coating the skin; 1 is attributed for no film and 10 for a significant film. • Slipperiness: the ease of moving the fingers on the skin; 1 is attributed for a sensation of drag and 10 for a slippery feel. • Silkiness: the evaluation of a silk-like perception on the skin; 1 is attributed to a silky feel (i.e., velvety) and 10 to a rough feel.

Methodology of Evaluation Appearance in the jar. • Sample jars are placed approximately 50 cm from the face of each panelist. • The panelist evaluates the following parameters for three jars concurrently. Pickup. • Using a spatula, 0.1 g of the sample is deposited on the thumb. For each parameter, the panelist tests each sample separately. For

956

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

example, for firmness, 0.1 g of the first sample was put on the thumb, the panelist executes the procedure and removes the cream. The second sample is put on the same thumb, the panelist executes the procedure and removes the sample. The panelist tests the third cream in the same manner. Before absorption.

the parameters described above in the “before absorption” section. After absorption. • By observing the three areas or by touching them with the same finger, the panelist evaluates the parameters listed above for this portion of the test.

• Using a spatula, 0.04 g of each sample is deposited on each site. The panelist evaluates

References

· Vogue (Feb. 2000) · Vogue España (Feb. 2000)

1. Articles · Dow Corning Corporation Profile, Dow Corning Corporation (2000) · Wortel, V. A. L. and Wiechers, J. W., Skin Sensory Performance of Individual Personal Care Ingredients and Marketed Personal Care Products, Food Quality and Preference, 11:(1-2)121-127 (Jan. 2000) · Mapsy™, Women, Firmenich (1996) · Mapsy™, Men, Firmenich (1996) · Norme Française, NF ISO 5492, (Mai 1992) 2. Advertisement extracts from following feminine and beauty magazines · Advantages (Feb. 2000) · Allure (Jan. 2000) · Brigitte (2/2000) · Cosmetique Magazine (Feb. to Jun. 2000) · Cosmopolitan (Feb. 2000) · Cosmopolitan (April 27/May 1, 2000) · Elle (Feb. 2000) · Elle, French Ed., (Feb. 7, 2000) · Elle, Spanish Ed., (Feb. 2000) · Femme (Feb. 2000) · Fireundin (4/2000) · Harpers and Queen, British Ed. (Feb. 2000) · Marie Claire (Feb. 2000) · Petra (Feb. 2000)

· Votre Beauté (Feb. to Jun. 2000) 3. List of interesting web sites for study · http://www.avon.com · http://www.beiersdorf.com · http://www.ccb.com · http://www.chanel.fr · http://www.clarins.com · http://www.clinique.com · http://www.covergirl.com · http://www.ctfa.org · http://www.decleor.com · http://www.dior.com · http://www.djouvance.com/fr · http://www.dricaud.com · http://www.drugstore.com · http://www.elizabetharden.com · http://www.esteelauder.com · http://www.guerlain.com · http://www.loreal.com · http://www.pg.com · http://www.pondsinstitute-india.com · http://www.revlon.com · http://www.roc.com · http://www.shiseido.co.jp/e/index.htm · http://www.yves-rocher.fr

Glossary

A Accelerant: Alternative name for chemical enhancer. Acrids: Pungent, bitter tasting substances. Active: An ingredient in a formula which is sought for its special but non-medicinal performance. Any ingredient upon which the marketing claims for a specific performance benefit for a consumer product is either made or implied. Active Cosmetics: Skin care products designed to have an effect on health as well as appearance. Acylceramide: An unusual linoleate-containing ceramide found in the stratum corneum. Acylceramide is important for the organization of lipids in the intercellular spaces of the stratum corneum and for permeability barrier function. Acylglucosylceramide: An unusual linoleate-containing glycosphingolipid found in the noncornified layers of keratinizing epithelia. It is thought to be involved in the formation of lamellar granules and is the precursor of the acylceramide. Alkoxy Silane: Compound containing an Si-O-C group. Alkyl Methyl Siloxane: Silicone copolymer, where some of the methyl groups are substituted by hydrocarbon chains of variable alkyl chain length.

Allergic Contact Dermatitis: A delayed type IV allergic reaction of the skin with presentation of erythema, edema and itching. Alpha-hydroxyacid (AHA): An ingredient used in cosmetic and therapeutic skin care. Alveolar: The best example of alveolar structure offered by mother nature is the human lung, the lung and its alveolus having been described by Professor Mandelbrot as a fractal structure. Amphipathic: Constructed of both hydrophilic and hydrophobic moieties. A molecule that contains discrete polar and nonpolar regions that favor self-association into micelles and condensed phases depending on concentration and conformation. Amphiphile: A molecule with a polar head group and a nonpolar chain. Such molecules spontaneously self-assemble in polar solvents such as water. Amphoteric: A substance that is capable of reacting chemically as either an acid or a base. Amylopectin: The branched glucose polymer with a higher molecular weight found within the starch granule. Approximately 97% of the glucose linkages in amylopectin are a-D-(1 → 4) linkages, and the remaining linkages are a-D-(1 → 6) glucopyranosyl linkages. Amylose: The lower molecular weight, linear polymer containing a-D-(1 → 4) glucopyranosyl linkages found within the starch granule.

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Anhydrous: Without water; formulations made with ingredients that do not contain water.

B

Anionic Surfactant: A negatively charged surfaceactive molecule.

Bilayer: A configuration of molecules with a repeat unit of two; for amphiphatic molecules the repeat unit can be thought of as matching polar groups, or non-polar groups in a z-axis orientation.

Anisotropic: Having properties, which vary depending on the direction of measurement, in liquid crystals, this is due to the alignment and the shape of the molecules. Anther: The pollen-bearing male organ of a flower. Anti-irritant: An agent that prevents skin irritation. Anti-microbial: A chemical agent that prevents the growth of microorganisms. Anti-mycotic: An agent that prevents the growth of fungal organisms. Antioxidant: Substances added to products to inhibit reactions promoted by oxygen, thus functionally avoiding the onset and progression of oxidation and rancidity. Similar health benefits are effected at the cellular level in the body. Chemical compound that scavenges as free radicals which attack at bioactive substances and threby provides protection against oxidation. A molecule that stabilizes the excess energy of an electron in an excited state and dissipates it as a non-damaging energy emission. A chemical compound that scavenges radical oxygen species (ROS). Aqueous Phase: Water portion of hydrophilic polyurethane formulation that can contain active ingredients and reacts with a prepolymer. Atelocollagen: A molecule of collagen that is characterized by a helicoid aspect terminated at the ends of the chains by telopeptides. Atelocollagen is a soluble collagen with the telopeptide ends removed. Atopic Dermatitis: A presentation of eczema-like symptoms due to a genetically impaired skin barrier and enhanced hypersensitivity to environmental allergens.

Bioactive: A substance that can be acted upon by a living organism or by an extract from a living organism. Bioavailability: Nutritional bioavailability encompasses availability, absorption, retention, and utilization of nutrients. Absorption in vivo is a key factor for the nutrient to have the suggested biological significance. Biodisponibility, or the availability of an active compound to be able its therapeutically effect for a longer period. Biodelivery System: A delivery system that has been designed to be sensitive and protect against a tendency for biodegradability. Bioenhancer: bioavailability.

An

agent

that

enhances

Biological Humors (Dosha): According to Ayurveda science, there are three primary life forces: Vata Pitta, and Kapha. Together, these determine the life processes of growth and decay. Biomarkers: A measurable parameter (i.e., change in enzyme level, change in blood pressure, change in heart rate, etc.) that predicts the later development of disease. Birefringent: Liquid crystals often possess optical properties that are a function of their stereochemical orientation. Birefringent materials, such as lamellar liquid crystals, generally have two different indices of refraction.

Autocrine: Production of soluble growth factors by the same cell that uses them for growth control.

Bi-univocal: Two sets of elements are said to be in bi-univocal relationship when each element of the first set can be connected to one and one only element of the second set and when at the same time each element of the second set can be connected to one and one only element of the first set.

Axilla Bacteria: Bacteria commonly found in underarm environments.

Brownian Motion: The irregular movement of extremely minute particles when suspended in a liquid.

Ayurveda: Literally means the “Science of Life” comprising a system of life-style recommendations, along with the use of specific herbs and minerals in the management of disease conditions.

Bulk Cubic Phase: Cubic liquid crystalline material in its bulk state. That is, cubic phase that has not been dispersed into cubosome particles. Bulk cubic

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phase has a gel-like appearance but is a single thermodynamic phase, unlike gels.

Chalone: A postulated peptide that regulates cell growth by acting as a feedback inhibitor of cell proliferation.

C

Chaotropic: Certain substances, usually ions (e.g., SCN-, ClO4-, guanidinium), that disrupt the structure of water and thereby promote the solubility of nonpolar substances in polar solvents (e.g., water).

CARB: California Air Resources Board. Candidiasis: Disease caused by infection with a fungi belonging to genus Candida. This occurs due to disturbed microfloral balance that occurs as a result of the use of certain drugs; can also occur during pregnancy and in disease conditions including diabetes mellitus and Cushing’s Syndrome. It may also be caused, due to, poor hygiene.

Chitins: Powdery substances that are extracted from the shells of crustaceans such as crab, shrimp and lobster. Clathrate: The trapping of molecules in cagelike holes or enclosures in a crystal or polymer matrix.

Carboxylic Acids: Organic compounds with a COOH group.

Coenzymes Q: Also called ubiquinones. They are involved in electron transport in mitochondrial membranes via the cytochrome system.

Carotenes: Orange-yellow pigments present in plants. These are antioxidants that react directly with free radicals and prevent lipid peroxidation. It has been proposed that a high intake of Beta- carotene prevents the development of cancer. A family of plant-derived molecules related to vitamin A.

Collagen and Elastin: These are protein building blocks of skin and hair that provide toughness, elasticity and softness to the skin and hair. With age, through enzymatic action, the collagen gets fragmented and the elastin is broken down leading to wrinkling of the skin.

Cast Foam: A method of producing hydrophilic polyurethane foam by allowing the outflow of a reaction mixture to be extruded on to a moving conveyor either as free rise foam, or sandwiched between two pieces of paper.

Comedone: A clogged pore. An open comedone is commonly called a blackhead; a closed comedone is commonly called a whitehead; non-comedogenic means not likely to clog pores.

Catadyn Reaction: This classical formation of silver crystals by reaction between silver nitrate and sodium chloride and subsequent reduction has been used in the Pharmacopoeia for more than a century.(17) Cationic Surfactant: A positively charged surface– active molecule. Cellulite: Fatty deposits that give the skin uneven and dimpled texture. Generally occurs in the thighs giving an “orange peel” appearance. Ceramide: A simple sphingolipid consisting of a fatty acid and long chain base connected through an amide linkage. A group of amido sphingolipids formed by linking a fatty acid to sphingosine. A major component of the stratum corneum lipids. Plays an important role in maintenance of skin barrier properties. They are natural lipids that form the part of the intercellular cement that helps to maintain the integrity of the tissue or the permeability barrier to the loss of water from the underlying epidermis.

Comedogenic: Generating comedones. Complexation: Complexation refers to the technique of making “salts” of two large molecules. For example, consider a solution containing sodium lauryl sulfate and stearyl alkonium chloride. Since both the chloride and the lauryl sulfate have a (-) charge and both stearyl alkonium and sodium ion have a (+) charge in aqueous solution, several combinations of the (-) and (+) are possible. If the energetics are such that one such combination of (+) and (-) disrupt more hydrogen bonding in water, that combination will be forced preferentially out of solution. In their pioneering work (May 1981), Lucasssen and Giles showed that “mixed” surfactant systems (i.e. anionic / cationic) often produced synergistic surface activity. The mixed system described above results in a complex of stearalkonium sulfate and a large, water-insoluble precipitate develops. This behavior produces the lowest free energy state system.

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Complex Coacervation: Technology of microencapsulation based on two polymers carrying opposite charges.

Crystalline Phase: A condensed state in which molecules are packed with highly regular configuration and conformation.

Consumer Products: Any product sold directly to consumers without regulatory approval, and/or medical supervision and approval this information includes cosmetics.

Cubosome: Dispersed particle of cubic liquid crystalline phase, usually with a particle diameter between 50 nm and 1 µm.

Controlled Delivery: Purposeful delivery of the active substance to the target cell, tissue, or organ by means of specially designed devices, (e.g., microparticles and microcapsules).

Cyclomethicone: Silicone fluid, cyclic polydimethylsiloxane polymer.

Controlled (or Time) Release System: System which delivers active ingredients at a predetermined, specific rate for a definite period of time. Cornified Envelope: A thick layer of cross-linked protein at the periphery of the cells of the stratum corneum. It confers physical and chemical resistance to the stratum corneum.

Cyclic: Cyclomethicones like D4, D5, and D6.

Cylasphere: Proprietary technology from Coletica, based on acacia and alginate gums. Cytokine: Chemical derivatives that act like messengers to promote growth and differentiation of cells and tissues.

D

Cornstarch: The carbohydrate portion of the corn kernel comprised of about 24%-30% amylose and 70%-76% amylopectin.

Dansyl Chloride Cell Turnover: A testing method in humans to evaluate epidermal cell turnover and stratum corneum exfoliation.

Cosmeceutical: A cosmeceutical is an ingredient with medicinal properties that manifests beneficial topical actions or provides protection against degenerative skin conditions. As cosmetic preparations thought to have more than cosmetic properties; cosmeceuticals are not legally identified as different from cosmetics. Cosmeceuticals are in unofficial classification of skin-treatment products using functional cosmetic ingredients. Refers to any cosmetic treatment that offers some level of therapeutic effect. Cosmeceuticals fall in the gap between cosmetics and pharmaceuticals, offering long term benefits to the hair and skin. In the U.S., those products that serve as a cosmetic and a drug must comply with over-the-counter drug regulations. Examples of “cosmetic-drugs” include sunscreens, antiperspirants, antimicrobials, acne products, anti-dandruff, hair loss and skin lightening agents. Anti-aging products that reverse the signs of aging and stimulate cellular regeneration are currently the areas of greatest growth.

D5: Decamethylcyclopentasiloxane.

Cosmetic: Topical preparation intended to improve appearance. Cosmetic, Toiletry, and Fragrance Association (CTFA) Regulations: Establishes requirements and standards for cosmetic compositions.

Decapsulation: Separation of encapsulated material from the capsule; release. Decoction: Use of boiling as a method of extraction; also, the result of such extraction. Degree of Substitution: Ratio of methyl groups that are replaced by other functional groups. Delayed Hypersensitivity: A type IV allergic response mediated by the cellular immune system involving the transport of an allergen by activated Langerhan’s cells to the local lymph nodes and activation of T-cells which then return to the site of exposure resulting in the typical signs and symptoms of a sensitization reaction. Delivery Systems: A vehicle (can be a semi-solid formulation) or a particulate system (such as a liposome or a porous particle) that carries an active ingredient, or allows its penetration across a tissue or sub-tissue, cell or cell organelles. Components operating in combination to move or change material to make it useful. A fluid or particulate envelope that surrounds or imbibes an active ingredient to control penetration and/or enhance stability. Any vehicle with the capacity to make actives available to a specific site, at a pre-selected rate of release, concentration, and timing.

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Dendrites (in the Epidermis): Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell. Desmosomes: Specialized proteinaceous junctions between adjacent cells. They serve to link the cells together.

Edema (Dermal): Swelling of the skin due to localized accumulation of extracellular fluid in the dermis resulting from a sensitization reaction, or in some instances exposure to an irritant. Edisonian: Trial and error method of experimentation comparing active ingredients.

Desquamation: The process by which cells are sloughed off at the skin surface.

Efficacy: The extent to which a given treatment or product produces beneficial results.

Detergentibility: A rating of the potency with which emulsifiers form micelles by mixing with fatty substances; high-detergentibility emulsifiers easily form micelles but have harsh effects on skin; lowdetergentibility emulsifiers do not harm skin but are not effective emulsifiers.

Emollient (Emolliency): A substance applied to the skin to plasticize or soften its texture and modify its tactile properties. An ingredient which contributes to a skin soothing and softening effect when applied on the skin.

Differentiation: The transformation of a keratinocyte and its properties as it travels upward through epidermal cell layers including the granular layer, spinous layer, and stratum corneum. Dihydrosphingosine: One of the common longchain bases found in ceramides and other sphingolipids. Chemically, it consists of an 18-carbon aliphatic chain with hydroxyl groups on carbons 1 and 3 and an amino group on carbon 2. Dimethicone: Silicone fluid, basic linear polydimethylsiloxane polymer, with variable degrees of polymerization, made of a silicon-oxygen backbone, grafted with methyl groups on the silicon atom; hydrophobic. Dispersion: The suspension of droplets of an immiscible liquid or the suspension of particulates in a continuous liquid external phase. An aqueous colloidal mixture of oil droplets (dispersed phase) in a continuous bulk water phase. Disulfide Linkages: A –S-S- linkage commonly formed between two cysteines in different positions along a protein chain or between cysteines in two different protein molecules. In stratum corneum it is one of the linkages that helps to stabilize the cornified envelopes. D6: Dodecamethylcyclohexasiloxane.

E Eczema: A generic term for an inflammatory condition of the skin that may be related to a genetic predisposition that manifests itself as dry, scaly, and red patches of skin.

Emulsifier: Amphiphilic molecule that promote emulsion stability by reducing the interfacial tension between the immiscible phases. Surface active ingredient capable of forming emulsions. A detergentlike molecule that stabilizes an oil-in-water dispersion or a water-in-oil dispersion. Emulsion: A combination of oil and water. A two phase system consisting of two immiscible liquids, one of which is dispersed as finite droplets in the other. Mixture of silicone polymer in water stabilized by surfactants. A stable suspension of two liquid, immiscible phases. The phases are present either as oil drops-in-water or water drops-in-oil. Encapsulation: Placement of material within a capsule; also, the result of such placement. Engulfing a material with a coating that can serve as a protectant and a carrier of that material. Endocytosis: Incorporation of substances into a cell by phagocytosis (the engulfing by phagocytes), or pinocytosis (the uptake of fluid by a cell by invagination and pinching off of the plasma membrane). Entrapment: The process of incorporating an ingredient into a porous polymeric matrix. Enzymatically Activated: Transformed from inactive to active due to an enzymatic activation. Enzyme: A protein that contains a catalytic site for a biochemical reaction. Epidermis: The superficial layers of the skin laying above the dermis composed of the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. This viable layer of the skin is responsible for metabolism and detoxification of a number of compounds it is the location

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of langerhan cells which are the immune systems first line of defense against foreign bodies. Epithelial cells: Cells that cover the surface of skin, mucous, and serous surfaces. Erythema: Skin redness resulting from congestion or injury of the capillaries.It is often due to inflammation caused by irritants and redness of the skin due to capillary dilation. Essential Fatty Acids (EFA): A group of polyenoic organic acids (linoleate- and linolenoate-type) that promote growth and good health of animals and human beings, but are not synthesized in their organisms. The only source of EFA for animals is nutrition. Estradiol: A natural estrogenic hormone that is a phenolic alcohol C18H24O2 secreted chiefly by the ovaries. It is the most potent of the naturally occurring estrogens, and is administered in its natural or semi-synthetic esterified form; especially to treat menopausal symptoms. Excipient: An ingredient in a formulation that does not impart a pharmaceutical activity. Exfoliation: Loss of surface cells from the stratum corneum.

Flooding Compound: Cable filler traditionally based on petrolatum or materials with similar consistency for water-blocking and adhesion functionality in telecommunication cable products. Fluorescein Isothiocyanate (FITC) Dextrans: Dextrans are hydrophilic, high molecular weight, polysaccharides. These compounds are biologically inert due to their uncommon poly-(α-D-1,6-glucose) linkages, which render them resistant to cleavage by most endogenous cellular glycosidases. Dextrans can be conjugated with a fluorescent moiety such as fluorescein isothiocyanate. The passage of such fluorescent molecules through tissues such as skin can then be tracked and monitored This monitoring offers valuable data on skin penetration routes. Foam Film Coatings: A method of coating a very thin hydrophilic polyurethane foam reaction mixture onto nonwoven, or paper substrates, using textile coating techniques. Foam Laminates: A method of producing hydrophilic polyurethane foam by causing the outflow of the reaction mixture to be extruded onto nonwoven material on a moving conveyor and allowed to rise to a given height.

F

Follicle: The tubular epithelial sheath that surrounds the lower part of the hair shaft and encloses at the bottom a vascular papilla supplying the growing basal part of the hair with nourishment. Small sac- or sheath-like anatomical formation (the hair follicle contains a hair). Hair follicle inflammation is folliculitis.

Fantesk®: A patented process of forming a stable oil-in-water emulsion by jet cooking.

Food and Drug Administration (FDA) Regulations: Provide requirements and standards for pharmaceuticals and nutraceuticals.

Exogenous: Something developing or originating externally. Explant: Portion of intact viable biological tissue.

Fibroblast: Spindle-shaped cell of conjunctive tissue, responsible for the synthesis of the fibres and basic substance of this tissue; in the dermis, the fibroblasts synthesize collagen and elastin. Immuno-cosmetics focus on regulating the skin through these immune mechanisms. Filmogenic: Able to form a film. Flavonoid: A polyphenolic compound found in food and having antioxidant properties (e.g., quercetin dihydrate).

Fourier Transform Infrared (FTIR): A method of infrared evaluation used to identify structure and identity of materials. Franz Cell: A method for measuring the skin permeation ability of an active compound to diffuse through the skin or to be stored by the skin for sustained delivery. Functionalization: The modification of a material to add a specific function. An example is the addition of ionic surfactants to a cubic phase in order to increase the affinity of the phase for charged actives.

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G Gel: A gel is a crosslinked, and thus insoluble, polymer network in which a solvent is held. Cosmetic gels contain polymers such as cellulose polymers, starch, pectin, or acrylic acid polymers (Carbomer) which hold active ingredients dispersed in alcohol or water. Gelatinization: Hydration of the starch granule initiated by heating aqueous starch granule dispersions and thus weakening the hydrogen bonds between the glucose polymers, resulting in swollen starch granules. Gel Phase: A highly ordered, nearly crystalline state of organization within a lipid bilayer. Ghosting: Residue deposited on the skin after topical application. Glass Transition Temperature (Tg): A temperature chosen to represent the temperature range over which the glass transition occurs. This is defined as a reversible change in an amorphous material, or in amorphous regions of a partially crystalline material, from a viscous or rubbery condition to a hard and relatively brittle condition. Glycosaminoglycan: A macromolecule found on the surface of eukaryotic cells which is thought to play a role in the cell’s recognition of other cells or of a substrate. Repeating units of disaccharides which contain amino functional sugars, at least one of which have a negatively charged side group such as carboxylate or sulfate. The amorphous ground substance of the dermis, as for example, hyaluronic acid. Group Opposites: This concept describes the insolubility of different classes of materials in each other. Specifically, oil and water do not mix and are therefore group opposites. Oil is referred to as a hydrophobic material (literally, it hates water), and is itself oleophilic (oil loving). Water is referred to as an oleophobic material (literally, it hates oil), and is itself hydrophilic (water loving). This concept has been extended to include silicone materials, since water, oil and silicone are three mutually insoluble materials. Silicone is referred to as both an oleophobic material (literally it hates oil) and a hydrophobic (literally, hates water). It is itself siliphilic (silicone loving). Water and oil are both siliphobic (literally, silicone hating).

Growth Factor: A substance, usually a peptide, that must be present to permit cell proliferation.

H Haemostatic Properties: Able to induce haemostasis; able to stop bleeding. Hausdorff Dimension: This is a generalization of the normal concept of dimension instinctive as far as 1, 2 or 3 dimensions are concerned, to spaces which can be at integer dimensions or decimal dimensions. HMDS: Hexamethyldisiloxane. High Performance Liquid Chromatography (HPLC): A chemical tool for quantifying and analyzing mixtures of chemical compounds. An analytical technique based on the separation of mixture constituents using chromatography in small columns under solvent pressure. 3D HLB System: The system is an expansion of the traditional HLB system developed by Griffin in the 1950s. It considers the importance of the presence of not only the weight percentage of watersoluble group, but also the type of non-water-soluble group present. Since the introduction of silicone moieties together with fatty moieties into surfactants, there is a need for a consideration of the ratio of these two mutually insoluble phases. Instead of using one value, the system, first proposed by O’Lenick in 1996, features two values. The first is for the weight percentage of water-soluble species in the molecule, while the second is for the weight percentage of silicone soluble species in the molecule. Homogeneous: Dispersed droplets in a suspension that are uniform in size and appearance. Humectant: A substance that promotes retention of moisture in the skin. A compound that improves the water-holding capacity of a moisturizing formulation. Hydrocolloid gel: A water soluble polysaccharide that forms a colloidal gel, (e.g., gelatin). Hydro-entangled: A nonwoven manufacturing method that uses jets of water to entangle fibers forming a continuous fabric substrate that does not require chemical binders to hold fibers in place.

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Hydrolysis: Reaction of water with a reactive SiX bond where X is commonly a halide or an alkoxy group. Hydrophilic: Compatible with water; dissolving in, absorbing, and mixing easily with water. Watersoluble or water-seeking materials. This term describes a molecule, or portion of a molecule in a surfactant that is literally water-loving. It is, therefore, both siliphobic (silicone-hating) and oleophobic (oilhating). Of or pertaining to molecules that are water-soluble. Hydrophilic Polyurethane: A urethane product that has an affinity for water and will readily absorb vast amounts water. Hydrophobic: Incompatible with water; not dissolving in, absorbing, or mixing easily with water. Oilsoluble or water-repelled materials. This term describes a molecule, or portion of a molecule in a surfactant that is literally water-hating. It is, therefore, either siliphilic (silicone-loving) or oleophilic (oil-loving). Of or pertaining to molecules that are insoluble in water and soluble in oil. Hydrosilylation: Reaction of an Si-H bond with an unsaturated group in the presence of a metal catalyst.

α-hydroxyacids: Organic compound with a –C(OH)-COOH group. 6-Hydroxysphingosine: One of the long-chain bases found in ceramides and other sphingolipids. Chemically it consists of an 18-carbon aliphatic chain with hydroxyl groups on carbons 1, 3, and 6, an amino group on carbon 2 and a double bond between carbons 4 and 5.

four symptoms: redness, heat, edema, and pain. A complex pathologic process that results following exposure to noxious chemicals or products. Produces tissue destruction in localized cells and manifests itself with clinical signs of redness, heat, swelling, pain, and sometimes loss or limitation of function. Some, or all of these signs may be present. In Silico: Experiments that are performed in a glass container. Intercalation: Insertion into a pre-existing structure, such as molecules into membranes. Interfacial Polymerization: Encapsulation technology based on the reaction of two reactive monomers solubilized in two different immiscible solvents, at their interface. Interfacial Tension: The imbalance of intermolecular forces that occurs at the interface between two immiscible liquids. Intradermal: Designed for movement within or between the layers of the skin. Investigational New Drug (IND): An application to the FDA requesting permission to test a new pharmaceutical or biological compound or to test an existing product for a new use in humans. This is the first official notice from an investigator or sponsor to the FDA informing the agency of the intent to test in humans. The application will contain, at a minimum, the physical characterization of the test material and dosage form, preclinical safety and efficacy data, manufacturing information, dosing form, and strength information. It also will contain a clinical plan that describes, at a minimum, the first in man clinical trial protocol.

I

In vitro: Refers to biological tests conducted outside of the body in an artificial environment typically referring to cell or tissue based models.

Ichthyosis: A class of skin disorders characterized by abnormal keratinization and excessive skin scaling.

Ion-pairing: An ionic bond between a positively charged and a negatively charged molecular species, thereby, creating a novel neutral compound.

Immediate Hypersensitivity: A type I allergic reaction mediated by IgE antibodies that produces an immediate allergic reaction in the patient following exposure to a chemical or material.

Irritation: The signs and symptoms of inflammation of the skin.

Immiscible: Un-mixable, such as oil and water. Inflammation: A set of reactions occurring at a point irritated by a pathogenic agent, and showing

Isopeptide Linkages: A kind of amide linkage that can be formed between the functional groups on the side chains of glutamine and lysine on adjacent protein molecules. In stratum corneum, it is one of the linkages that helps to stabilize the cornified enve-

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lopes. Isopeptide linkages are formed through the action of an enzyme called transglutaminase 1. Isoprenoid: Class of organic compounds made up of two or more structural units derived from isoprene.

Lamellar Liquid Crystal: A repeating sheet-like orientation of amphipathic bilayers in which the hydrocarbon chains of the amphipathic molecules are in a disordered or fluid conformation. Leaflet: Monolayer of phospholipids. Linear Polydimethylsiloxane: Dimethicones.

K

Keratinization: The epidermal process by which a living keratinocyte converts to a non-living, keratinfilled corneocyte.

Linoleate: An ester of the fatty acid, linoleic acid. Linoleic acid is derived from vegetables or vegetable oils and is required in the human diet. It is found in the acylglucosylceramide that is thought to be involved in formation of lamellar granules in the epidermis. It is also found in a related acylceramide that is thought to be required for the proper organization of lipids in the stratum corneum.

Keratinocytes: The major type of cell in the epidermis. It makes keratin proteins. An epidermal cell that produces keratin.

Lipid: An oil-soluble bio-molecule that can be extracted with organic solvents such as chloroform, acetone, and methanol.

Keratinohyalin granule: An irregularly shaped, proteinaceous inclusion that can be seen especially in the epidermal cells just below the stratum corneum.

Lipid Bilayer: Natural organization of phospholipids in two leaflets with polar head groups pointing outside.

Keratin: Fibrous protein-rich in sulfurated amino acids, a primary constituent of hair, nails, and skin.

Keratolytic: Relating to, or causing keratolysis, which is the process of breaking down, or dissolving keratin. Able to induce the keratin removal. Kraft Temperature: The temperature for a given aqueous surfactant below which the surfactant is not soluble.

L Lactic Acid Sting Test: A testing method in humans to evaluate stinging potential of test compounds in a population that is reproducibly sting-responsive to lactic acid. Lamellar: Sheet-like; infinite molecular regularity in the x-y plane. Lamellar gel: A repeating sheet-like orientation of amphipathic bilayers in which the hydrocarbon chains of the amphipathic molecules are in the fully extended, all-trans conformation. Lamellar Granule: A small organelle unique to keratinizing epithelia. It secretes lipids and enzymes into the intercellular space. This is essential for the formation of the permeability barrier.

Lipophilic: Having an affinity for fat. A property pertaining to a compounds ability to dissolve in oil. Liposomes: These are microscopic spherical vesicles that form when phospholipids are hydrated. They can be loaded with drugs, vitamins, and cosmetic materials and employed as delivery systems. Liposomes can be custom designed for different needs by varying the lipid content, size, surface charge, and preparation method. An artificial vesicle that is composed of one or more concentric phospholipid bilayers and is used especially to deliver compounds to body tissues and cells. Microscopic droplets with a molecular structure identical to that of cell membranes. Their closed structure means that active ingredients may be introduced into their internal environment. A hollow phospholipid bilayer vesicle that envelopes an aqueous core. Both water-soluble and oil-soluble materials can be encapsulated. Liquid Crystalline Phase: Generally, a bilayer in which the aliphatic chains are not highly ordered. This is the state of most biological membranes. Liquid Crystals: An intermediate physical state that exists when a solid is converted to a liquid that possesses the properties of both states. Thermodynamic liquid crystalline phases often occur between the

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crystalline and the isotropic liquid phase of rod like molecules. Lycopenes: A carotene molecule found in tomatoes that has antioxidant properties.

M Maimonides: Moshe ben Maimon (1135-1204), rabbi, physician, philosopher, and prolific writer. Also known as “the Rambam.” Matrix Metallo Proteinase: Enzyme able to degrade extracellular matrix main protein constituents. Melanocytes: Special cells in the skin and the eye that synthesize melanin pigments which provide color to skin and hair. Metabolism: Breakdown or oxidation of molecules to provide energy (catabolism) and the building up of more complex molecules (anabolism) through a series of enzymatic reactions in all the living organisms. Micelles: We are using the Davidovitz mathematical model for the crystalline part of polymers, where the chains are parallel to each other. In this model, the polymer crystals are said to have a geometry close to the one found in aggregates of surfactants. Microcapsule: A spherical one- or multilayered envelope that contains in its inner cavity a core substance. Varies in size between 10 mm and 1 mm. Products that have a polymeric shell that surround a liquid or solid core containing the active. Microencapsulation: A process resulting in formation of micrometer-size devices like microcapsules, or microparticles. These contain an active substance in their inner cavity or core. The process of entrapping an active material with a shell or coating. The process in which an ingredient is literally encapsulated by a continuous, usually non-permeable, membrane. Microparticle: A solid spherical particle that contains a dispersed core substance, and varies in size between 10 mm and 1mm. Microspheres: Polymeric beads that contain a solid or liquid material physically entrapped within a porous polymer matrix.

Microsponge: A patented highly cross-linked porous polymer made from a variety of monomers; particles are spherical and the pores can hold a variety of ingredients. Miniaturization: The process of designing or constructing in small size. Mix Head: That portion of production equipment that contains rotating blades in which the urethane prepolymer and aqueous phases are brought together under controlled temperatures and expelled at a given rate into a mold or onto a conveyor. Moiety: A group in a molecule. Moisturizer: Ingredient that confers moisturization, hydration, to the upper layers of the skin. Molded Foams: A method of producing hydrophilic polyurethane foam shaped items by causing the outflow of the reaction mixture to be extruded into a mold and cured. The cured foam takes the shape of the mold. Molecular Brush: As the paint industry has replaced classical paint brushes with polyurethane foam applicators, the cosmetic industry uses micro-sponges to uniformly deliver products to the skin. The fractal polymer is equivalent to a nano-sponge with a fractal interface at the skin contact governed by change in interfacial energy and mass exchange. Multilamellar: A liposome containing phospholipids in a series of concentric bilayers.

N Nano sponges: Porous structures in the nano-size range. Nasolabial: The crease between the nose and the cheek. Negative Control: A compound used in a clinical study that is anticipated to produce no meaningful changes in response and is, therefore, used as a baseline response. Any values or responses that are not statistically different from the negative controls are assumed to be normal, or not clinically significant. Neo-Colloidal State: If a colloidal state is defined as representing particles bigger than molecules but much too small to be seen by the unaided eye, the

GLOSSARY

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state of the substances adsorbed at the surface of the fractal polymer is even more finely divided.

cal examination must all fall into normal ranges without the assistance of any medication.

Neurohormones: Hormones produced in specialized nervous tissue (e.g., Serotonin, oxytocin, noradrenaline).

Nutraceutical: Any substance that may be considered as food, or part of a food, and provides medical or health benefits including the prevention and treatment of disease.

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of certain nerve cells and excite or inhibit the functions of the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, noradrenaline, adrenaline, dopamine, glycine, gaminobutyrate, glutamic acid, substance P, enkephalins, endorphins and serotonin. New Drug Application (NDA): An application made by a sponsor to the FDA that requests approval for marketing of a new or modified pharmaceutical or biologic. The NDA will contain sections related to: preclinical studies, clinical studies, manufacturing details, and proposed labeling. Any other information the sponsor feels relevant to the FDA’s ability to review and approve a new drug, is also included. The application is reviewed by a team of scientists including: physicians, pharmacologists, toxicologists, statisticians, chemists, and others, as needed, to ensure that the proposed pharmaceutical is both safe and efficacious against the diseases indicated. Non-comedogenic: The application of the ingredient does not induce formation of comedo. Non-Steroidal Anti-Inflammatory Agent (NSAID): A large group of anti-inflammatory agents that work by inhibiting the production of prostaglandins. They exert anti-inflammatory, analgesic, and antipyretic actions. Normal Healthy Volunteer (NHV): A potential subject of a clinical trial that presents with no clinically significant health findings. As the inclusion and exclusion criteria of clinical trials varies widely so does this definition. For cosmetic studies a person may present with multiple chronic disease states that are controlled with medication and be considered a NHV because no condition impacts the interpretation of the study data and does not increase the risk of the subject for adverse events. In pharmaceutical trials a NHV is often one in good general health with no chronic conditions that do or do not require medication. Typically, blood pressure, ECG, blood and urine chemistries, as well as results from a physi-

O Occlusion: Covered by an impermeable material to enhance penetration. Occlusive: A property of certain dressings and ointments that restrict free gas exchange between the skin surface and surrounding air. In particular, the moisture-retaining properties of such coverings can cause hydration of the skin. An occlusive material acts as a barrier, preventing the passage of other substances. D4: Octamethylcyclotetrasiloxane. Oleophilic: This term describes a molecule, or portion of a molecule, in a surfactant that is literally oil loving. It is, therefore, both siliphobic (silicone-hating) or hydrophobic (water-hating). Oleophobic: This term describes a molecule, or portion of a molecule, in a surfactant that is literally oil hating. It is, therefore, either siliphilic (silicone-loving) or oleophilic (oil-loving). Organelles: Specific, usually sub-cellular particles of membrane-bound organized living compounds. Present practically in all eukaryotic cells. OTC: Ozone Transport Commission.

P Patch Types: • Occlusive: a patch designed with an impermeable backing that does not allow any moisture or air to pass out of the area under the patch. This is the most aggressive patch type and often greatly exaggerates the exposure. • Semi-occlusive: a patch designed to allow air and moisture to escape from under the patch area but still maintains contact between the test material and

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS skin. This often is more “realistic” but can minimize exposure resulting in decreased sensitivity of the study. • Open: a situation where a product is applied to the skin with a completely breathable patch that allow the product to evaporate from the skin. This is often used for volatile test materials that are not expected to remain in contact with the skin for prolonged periods of time. In some situations no patch is used and the product is applied directly to the skin without a covering.

Pay-out: Yielding results, deliver material to the desirable site. Percutaneous: A global term describing the passage of compounds through the skin. Pharmaceuticals: Any chemical, chemical composition, or biologic that is designed and administered to patients to ameliorate the signs and symptoms of an acute or chronic health condition. Pharmacodynamics: The study of uptake, movement, binding, and interactions of a pharmaceutical at their tissue or sites of action. Pharmacokinetics: The rate of absorption, half life period, excretion and related aspects of an administered drug. The movement of a pharmaceutical within the body that is impacted by the rates of: uptake, distribution, binding, elimination and biotransformation. Phase Change Materials (PCM): Substances that have the capability of absorbing or releasing thermal energy. Phospholipid: A building block of cell membranes and liposomes. Photostabilizer: Organic group that prevents degradation by UV light. Phytosphere: Proprietary Technology from Coletica, based on proteins and/or polysaccharides from plants. Phytosphingosine: One of the common long-chain bases found in ceramides and other sphingolipids. It is like dihydrosphingosine, except that it has an additional hydroxyl group on carbon 4.

Piper Nigrum: Black pepper, the commonly used pungent table spice, is the fruit of this vine. It is native to the Malabar region in Southwestern India. Piper Longum: Long pepper. The name “pepper” is derived from the Sanskrit name of long pepper, pipali. Long pepper is more pungent than black pepper and was known in Europe much earlier than black pepper. Pilosebaceous: Of or relating to hair and the sebaceous glands. Relating to the hair follicles and sebaceous glands. Plagette: A small individual nonwoven pad that can be adhered to one side of peel apart plastic films or packaged in a pouch and is filled with a topical skin care treatment. Polarizer: A device, which in the transmission of electromagnetic radiation, confines the vibration of the electric and magnetic field vector to one plane. Polymorphism (of Lipids in the Stratum Corneum): The quality or state of existing in or assuming different forms. The property of crystallizing in two or more forms with a distinct structure, that are usually gel and liquid crystals forms. Polytrap: A patented non-porous polymer made from Lauryl Methacrylate and Ethylene Glycol Dimethacrylate. Positive Controls: A control in a clinical study is one that produces an anticipated effect that is at or near the maximum value of a scoring range. For example, in a cumulative irritation study, a compound that produces irritation at or near the maximum value of the scoring system. Preclinical: Refers to any in vitro or in vivo test, study or assay that is conducted in non-human models. These studies are typically conducted prior to the clinical trials. Pregelatinized Starch: Starch that has been partially or fully gelatinized and then dried. Prepolymer - A controlled reaction mixture between an isocyanate and a polyol that results in a prepolymer pre-curser for producing polyurethane reaction products. Prodrug: A compound that is converted within the body into its active form that has therapeutic effects. Useful when the active drug has systemic toxicity,

GLOSSARY

969

or is absorbed poorly by the digestive tract, or is broken down by the body before it reaches its target. Provitamin: Precursor of the vitamin which is in an inactive form. Proximity: Nearness in molecular range. Pseudoplastic: The loss of viscosity with increasing shear rate that demonstrates immediate recovery once the stress is removed.

R

Second Generation Liposomes: Liposomes with greater stability due to the protection of their structure using a coating based on biodegradable polymers. Sensitization: The action of making a living being capable of reacting in a particular way to the contact of a chemical or physical agent. This is an immunological phenomenon. Serotonin: Best known actions are to regulate the sleep and waking periods (circadian rhythms) and to produce a sense of calmness or reduced anxiety. It is concentrated in the platelets, central nervous system, and intestinal walls.

Reticulation: Reaction performed in order to covalently bind two polymers to each other.

Sequential Release System: Delivers multiple ingredients at different predetermined period of time.

Reticulate: Urethane foam cell structure, large or small in size, in which the cell walls have burst so that an open pathway exists through the cured foam from one side to the other. Liquids and gases can pass freely through the foam.

Shaped Foams - A method of producing hydrophilic polyurethane foam shaped items by causing the outflow of the reaction mixture to be extruded into a given shape using a form on a moving conveyor and allowed to cure.

Retrogradation: The phenomenon that occurs when cornstarch is slurried in water, heated to rupture the starch granule, and then cooled.This results in a rigid gel due to realignment and reassociation of the glucose polymers found in the granule.

Shelf life: Time it takes to lose the initial biological activity.

Rheology: The measure of the flow characteristics of a fluid. Risk-to-benefit Ratio: A subjective, often abstract, analysis of a compound or products ability to produce a benefit to a consumer or patient versus the probability that the same product or compound will produce an adverse effect.

Silicic-acid Esters: Fully hydrolyzed silicon compounds containing, in the simplest form, 4 alkoxy groups per Si atom (e.g., Si(OR)4). Silicone Elastomer: Cross-linked polydimethylsiloxane, to such an extent that the material gels in diluents such as cyclomethicone or low viscosity dimethicone. Silicone Emulsion: System developed to allow easy incorporation of silicones in aqueous based formulations, comprised of cationic, nonionic, or anionic surfactant systems.

S

Silicone Gum: Polydimethylsiloxane of very high viscosity, usually dispersed in lower viscosity fluids.

Schiff-base: A compound containing a C=N bond that is formed by the reaction of a primary amine with an aldehyde or ketone.

Silicone Polyether: Silicone copolymer, where some of the methyl groups are substituted by hydrophilic ethoxylated and/or propoxylated pendant chains.

Sebaceous: Small subcutaneous glands, usually connected with hair follicles. They secrete an oily semifluid matter, composed in great part of fat. The fat softens and lubricates the hair and skin. Sebum: Natural oils in the skin and scalp that lubricate and protect.

Siliphilic: This term describes a molecule, or portion of a molecule in a surfactant that is literally silicone-loving. It is, therefore, both oleophobic (oil-hating) or hydrophobic (water-hating). Siliphobic: This term describes a molecule, or portion of a molecule in a surfactant that is literally

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

silicone-hating. It is, therefore, either hydrophilic (water-loving) or oleophilic (oil-loving). Silyl hydride: Compound containing an Si-H group. Simple Co-acervation: Encapsulation technology. Based on the gellification of a substance used to produce the membrane of spheres or capsules. Examples include contact of the corresponding gellifying parameter (calcium for alginate, cold for waxes, etc.) or two reactive monomers solubilized in two different immiscible solvents, at their interface. Skin Barrier: The barrier of the epidermis provided by the stratum corneum. The normal skin barrier is relatively impervious to water, large molecules, bacteria and viruses. Many fat soluble liquids and solvents are capable of penetrating the skin barrier. SnapPack™: A disposable device for the delivery of a combination of liquids, flowable gels and powder formulations via a thermoformed multi-chambered system. Sonophoresis: A novel application of ultrasonic energy. Ultrasound is used to perturb and permeabilize the intercellular lipids of the stratum corneum. this facilitates the enhanced delivery of drugs and / or skin actives. Sphingosine: One of the common long-chain bases found in ceramides and other sphingolipids. It is like dihydrosphingosine, except that it has a double bond between carbons 4 and 5. Starch Granule: A highly structured, semi-crystalline organization of two polymers, amylose, and amylopectin. Stem cells: In the epidermis, stem cells are quiescent and they only rarely divide. However, in response to injury they undergo several rounds of replication. During such replication, one of the daughter cells remains a stem cell, while the other daughter cell (transient amplifying cell) undergoes several rounds of replicating itself. All of the cells produced by replication of the transient amplifying cells enter into replication. This provides a mechanism for wound repair. Steric Hindrance: A mechanical interference in molecular interaction due to moieties present molecules attempting to react with each other Stratum Corneum: The outer portion of the epidermis consisting of dead, keratin-filled cells embed-

ded in a lipid matrix. The outermost layer of human skin consisting of terminally differentiated corneocyte cells embedded in a lipid bilayer matrix. The stratum corneum forms the barrier to water loss from the body surface. It blocks the ready entry of harmful materials from the environment. The outer layer of the epidermis consisting of several layers of flat non-nucleated epidermal cells that provides significant protection from insult due to exposure to noxious chemicals and environmental stimuli. Substantivity: This term relates to the ability of a molecule to end up on the substrate when deposited from aqueous solution. This may occur for example, with the deposition of a cationic conditioner onto hair. Substantivity is a result of the energetics of solution. It can be achieved through incorporation of a hydrophobic material, a cationic charged material, or a polymeric substrate. Supersaturation: This is the dissolving of a larger quantity of solute in a solution, than would normally be possible. It can occur because surface energy is required to condense a drop from a vapor, and the energy barrier is difficult to overcome unless nucleation centers (condensation nuclei) are present, in which case the drop only needs energy to overcome surface tension forces spread over a fraction of its surface area. Surface Immobilization: Active substances can be immobilized onto the surface of a fractal polymer by the same techniques used to immobilize enzymes on porous surfaces. This immobilization is not always permanent as such it can be used in a delivery system by, for example, change of pH to stereo-specifically “release” and deliver active molecules to the skin. Surfactant: An amhiphilic molecule that modifies the surface tension of liquid/liquid and liquid/air interfaces. Sustained Release System: System generally used for short periods of time, which requires repeated administration and is influenced by environmental conditions; sometimes called “slow release.” Syneresis: The phenomenon of gels exuding water over time. Systemic Exposure: Exposure to the entire organism, not an exposure limited to a specific site or target (i.e., skin).

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971

T Tactile: Pertaining to the sense of touch.

Tocopherols: Originally, name given to vitamin E, but now a generic term for vitamin E and compounds chemically related to it.

TanDerm™: A small packet that becomes a wipe and utilizes two peelable heat-sealable films to form a slim pouch containing two individual separated applicator plagettes impregnated with different formulations that will mix in situ when wiped on the skin. The plagettes are attached side-by-side, but separated by a heat seal area to the bottom of the inside surface forming a “peel apart” wipe.

Transdermal: Entering through the dermis or skin, as in administration of a nutrient or therapeutic substance applied to the skin in appropriate formulations. Designed for absorption through the skin into the bloodstream.

Targeted Delivery: Transportation or modification of an active so that its activity is only available to a narrowly-defined receptor.

Transition Temperature: The temperature at which certain molecules change state or structure from a lower energy assembly to a higher energy assembly.

Targeting: Mobilizing a material and creating preferential conditions for it to interact with a specific other material and exclude certain materials. Target Population: The group of individuals to which a product or compound is designed for use. Technology: Set of tools that are protected by patents and that could be applied to different active compounds. Thalasphere: Proprietary Encapsulation Technology from Coletica, based on marine atelocollagen. Therapeutic Index: A measure of the relative desirability of an active for the attaining of a particular therapeutic end that is usually expressed as the ratio of the largest dose producing no toxic symptoms to the smallest dose routinely producing the desirable effect. Thermogenesis: Heat production in vivo, which is linked to metabolic processes in the body. Thermonutrients: Nutrients which produce heat in the body. Thermoreceptors: Afferent nerve endings sensitive to heat, capable of receiving and transmitting stimuli. Third Generation Delivery System: A delivery system that has been designed to specifically target different cell types or specific tissue or area of a tissue. Thixotropy: The loss of viscosity with time at constant shear rate that shows a delayed recovery once the stress is removed.

Transglutaminase 1: The enzyme that introduces isopeptide linkages in creation of the cornified envelope.

Transport: Causing a material to cross a barrier. Trigger: A mechanism whereby an active is released from an encapsulate. Examples would include moisture, pH, heat, or shear. TwinDerm™: A “back-to-back” impregnated two sided pad delivery system that keeps the individual steps of a skin care regimen independent but readyto-go in a unit-dose, peel apart packet.

U Unilamellar: A liposome containing phospholipids in a single spherical bilayer.

V Vectors: Product of encapsulation developed to target a cell or an area of a tissue. Vehicle: A carrier designated to mobilize material to a distant location overcoming obstacles in its path. Vernix Caseosa: A mixture of lipids, cells, water and other ingredients produced during fetal development and coating the skin surface during the last trimester of gestation. Viscosity: The resistance of a fluid to flow as measured by the ratio of shear stress to shear rate. Volar: The inner surface of the forearm from the wrist to just below the elbow crease. Located on the same side of the body as the palm of the hand.

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DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

VOC: Volatile Organic Component. Volume of Distribution: The volume of the body that a compound distributes itself; compounds can distribute themselves in several compartments such as: serum, extracellular fluid, systemic (whole body), specific target organs (i.e., liver, kidneys, CNS, etc.).

W Wood’s Lamp: Ultraviolet light used to evaluate fluorescence for diagnostic purposes in dermatology.

X Xerotic: Dry, scaly skin reflecting abnormal desquamation (normal release of skin surface cells) and low water binding capacity. X-ray Diffraction: An analytical method used to identify the structure or identity of a crystalline material based on the scattering of x-rays by atoms.

Suppliers/Vendors 5ème Sense 18, rue de Monttessuy 75007 Paris, France Tel: 33-1-47-53-79-16, Fax: 33-1-45-55-29-39 www.cinqiememesens.com Abitec Corporation P.O. Box 569 Columbus, Ohio 43216 Tel: 614-429-6464, Fax: 614-299-8272 Acros Organics Division of Fisher Scientific 2000 Park Lane Drive Pittsburgh, Pennsylvania 15275-9952 Tel: 973-889-6300, Fax: 973-644-9369 Active Organics 1097 Yates Street Lewisville, Texas 75057-4829 Tel: 972-221-7500, Fax: 972-221-3324 www.activeorganics.com AdvantaChem 5900 Central Avenue St. Petersburg, Florida 33707 Tel: 813-426-3281 www.AdvantaChem.com

Akzo Nobel 2153 Lockport-Olcott Road Burt, New York 14028 Tel: 800- 906-7979, Fax: 419-229-0233 Akzo Nobel Chemicals 300 South Riverside Plaza Chicago, Illinois 60607 Tel: 312-906-7889, Fax: 312-906-7838 Akzo Nobel Functional Materials LLC 300 South Riverside Plaza Chicago, Illinois 60606 Tel: 800-906-7979, Fax: 312-906-7782 Akzo Nobel Inc. 525 West Van Buren St. Chicago, Illinois 60607 Tel: 312-544-7000 Alban Muller International 8 Rue Charles Pathé 94300 Vincennes, France Tel: 33-1-48088100, Fax: 33-1-48088101 Alzo International Inc. 650 Jernee Mill Road Sayerville, New Jersey 08872 Tel: 732-254-1901, Fax: 732-254-4423

A.E. Staley Manufacturing Company 220 E. Eldorado Street Decatur, Illinois 62525 Tel: 217-423-4411, Fax: 217-421-3167

Amend Drug & Chemical Co. Irvington, New Jersey 07111 Tel: 201-926-0333, Fax: 201-926-4921 www.amenddrug.com

Ajinomoto U.S.A. West 115 Century Road Paramus, New Jersey 07652 Tel: 201-261-1789, Fax: 201-261-7267

Angus 1500 East Lake Cook Road Buffalo Grove, Illinois 60089 Tel: 847-215-8600, Fax: 517-832-1465 www.angus.com

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Aqualon Co. 2711 Centerville Road Wilmington, Delaware 19850-5417 Tel: 302-996-2000, Fax: 302-946-2296

Bio-Botanica 75 Commerce Drive Hauppauge, New York 11788 Tel: 631-231-5522, Fax: 631-231-7332

Austin Research Laboratory P.O. Box 15730 Austin, Texas 78761 Tel: 512-459-6543, Fax: 512-483-0925

BioChemical 925 Lakeville Street, Suite 206 Petaluma, California 94952 Tel: 707-263-1475, Fax: 707-263-7844

Australian Essential Oil 575 Myall Creek Road, P.O. Box 158 Coraki NSW 2471 Australia Tel: 61-2-66832124, Fax 61-2-66832603

BP, distributed by Lipo Chemicals, Inc. 200 East Randolph Drive Chicago, Illinois 60601-7125 Tel: 800-621-4567

Barnet Products Corp. 140 Sylvan Avenue Englewood Cliffs, New Jersey 07632 Tel: 201-346-4620, Fax: 201-346-4333 www.barnetproducts.com

Cabot Corporation, USA 25051 Estecreek Drive Cincinnati, Ohio 45232-1446 Tel: 513-482-3000, Fax: 513-482-55003

Bell Flavors & Fragrances 500 Academy Drive Northbrook, Illinois 60062 Tel: 847-323-4387, Fax: 847-291-1217 Belmay, Inc. (Belmay Fragrances) 200 Corporate Blvd. South Yonkers, New York 10701-6806 Tel: 914-376-1515, Fax: 914-376-1784 www.Belmay.com Bernel Chemical Co., Inc. 174 Grand Avenue Engelwood, New Jersey 07631 Tel: 201-569-8934, Fax: 201-569-1741 www.bernel-chemicals.com B.F. Goodrich (Noveon, Inc.) 9911 Brecksville Road, Cleveland, Ohio 44141-3247 Tel: 800-379-5389 www.noveoninc.com BF Goodrich Company, (Noveon, Inc.) Chaussee de Wavre, 1945 11 60 Brussels Belgium Tel.: +32/26781953, Fax.: +32/26782002

Cabot Corporation 700 E. US Highway 36 Tuscola, Illinois 61953-9643 Tel: 217- 253-3370, 800-222-6745 Fax: 217-253-4334 Cardinal Nutrition 1000 West 8th Street Vancouver, Washington 98660 Tel: 360-693-1883 Caschem Inc. 40 Avenue A Bayonne, New Jersey 07002 Tel: 201-858-7900, Fax: 201-858-0308 Centerchem, Inc. 20 Glover Avenue Norwalk, Connecticut 06850 Tel: 203-822-9800, Fax: 203-822-9830 www.Centerchem.com Children’s Hospital Research Foundation Joseph D. Fondacaro Director, Technology Transfer 3333 Burnet Avenue Cincinnati, Ohio 45229-3039 Tel: 513-636-7695, Fax: 513-636-8453 www.cincinnatichildrens.org

SUPPLIERS/VENDORS Clariant Corporation 624 E. Catawba Ave. Mount Holly, North Carolina 28120 Tel: 704-822-2528, 800-548-6902, Fax: 704-822-2241 Cognis Corporation 300 Brookside Avenue Ambler, Pennsylvania 19002-3498 Tel: 215-628-1000, 215-628-1476, Fax: 215-628-1450 www.cognis.com

975 CP Kelco 8355 Aero Drive San Diego, California 92123 Tel: 858-292-4900, 800-535-2687, Fax: 858-292-4901, 704-822-2528 www.cpkelco.com CP Kelco U.S., Inc. Suite 3700, 311 South Wacker Drive Chicago, Illinois 60606-6627 Tel: 312-554-7800, 800-535-2687, Fax: 312-554-7804, 312-554-7810

Cognis Care Chemicals 1301 Jefferson Street Hoboken, New Jersey 07030 Tel: 201-659-1200, Fax: 201-659-2050

Croda 7 Century Drive Parsippany, New Jersey 07054 Tel: 973-644-4900, Fax: 973-644-9222 www.croda.com

Cognis Corporation 5051 Estecreek Drive Cincinnati, Ohio 45232-1446 Tel: 513-482-3000, 800-543-7273, Fax: 513-482-5503 www.cognis.com, www.cognis-us.com

Crompton 771 Old Saw Mill River Road Tarrytown, New York 10591-6716 Tel: 914-593-4136, Fax: 914-593-4137

Coletica S.A. Commercial Department 83 rue de Villiers 92200 Neuilly Sur Seine France Tel: 33 (1) 47-45-35-00, Fax: 33-4-78-58-09-71 [email protected] Collaborative Laboratories 3 Technology Drive East Setauket, New York 11733 Tel: 516-689-0200, Fax: 516-689-0205 Collaborative Laboratories 50 East Loop Road Stony Brook, New York 11790 Tel: 631-689-0200, Fax: 631-689-2904 www.collabo.com Colonial Chemical Inc. 225 Colonial Drive South Pittsburg, Tennessee Tel: 423-837-8800, Fax: 423-837-3888 www.colonialchem.com

Custom Ingredients, Inc. 712 Wilson Street, P.O. Box 772 Chester, South Carolina 29706 Tel: 803-581-5800, Fax: 803-581-5802 Danisco Langebrogade 1, P.O. Box 17 DK - 1001 Copenhagen K, Denmark www.danisco.com Degussa Corporation 379 Interpace Parkway, P.O. Box 677 Parsippany, New Jersey 07054 Tel: 973-541-8000, Fax: 973-541-8103 Delta Plastics 106 Delta Place Hot Springs, Arkansas 71913 Tel: 501-760-3000, Fax: 501-760-3005 Desert Whale 2101 E. Beverly Drive Tucson, Arizona 85719 Tel: 520-882-4195, Fax: 520-882-7821

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Desert Whale Jojoba Co., Inc. 3650 Touhy Avenue, PO Box 549 Skokie, Illinois 60076 Tel: 520-882-4195 www.desertwhale.com D.H. Litter Co. 565 Taxter Road Elmsford, New York 10523 Tel: 914-592-1077, Fax: 914-592-1499 Dow Chemical USA P.O. Box 1206 Midland, Michigan 48686-0994 Tel: 989-832-1560, 800-447-4369, Fax: 989-832-1456 www.dowchemicals.com DuPont Specialty Chemicals 1007 Market Street Wilmington, Delaware 19898 Tel: 800-441-7515 Dussek/Campbell 3650 Touhy Avenue, P.O. Box 549 Skokie, Illinois 60076 Tel: 847-679-6300, Fax: 847-679-6312 Eastman Chemical Company P.O. Box 511 Kingsport, Tennessee 37662 Tel: (423) 229-2000, Fax: (423) 229-2145 ExxonMobil Chemical Company 13501 Katy Freeway Houston, Texas 77079 Tel: 281-870-6000, Fax: 281-870-6661 Fanning Corporation 2450 West Hubbard St. Chicago, Illinois 60612-1408 Tel: 312-563-1234, 312-563-0087 Finetex Inc. 418 Falmouth Ave., P.O. Box 216 Elmwood Park, New Jersey 07407 Tel: 201-797-4686

Fisher Scientific Tel: 800-766-7000 www.fischersci.com FMC Avenue Louise 480-B9 1050 Brussels, Belgium Tel: 32-2645-9211, Fax: 32-2640-0564 www.fmc.com FMC Corporation 1735 Market Street Philadelphia, Pennsylvania 19103 Tel: 215-299-6000 www.fmc.com FMC Biopolymers Inc. 1735 Market Street Philadelphia, Pennsylvania 19103 Tel: 215-299-6420, Fax: 215-299-6669 Frank B Ross 22 Halladay Street, P.O. Box 4085 Jersey City, New Jersey 07304 Tel: 201-433-4512, Fax: 201-332-3555 Freeman Industries 100 Marbeldale Road Tuckahoe, New York 10707 Tel: 914-961-2100, Fax: 914-961-5793 Gateway Surgical Inc. 200 Long Road St.Louis, Missouri 63005 Tel: 636-537-5446, Fax: 636-536-0212 Gattefosse Corporation 372 Kinderkamack Road, Westwood, New Jersey 07675 Tel: 201-358-1700, 201-358-4050 www.gattefosse.com Goldschmidt PO Box 1299 Hopewell, Virginia 23860 Tel: 804-541-8658, Fax: 804-541-8689 Grant Chemical Company P.O. Box 360, 125 Main Avenue Elmwood Park, New Jersey 07407 Tel: 201-791-6700, Fax: 201-791-0038

SUPPLIERS/VENDORS

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Hampshire 2 East Spitbrook Road Nashua, New Hampshire 03060 Tel: 800-477-4369

Jeen Chemical 24 Madison Road Fairfield, New Jersey 07004 Tel: 973-439-1401, Fax: 973-439-1402

Hansotech Inc. 144 Woodbury Road Woodbury, New York 11797 Tel: 516-692-6890 www.hansotechinc.com

J. M. Huber Corporation P.O. Box 310 Havre de Grace, Maryland 21078 Tel: 410-939-3500, Fax: 410-939-8964

Hercules Inc., Aqualon Division 1313 North Market Street Wilmington, Delaware 19850 Tel: 302-996-2000, Fax: 302-996-2279 www.herc.com Honeywell 101 Columbia Road Morristown, New Jersey 07962 Tel: 973-455-2145, Fax: 973-455-6154 IGI, Inc. 105 Lincoln Ave. Buena, New Jersey 08310 Tel: 856-697-1441, Fax: 856-697-2259 Inolex Chemical Company Jackson and Swanson Streets Philadelphia, Pennsylvania 19148-3497 Tel: 800-521-9891, Fax: 215-271-2621 Istituto Erboristico L’Angelica SpA Via Stradelli Guelfi 47 40064 Ozzano Emilia (BO), Italy Tel: 39-051-795002, Fax: 39-051-795003 Jarchem Industries 414 Wilson Avenue Newark, New Jersey 07105 Tel: 973-344-0600 www.jarchem.com Jason Natural Products Consumer Relations 4600 Sleepytime Drive Boulder, Colorado 80301 Tel: 1-800-JASON-01 (527-6601)

KIC Chemicals, Inc. 84 Business Park Drive Armonk, New York 10504 Tel: 914-273-6555, Fax: 914-273-6760 KOBO Products Inc. 690 Montrose Ave. South Plainfield, New Jersey 07080 Tel: 908-757-0033, Fax: 908-757-0905 Kraft Chemical Company 1975 N. Hawthorne Avenue Melrose Park, Illinois 60160 Tel: 708-345-5200, Fax: 708-345-0761 Kuhs Laboratories GmbH + Co. Lingertstraße 21 79541 Lörrach-Hauingen/Germany Tel: +49/7621959721, Fax: +49/762152133 Laboratoire Bomann 101-103 Rue Henry Dunant 92700 Colombes, France Tel: 33-1-46499191, Fax: 33-1 46499080 Laboratoires Seporga 655 Route du Pin Montard, 09604 Sophia Antipolis, France Tel: 33-4-92941606, Fax: 33-4-92941600 Laboratoires Serobiologiques (Cognis) 300 Brookside Ave. Ambler, Pennsylvania 19002 Tel: 215-628-1447, Fax: 215-628-1450 LCW Les colorants Wackherr, 7 rue de l’industrie, 95310, St Ouen l’Aumône, France Tel: 33-1-3448-5700, Fax: 33-1-3464-4440 www.lcw.com

978

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Lonza 17-17 Route 206 Fair Lawn, New Jersey 07410 Tel: 201-794-2400 Fax: 201-794-2597, 201-794-2515 www.lonza.com McIntyre Group Ltd 24601 Governors Highway University Park, Illinois 60466 Tel: 708-534-6200 www.mcintyregroup.com Merck KgaA Frankfurter Strasse 250, D-64293 Darmstadt, Germany Tel: 49-61-51-72-7869, 49-61-51-72-20-98, Fax: 49-61-51-72-8333, 49-61-51-72-36-3 www.merck.com Mallinckrodt Chemical Inc. 16305 Swingley Ridge Drive Chesterfield, Missouri 63017 Tel: 314-539-1600 National Starch and Chemical 10 Finderne Avenue, PO Box 6500, Bridgewater, New Jersey 08807 Tel: 888-331-6212, Fax: 908-707-3664 www.nationalstarch.com National Starch and Chemical Tri-State International Office Center 25 Tri-State International, Suite 120 Lincolnshire, Illinois 60069 Tel: 847-945-7500 www.nationalstarch.com National Starch and Chemical Co. 742 Grayson Street, Berkeley, California 94710-2677 Tel: (510) 548-6722, Fax: (510) 841-3150 Nattermann Phospholipid GmbH (Rhone Poulenc) P.O. Box 350120, 50792 Köln/Germany Tel: +49/(0)2215092258, Fax: +49 (0)2215092816

Nipa Clariant 4331 Chesapeake Drive Charlotte, North Carolina 28216 Tel: 800-538-8397, Fax: 704-395-6670 www.clariant.uk NIPA Laboratories/Clariant 625 E. Catawba Avenue, P.O.Box 866 Mt. Holly, North Carolina 28120 Tel: 704-822-2258, Fax: 704-822-2241 Noveon 9911 Brecksville Road Cleveland, Ohio 44141-3427 Tel: 216-447-5000, 800-379-5389, Fax: 216-447-5669, 216-447-5740 www.noveon.com Payan et Bertrand PO Box 61057, 28 Avenue Jean XXIII Grasse cedex 06131, France Tel: 33-4-93-40-14-14, Fax: 33-4-93-40-10-30 www.payanbertrand.com Pentapharm Ltd. Distributed by Centerchem Inc. Engelgasse 109, CH4002 Basel, Switzerland Tel: 41 61 706 48 48, Fax: 41 61 319 96 19 Phoenix Chemicals Tel: 908-707-0232 www.phoenixchem.com Phytochem USA Inc. P.O.Box 203 Roslyn Heights, New York 11577 Tel: 718-359-5600, Fax: 718-264-8880 Pilot Chemical 11756 Burke Street Santa Fe Springs, California 90670 Tel: 800-707-4568 Presperse, Inc. 141 Ethel Road West Piscataway, New Jersey 08854 Tel: 732-819-8009, Fax: 732-819-7175

SUPPLIERS/VENDORS Purac America Inc. 111 Barclay Boulevard Lincolnshire Corporate Center Lincolnshire, Illinois 60069 Tel: 847-634-6330, Fax: 847-634-1992 Quimasso France Cap Vaise, Bat. C-14 Gorge de Loup, 69009 Lyon Tel: 33-4-78-64-07-97, Fax: 33-4-78-83-07-29 www.quimasso.com Rhodia CN 7500, Prospect Plains Road Cranbury, New Jersey 08512-7500 Tel: 609-860-4000, 609-305-8300, Fax: 609-860-0138, 609-800-0466 www.rhodia.com R.I.T.A. Corporation P.O. Box 1487, 1725 Kilkenny Court Woodstock, Illinois 60098 Tel: 815-337-2500, Fax: 815-337-2522, 815-337-2523 www.ritacorp.com Roche Vitamins Inc. Division of Hoffmann-La Roche, Inc. 45 Waterview Blvd., Parsippany, New Jersey 07054-1298 Tel: 973-257-9420, 973-257-8332, 800-526-0189, Fax: 973-257-8580 www.roche.com Rohm and Haas Company 100 Independence Mall West Philadelphia, Pennsylvania 19106-2399 Tel: 215-592-3000, Fax: 215-592-3377 Rona, EM Industries 7 Skyline Drive Hawthorne, New York 10532 Tel: 914-592-4660, Fax: 914-592-9469 www.emindustries.com Roquette America 1417 Exchange Keokuk, Iowa 52632 Tel: 800-223-5305, Fax: 319-526-2359

979 Rovi GmbH Breitwiesenstr. 1, 36381 Schlüchtern/Germany Tel: +49/(0)666196760, Fax: +49(0)666196760 R.T. Vanderbilt Company, Inc. 30 Winfield Street Norwalk, Connecticut 06855 Tel: 203-853-1400, Fax: 203-853-1452, 203-838-6368 www.rtvanderbilt.com Ruger Chemical Co. 83 Cordier St, P.O. Box 35435 Irvington, New Jersey 07111 Tel: 800-274-7843, 973-926-0331, Fax: 973-926-4921 Sarcga Aiglon P.O.Box 1487 Woodstock, Illinois 60098 Tel: 815-337-2500, Fax: 815-337-2522 www.aiglon-france.com Sasol Germany GmbH-Witten Distributed in the US by Sasol North America Inc., Arthur-Imhausenstr 92, D-58453 Witten, Germany Tel: 49 2302 925 537, Fax: 49 2302 925 358 Scher Chemical Industrial West Clifton, New Jersey 07012 Tel: 973-471-1300, Fax: 973-471-3783 Schulke & Mayr Postfach, 22840 Norderstedt, Germany Tel: 49-40-521-00-0, Fax: 49-40-521-00-244 www.seppic.com Schulke & Mayr C/O Air Liquide America L.P., 400 Valley J Road-Suite 100 Mt.Arlington, New Jersey 07856 Tel: 973-442-0700, Fax: 973-442-7222

980

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS

Sederma, Inc. 7 Century Drive Parsippany, New Jersey 07054 Tel: 973-993-2973, Fax: 973-644-9222 www.crodausa.com

SurfactantsBeiersdorf AG Unnastrasse 48, 20245 Hamburg Tel: +49(0)40-4909-0, Fax: +49(0)40-4909-3434 www.Beiersdorf.com, www.Nivea.com

Seegott, Inc. 47 Copper Penny Road Flemington, New Jersey 08822 Tel: 888-733-4688

Sutton Laboratories 116 Sumit Avenue Chatham, New Jersey 07928 Tel: 201-635-1551, Fax: 201-635-4964

Seppic 30 Two Bridges Road, Suite 210 Fairfield, New Jersey 07004-1530 Tel: 973-882-5597, Fax: 973-882-5178

Symrise Inc. 300 North Street Teterboro, New Jersey 07608 Tel: 201-462-5425, 201-288-3200, Fax: 201-462-5439, 201-462-2200

Sigma-Aldrich 3050 Spruce Street St. Louis, Missouri 63103 Tel: 800-521-8956 www.sigmaaldrich.com Spectrum Chemical Mfg. Corp. 755 Jersey Avenue New Brunswick, New Jersey 08901 Tel: 800-342-6615, Fax: 877-656-5788 Spectrum Chemical Mfg. Corp. 14422 S. San Pedro Street Gardena, California 90248 Tel: 800-516-8000 Stearinerie Dubois Fils 86 rue du Dome 92514 Boulogne Cedex, France Tel: 33-1-46-10-07-30, Fax: 33-1-49-10-99-48 Strahl & Pitsch Inc. 230 Great East Neck Road West Babylon, New York 11704 Tel: 631-587-9000, Fax: 631-587-9120 Sun Chemical Corp. 5020 Springrove Av. Cincinnati, Ohio 45232 Tel: 800-543-2323, www.sunchemical.com

Takasago 11 Volvo Drive Rockleigh, New Jersey 07647 Tel: 201-767-9001, Fax: 201-784-7244 www.takasago.com Tessenderlo Group PB Leiner USA 7001 Brady Street, Davenport, Iowa 52809 Tel: 563-386-8040, Fax: 563-391-1138 3M Consumer Health Care Lab 3M Center, 270-3N-03, Saint Paul, Minnesota 55144 Tel: 651-736-5190 Tri-K Industries Inc. 151 Veterans Drive, P.O.Box 128 Northvale, New Jersey 07647-0128 Tel: 201-750-1055, 800-526-0372 Fax: 201-750-9785 United State Department of Agriculture Division of Agricultural Resource Utilization Peoria, Illinois Uniqema Americas 3411 Silverside Road, P.O.Box 15391 Wilmington, Delaware 19850 Tel: 302-887-3000 (Ext. 3507) Fax: 302-887-3525

SUPPLIERS/VENDORS

981

USB Corp. 26111 Miles Road Cleveland, Ohio 44128 Tel: 216-765-5000, Fax: 216-464-5075

Vevy Europe 45 Feldland Street Bohemia, New York 11716 Tel: 631-567-0303

Universal Preserv-a-chem, Inc. 33 Truman Drive South Edison, New Jersey 08817 Tel: 732-777-7338, Fax: 732-777-7885 www.upichem.com

Witco, Performance Chem. Grp. P.O. Box 336 Petrolia, Pennsylvania 16050 Tel: 800-424-9300

V.MANE FILS s.a. 620 Route de Grasse, 06620 Le Bar-sur-Loup, France Tel: 33-4-93097000, Fax: 33-4-93425425 Vesifact AG Jöchlerweg 4, CH 6342 Schweiz, Baar 2 Tel: +41/317697010, Fax: +41/317697020

Western Flavors & Fragrances 4555 Las Positas Road Livermore, California 94550-9615 Tel: 925-373-9433 Zenitech LLC P.O. Box 44 Old Greenwich, Connecticut Tel: 203-698-0429, Fax: 203-698-0312 www.Zenitech.com

Trademarks Trademark Abil EM 90®

Property of

Goldschmidt GMBH Corp. Actiquench GTP 20 Active Organics Activera Liposomes Active Organics Actizyme E3M-M Active Organics ® Aculyn Rom & Haas Acuscrub 52 Allied Signal Aesthetic Modifier-100 Collaborative Labs. Aesthetic Modifier-200 Collaborative Labs. Aesthetic Modifier-300 Collaborative Labs. Aesthetic Modifier-400 Collaborative Labs. Aesthetic Modifier-500 Collaborative Labs. Aesthetic Modifier-600 Collaborative Labs. Aesthetic Modifier-700 Collaborative Labs. Aesthetic Modifier-750 Collaborative Labs. Aesthetic Modifier-900 Collaborative Labs. Ajidew® N50 Ajinomoto U.S.A. Aminocell™ Advantachem ® Amonyl 380 BA Seppic ® Amphisol K Roche Vitamins Arlacel 165 Uniqema Behensil Biosil Technologies Benzalkonium Chloride Sigma-Aldrich Chemical Company ® Bioclin Sebo Care Impure Skin Cream Ganissini ® Sabinsa Bioprene Biosil Basics Biosil Technologies Bio-Terge AS-40 Stepan Company Biowax Biosil Technologies ® BotaniCell Clinical Research Brij 93 Uniqema

Trademark C30-45 Alkyl Methicone Cab-O-Sil Calamide C Carbomer Ultrez Carbopol Carbopol 940 Carbopol EDT 2001 Carbopol Ultrez 10 Carbopol® 980 Carnation Mineral Oil Celite SFSF Celquat H-100 Ceraphyl 368 Ceraphyl 375 Ceraphyl 847 Cerasynt 945 Cerasynt IP Cerasynt Q Ceritol® HE Cetiol HE Cetiol OE Cetylsil Chitosphere™ Chlorelline Chronospheres® Cithrol GMS CITRICIDAL® Cococin™ Cocosil

Property of Dow Corning Corp. Cabot Corporation Pilot Chemical Noveon Noveon Noveon Noveon Noveon Noveon Witco, Performance Chem. Grp. Celite Corp. National Starch and Chemical Co. ISP ISP ISP ISP ISP ISP Cognis Corp. Cabot Corporation Cabot Corporation Biosil Technologies IVREA Inc. R.I.T.A. Corporation Arch Personal Care Croda Samual Allen Associates Sabinsa Biosil Technologies

984 Trademark Codiavelane BG Cosmitiq® Cosmoperine® Crodacol C-95NF Crodacol SC-50 Crodamol GTCC Crodamol ML Crodamol OHS Cylasphere® Cyclopentasiloxane Dantogaurd DC 193 Surfactant DC-200 Fluid DC-245 Fluid Dermonectin Dimethicone Copolyol Dispersicles™ Dissolvine NA-3T DMDM Hydantoin Dow Corning® 200-100 Dow Corning® 245 Fluid Dow Corning® 2501

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Property of

Presperse Inc. Euracli Sabinsa Croda Croda Croda Croda Croda Coletica Dow Corning Corp. Lonza Dow Corning Corp. Dow Corning Corp. Dow Corning Corp. Vevy Europe Dow Corning Corp. Elsom Research Akzo Nobel Custom Ingredients Inc. Dow Corning Corp. Dow Corning Corp. Cosmetic wax Dow Corning Corp. Dow Corning Corp. Dow Corning® 344 Dow Corning® 5324 FluidDow Corning Corp. Dow Corning® 556 Fluid Dow Corning Corp. Dowicil® Dow Corning Corp. ® Dowicil 200 The Dow Chemical Co. Polyurethane Systems ® National Starch and Dry-Flo/AC Chemical Echo-Derm™ AdvantaChem Edenol 302 Cognis Corp. ® Emulium Delta Gattefosse S.A. Emulgade SE Cognis Corp. Emulgin B2 Cabot Corporation Encapsulence™ Ciba ® Enteline 2 Presperse Inc. Eutanol G Cognis Corp. Euxyl K-400 Schulke & Mayr Finsolv TN Finetex Inc.

Trademark Firming Liposomes Flonac MS-10C Flonac MS-60C Gafquat® Ganes P-904 Generol 122E-16 Germaben II Germall II-ISP Germazide MPB Humectant Liposomes HYDRAsense ® HydroElegance™ Hydrolite 5 Hypol 2002

Property of

Collaborative Labs. Presperse Inc. Presperse Inc. ISP ISP Henkel Corp. ISP/Sutton Sutton Laboratories Collaborative Labs. Collaborative Labs. Goemar S. A. Labs 3M Symrise Inc. The Dow Chemical Co. Polyurethane Systems Hypol 3000 The Dow Chemical Co. Polyurethane Systems InstaFirm™ AdvantaChem Isopar K ExxonMobil Chemical Company ® Rhodia Jaguar CS13 Kathon CG Rohm and Haas Company Keltrol CGRTCP Kelco, Inc. Lamapon S Cognis Corp. ® Lipo Bee Lipo Chemicals, Inc. Lipo Crystal Capsules™ Lipo Chemicals, Inc. LipoCapsules™ Lipo Chemicals, Inc. Lipocol C-10 Lipo Chemicals, Inc. Lipocol C-2 Lipo Chemicals, Inc. Lipocol S Lipo Chemicals, Inc. LipoLight™ Lipo Chemicals, Inc. Lipomol™ Lipo Chemicals, Inc. ® LipoMulse Lipo Chemicals, Inc. Lipomulse™ Lipo Chemicals, Inc. Liponate™ Lipo Chemicals, Inc. Liponate NPCG-2 Lipo Chemicals, Inc. Liponate PS-4 Lipo Chemicals, Inc. Liponate SS Lipo Chemicals, Inc. Liponic™ Lipo Chemicals, Inc. Lipopeg™ Lipo Chemicals, Inc.

TRADE NAME INDEX Trademark

985 Property of

Lipoquat™ Lipo Chemicals, Inc. Liposerve™ Lipo Chemicals, Inc. Liposome Centella Sederma, Inc. Liposomes C and E Collaborative Labs. Liposomes Cetella Collaborative Labs. Lipospheres™ Lipo Chemicals, Inc. Lipospheres™ Lipo Chemicals, Inc. Lipoval™ Lipo Chemicals, Inc. Lipwax D Lipo Chemicals, Inc. Magnesium Aluminum Silicate (Veegum Ultra) R.T. Vanderbilt Company, Inc. MatrixyL Sederma, Inc. Melarrest L Collaborative Labs. ® MicroPore 3M Moisture Lock™ AdvantaChem Moisturizing Liposomes Collaborative Labs. Myritol® Cognis Corp. Myritol 318 Cognis Corp. Myritol 331 Cabot Corporation Nanosomes™ Elsom Research Nanotopes™ Ciba Specialty Chem. ® Nano-Phytosphere Coletica ® Nano-Thalasphere Coletica Natipide II Nattermann Phospholipid GmbH Naturechem OHS Caschem Inc. NeoFat 1855 Axzo Palmitoleic Acid Sigma-Aldrich Chemical Company ® Roche Vitamins Inc. Parasol 1789 ® Parasol 5000 Roche Vitamins Inc. ® Parasol HS Roche Vitamins Inc. ® Parasol MCX parsol Roche Vitamins Inc. PEG-12 Dimethicone Crosspolymer Dow Corning Corp. ® Noveon Pemulen Perfluorodecalin Sigma-Aldrich Chemical Company Permethyl® 102A Presperse Inc. Phenoxyethanol Kraft Chemical Co. Phenyl Trimethicone Dow Corning Corp.

Trademark Phytosphere® Phytotal SL Plantaren 2000 Pluronic L-62 Pluronic P75 Poly-Pore® Polytrap® Polytrap 6035 Polytrap 6038 Polytrap 6500 Polytrap 6603 Polytrap 7100 Polytrap 7150 Probiol Procetyl AWS Propyl Paraben Propylene Glycol PureGel® PVP/VA E-535 PVP/VA W735 PVP-K-90 PVP-VA E-635 PVP-VA E-735 Retin-A® Micro RetiSTAR™ Rhodasurf L-790 Rita Pro 300 Rovisme ACE Rovisome C Rovisomes Salidex

Property of Coletica Sederma, Inc. Cognis Corp. BASF Corporation BASF Corporation Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Amcol Health & Beauty Sol., Inc. Kuhs Laboratories GmbH + Co. Croda Spectrum Chemical Mfg. Corp. KIC Chemicals, Inc. Grain Processing Industries ISP ISP ISP ISP ISP/Sutton Johnson & Johnson BASF Corp. Rhodia R.I.T.A. Corporation R.I.T.A. Corporation R.I.T.A. Corporation Rovi GmbH Collaborative Labs.

986 Trademark Sandopan KST Sandopan LS-24 SanSurf Bisabolol SanSurf OC/OS Scavenol Schercamox S-AA Schercemol DISD ® SeaMollient Second Generation Liposome Sepicide HB2 Sepigel 305 Sicovit Pigments Silamine Siltech Silwax Smartvector® Solarease II Solarease OMC/B# Solarease Plus Solaveil Standamox LAO-30 Standapol® T Stearasil Steol CS-330® Steol CS-370 Structure Solance® SugaQuat Sunscreen Liposomes Tagravit™ Tagrol™ Tauranol WS-HP Tego Care 450 Tenderskin® Texapon K-1296 Thalasphere® Thixogel™

DELIVERY SYSTEM HANDBOOK FOR PERSONAL CARE AND COSMETIC PRODUCTS Property of Clariant Corp. Clariant Corp. Collaborative Labs. Collaborative Labs. Collaborative Labs. Scher Chemical Scher Chemical Collaborative Labs. Coletica Seppic Seppic BASF Corporation Siltech LLC Siltech LLC Siltech LLC Coletica Collaborative Labs. Collaborative Labs. Collaborative Labs. Uniqema Cognis Corp. Cognis Corp. Biosil Technologies Stepan Company Stepan Company National Starch and Chemical Colonial Chemical Inc. Collaborative Labs. Tagra Bio.Limited Tagra Bio.Limited Finetex Inc. Goldschmidt Kendall Cognis Corp. Coletica Bioderm Technologies

Trademark Tinoderm® Tinogard® TioSperse Ultra TN Tocopherol

Property of

Ciba Ciba Collaborative Labs. Sigma-Aldrich Chemical Company Triton-X 100 Sigma-Aldrich Chemical Company Tween® 20 Uniqema Unicept CA Universal Preserv-achem, Inc. Unichem LACA Universal Preserv-achem, Inc. Unichem SIHY 25 Universal Preserv-achem, Inc. Unisene 99K Universal Preserv-achem, Inc. Unitone DH Universal Preserv-achem, Inc. Univesene NA2 Universal Preserv-achem, Inc. Unojic A Universal Preserv-achem, Inc. Uvinul N-539-G BASF Corporation Velvatex BA-35 Cabot Corporation Velvetex BK-35 Cognis Corp. Vesisomes Vesifact AG Vexel Sederma, Inc. Vitagen Collaborative Labs. Vulca Starch National Starch and Chemical Co. Wacker Wacker Belsil® ® Wacker SLM Wacker White Protopet Witco, Performance Chem. Grp. Witconol TN Crodamol AB Croda Zenigloss Zenitech LLC ® Zilgel Oil Presperse Inc. ® Zilgel SM Presperse Inc. ® Zilgel VV Presperse Inc.

Index Index terms

Links

Index terms

Links

Active compounds

809

anti-microbial

810

better tolerance

813

bioavailability

798

keratolytic

810

long-term delivery

810

radio-labeled

812

518

Active cosmetics

128

Absorbency

748

Active delivery efficacy

382

Absorption

162

Active delivery vehicles

properties

748

drug and personal care

reducing

275

systemic

274

A A-B-A block copolymer

480

ABA-type triblock copolymers

595

Abil EM 90®

476 494

495 480 495

487

Abrasive materials skin cleansing

Acacia Acacia gum

804

encapsulation

356

751

loading, release, and partitioning

611

oil-soluble

780

oil-soluble and water-soluble

355

penetration

798

selection

522

side effects

344

solubilization and controlled release

605

stereochemistry

309

suspended

540

transported into the skin

305

water

522

water-insoluble

751

water-soluble

751

Accelerants as permeability enhancers

90

Accelerated stability testing

443

Acetone

721

Acetyl CoA carboxylase

106

Acid catalysis

199

Acid modifications

746

Acid phosphatase

90

Acne treatment Acrylate-based polymers

438

837

131

297

452

Acrylates/C10-30 alkyl/acrylate crosspolymer

304 606 818

805

549

Acrylates/carbamates copolymer

353

Actinic radiation

354

Active (core) material

324

Active agents

766

hydrophobic plant-derived

766

oil soluble

276

substantivity and persistence

836

564

874

304

615

combining two treatments

186

amine functions

Active ingredients

812

334 667

605

752

798

Active practitioners cosmetics and medicine

125

Active transportation

841

oil barrier

305

water barrier

305

Active-acid ingredients

744

Active-carrier particles

382

This page has been reformatted by Knovel to provide easier navigation.

987

988

Index terms

Links

Actives

304

339

590

636

concentration

216

controlled release

474

controlling mobilization

305

defined

7

delivery

337

examples of

694

improving passage

611

incompatible

273

ionization state

609

irritating

273

loading

292

oil-soluble

231

partitioning

609

physicochemical properties

609

premature leaching

342

properties

106

release

604

sensitive

327

solubilizing power

340

soluble and insoluble

750

transported into the skin

305

undesirable effects

339

unstable

216

Acyclovir

109

Acyl chains

287

592

Acylglucosylceramide

610

840

Adhesive patches

834

Adhesive polymers

840

Adipose tissue

139

Adsolubilization of fatty materials

506

Advertisements analysis

936

database

935

203

After-feel

327

Agar

186

Agar spheres

201

Age spots

863

Aging

112 438

hydrophilic polyurethane

516

signs

818

Agitators

145

AHA

881

activity

887

amino acid salts

885

bioavailability

882

controlled-release delivery

882

delivery systems

888

delivery technologies

889

irritation studies

882

molecular interactions

883

stinging sensation

882

AHA-based products

874

Air-ionizing electrode

479

440

288

838

293

as permeability enhancers

113

882

889

278 89

delivery vehicles

162

disadvantage of

592

fatty

622

function-based monomers

804

penetration enhancers

161

permeability enhancers

89

solvents

516

Aldehyde

671

Alga micrometer syringe

479

Alginate spheres

201

Alginates

186

encapsulation material

109

Alginic acid with chitosan

This page has been reformatted by Knovel to provide easier navigation.

276

450

202

Alcohols

Adhesion Adhesive compositions

Aesthetics

bioadhesive enhancer

84

835

800

Links

Albumin

80

degree of

598

610

83

phytosphingosine-containing

445

590

294 Acylceramide

Index terms

863

803

144

989

Index terms

Links

Aliphatic chains

Index terms

85

Aliphatic polyisocynates

515

Alkaloid black pepper

162

phytochemical

159

N-Alkanols 92

Alkoxy silane

668

162

Alternative medicine

124

Aluminium chlorohydrate

703

tetrachlorohydrex

92

delivery rate

Alpha tocopherols

Aluminium zirconium

N-Alkanoic acids delivery rate

Links

703

Aluminium zirconium trichlorohydrate

703

Aluminum foil deterioration test

774

Alveolar structure

401

AMCOL Health & Beauty Solutions ®

334

668

Amerchol’s Ucare polymer

691

materials

668

AMES test

103

monomeric or polymeric

668

Amides

550

Alkoxy silicones

Alkyl benzoate

permeability enhancers

thickeners

629

Alkyl dimethicone copolyols

687

Alkyl fatty acid esters

823

89

Amines 701

effect on foam Amino acids

Alkyl methicone

516 883

bioavailability

165

C30-45

689

esters

883

variants

689

glycine ethyl ester

888

Alkyl quats

644

permeability enhancers

90

Alkylmethylsiloxane (AMS)

686

zwitterionic

92

687

688

cetyl dimethicone

689

Amino-based monomers

low melting point

689

Aminoalditols

All trans configuration

570

aminoxylitol

All trans retinoic acid

863

Aminocyclitols

All trans retinoic acid (ATRA)

274

aminoinositol

See also Tretinoin Allin

779

671

Aminoplast polymers

198

glucosamine

232 218

Aminoxylitol

crosspolymers

218

Ammonium compounds quats

Alpha hydroxy acid Alpha hydroxy acid (AHA)

888

Aminoethylaminopropyl group

Allyl methacrylates

skin cream

888

Aminosaccharides

Allyl alcohol high concentrations

804

753 334 675 767 874 889

343 744 823 877

452 766 854 881

888 888 639

Ammonium hydroxide

885

Ammonium lauryl sulfate (ALS)

503

Ammonium persulfate

747

Amphipathic barrier

305

Amphipathic lipids

143

Amphipathic molecules

570

This page has been reformatted by Knovel to provide easier navigation.

90

990

Index terms

Links

Amphiphiles

287

positively-charged

610

Amphiphilic actives

596

Amphiphilic anchors

616

605 609

124

Hebrew

124

Sumerian

124

Amphiphilic ingredient

590

Amphiphilic lipids

142

588

Amphiphilic molecules

107 609

187

black pepper property

604

128

113

610

162

Anhydroglucose

742

746

Anhydrous cosmetic formulations

802

850

advantages Anhydrous delivery substrates

851 855

Anhydrous delivery systems

Amphoteric agent 884

Amphoteric AHA 887

drying the skin

853

multiple formulations

852

oven-drying stage

854

packaging requirements

855

formulations

886

salts

884

single skin-care formulations

852

technology

887

water and solvent components

854

Amphoteric amino acids

883

Anhydrous film coating

850

Amphoteric co-surfactants

691

Anhydrous lamellar phase

615

Amphoteric complexes

883

Anhydrous vehicles

884

tactile and rheological properties

Amphoteric formulation controlled-release mechanism

125

Anesthetics 188

arginine

Links

Egyptian

Androgen hormone

Amphiphilic block copolymer selfassembly

Amphiphilic triblock copolymer

Index terms

440

Anhydrous-coated products

883

coating method

855

886

significant novelty

851

Amphoteric substance

883

water-activated wipes

853

854

Amphoteric surfactants

539

Animal derived

193

200

Amylase

806

Animal toxicology data

918

Amylopectin

742 746

743 769

745

Anionic dye-based formulations

496

Anionic emulsion

448

742

743

745

Anionic surfactants

539

746

769

775

Amphoteric solutions bioavailable

Amylose

as permeability enhancers effect

Analgesic

89 491

black pepper property

162

Anionic/cationic complex

640

pepper

162

Anionic/cationic surfactant systems

636

Anisotropic crystals

541 132

Analysis of foam structure

502

Anointing oil

HPLC

223

Anthelmintics

lipids

293

Anchors

610

Ancient medicine

124

dermal penetration Anther

This page has been reformatted by Knovel to provide easier navigation.

160 122

991

Index terms

Links

Index terms

Anti-acne

Links

Antimicrobial activity

187

active agent

221

Antimicrobial agent

838

benefits

675

Antioxidant activity

222

drugs

854

Antioxidant vitamins

871

formulations

823

Antioxidants

OTC medication

854

pH

225

173 805 851

products

592

827

properties

593

598

treatments

853

Anti-aging

173

450

854

887

active agent

221

bioavailability

170

depletion of

779

physiologically active

865

active agent

221

properties

780

activities

763

property of piperine

163

activity

222

stability

231

benefits

675

tocopherol

225

claims

888

Antiperspirants

605

formulations

805

products

277

properties

780

skin care

883

treatment

861

vitamins

232

Antiviral drugs

Anti-inflammatory

450

Appearance

bioavailability

165

in the jar

938

piperine

163

variegated

540

Anti-irritant

836 404 889

actives

725

compositions

668

Antistatic properties hair

Appendageal absorption

actives

763

plant extracts

777

plant-derived

767

properties

780

Anti-parasitic

639 109

88

Appendages in stratum corneum

88

Applications delivery system

8

of PCM encapsulates

265

162

S4 formulations

542

Anti-wrinkling and skin exfoliants

766

structured surfactant formulations

537

Antibacterial compounds

496

Applicator plagettes

819

Antibacterials

854

AquaSapone’s AS102

316

Antiepilepserine

159

Aqueous dissolution rate

851

Antifungal agent

838

Aqueous gels

344

Antifungals

854

Aqueous phase

black pepper property

Antimicrobial black pepper property

162

changes

442

flexible foam

514

This page has been reformatted by Knovel to provide easier navigation.

438 824

450 850

669

725

992

Index terms

Links

Index terms

Links

Azone

Aqueous phase behavior monoolein

as permeability enhancer

605

Aqueous polymer solution

607

Aqueous solutions

610

Aqueous starch solution

608

Aqueous surfactant

604

Aqueous systems

Azone-propylene glycol

89 95

B Baby Boomers

818

636

Baby care products

232

film-forming properties

742

Baby oil

625

Aqueous-based products

685

Backbone

882

polymer

pH

765

Arbutin polarity

426

Arginine

883

glycolic acid

885

x-ray diffraction

885

885

886

514

Bacterial contamination

203

Bacterial flora

111

Bacterial growth in foams

517

Bacterial membrane lipids

285

Bactericides

805

Bacterio-static agent

404

Bacterium

122

139

Bandages

834

Aromatic polyisocynates

515

Barrier

Aromatically therapeutic

824

Artificial sebum

336

773

Ascorbic acid

162 771 873

576 779

®

Arlacel P135

476

Armadillo

480

495

84

Aroma sales point

577 862

See also Vitamin C

rate-limiting

104

Barrier function

85 571

modifying

89

stratum corneum

93

Barrier layer

103

bioavailability

165

Barrier properties

111

effective delivery

700

water-holding

556

Ascorbyl palmitate

865

Basal cell layer

139

Athletic tape wrap

836

Basal keratinocytes

Atomization

186

Basal layer

“Atopic” dermatitis

916

Basement membrane

78

Autoxidation

160

Bat-pollinated flowers

123

Bath and body products

327

Autumn olive (elaeagnus umbellata)

779

Bath crystals

752

Axilla bacteria

668

Bath powders

752

Axiovert

135

476

Bathing preparation

835

Ayurveda

158

159

Beads

114

Ayurvedic medicine

126

cellulose and lactose

326

Azelaic acid

810

suspended

540

163

This page has been reformatted by Knovel to provide easier navigation.

142

78

231

retinol palmitate

90

410

217

165

993

Index terms

Links

Beauty as health

126

Bee-pollinated flowers

123

Behenyl alcohol

573

“Benefit molecules”

182

Benoit Mandelbrot equation

397

Bentonite

336

Benzalkonium chloride

763

Index terms Bilayers lamellar

Links 548 570

Bile secretion 398 764

769

159

Bingham yield value

541

Bio-vectors

278

Bioactives

158

773

degradation

216

anti-bacterial agent

776

fragile

186

test results

768

Bioadhesion

189

Benzimidazoyl-benzazole

677

Bioavailability

162

Benzocaine

356

antioxidants

170

Benzofuryl-benzazole

677

beta carotene

159

enhanced by piperine

163

enhancement

158

Benzoic acid

90

Benzoyl peroxide vanishing cream

341

343

703

823

854

873

343

Beta carotene

nutrient

166

pepper enhanced

163

with piperine

159

159

bioavailability

165

Biochemical permeability enhancers

gastrointestinal absorption

165

Biochemical tools

444

with piperine

159

Biochemistry

927

Biodegradability

279

359

744

877

Betaine

487 691

489

494

of delivery system enzymatic digestibility

807

Biodegradable polymers

216

Bi-univocal relationship

401

encapsulation barriers

803

Bicontinuous cubic

610

611

liquid crystals

604

615

588

163

274

864

Bilayer membrane

590

592

593 595

597

Biodegradable-drug delivery system (Bio-DDS)

798

Biological epithelia

611

Biological humors

159

Biological lipids

610

Biological membranes

325

798

stabilize and crosslink

593

water

591

Biomonitoring devices

615

Bilayer organization

570

Bioperine®

159

163

Bilayer structures

105

Biopolymer

274

611

lamellae

696

Biotechnology

120

438

sheet

142

Biotin

703

Bilayer-forming ingredient

160

90

BHT (butylated hydroxytoluene)

615

159

Biodegradable microspheres

Betamethasone dipropionate (BMDP) 165

Bicontinuous nature

278

165

absorption

Beta hydroxy acids

160

591 This page has been reformatted by Knovel to provide easier navigation.

802

994

Index terms

Links

Index terms

Links

Birefringence

743

Braided “corn rows”

521

materials

541

Branched block copolymers

625

Bricks-and-mortar model

85 139

Broad-spectrum antiseptic additive

404

Bis(trimethylsilyl)hydroxycarboxylates promote new cell growth

675

α-Bisabolol

450

Black pepper

158

159

162

87

Bromine

delivery vehicles

162

effect on foam

516

oleoresin

160

Bromocresol purple

699

Blank liposomes

292

Bronchopulmonary disorders

159

Bleaching agents (sulfites)

852

Brownian motion

196

Bleaching reagents

747

Buffer ions

92

Blemish control

854

Buffers

92

445

827

Bulk cubic phase

605

606

packette Blistering skin disease

81

Block copolymers

623

624

629

difficult to handle

615

high-energy dispersion

604

without hydrotrope

607

polyester

624

styrene-butadiene

624

Bulk liquid crystal phase

591

Block polymers

189

Bulk surface treatments

607

Blood flow RU

379

Burst effect

809

Blood microcirculation

379

Butane diol glycol extender

Blood supply

515

skin

166

n-Butanol

BMDP

168

Butterfly-pollinated flowers

123

absorption spectra

169

Butylated hydroxytoluene (BHT)

864

permeation

170

Butylene glycol

876

Body lotion

749

Butylmethoxydibenzoylmethane

453

Body powders

741

87

C

Body temperature regulation

162

Cadherins

Body wash

751

Calcein

Borax

438

Botanicals

168

antioxidants

170

oils

777

Botanists

123

Bottom-to-top construction

401

permeation 438

permeation Bovine Spongiform Encephalopathy (BSE)

84 698 91

Calciene permeation

90

Calcium intracellular

Bovine serum albumin 90

91

189

194

104

80

Calcium alginate spheres

201

Calcium chloride (CaCl2)

803

Calcium soaps

622

California Air Resources Board (CARB)

716

This page has been reformatted by Knovel to provide easier navigation.

442

605

812

612

995

Index terms

Links

Index terms

Links

Carboxylic acid

671

Carboxymethylcellulose

594

Carcinogenicity

919

556

Carotenes

771

Capillary blood vessels

161

Carotenoids

Capillary number (Ca)

493

bioavailability

165

Capparis spinosa L

777

seabuckthorn

777

Capric/caprylic triglycerides

367

Camellia sinensis leaves

777

Cantor dust

397

398

Capacitance measurement barrier properties

375

510

Carrageenan

452

865

biopolymer

446

Caprolactam

401

Carrier effect

686

fraction

404

Carrier film

839

Capsaicin

162

oil-based dispersion

thermogenic effect Capsicum annuum

172

compatibility

162

delivery

377

non-compatible

377

273

performance

375

digested

195

starch film

751

environment

195

transport of actives

375

gelatin

192

Carrot (β-carotene)

777

particle size

261

Cast foam

523

physical forms

194

rupture

195

Casting

524

separation of

221

Catabolism

111

sizes

276

Catadyn Reaction

403

Capture-volume capacity

292

Cathepsin D

Carbamate units

514

Cationic emulsion

448

Carbohydrate coated

326

Cationic liposomes

286

delivering DNA

292

Cationic surfactants

539

laminated

soluble

536

Carbomer

452

538

as permeability enhancers

Carbon chains bilayers

Cavitands 548

microencapsulation

Carbon dioxide

Cavitation

81

89 187 91

Cavity prevention

838

in foam reaction

524

Cayenne peppers

162

supercritical

186

CDD array video camera

480

Carbonless paper

196

Cell differentiation

863

Carboxy silicone polymers

637

Cell membranes

Carboxylate head group

550

286 305

Carboxylate hydrophiles

551

This page has been reformatted by Knovel to provide easier navigation.

217

217

515

fluidity

382

524

foaming

324

382

95

defined

Carbohydrates

751

Carrier systems

162

Capsules

863

166

287 314

294 316

996

Index terms

Links

Index terms

Cell membranes (Continued) penetration

103

Cell replication

79

Links

Chemical barriers

305

Chemical degradation

231

Chemical emulsifier

316

Cellular binding proteins

863

Chemical encapsulation techniques

260

Cellular degradation

111

Chemical modification

742

Chemical moieties

667

Cellular junctions

81

Cellular retinol binding proteins

863

Chemical penetration enhancers

106

Cellulite

438

Chemical permeability enhancers

89

Cellulose

186

216

Chemical skin irritation

836

encapsulation material

109

Chemical-containing products

912

particles

109

Chemically modified starches

747

750

Chemistry and cosmetics

398

Chinese medicine

127

Chitins

854

Chitosan

186 274

Cellulosic products Cementsome

78

Centella asiatica

297

Centrifugation

698

Ceramides nomenclature

79

84

105

140

142

596

84

transition temperature Cetearyl alcohol dispersion

bioadhesive enhancer

278

complex coacervates

278

294

matrix

276

316

microparticles

219

450

Chitosan-entrapped retinoic acid

Cetyl dimethicone copolyol

495

Chitosphere™ encapsulation

Cetyl alcohol

316

waxes

573

technology

622

Cetyl dimethicone

475

476

485

689

Cetyltrimethylammonium bromide

610

Cetyltrimonium chloride

639

Chain fluidity

480

220

Chlorinated solvents

220

Chlorohexadiene gluconate

703

Chloromethylsilane monomers

718 717

Challenge phase

921

Chlorpheniramine maleate

609

Challenge testing

542

Cholesterol

Challenges

189

83 142

Chaos science

79 396

Chaotropic agents penetration enhancers

161

216

277

516

Chlorosilanes

Chalone

188

Chlorine

572

138

611

279

sensitive to

of formulations

161

275

Chlorinated solvent systems

effect on foam 640

746

synthesis inhibitor Cholesterol sulfate

81 143

Chronic exposure effects

916

ChronoFlex®

354

Chelating agent

445

Chronospheres

353

Chelating molecules

163

chemistry

354

This page has been reformatted by Knovel to provide easier navigation.

140

90

Choline

®

85 314 90

356

359

997

Index terms

Links

Index terms

Chronospheres® (Continued)

Links

Clonidine transdermal

89

converter

357

delivery system

358

Cloud point

diffusion delivery

357

Cloudiness

entrapment system

359

glass transition temperature

355

glycolic acid

353

359

manufacture

357

358

water-soluble actives

357

Chymotryptic enzymes

112

Cidofovir

109

Cinnamate

688

Circadian rhythms

161

Citric acid

202

703

Coacervates

509

Citricidal

768

771

granular

505

Clathrate systems

440

lamellar

505

partitioning

502 510

spherulitic lamellar phase

217

Clay facial treatments

122

539

Clustering of products

937

Co-reactive actives

836

Co-structurants

539

Coacervate foams

501

Coacervate gels

510

504

510

503

504

188

196

197

324

325

Coacervate particles dispersability

Clathrates microencapsulation

197

Coacervation

Clays

510

suspended

540

complex

803

Cleansing agent

438

encapsulation

218

Cleansing cloths

523

simple

801

Cleansing foam

517

simple and complex

800

Cleansing packette

827

Cleansing products

592

Cleansing wipes

523

water-activated

Coagulation interparticle

108

Coated textile fabrics

521

514

Coating methods

852

Clear products

327

Coatings

Clear shampoos

691

Clear surfactants

538

Cleaved enzymatically

161

853

on nonwoven substrates

Clinical research 19th century Clinical safety testing constructing a program

912 913

926

915

Clinical studies

913

Clinical testing

912 924

Clomethiazole (CMZ)

609

803

913 927

916 928

522

Cocamido propyl betaine (CAPB)

503

Cocoa butter

450

Coconut water

173

Codification of product

404

Coenzyme Q10

160

bioavailability

165

with Bioperine

160

Cold cream preparation

438

Cold-water soluble

747

Cold-water swellable

747

This page has been reformatted by Knovel to provide easier navigation.

165

998

Index terms

Links

Coletica

Index terms

Links

Compression-decompression

804

isotherms

Coleus forskohlii

481

Concentration gradient

bioavailability

168

extract

165

Collagen

161

399

594

Concentration of actives

274

799

805

863

Condensation reaction

718

requirements

411

boosters

805

Conditioners

725

encapsulation material

109

Conditioning benefits

691

Collagen dressings

Conductivity measurements

filmogenic properties

799

haemostatic properties

799

emulsion characterization

Collagen fibers biosynthesis

881

552

Conjugate coacervate co-phase

501

Constant release rate

695

Collagen-based Thalaspheres®

Constipation

159

277

Consumer care applications

496

Collagenase enzyme

113

Consumer challenges

138

Collimated beam

480

Consumer communication

935

Colloid

196

Consumer test

952

Colloidal stabilization

604

Consumers

Color

expectations

sales point

139

Color cosmetics

204

shine

854

685

Color foundation

824

Colored microcapsules

325

Colored pigments

326

suspended

725

540

185

Contact dermatitis

446

Contraceptive patches

304

Contraceptive sponge

524

Controlled delivery

216

Controlled release

326

applications

604

with chitosan

274

Combination polymers

522

delivery

882

Combing characteristics

642

mechanisms

186

Combining two treatments

818

microencapsulation

217

systems

611

technology

883

of water soluble

222

Controlled volatility

726

Convective heating

608

Cookbook programs

924

Complex coacervates chitosan Complex coacervation

278 196 276

Complex lipids

285

Complex precipitation

275

Complexation

196

Complexes silicone Complexing agents

197 324

636

218 693

Cooling effect localized

265

637

of shaving cream

265

888

of skin cream

265

Cooling sensation

262

This page has been reformatted by Knovel to provide easier navigation.

326 605

883

999

Index terms

Links

Index terms

Cooperative Research and Development Agreement

762

Core lamellar

501

material

324

Corneocytes

104

502 142

Links

Cosmetic emulsion

861

Cosmetic formulations

798

solid anhydrous

851

surfactants

371

vitamin C derivative

812

vitamin E

222

filled

111

shapes

82

range of volatility

716

Corneodesmosomes

104

Cosmetic marketers

138

Corneometer

773

Cosmetic oils

295

Cornification

863

Cosmetic products

338

Cosmetic industry

See also Keratinization Cornified cells Cornified envelopes Cornstarch

Cosmetic vehicle 160

anhydrous and aqueous

80

Cosmetic waxes

336

743

748

762

769

780

356 850

Cosmetic/cosmeceutical FPEC applications

403

basic, unmodified

741

industry

396

native

742

Cosmetics

slurry

763

304 697

Correlation

applications

440

110

aqueous-based

440

Corticosteroids

161

delivery systems

767

Cosmeceuticals

4 128 343

humectant

770

medicinal activity

304

problems

438

products

439

in vitro and in vivo

106 304 766

126 334

advancements

316

bioavailability

165

Cosmetics and Pharmaceuticals

biochemical description

304

Cosmospheres

delivery systems

305

benefits

326

development

304

sizes

326

trend for advancement

314

Cottonseed oil

450

Cosmetic actives

366

Covalent bonding

400

encapsulated

382

Cream formulations

230

Cosmetic agents topical delivery Cosmetic applications

800

725

facial powders

741

microencapsulation

799

regulatory approval

766

skin-care products

852

trigger the release

800

7 323

Cream mixture

835

spreading 798

525

Creaminess at pickup

938

Creaming

108

Creams and lotions

725

Creamy appearance

538

This page has been reformatted by Knovel to provide easier navigation.

474 766

326

773

605

1000

Index terms

Links

Index terms

Links

thermal, mechanical, and electrical

Critical micelle concentration (CMC)

288

Critical packing factor

590

Cross polarized light

571

Cubic-to-lamellar morphologies

611

Crosslinked starches

746

Cubosomes

595 606 615

properties

Crosslinking chitosan chains

275

degree of

695

Crosslinking agent

197

sulfur

624

Crust lamellar

501

Cryo-electron micrographs

367

Cryo-TEM

293

Cryogenic Transfer Transmission Electron Microscopy

697

Crystal immobilization

403

Crystalline phases

570

Crystalline polymer

401

504 607

606

Crystals 541

CTFA approved ingredients

222

Cubic gel phase

595

Cubic phase

588

delivery vehicle

609

effects

611

functionalization

610

hygroscopic

615

liquid crystal

606 609

nanostructured

611

particles

609

permeable to water

612

property enhancement

605

test formulation

612

615

dispersions

607

physical properties

605

physicochemical properties

605

precursors

608

609

production

605

607

starch-encapsulated

615

via dilution

607 886 924

bioavailability

165

with Bioperine

160

bioavailability

447

anisotropic

608

605

Curcuminoids

Crystalline transition temperature Crystallization process

605 608

917 926

920

Curcumin

548

404

gel-to-liquid

604 607

application

Cumulative irritation

Crystalline prepolymer micelles

611

173 168

Curved lipids

107

Custom-formulating materials

127

Cyclic polydimethylsiloxanes

719

Cyclic silicones

684

Cyclo-oligosaccharides

804

Cyclodextrin

187

719 308

314

316 610

611 607

delivery vehicles

162

powders

802

Cyclohexane

200

Cyclomethicone

114

337

357

450 716

576 721

693

608 crosslinking

693

evaporation

694

thickeners

629

Cyclopentasiloxane (D5)

702

®

805

Cytokeratins

80

Cylasphere Cytokines

This page has been reformatted by Knovel to provide easier navigation.

111

438

1001

Index terms

Links

D

Index terms

Links

pathways

140

d-elements

231

sales point

139

D-panthenol

379

systemic

411

D-spacing

538

topical

140

D-squame®

803

D-units

718

Dandruff

874

Delivery films

Dansyl chloride cell turnover model

887

Zeina B860

410

Delivery carriers 719

nonwovens

853 750

751

Delivery of active agents

Database

undesirable physical forms

834

of advertisements

936

safety complaints

927

Delivery of actives

De Gennes limit

396

controlled release

687

Decamethyl cyclopentasiloxane

721

diffusion-controlled

356

Decamethyl cyclosiloxane

766

sequential release

687

Decoction

129

Delivery of agents

438

Delivery of nutrients

Decorative effects variegated

oral

541

Delivery substrate

Defects membrane bilayers

Delivery System Movement

107

Delivery systems

Deficiencies of delivery systems

142

Deformation-based decay

367

Degradable polymers

216

Degradation

164 852 4 95 137 314 371 452 597 798

of actives

233

chemical

231

benefits of phospholipids

594

protection from

217

bioadhesive

278

vitamin F

228

capabilities

141

controlled

216

Dehydration-rehydration loading of liposomes

292

cosmetic products

913

vesicles

296

cosmetics and medicine

124

current technologies

128 444

Delivery

410

424

definition

410

cyclodextrin-based structure

dermal

414

defined

importance of formulation type

424

233

7

102

design

102

106

development

308

importance of physico-chemical characteristics

424

economically efficient

403

injection

140

effective

140

from microemulsions

418

oral

140

419

120 182 334 403 453 668 917

efficacy factors encapsulation

This page has been reformatted by Knovel to provide easier navigation.

8 686

121 193 366 438 454 686

1002

Index terms

Links

Index terms

Delivery systems (Continued)

Links

Dendritic shielding

218

Deodorants

496 836

entrapment

686

enzymatically activated

810

FPEC

405

actives

726

improvements

142

compositions

668

injectable

123

injectable and oral

304

pH

225

intradermal

121

thioglycolates

837

multicomponent

189

Derivatized silicones

677

natural

122

Dermabrasion

518

optimal

115

Dermal abrasives

854

oral

123

origins

124

Dermal absorption

918

piperine

159

polymeric

444

primary goal

874

primary use

724

qualities

274

retinol

277

safety

172

sexual reproduction

121

sticks

725

targeted

110

technological

122

technologies

699

template technology

314

topical

122

transdermal

121

two-in-one product

818

Dermatological products

vehicle development

439

aesthetic considerations

440

volatile fluids

917

boundary

438

Delivery vehicles

162

OTC and Rx

874

Rx

440

tetrahydropiperine Dermal and transdermal delivery inverse correlation? defective synthesis Dermal delivery

419

123

419

as function of formulation type

419

measurements in vitro

419

Dermal irritation

919

Dermal penetration

919

Dermal sensitization

919

Dermalab evaporimeter

612

by occlusion

834

609

exotic

605

liposome

122

Dermatology

Delivery/carrier system

934

Dermis

Denaturation

276

Dendrimers

109

Dermatological research multiple topical preparations

396

417

421

921

Dermatitis

273

308

888

as a function of polarity of penetrant

cubic phase

112

165

Dermal components

122

Dendrites

725

Depilatories

animal

See also Molecular trees

669

microcirculation

93

824 818 438

912

78

103

161

410

103

Dermis-epidermis junction

113

Desaturases

112

This page has been reformatted by Knovel to provide easier navigation.

139

1003

Index terms

Links

Index terms

Links

Desmocollins

84

Digestion

121

Desmogleins

84

capsules

195

Desmosomes

78

Diglycerol

484

81

breakdown products

83

Dihydrosphingosine

electron-dense

83

Dilatant viscosity

626

plaques

81

Diltiazem-HCl

609

Dilution

196

84

122

84

Desquamation

80

regulated

112

cubosomes

605

606

Detackifiers

750

Dimethicone

Detergent dialysis

288

Detergent-resistant membranes

296

114 357 717 726

335 449 719 766

292

Detergents foam

502

effect on stability

225

penetration enhancers

161

low viscosity

693

Dextran

608

methacrylated

Dimethicone copolyols

609

DHEA 165

backbone hydrocarbon chains

701

foam generation

692

Dialcohol/dicarboxylic acid

804

Dimethiconols

Dialysis

698

Dimethylacetamide

Diamine/dicarboxylic acid

804

Diamond bicontinuous phase

607

Dibenzoylmethane UV screens

675

Diblock copolymers

625

as permeability enhancers

278

Differential concentration

309

hydrolysis and condensation as permeability enhancers Dimethylsiloxanes

80

Diffusion

411

719 89 693

as permeability enhancers

809

89

DIN 5033

379

Dioic acid

427

Dioleoyl phosphatidylcholine

610

capability

104

Dipalmitoyl phosphatidylcholine film 483

cell

413

Diphenylmethane diisocyanate

515

cells

412

Diphenylpicrylhydrazyl radical test

779

416

coefficients

88

Discolor upon aging

516

Fick’s laws

93

Disease pathogens

122

passive

87

Disodium cocoampho diacetate

503

Dispensatory of the United States

127

Dispersant-inhibitors

622

Dispersed lamellar phase

536

rate stratum corneum Diffusivity

103 94 411

722

Dimethylsulfoxides

881

process

89

Dimethylformamide

626

Differentiation normalized

724

Dimethyldichlorosilane

610

Diethylaminoethyl (DEAE)-dextran bioadhesive enhancer

699

See also Silicone polyethers

217

bioavailability

690

186

195

This page has been reformatted by Knovel to provide easier navigation.

429

337 576 722

1004

Index terms

Links

Index terms

Links

fragmentation

493

milling

509

recoalescence

493

749

size distribution

324

Dispersion method

199

Drug bioavailability

Dispersion of Polytrap

338

Dispersion of sunscreen

446

Dispersosomes™

314

Dispersed phase

607

Dispersicles™

130

314

316

Dispersing bath powder ideal flow properties

in the body Drug delivery systems

Dissolution speed of

old drugs

835

Dissolvable adhesive patches

834

Dissolvable patch

842

Distearoyl phosphatidylglycerol

610

Disulfide linkages

80

Divalent ion

92

Divinylbenzene

338

DMSO

161

DNA

438

delivering to skin

292

repair enzymes

297

Drug metabolism

841

micropores or channels

912

Doppler measurements

379

regulated efficiency

159

Double emulsion

219

Double refraction

541

Dow Corning® 2501 cosmetic wax

691

Dow Corning® 5200 formulation aid

691

Dow Corning® 5324 fluid

691

Downsizing

129

DPPH radical scavenging

170

Drivers

934

creams

938

sensory profile analysis

938

Droplet deformation and breakup

493

163 611 216 92

Drug-containing liposomes

596

delivery

769

Drugs

703

Drugs and cosmetics

304

Drugs industry

766

4

Dry powder microcapsules

192

Doshas

308

Drug transport

Dosage controlled

305 605

Drug release

83

85

Doppler imaging

121 474 813

Drug passage

Dodecamethylcyclohexasiloxane (D6) 721 Domain mosaic model

801

194

Dry skin

558

DRY-FLO/AC®

767

837

DRY-FLO/AF® 314

493

starch

765

Drying of capsules

221

Dryness

612

Du Nouy ring method

552

Dual treatment delivery

819

“Due diligence”

913

Duplex film compression isotherm

485

Dynamic equilibrium state

366

Dynamic light scattering (DLS)

368

Dynamic surface tension relaxation

494

Dyspepsia

159

This page has been reformatted by Knovel to provide easier navigation.

369

439 611

1005

Index terms

Links

E Eau de toilettes

592

EB. See Epidermolysis bullosa (EB) Eccrin sweat glands

161

Echo-Derm™ delivery system

142

EFA. See essential fatty acids Effectiveness of active

103

Efficacy

Index terms

Links

Emollients

625

natural

854

suspended

540

Emulsification

121 316

3-phase

187

of active liquid

324

of oils

767

128 552

192 564

Emulsifier-based products

claims

912

evaluation

575

problems

443

Eflornithine HCl

837

Emulsifiers

129

431

438

Egg shell membrane

170

442

750

768

Elaeagnus umbellata (autumn olive)

779

Elastic fibers improved quality

881

Elastic gel

774

Elastin

863

Elastomer backbone

694

Elastomeric films

628

Elastomeric polymers

625

Elastomeric silicone polyether

694

homogeneous blends of vitamin E Elastomers thermoplastic Electrical resistance

cause irritation

554

delivery system without

276

polymeric

561

sodium stearyl phthalamate

549

surface-active nature

446

Emulsifying agents

187

Emulsion droplets

576

Emulsion stabilizer

559

sodium stearyl phthalamate 702

694 622 624

548

Emulsion-based products

596

Emulsion-based vehicles

444

Emulsions

128

130

132

224 421 453

225 438 700

418 442

884

Electrolytes

597

amounts

537

conductivity measurements

552

co-structurant

539

formulations

574

Electrometer output

480

manufacture

445

Electronic Industry

697

multiple-phase

553

91

oil-in-water

201

220

Electrophoresis

611

preparation

220

487

Electroporation

92

rheological profile

564

stability

561

thickeners

622

vesicles

598

water-in-water

217

without heating

443

Encapsulated actives

102

Electroosmotic effect

Eleidin

161

Elongational viscoelasticity

744

Elution rate

356

Embryo capsule

218

Emollient oils surfactants

851

93

degree of penetration

This page has been reformatted by Knovel to provide easier navigation.

808

446

802

548

1006

Index terms

Links

Index terms

Encapsulated actives (Continued)

Links

Endocytosed nanoparticles

110

membrane

804

Endogenous epidermal metabolism

612

release of

800

Endpoints

919

trigger for release

801

Energy state

636

Enhanced functionality

873

Encapsulated vitamins stability

224

Encapsulating film

752

Encapsulation

123 192 324 798

Enhancers 182 305 590 799

184 308 687

permeability

89

Enlarged pores

855

Enteric delivery encapsulate drugs

769

Entrapment

applications

204

barriers

803

benefits of

203

“chemical”

188

Chitosphere™ technology

279

cosmeceuticals

308

cost-effective alternative

700

of drugs

799

efficiency

290

enzymatically activated

813

customization

339

extrusion-based

186

Entrapped retinol

801

hot melt technique

219

Environmental conditions

main capabilities

808

market trends

189

Environmental stressors

373

material

109

Environmental-prone oxidation

374

methods

217

molecular

187

Enzymatic degradation

807

monomolecular

217

Enzymatic hydrolytic activities

802

new and smarter

804

Enzymatic metabolism

111

no release

686

”non-chemical”

186

Enzymatic penetration enhancers

106

products

183

Enzymatic reactions

111

reduces toxicity

273

Enzymatically activated encapsulates

798

solvent removal technique

220

systems

114

Enzymatically activated encapsulation

798

technology

799

Enzymatically cleaved ester linkages

669

urea-formaldehyde membrane

188

Enzyme modifications

746

of vitamins

222

Enzymes

112

water-soluble actives

199

Encapsulence™ trademark

260

penetration enhancement

161

permanent

260

spheres

323

Entrapped active compounds

292

trigger the release

801

Entrapped emulsion

443

Entrapped ingredients

339

Entrapped polymer

sensitive to

219

193

Envoplakin

438

83

interaction with piperine

163

mammalian

279

metabolism

163

This page has been reformatted by Knovel to provide easier navigation.

374

438

1007

Index terms

Links

Epidermal thickness normalized Epidermal-dermal interface

Index terms

863

Ester moiety

669

881

Esterification

746

Esterified prodrugs

378

Estradiol

162

78

Epidermis

Links

78 160

103 161

139 410

permeation

88

active compound

809

release rate

695

actual transport route

367

solubility

695

five-layered

160

transdermal

keratinization process

112

Eternal life

125

lipids

166

Ethanol

606

skin layer

103

affects barrier

105

suprabasal

78

high concentrations

232

81

Epidermolysis bullosa (EB)

89

injection

288

Epidermopoeisis

771

penetration enhancers

161

Epilepsy

159

Ethanol-water systems

®

342

enhance penetration

Epiquin

See also Hydroquinone formulation

Ethanolic extraction

810

863

Etherification

746

Epithelial tissue

277

Ethnic hair care

520

Ethoxylated fatty alcohols

850

Ethoxylated polyhydroxystearatebased emulsifiers

377

Ethyene glycol distearate (EGDS)

503

Ethyl acetate

721

78

Epsilon caprolactam

403

Equilibrium partition value

609

Equilibrium spreading pressures (ESP)

480

Equipment

Ethyl butylacetylaminopropionate

577

hydrophilic polyurethane products

524

Ethyl cellulose

200

meter mix

524

precipitation

219

Erosion of polymers Erythema

216 359

612

Erythrocytes number and velocity Erythropoietin delivery by sonophoresis Essential fatty acids

91 222

Essential oils as permeability enhancers delivery vehicles

89 162

Ester linkages enzymatically cleaved

Ethylene glycol dimethacrylate

335

Ethylhexyl methoxycinnamate

453

669

450

339

Eucerin water-in-oil emulsion

379

292

105

Epithelial cell growth Epithelium

608

612

European Commission Directives

914

European Union (EU)

914

Evaporation number

719

Evaporation rates

717

complete range

723

Evaporation time

719

Ex vivo experiments

807

Exfoliates suspended

This page has been reformatted by Knovel to provide easier navigation.

540

721

721

1008

Index terms

Links

Index terms synthesis inhibitor

Links 90

Exfoliating cleanser

337

Exfoliation

887

Fatty acids-propylene glycol

Exogenous lamellar gel

571

Fatty alcohols

378

Fatty esters

850

Exogenous water

95

paradoxical addition

615

Fatty quaternary compounds

637

topical application and removal

612

Fatty quats

640

Exotic materials

604

FDA

913

Expanded lamellar phase

536

Exposure/use concentration

917

See also Food and Drug Administration (FDA)

Extraction

129

protocol

576

organic solvent

220

regulations

124

Extraordinary ray

541

requirements

404

Extrusion-based encapsulation

186

Federal Food and Drug Act

913

Eye irritation

640

Eye shadow

837

Federal Food, Drug, and Cosmetic Act

127

Federal Modernization Act

914

Federal Trade Commission (FTC)

127 127

537

F Face tonics

592

Federal Trade Commission Act

Facial cleansing cloths

523

Feel sales point

Facial makeup

622 639

139

Fentanyl

removal

518

Facial masks

751

Facial moisturizer

877

Fenugreek

837

Facilitated diffusion process

334

Fertilizers

160

Fair Packaging and Labeling Act

127

Ferulic acid

112

transdermal

89

Fevers

Fantesk™ starch-oil composites

763

reducing

159

technology

762

Fibroblasts

113

Faraday box

479

Fick’s law

Farnesol

810

Fat-soluble isoprenoid

277

Fat-soluble materials

326

Fatty acids as permeability enhancers

93 411

Filaggrin degradation

84

166

222

326

89

90

187

Fillers polystyrene domains

80 111 835 625

Film coatings

delivery vehicles

162

control

522

essential and non-essential

140

on nonwoven substrates

522

long chain polyunsaturated

112

Film formers

627

penetration enhancers

161

Film-forming ability

751

soaps

622 This page has been reformatted by Knovel to provide easier navigation.

103

104

1009

Index terms Film-forming polymers flexibility

Links 823

835

Index terms 838

hair care

839

Film-forming technology

744

Filmogenic properties

799

Filtration

129

Foam products

750

Links 519 519

Foaming mechanism

515

Foams

501

502

analysis

502

aqueous phase

514

516

327

casting

523

524

First aid bandage

836

delivery products

520

“First pass” effect

111

fraction technique

481

"First pharmacoepia"

124

hydrophilic polyurethane

515

Fissuring

446

hydrophilic urethane

521

lamella

503

laminates

523

manufacturing

524

“nano”

521

open celled

519

polyurethane prepolymers

520

S4 formulation

542

shampoo

509

stabilizer

725

structure

517

Fines undesirable

FITC-dextrans

92

5-Fluorouracil

341 417

permeation

88

Flaking/cracking problem

852

Flatulence

159

414 419

416

Flavonoids high levels Flavors

777 192

Flexible foam aqueous phase

514

Floc-coacervates

505 510

Flocculation

509

Flooding compounds

623

Fluid bed process

752

Fluidity of membrane

85

of stratum corneum

89

Fluorescein

699

Fluorescence

114

noticeably rapid release Fluorescent microscopy

444 811

Fluorine effect on foam

516

Flux across membrane

103

Foam boosting effects

692

Foam lamella

502

Folic acid 507

509

517

518

304

766

703

Follicular delivery route

162

Follicular pathways

113

Follicular penetration

298

Food and Drug Act of 1906

912

Food and Drug Administration

341

Food and Drug Administration (FDA) 127 Food and Drug Cosmetic Act

128

Food applications

444

Food, Drug and Cosmetic Act

914

Food emulsifiers

604

Food flavoring

192

Food processing techniques

762

Foods prepared

192

Foreseeable misuse

919

Formaldehyde reticulation

803

Formulation mapping

414

This page has been reformatted by Knovel to provide easier navigation.

415

1010

Index terms

Links

Index terms

Links

421

advertisements

324

Formulations

194

challenges

141

delivery

671

composition influence

377

encapsulated

192

delivery-optimized

430

hydrolysis and release

671

design

102

silicone delivery systems

669

development

934

Fragrant silane precursors

669

flexibility

344

Fragrant silicone polymers

675

influence on skin delivery

432

Franz cell

375

919

liposomal fluids

592

Franz cell diffusion

807

809

manufacturing

750

stability-optimized

430

Franz cell in vitro diffusion method

875

targeting

140

Franz diffusion cell studies

877

topical

102

Franz diffusion system

695

viscosity

411

Free fatty acids

573

Free glycolic acid

889

Free vitamin A

376

Free vitamin E

375

Forskolin

225

171

bioavailability

168

permeation

165

170

Foundations

725

837

Fourier transform infrared (FTIR)

571

572

Free volume theory 574

381

94

Free-flowing powders

336

salt forms

885

Free-radical scavenging

170

Fractal broom

403

Freeze-dried liposomes

296

Fractal chemical structure

401

Freeze-fracture TEM

293

Fractal compression

396

Freeze-thaw cycling

542

Fractal curves

399

French Press process

290

Fractal dimension

401

French Technical Research Center

799

Fractal geometry

396

Fruit acids

703

application

404

Fruit derived extracts

777

apply to chemistry

397

FTC. See Federal Trade Commission

point of view

400

Fractal membrane

397

Functional cosmetics

Fractal molecular sponges

404

Functional materials

Fractal molecules

400

(FTC)

in aqueous phase

124 521

Functional silicone

Fractal poly-epsilon caprolactam (FPEC)

401

403

dimethicone

717

Fractal polymers

109

401

Functionalization

609

small quantity

403

second approach

610

Fungal growth

Fractal space intersections

401

Fractal sponges

404

Fragrances

445

668

836

941

805

in foams

517

Fungicides

160

Fungus

122

This page has been reformatted by Knovel to provide easier navigation.

304

1011

Index terms

Links

Index terms

G Gamma interferon delivery by sonophoresis

91

Gamma-linolenic acid

143

Gargles

159

Gastrointestinal absorption

163

Gastrointestinal disorders

Links

Gemini-type surfactant

551

Gene delivery systems

286

Gene transfection

110

Generally Recognized As Safe (GRAS) 165

769

Generator

399

159

Genetic promoters

438

Gastrointestinal function

163

Ghosting

274

Gastrointestinal uptake

158

Giant unilamellar vesicles (GUV)

286

Gel coacervates

502

503

Ginger

159

Gel formation

598

769

Ginger (zingiberol, gingerol)

777

of lamellar phases

597

598

Gingerol

of liposomes

595

596

Gel formulation

225

Glabridin

Gel particles

510

Glands

Gel phase domains

thermogenic effect

85

in dermis

162 112 161

Gel system

276

Glass transition temperature

355

Gel technologies

188

Glitter suspensions

540

Gelatin

186

Glittering pigments

836

188

803

capsules

192

Glossy layer

410

coacervation

196

Glove-in-a-glove

762

composition

196

Glucocorticosteroids

107

encapsulation material

109

Glucosamine

274

precipitation

219

solution

196

Gelatinization

747

hydration

743

Gelation

401

Gelled hydrogenated polyisobutene

450

enzymes 750

623

Gelled silicone

450

Gellifying agent

801

Gelling agents

627

Gelling polymers

629

Gels

377

delivery levels

418

polymer-based

629

viscosity

626

775 278

888

703

770

421

279

Glucosammonium cation

889

Glucosidic bond breakage

747

Glucuronic acid

163

Glutaraldehyde

275

cross-linking agent

694

Gelled oil

627

Glucosaminidases

Gelled matrix three-dimensional

278

197

Glutaraldehyde reticulation

803

Glycerides

143

Glycerin

612

Glycerin-based lotion

615

Glycerol

588 780

Glycerol monooleate (GMO)

552

Glyceryl monoesters

573

Glyceryl monostearate

316

This page has been reformatted by Knovel to provide easier navigation.

588

1012

Index terms

Links

Index terms

Links

Green tea extract

170

888

bioavailability

168

888

permeation

165

Group opposites

636

Glyceryl stearate

549

Glycinamide Glycine ethyl ester

552

573

Glycol distearate

170

suspended

540

Growth factors

111

438

Glycol extender

515

Guar gum

476

751

Glycolate anion

889

Guest molecules

Glycolic acid

675 881

703

physical and chemical properties

874

Gums natural

875 186 203

arginine solution

886

diffusion

359

non-amphoteric

886

stinging and burning

885

H

326

3

275

Haemostatic properties

799

Glycolipid-containing liposomes

Gyroid bicontinuous phase

H testing

Glycols penetration enhancers

161 80

Glycoproteins transmembranal

84

Glycosaminoglycans

799

biosynthesis

growth inhibitors

837

growth promoters

496 496

Hair and skin conditioner

496

Hair care

225

232

327

605

725

818

519

286

color

496

520

161

conditioning

520

642

685

deposition of actives

510

ethnic

520

fixatives

496

foam products

519 104

810

Grading scale selecting

921

Granular coacervates Granular layer

503

504

78

410

505

follicles

Granules lipids

837

cleansing

Glycosphingolipids Goose bumps

610

Hair and skin cleansers

881

in liposomes

607

Hair

Glycolysis anaerobic

188

811

111

Grape seed oil

450

GraphiSenses

934

characteristics

949

sensory evaluation

938

sensory profiles

941

Gravimetric Absorbency Testing System (GATS)

748

Gravimetric system

612

91

937

949

952

gloss sprays

725

market

521

oil removal

510

shampoo

519

styling gels

725

test formulas

642

tonics

592

treatments

173

Half-life

This page has been reformatted by Knovel to provide easier navigation.

226

725

1013

Index terms

Links

Halogen-based compounds

Index terms

516

Halogen-containing molecules preservatives

517

Links

High shear, high pressure process

448

449

High shear process

141

606

High shear rates

447

High shear techniques

187

Handbook of Domestic Medicines and Common Ayurved

159

High surface potential

488

Hard phase copolymer

624

Highly volatile substances

721

Hausdorff dimension

396

Hildebrand solubility parameter

Head group aqueous characteristics

570

HIV

Headgroups

287

Health care

126

practitioners

infections

89 918

HLB

128

emulsifiers

475

Heat-seal configuration

819

surfactants

475

Heat-stable active agents

840

system

637

Helmholz double layer

764

HLB-independent emulsifier

Hemorrhoids

159

HMDS. See Hexamethyldisiloxane

Henderson-Hasselbalch equation

882

HMGCoA reductase

106

Heparanase-1

112

Homogeneous appearance

442

HEPES buffer

92

Horny cell layer

139

Heptaglycerol

484

Horny layer

375

487

549

142

See also See stratum corneum

Herbal extracts bioavailability

165

Hot melt encapsulation

186

219

with Bioperine

160

HPLC analysis

223

224

Herbicides

160

Human body temperature

262

Hexadecane

475

488

Human clinical trial

918

Hexamethyldisiloxane (HMDS)

716

719

Human sebum

776

723

Human serum albumin

799

Hexamethylene diisocyanate (HDI)

515

Human skin

590

Hexyl isostearate thickeners

629

bicontinuous cubic phase

605

High density polyethylene (HDPE)

623

biopsy

808

High density polymers

404

Humectants

628

High energy processes

606

Hummingbird-pollinated flowers

123

High energy ultrasound

611

Hyaluronic acid

356

biopolymer

279

penetration enhancement

162

High performance liquid chromatography (HPLC)

771 812

803

722

808

Hydrated granules

743

High pressure, high shear dispersions

450

Hydrated thickening agent(s)

452

High pressure, high shear processing

452

Hydration

607

High pressure homogenization

592

High pressure liquid chromatography (HPLC)

373

375

controlled

326

cubosome formation

605

695

This page has been reformatted by Knovel to provide easier navigation.

615

495

1014

Index terms

Links

Index terms

Links

Hydrophilic and lipophilic

Hydration (Continued) enhancement effect monoolein-ethanol solution of skin Hydration dermatitis

93

emulsifiers (HLB)

450

609

Hydrophilic emulsifiers

475

93

Hydrophilic group

588

93

Hydrophilic medications

354

Hydro-entangled process

853

Hydroalcoholic extract

779

external water phase

695

Hydroalcoholic gels

162

Hydrophilic molecules

106

Hydrocarbon chains

570

liquid behavior

570

Hydrophilic permeants

Hydrocarbon oils

629

Hydrophilic polyurethanes

Hydrocarbon permeability enhancers

Hydrophilic moiety

permeation route

89

Hydrocolloid emulsions starch:oil-in-water

766

Hydrocolloid gel emulsions

767

choice of oil

769

Hydrocortisone

414 594

770 417 766

780 419

Hydrocortisone acetate transport of

94

87 88 514

laminated

523

manufacturing

524

molded

524

prepolymers

522

Hydrophilic portions

610

Hydrophilic prepolymer

514

Hydrophilic products

403

Hydrophilic properties

95

Hydrophilic solids

851

Hydrodynamic shear rate

493

Hydrophilic stabilization

570

Hydroentangling

840

Hydrophilic surfactant

487

Hydrogen bond acceptors

89

Hydrogen bonding

399 570

476

Hydrophilic-lipophilic balance (HLB) 839 400 636

404

Hydrophobes

448

Hydrophobic actives

290

Hydrogen chloride

719

Hydrogen peroxide

747

Hydrolysis

700

Hydrophobic fluid formation

447

degree of

838

Hydrophobic group

588

fragrance

671

Hydrophobic interaction forces

367

of lipids

292

resistant to

373

Hydrophobic lipid molecules

140

Hydrophobic micelles

449

Hydrophobic films water resistance 746

Hydrolytic cleavage mechanism

668

Hydromer

354

Hydrophilic actives

290 596

356

encapsulation

591

592

penetration

104

poor delivery system

765

Hydrophilic adhesives

840

576

Hydrophobic moiety internal oil phase 590

695

Hydrophobic molecules

161

Hydrophobic phase-change materials

262

Hydrophobic plant ingredients

766

Hydrophobic polymers

335

Hydrophobic stabilization

570

This page has been reformatted by Knovel to provide easier navigation.

515

853

404

841 292

841

1015

Index terms

Links

Index terms

Links

Hydrophobic substances

279

In situ polymerization

198

Hydrophobic treatments

636

In vitro data

918

Hydroquinone

337

In vitro enzymatic digestion

807

Hydrosilylation

693

In vitro percutaneous absorption

919

Hydrotrope

606

In vitro skin permeation studies

876

342 607

343 608

application

609

In vitro studies

913

dilution process

606

Incompatible formulations

822

452

Incomplete block design

938

Hydroxethyl cellulose Hydroxpropyl methyl cellulose (HPMC) Hydroxyacid

IND/NDA 93

approval process

883

bimodal chain

85

Hydroxyceramide

80

914

Indomethacin transdermal delivery 82

110

Induction phase

921

Hydroxyethylcellulose (HEC)

476

Industry experts

936

Hydroxyl functionality

488

Infections

122

484

HIV

918

repulsion Hydroxypropyl cellulose

751

Infinite dosing

417

Hydroxypropyl methylcellulose

751

Infinite perimeter

398

Inflammation

159

Inflammatory response

111

Inflection point

481

Hydroxypropyl starch film-forming properties

751

phosphates

753

Hydroxypropylation

750

Hydroxypropyltrimonium chloride

691

Hydroxysphingosine

84

Hyper-branched polymers

Ingredient absorption 85

396

See also Molecular trees

aqueous-based

748

Ingredient coatings

686

Ingredient compatibility

873

Ingredient selection

Hypercium peforatum (hypericin)

777

importance for delivery

424

Hypericin (hypercium peforatum)

777

systematic approach

424

Hypersensitivity

921

Hypodermis

139

Hypothetical multistep process

764

Ingredients 410

874

Identity card

940

Imhotep

225

Inhalation

I Ichthyosis

effect on stability

949

drug delivery

605

safety and risks

917

sensitization

921

Inhibitor polymers

94

125

Injectable vehicles

308

Immiscible liquids

540

Injectible delivery

123

Immune signaling compounds

111

Injections

140

Immune system response

110

This page has been reformatted by Knovel to provide easier navigation.

1016

Index terms

Links

Index terms Interferon

Inks encapsulating fragrances

delivery by sonophoresis

192

Inorganic sunscreen

scale-up

See also Titanium dioxide 559

Insect bites or poison ivy exposure

837

Insect repellants

577

Insecticides dermal penetration Insertion molecule

91 443

Internal aqueous phase

563

insulin

474

Internal phase

196

Internal rupture

195

162

Interparticle coagulation

108

160

Interparticle exchange

366

160

Intracellular delivery

110

Intracellular penetration

110

836

Insecticidal black pepper

166

Intermediate phase

689

Inorganic sunscreens

Links

591

593

Instability

Intradermal delivery vehicles

314

end products

216

Intradermal penetration

304

Instant starches

747

Intradermal transport

309

Intradermal vehicles

121

Inverted microscope

476

Investigational New Drug (IND)

914

Insulin delivery by sonophoresis

91

permeation

90

Insulin-like growth factor receptor (IGFR)

779

Integrative medicine

128

Intelligent polymers

595

Interactive vehicles

314

Intercellular diffusion

298

Intercellular lamellae

82

Intercellular lipids

82

domain organization

105

volume

104

Intercellular pathway

87

Intercellular penetration

91

Involucrin

597

Interface adsorption

494

104

693

Ion pair formation

773

Ionic surfactants

605 610

permeation

104

Iontophoresis

91 106

transport conduits during

382

Interfacial phase inversion process foaming agent

Ion pair complexes

Ionized molecules

87 367

108

loading and release properties 166

Intercellular spaces Intercorneocyte pores

Ion concentration

Irritating actives

273

Irritation

146

161

eye

554

640

93 173

800

primary

917

217

salicylic acid

109

Interfacial reactions

401

skin

274

Interfacial tension

440

testing

922

767

554

334

iontophoretic-induced

552

93

Irritancy

potential

microencapsulation

92

88

401

Interfacial polymerization

83

Ionized ketoprofen

161

volume

80

This page has been reformatted by Knovel to provide easier navigation.

554

1017

Index terms

Links

Irritation potential

886

ISO 7724/1

379

Index terms Keratinocytes

196

Isoniazid

autocrine growth

779

differentiation

112

Keratinohyalin granules

78 78

gastrointestinal absorption

165

Keratinosome

with piperine

159

Keratins

Isopeptide linkages

80

78

molecular weights

83

515

Keratohyalin

161

Isopropyl myristate thickeners

629

granules

80

Isopropyl palmitate (IPP)

552

Keratolitic agent

113

Isopropyl palmitate thickeners

629

Keratolytic activity

874

Isotherm helium desorption

401

Ketoconazole

414

Kettle dwell time

453

Key and lock relationship

123

J Jet-cooking process

762

Knifebox

358

JIS Z8722

379

Kojic acid

112

Kolbe-Schmidt process

873

Krafft Temperature

610

Krause’s end bulbs

161

Jojoba oil 629

Jordan-King Modified Draize protocol

921

RIPT

921

L

777

L-selenomethionine

Juglone (walnut) Junctional proteins Junk food diets

84 163

bioavailability

165

gastrointestinal absorption

165

83

417

419

451

Lα dispersions

448 452

450 453

777

Lα phase dispersions

448

449

Keltrol T

576

Lα phospholipid assemblies

447

Keratin

161

Lα-based systems

454

Keratin filaments

276

Lactic acid

in corneocytes

111

359 881

K Kaempferol ®

399

Keratin genes

formulations

887

defective

81

sting test

885

types

83

stinging and burning

885

Keratinization

112

marker Keratinized cells

863

888

81 160

675

Lag time penetration

See also Cornification

160

83

Isophorone diisocyanate (IPDI)

thickeners

111

166

Isoelectric point gelatin

Links

104

Lamellae interdigitation

This page has been reformatted by Knovel to provide easier navigation.

87

107

703

1018

Index terms

Links

Index terms

Lamellar arrangements in stratum corneum

82

Lamellar bodies

78

140

Laser ablation

611

Laser-Doppler procedure

379

Lateral reticulation

400

Lamellar coacervates

505

Laundry composition

Lamellar films

502

pro-fragrant silicone

Lamellar gel

573

577

lipids

571

network

549

551

559

564

oil phase

573

phase

570

system

572

Lamellar granules

553

573

Lauryl methacrylate

335

Layers

111

Lamellar liquid crystal

553

Lamellar liquid crystal phase

570

194

Lecithin

143

326

366

367 551

378 770

382

Lamellar membranes

140

Lamellar phase

548 597 612

dilution approach

592

formation

610

stable assembly

447

Lamellar structure

326

ultrapure 607 591 610

107

Laminar flow

493

Laminated cast foam

524

113

Langmuir trough

481

Lanolin

450

Lanolin alcohol

612

Laplace equations

480

Laplace pressure

475

Lidocaine

609

rapid expansion Light extinction

371

Light microscopy

807

Light mineral oil (LP)

475

491

Light scattering

371

607

piggy-back

subcategories

286

516 399

Linear polydimethylsiloxanes chain length

161

719

Linear triglycerol

484

Linear volatile dimethicones

726

Linear volatile silicones

718

722

fluids

723

725

Linoleate

222

Linoleate chains 491

493

719

Linear Technology

83

Linoleic acids

80 228 769

143 592 773

226 598

Linolenic acids

112

226

228

592

598

495 Large unilamellar vesicles (LUV)

605

Linear molecules

523

Langerhans cells

397

hydrophilic polyurethane

Laminates hydrophilic polyurethane foams

Lefebvre Scientific Foundation

Light stability

538

Lamellar vesicular systems

286

Life-sciences industry 588 598

Lamellar structured surfactants opacity

103

Leave-on products

78

of lipids

671

Lauryl alcohol

skin

573

Links

286 This page has been reformatted by Knovel to provide easier navigation.

1019

Index terms

Links

Index terms

Links

Linseed oil

773

Lipophilic ingredients

850

Lip color

837

Lipophilic materials

276

Lipase

222

Lipophilic molecules

Lipid barrier

139

142

Lipid bilayers

588

591

445

permeation route Lipophilic phase

87 144

Lipophilic plant actives

Lipid envelope corneocytes

hard-to-formulate

105

763

Lipid film

289

Lipophilic polymeric surfactant

487

Lipid matrix

142

Lipophilic polymers

335

Lipid Replacement Therapy

316

Lipophilic products

403

Lipid-protein-partition theory

89

Lipophilic properties

95

Lipids

80

Lipoplexes

292

607

Lipoprotein coated

326

analysis

293

Liposomal (lamellar) gels/creams

breakdown

111

co-surfactant interactions

368

concentration of

285

di-alkyl

551

fluidization

105

intercellular

82

ionizable

85

lateral packing

431

marine-derived

287

moisture barrier

574

oxidizing

292

stratum corneum

105

Lipophiles

571

new 595 Liposomal bilayer

84

defined

trilaminar units

166

stability Liposomal cosmetic gels traditional

450

Lipophilic molecules

106

stratum corneum

104

Lipophilic actives

335 590

337 596

encapsulation

590

592

in Chitospheres™

279

356

Liposomal systems

597

Liposomal vesicles

595

595 598

107 124

316

588 594

Liposome extruder

290

Liposome preparation

166

existing methods

588

590

Liposome technology

187

367

Liposome-DNA complexes

292

Liposome/polymer interaction process

593

104 452

This page has been reformatted by Knovel to provide easier navigation.

596

596

Liposome dispersions

Lipophilic dispersions particle size

594 597 592

Lipophilic compounds permeation

588

Liposomal dispersions

dispersions

82

597

439

Liposome

597

187

Liposomal delivery systems

stabilizers 549

596

594

591

596

1020

Index terms

Links

Liposomes

Index terms

Links

88

107

141

regions

607

161 323 369 444 591

305 325 375 453 592

314 366 379 590 697

transition temperatures

548

unit cell dimension

610

Liquid droplets emulsion

607

Liquid gel

373

Liquid hydrocarbons

823

Liquid logos

541

Liquid makeup

752

286

Liquid precursors

606

characterization of

292

Liquid trademarks

541

classified

286

Lithium soaps

622

enhance follicular delivery

113

Lithospermum offiinale

entrap

161

first development

798

fusion

295

liposomes

292

oxidation

107

Localization

113

penetration

298

Localized transport regions (LTRs)

performance

377

Lochhead-Goddard effect

501

phospholipid-based

277

Locust bean gum

751

production

288

protein-based

809

size

107

290

293

Long chain alcohols

675

stability

296 596

453 598

593

Long chain alkyl groups

687

storage

296

Long pepper

158

structure

287

Long textured phenomon

744

subcategories

286

and surfactants

295

testing

294

three-dimensional network

595

types

290

unilamellar vesicular carriers

benefits

326

bilayer structures

314

blank (empty)

292

carrier system

378

characteristics

(napthoquinones) Loading

290

92

liquid

541

Loricrin

80

Lotions

686

sprayable

564

Low density polyethylene (LDPE)

623

Low density polymers

404

141

Low polarity anchors

610

106

Low shear rates

607

326

Lubricants

725

Liquid acrylate comonomer

355

viscosity

Liquid agitation

493

Lubriderm

Liquid crystal

431

447

572

604

294

502

Logos

Lipstick

lipid bilayers

777

877

571

vitamin E

622 771

LVT Brookfield viscometer synchro-electric model

This page has been reformatted by Knovel to provide easier navigation.

476

159 83

1021

Index terms

Links

Lycopenes

Index terms Marine-derived lipids

771

Links 287

Market

Lye-based soap 438

encapsulation

182

Lymphatic vessels

161

Market positioning

938

Lysine

883

Market trends

188

Lyso-lipids

287

Marketing benefits

822

Lysosomal enzymes

112

potash or lye

292

Marketing of pharmaceuticals European regulation

Lysozyme enzymes

279

718

912

Marketplace

M M-units

189

719

Macrocapsules

effective

443

trends

934

Mascara

725

Matrix

defined

261

Macromolecules

107

Magnesium aluminum silicate Magnesium ascorbyl phosphate

chitosan 399

400

276

Matrix materials

277

452

Matrix metallo-proteinase

811

802

Matrix polymers

200

812

Matrix system

109

Maimonides

125

Matrix-type capsules

194

Makeup

877

Meadowfoam oil

769

application

854

Measurement

foundation

518

skin penetration

412

removal

518

Mechanical agitation

338

Malarial infections

159

Mechanical barriers

305

Malnutrition

163

Mechanical rupture

195

Maltodextrin

186

Mechanical skin irritation

836

Mammalian enzymes

279

Mederi

126

Mandelbrot equation

398

Medical applications

444

605

Medical device industry

354

357

vitamin C derivative

Mannitol

90

Manufacturing

751 399

402

863

Medical disorders

hydrophilic polyurethane products

524

processes

358

protocols

445

thin-film coatings

525

Maps

10

Marigold-calendula officinalis (calendulin, querce

777

Marine atelocollagen

805

Marine collagen

805

Marine sponge collagen

109

treatment of

439

Medicament

835

Medicine

126

divine gift

124

modern

127

traditional

127

Meditari

126

Meditation

126

Meissener’s corpuscles

161

This page has been reformatted by Knovel to provide easier navigation.

159

934

1022

Index terms

Links

Melanin production

112

Melanocytes

113

Melanosomes

112

Melt blowing

840

Methyltrichlorosilane 161

Melting points hydrocarbons

262

Membrane bilayers defects

107

Membrane coating granules

112

Membrane deformation

367

Membrane design

813

Membrane encapsulation

193

Membrane leakage

699

Membrane lipids

285 110

cell

286

types

196

Memorandum of Understanding

Messy to apply

622

Metabolic changes

111

Metabolic permeability enhancers

142

199

90

703

Microbeads

217

Microbial activity

744 538

Microcapsules

517 192 799

benefits

325

defined

261

development

798

elastic wall material

233

gelatin based

196

physical forms

194

size 217

324

stability

223

suspended

540

vitamins

226

wall material

228

Microchannels

88

162

Metabolic wastes

160

Metabolism

111

enzymes

163

“first pass” effect

111

Meter mix equipment

524

Methacrylated dextran

217

advantages

217

Methanol

721

applications

204

biodelivery system

811

categorizations

182

chemical synthesis

260

coacervation

219

release of active Methyl cellulose (MC) Methyl methacrylate

359 93 339

217 800

323 802

274

Microcirculation

Metabolic rate

Method of application

448

288

Miconazole nitrate

of foam

161 161

Micelles

Microbiological properties

127

Merkel cells

627

in surfactant systems

Mercaptoethanol penetration enhancers

540

Microbial spoilage

Membranes biodegradable

718

Mica suspensions concentration critical

195

Links

Mica suspended

Melting shell material

Index terms

161

in dermis

103

Microelectronics

396

Microemulsions

162

stability Microencapsulation

This page has been reformatted by Knovel to provide easier navigation.

483 181

182

192

801

184

1023

Index terms

Links

Index terms

Microencapsulation (Continued)

Links

Microsyringe

480

methods

217

Microtechnology

120

oils

222

Microvesicles

145

physical methods

260

Mid-segment elastomers

624

process

324

Miglyol

367

salting-out

219

selection of

193

vitamins

222

Microfluidization

334

Mildness in topical applications

233

Milled droplets

290

Microneedles

defined

pain 91 560

Micronizing

121

Microparticles

108

size

109

spongy-like

218

Microscopic examination

476

Microspheres

113 802

chitosan-based

277

development

798

hydrogel-like

217

sensitivity

807

synthetic

88

wheat protein

droplets

109

261

274

509

Mineral nutrients 109

806

bioavailability Mineral oil

202

800

165 337

450

748

764

779

780

Miniaturization

120

121

technology

130

Minimal erythema dose (MED

379

Minoxidil

837

Mix head

524

speed

522

Mixed micelles

368

Mixers

145

575

Mixing

802

Microsponges

509

Milling

802 acacia gum

554

Millicapsules

90

Micronized TiO2

375

274

344

801

high-shear Mixing conditions

233 765

MM. See Hexamethyldisiloxane

cosmetic and pharmaceutical products

341

entrapments

340

Mobilization 342

343

305

Models

344

bricks-and-mortar

leaching

341

domain mosaic

85

manufacturing

339

permeation

88

mechanism of action

340

single gel phase

86

open structure

340

stratum corneum barrier

85

particles

339

polymers

338

protocol

921

prescription products

341

RIPT

926

suspended

540

Modified starches

743

technology

342

food industry

744

343

104

139

Modified Draize

This page has been reformatted by Knovel to provide easier navigation.

746

1024

Index terms

Links

Moisturization

450

Moisturizers

590

558

Moisturizers

Index terms

Links

Monomolecular encapsulation

188

Monomolecular layers

396

Monoolein

604

SPF 15 formulation

336

aqueous phase behavior

605

therapeutic cream

556

biocompatibility

611

Moisturizing effect

549

cubic phase

610

encapsulation

608

hydrotropic solution

608

Molds hydrophilic polyurethane foam

524 403

Molecular brush shape

396

precursor solutions

607

Molecular complexing

883

system

605

Monoolein-water

612

611

AHA technology

889

candidates

888

admixture

615

187

cubic phases

611

Mosquito cage testing

Molecular generator 401

Moving belt

Molecular micelle

110

casting

Molecular modeling

550

fractal dimension

606

Monoolein-ethanol

Molecular broom effect

Molecular encapsulation

217

551

577 523

Muco-adhesive components

834

sodium stearate phthalamate

551

Mucosal membrane

278

sodium stearyl phthalamate

550

Mueller-Rochow process

718

Multilamellar liposome

314

Multilamellar vesicles

141 590

286 696

288

Multiple emulsions

474

548

553

Molecular packing of lipid bilayer

292

Molecular permeation

94

Molecular repulsion process

485

Molecular shape minor change

310

Molecular trees

396

403

See also Dendrimers; Hyperbranched polymers Molecular volume

94

Molecular weight

94

affects penetration

161

delivery enhancement

636

liposomes

290

polycation

507

Molecules

formation

493

formulation

487

long term stability

495

main applications

496

separation

489

Multiple-phase emulsions 421

548 700

entrapped vitamins

702

polar

703

variations

703

Multivesicular vesicles (MVV)

286

Mummification

125

largest that penetrate

104

Mutagenicity

103

self-assembling

401

Myristyl alcohol

573

Monohydric alcohols

839

Monolayer stability limit (MSL)

480

This page has been reformatted by Knovel to provide easier navigation.

488

549

288 919

553

1025

Index terms

Links

Index terms

N

Links

Nanotopes-encapsulated D-panthenol

379

279

Napthoquinones (lithospermum offiinale)

777

®

806

National Formulary

127

®

Nano-Thalasphere

806

Natipide II

594

Nanocapsules

217

799

261

274

N-acetylglucosamine enzymes Nano-Phytosphere

defined

proliposomes

596

Natural delivery system

444

complex

122

liposomes

295

targeted

122

pre-formed

296

Natural fatty acid

763

Nanoemulsification

316

Natural ingredients

823

827

Nanoemulsions

366

Natural moisturizing factor (NMF)

93

770

nonaqueous

187

Natural oils

450

particulates

314

Natural polyols

804

Nanodispersions

Nanoencapsulation

130

801

Natural preservatives

771

810

“Natural” profile

940

Nanofilm

523

Nature

121

Nanometer-range technologies

131

Needles

Nanoparticles

187

non-deformable structures

size

366

microdimensional

109

122

Neo-colloidal state

399

130

Nanospheres

142

Nernst-Planck flux equation

sensitivity

807

Neurohormones

160

Nanosponges

404

801

Neurological disorders

159

Nanotechnology

120

130

396

Neurotransmitter

Nanotopes™

367 374 381

369 375 382

371 379

“Substance P”

378

empty

379

emulsions

377

encapsulation

373

environmental stressors

373

experimental procedure

379

improved performance

382

particles

368

performance

377

preservative influence

368

stability

371

technology

367

316

Nematode

Nanosomes™

efficient carrier system

314

90

Neutrogena Clear Pore® Gel

162 878

New delivery system clinical evaluation New Drug Application (NDA)

374

91

924 341

New product vs. existing product comparative analysis Niacin

918 703

Nicotine 370

patches transdermal

304 89

Nifedipine transdermal delivery Niosomes vesicular carriers

This page has been reformatted by Knovel to provide easier navigation.

94 588 106

440

914

1026

Index terms

Links

Nitrocellulose

Index terms Nuclear magnetic resonance (NMR)

200

Links 293

Nucleic acids

Nitroglycerine 89

denature

446

Nivea

605

polymers

445

NON VOC

723

Non-amphoteric AHA solutions

886

transdermal

725

Nutraceutical industry

162

Nutraceuticals

4 163

Non-amphoteric amino acid amides glycinamide Non-amphoteric neutralizers ammonium hydroxide

888

bioavailability

165

885

delivery vehicles

162

884

via skin

162

Nutrient absorption

163

886

Nutrient bioavailability

166

Non-aqueous emulsions

700

Nutritional deficiencies

163

Non-cohesive starch coating

607

Nylon

804

Non-deformable structures

810

Nylon

612

Non-Newtonian fluid

626

Nylon particles

113

Non-phospholipid vesicles

591

Non-amphoteric solutions bioavailable

Non-polar chemical enhancers Non-polar hydrophobes

447 161

Nonbiodegradable polymers

279

Nonhydrated granules

743

Nonionic emulsifion

444

Nonionic emulsion

448

Nonionic surfactants

539

as permeability enhancers

Octamethylcyclotetrasiloxane (D4) smallest molecules

521

Nourishment Novasomes

591

Novel delivery systems

396

Novel high-technology solutions

766

Novel ingredients

744

556

557

556 265

741

721 716

Octyl glucoside

610

Octyl palmitate

475

thickeners

629

Octylmethoxy cinnamate

839

160

95

Octadecenedioic acid. See See dioic acid

853

via skin

Occlusive vehicles

in PCMs

Nonwoven techniques Nonwoven textile fabrics

876

Octadecane

522

making the carrier

93

DPM values

Nonwoven substrates film coatings

Occlusive transdermal patches Occlusivity

89

Nonwoven production technology

165

O

89

Non-steroidal anti-inflammatory agents (NSAID)

158

703

Odland body

78

Oil absorption

748

Oil dispersions

448

Oil floc-coacervates

505

Oil immersion microscopy

699

Oil of anointing

132

Oil on water

124

This page has been reformatted by Knovel to provide easier navigation.

491

162

1027

Index terms

Links

Oil phase

629

changes

442

concentration

224

desired rheological properties

443

effect on stability

224

ingredients

763

lower interfacial tension

494

rheological properties

765

Index terms as permeability enhancers

696

penetration enhancers

Oil soluble active agents

black pepper 225

276

Oil-based systems 621

Oil-dispersible actives

233

Oil-in-water dispersions fluid lamellar Oil-in-water emulsions

447 201 226 377 573 780

161

224 231 548 622 863

225 373 549 700 865

159

Oligomerization process

484

Oligomers

838

different lengths

510

rheological modifiers

90

Oleoresin

Oil removal from hair

Links

Oligopeptides

445

Oligosaccharides

799

Oligosiloxanes

718

Olive oil

450

Omega-3 fatty acids

143

Omega-6 unsaturated fatty acid

143

One-phase vehicle

108

Opaque creamy appearance

538

surfactants Opaque shampoos solubility group

636

855

Optical properties

114

Oil-insoluble solute

475

Optically variegated compositions

540

Oil-soluble actives

233

Oral care

838

Oil-soluble materials

611

Oil-soluble opposites

637

Oil-soluble plant actives

777

Oil/water interface

494

rapid dissolution Oral delivery low order

541

Ordinary ray

rheologically modified

622

Organelles

suspended

540

624

Oleic acid

105 769

112

684 548

223

Olefinic copolymers

123

Order-disorder transition

microencapsulated

308

110

834

Oral toxicity

552

Oils

Old drugs

164

Oral cavity

442

438

140

Opposites

Oil-in-water lotions

Oily skin

777

691

541

220

773

538

Optical anisotropy

Oily microparticles

804

Opaque lamellar structured

851

interfacial tension

874

401

cosmetic lotion

356

160

80 140

structure

78

Organic acids linolenoate

615

768

222

Organic-based materials

716

Organic ingredients

823

Organic polymers

324

This page has been reformatted by Knovel to provide easier navigation.

1028

Index terms

Links

Index terms

Organic quats

639

P

Organic solvents

219

Pacinian corpuscles

Organics combination

561

Packaging

Organo-chloride molecules

404

Organofunctional groups changes of properties

Links 161

for consumers

138

sales point

139

Packing

684

lipids

Organosilicones

431

Pain

fluids

685

materials

637

microneedles

synthesis of

719

receptors

162

883

reduction

162

relief

132

stimuli

162

Ornithine Osmium tetroxide post-fixative

82

Osmium vapor

87

91

Palmitic acid

573

495

Palmitoleic acid

773

technology of release

802

Panelists

variations

801

Osmotic pressure

volunteer Pantothenic acid

Osmotically active corneocytes

physical properties

Ostwald ripening 475

Para-amino benzoic acid

OTC GMP manufacturing facilities

855

Parabens

Outlast®

262

Over-the-counter (OTC)

338 873

preservatives 440

827

Paraffin oil plasticizer Paraffinic hydrocarbons

drug914

938 703 852 356 517 228

764

231

233

262

Parathyroid hormone

formulations

343

product applications

874

delivery

93

products

916

Parsol 1789

675

Particle size

608

89

analysis

480

Oxidases

163

capsules

261

Oxidation

746

dispersion

199

326

distributions

368

Oxidative degradation

233

nanocapsules

278

Oxidative reactions

273

PCM encapsulates

263

OxyTega-based systems

775

terminology

274

Ozone Transport Commission (OTC)

716

Particle stability

369

Oxazolidines as permeability enhancers

prevention

776

Paper products

111

physical-chemical properties

162

747

Particles micro and nano This page has been reformatted by Knovel to provide easier navigation.

109

1029

Index terms

Links

Index terms Penetration

Particles (Continued) suspensions

chemical enhancers

536

depth

Particulate active carriers number and size Particulate light scattering

371

enhance

104

expression of results

413

in-vitro measurement

412

in-vivo measurement

413

lag time

104

of liposomes

298

measurement of skin penetration

412

540 95

octanol/water

411

Partitioning

414

425

411

of coacervates

503

of the skin

103

Passive loading

290

Patchless patch

823

Pathways

91

for delivery

140

follicular

113

intercellular and transcellular

87

penetration

80

pilosebaceous shunt

510

104

161

time

403

via hair shafts

161

via sebaceous glands

161

Penicillin

912

Pepper

158

See also Black pepper pungency

163

thermogenic effect

162

104

Pepper extract

165

88

Peptide bond

805

Peracetic acid

747

Perception

325

initial

263

138

Percutaneous absorption

Pearlizers suspended

of liposomes

540

Percutaneous penetration

Peeling cosmetics pH PEG-30 dipolyhydroxystearate

476

PEG-800 distearate

596

PEG-polyhydroxystearate copolymers 475

592 274

Percutaneous transport

225

chitosan

481

483

275

“Perfect product”

138

Perfluorodecalin (PFC)

775

Pemulen

549

Perfluoropolymethylisopropyl ether

449

Pendant ethoxylated chains

693

Perfume

125

very low odor

Pendant hydrophilic ethoxylated chains Penetrant polarity gap calculation Polarity of the penetrants

Perfumed soap

691 426 426

427

725 668

Periplakin

83

Peristalsis

122

419 This page has been reformatted by Knovel to provide easier navigation.

106

80

159

145

PCM encapsulates

pathway

“Pepper Contract”

Payloads actives

87 104

Particulates Partition coefficient

161

effectiveness

109

suspended

813

366

Particulate systems closed

Links

159

162

1030

Index terms

Links

Index terms

Permeability barrier

81

Links

active ingredients

396

applications

401

coefficient

411

delivery systems

396

prediction of skin permeability

412

sponge

399

using chitosan

274

unique properties

615

89

Personal care market

438

93

Personal care practitioners

128

Personal care products

366 439 684

Permeability enhancers supersaturation Permeation pathways

111

pH

104

routes

106

stratum corneum

94

topical Permeation enhancers elastic vesicles

671

broad range

687

158

165

formulation

604

hydroalcoholic-based

592

starches

743

Pesticides

160

159

Permeation model

beyond skin and hair 160

93

tetrahydropiperine

913

158 105

by hydration

applications

173

dermal penetration

88

Petrolatum

Permeation pathways polar and non-polar

87

Permeation routes lipid-soluble molecules

87

water-soluble molecules

87 169

Personal care

124

126

Personal care actives

353

675

851

emulsified

834

encapsulation

590

entrapped

343

337

450

612

773

779

cream

443

moisturizing cream

556

above isoelectric point

196

effect on stability

224

of gelatin solution

196

of liposomes

296

optimum

292

range

292

variation

111

773

PhaCo-Cells

375

Personal care cosmetic formulations

590

Pharmaceutical agents

Personal care delivery systems

120

benzalkonium chloride

744

121

751

590

766 Personal care formulations

741

film devices for delivery

834

microencapsulation

799

topical delivery

835

aqueous-based

746

Pharmaceutical device industry

354

miniaturization

129

Pharmaceutical dosage forms

592

retinol

864

Pharmaceutical industry

4

Pharmaceutical products

438

Personal care industry

4

615

335

801

440

573

686

manufacture and distribution This page has been reformatted by Knovel to provide easier navigation.

438 605

160

pH-sensitive polymers

Personal care applications

371 454 874

pH

Permeation study

adjuvants

700

914

225

801 377

357

454

1031

Index terms

Links

Index terms

Links

Phospholipid vesicles

162

403

Phospholipid-based liposomes

187

Pharmaceutical transdermal patch

926

Pharmaceuticals and cosmetics

103

Phospholipid-based membrane systems

367

Pharmacokinetics

812

Phospholipids

Pharmacological field

697

Phase conditions

108

Phase diagrams

196

Phase inducer

200

219

Phase separation

105 324

196 840

Pharmaceutical products (Continued) molecular trees

microencapsulation

200

219

Phase transitions

611

Phase-change materials (PCMs)

260

Phase-transition temperature

553

Phenol butylamine

609

Phenoxyacetic acid derivatives

771

Phenyl trimethicone

450

261

685

Phenytoin bioavailability

163

gastrointestinal absorption

165

with piperine

159

piperine enhanced

163

Phosphate esters

378

Phosphatidylcholine

143

316

588

592

phospholipase C

90

stereochemical assemblies

446

Phosphatidylcholine (PC) benefits

598

Phospholipase

90

Phospholipid bilayer

366

sphere

141

unilamellar or multilamellar

447

Phospholipid composition

143

Phospholipid dispersions

286

Phospholipid membranes

143

Phospholipid molecules

767

141

142

187

285 296 316 697

286 305 325

287 314 588

924

926

benefits

593

identical-chain

326

stratum corneum lacking

111

Phosphomolybdotungstic acid

170

Phosphorylation

163

Photo irritation

917

Photo-aged skin

888

Photo-aging

297

Photo-bleaching effect

771

Photo-damaged skin

334

Photo-initiated reaction

354

Photo-protective effect

771

Photoallergenicity

918

922

Photochemical instability

274

444

687

See also Photosensitization

Philipof equation

liposomes

277

retinol 446

277

Photoinitiator

355

358

Photosensitization

918 926

922

924

922

See also Photoallergenicity Photostabilizer

677

Phototoxicity

916

918

924

926

Phyosterols (rosmarinus)

777

Physical encapsulation techniques

260

Physical enhancement techniques permeability

90

Physical microencapsulation

217

Physical penetration enhancers

106

Physical properties modification of

This page has been reformatted by Knovel to provide easier navigation.

396

1032

Index terms

Links

Physically modified starches

Index terms

747

Physicochemical properties of permeant

92

Physiologically active ingredients

453

Phytantriol

605

Links

Pituitous phenomon

744

Pituitous xanthan gums

744

Pityrosporum ovale dandruff

Phytochemical

802

PK study

926

Placebo day cream

381 819

alkaloid

159

Plagettes

capsaicin

162

Plakins

158

Planetary agitators

145

158

Plant actives

771

Plant extracts

326

Phytochemistry of pepper Phytonadione

344

®

805

Phytosphere

812

rich in polyphenols

nano-

806

Plant sterols

plant proteins

806

Plant-derived actives

Phytosphingosine

84

hydrophobic

Phytosphingosine-containing acylceramide Pig skin

84

777 770 770

Plant-derived oils 84

thickeners

84

629

Plaque and gingivitis

838

Pigmentation

112

Plastic surgery techniques

375

Pigmented formulations

518

Plasticizers

Pigmented skin

888

195 839

Pigments

854

suspensions

540

627

amount of

839

paraffin oil

231

Pilosebaceic pathway

104

shell material

195

Pilosebaceous delivery

162

tricaprylin

228

Pilosebaceous pathway

104

volatile dimethicones

725

Plasticizing formulation

823

Pilosebaceous units

113

88 113

Pliability

Pilot batches

452

skin

Piper longum

158

delivery into

159

163

166 Piper nigrum

158

Piper species

159

Piperaceae

158

Piperine

159 163

enhances bioavailability

159

thermogenic effect

162

thermoregulation

162

Pitta dosha

823

163

166

85

Pluronic™

839

PMU encapsulation

198

PMU process

198

Polar acetylsalicylic acid esters permeation 160 164

162 166

Polar association Polar chemical enhancers

93 624 89

Polar compounds penetration Polar lipids

126 This page has been reformatted by Knovel to provide easier navigation.

104 604

750 840

838

1033

Index terms

Links

Index terms as permeability enhancers

Polar oils compatibility of

694

Polar pathways

87

Polar pores pathway

Links 89

Polyalkylcyanoacrylate 88

105

105

microcapsules

217

Polyalkylene oxide

694

See also Polyether

Polar solvent-in-oil emulsions

700

Polyamides encapsulation material

Polar solvent-in-oil (ps1) non-aqueous

703

film-forming properties

Polarity

109 805

703

Polyanhydrides

216

703

Polyanionic-polycationic insoluble polymer

803

421

Polybutadiene

624

Polar solvents non-aqueous

elastomeric copolymers

625

opaque

625

boundaries

426

calculation

426

of the formulation

425

Polycarbonate membranes

590

formulation and stratum corneum

425

Polycation floc-coacervates

507

of multiphased formulations

425

Polycation molecular weight

507

of the penetrating molecule

425

skin layers

411

Polycation/surfactant/water complexes

502

of the stratum corneum

425

Polycations

501

427

Polarizing crystals

541

Pollination

122

124

Poloxamer

407

607

Poly (DL-lactide-co-glycolide)

deposition on hair

764

Polydimethylsiloxane (PDMS)

684

110

Polydimethylsiloxane fluids

765

Poly (lactide-co-glycolide)

109

Polydimethylsiloxanes

449

Poly(ethlyene glycol) (PEG)

593

elastomeric copolymers

625

Poly(ethylene-propylene) elastomeric copolymers

625

610

preparation of

718

Polyenoic acids

222

Polyesters

216

Polyether

694

593

See also Polyalkylene oxide

Poly-Pore delivery system

877

Polyether modified elastomers

Polyacrylamide

186

entrapped ingredients

702

microcapsules

217

silicone

694

Polyacrylate type polymers

637

Polyethylene

200

Polyacrylate-based thickeners

377

Polyethylene glycol

596

Polyacrylates

186

Polyethylene polymers

Polyalcohols

109

701 450

719

Poly(propylene oxide) (PPO)

encapsulation material

509

510

Polydimethylsilicone oil

Poly(ethylene-butylene)

401

Polyamino-polymer

Polar solvent-soluble active non-aqueous

216

grades Polyglycerol ester

This page has been reformatted by Knovel to provide easier navigation.

687

623 378

804

694 703 703

717

1034

Index terms

Links

Index terms

Links

enzymatic digestion

802

495

film properties

609

iodine value

484

foaming solutions

502

surface potential

483

fractal nature

402

Polyglycerols

484

nonbiodegradable

279

Polyisobutene

450

Polymethacrylates

Polyisocynates

515

encapsulation material

Polyglycerol ester of ricinoleic acid

475

476

480

Polyisoprene elastomeric copolymers

625

Polymer amphiphilic nature

Polymorphism

105

Polyol-in-silicone emulsions

700

Polyols

514

as permeability enhancers

344

prepolymers

Polymer beads suspended Polymer condensation Polymer inhibitors

540

Polyoxazoline polymer

196

Polyoxyethylene lauryl ethers penetration enhancers

94

109

89 874 835 161

Polymer to aqueous phase ratio

522

Polyoxyethyleneoxide

701

Polymeric compounds

718

Polyoxymethylene urea (PMU)

198

Polymeric emulsifier

561

Polypeptides

399

Polymeric encapsulates

261

Polyphenols

Polymeric gels

629

Polymeric lipids

285

Polyphosphate

275

Polymeric microcapsules

233

Polyquaternium coacervates

510

Polymeric particulate microspheres

113

Polysaccharides

799

Polymeric shell

217

Polymeric surfactants

488

Polymeric systems

from green tea extract

170

cationic

278

polymers

216

440

Polysorbate

316

Polymeric technologies

344

Polystyrene

Polymeric tethers

616

Polymeric thickener

452

pseudo-plastic water-soluble Polymerization

475

339 517

in situ

198

interfacial

803

stop at stages

401

as permeability enhancers

opaque

476

exothermic reaction

Polymers

604

605 89

biodegradable

216

chemistry

396

combinations

522

804 750

805

804

864

625

Polystyrene domains

624

Polytetrafluoroethylene

449

Polytrap®

344

applications

335

ideal carriers

335

lipophilic properties

338

mode of action

335

particles

336

polymeric family

335

polymers

337

technology

334

This page has been reformatted by Knovel to provide easier navigation.

401

625

337 338

1035

Index terms

Links

Index terms

Links

592

Pre-moistened wipes

519

long chain

112

Pre-polymer

198

Polyurethane

515

Pre-wetting step

835

acrylate-based oligomers

355

Precipitation

219

biomaterial devices

354

of polymer

276

chemical modifications

354

encapsulation material

109

hydrophilic

515

polymerization of

354

prepolymers

520

sheets

354

Polyunsaturated fatty acids

Polyurethane foam

354

Polyvinyl alcohol

838

encapsulation material

109

polymers

838

Polyvinylpyrrolidone (PVP)

Preclinical safety data

518

Porous microparticles

108 339

Porous particulate compounds

108 926

incident rates

926

Potassium hydroxide

889

Potassium permanganate

747

Potentiometer

480

Poultices

159

Pour-point depressants

622 194

precursors

605

Powdered cleansing products

Pre-formed nanodispersions

295

297

Premature release 359 514 514

Prescription drug remedies

823

Prescription pharmaceutical products

338

Preservation

125 542 542

in hydrophilic polyurethane

517

in surfactant systems

538

Prickle cell layer

78

Prilling encapsulation process

186

Prilocaine

609

Primary emollient

428

432

Primary irritation

917

920

Principal component analysis (PCA)

421

422

Print advertisements

608

Powdered cubosome precursors 607

Premature aging

747

Preservatives

752

liquid phase hydrotropic

607

Preservative efficacy testing (PET)

Powder microcapsules

Preload actives

microbiological

Post marketing adverse events

743

Preservative

Porous microspheres physical-chemical properties

Pregelatinized starch

hydrophilic

105 323

607

Prepolymer

576

Porous entrapment spheres

particle size distribution

Premoistened towelettes

92

virtual

517

prevent

105

transient

918

Precursor emulsion 516

Pores sizes

606

296

database

934

Pro-active

111

Pro-fragrant silicone

671

Pro-oxidant activity

222

Pro-vitamin A palmitate

373

Processing variables

443

Prodrug

161

This page has been reformatted by Knovel to provide easier navigation.

440

924

1036

Index terms

Links

Index terms Protein structures

Product by process

443

Product clustering

937

Product mapping

937

Product positioning

941

delivery by sonophoresis

Product stability

822

heat-sensitive actives

Profilaggrin

corneodesmosomes Proteins

peripheral

80

ProLipid lamellar gel

573

emulsions

575

577

denature

ProLipid systems 573

Propionibacterium acnes acne lesions

802

Propranolol

104 445 445 80 444

Prototype formulations

345

Pseudo-plastic thickener

495

Pseudoephedrine hydrochloride

609

Psoriasis

837

Pungency

163

163

Pungent phytochemical

162

gastrointestinal absorption

165

Pungent principles

172

with piperine

159

Pure food-grade starch

769

piperine enhanced

163

Purification

129

609

Pyrazinamide

with Bioperine

160

gastrointestinal absorption

165

Propylene glycol

703

with piperine

159

high concentrations

232

as permeability enhancers

89

Propylene glycol-in-silicone emulsions

Q

429 700

Propylene glycols 89

Quantum physics

396

Quartz

717

Quaternary amines

639

Quaternary ammonium

496

Propylmyristate

228

Quaternary system

608

Prostaglandins

222

Quaternized polymer

Protease

81

Protection

802

hair

693

Quats

639

of actives

192

fatty

640

benefits of encapsulation

203

silicone complex

640

Protection factor retinol palmitate Protective ingredients

90

805

Propylene glycol isostearate

as permeability enhancers

874

Pyrrolidones

Propylene glycol alginate emulsifying properties

606

91

bioavailability

Propranolol hydrochloride

605

Proteins and genes

573

pH range

Links

226

Quercetin

779

230

Quinine

159

114

R

Protein envelope corneocytes

105

Protein families

84

Radioactive electrode

479

Radiochemicals

415

This page has been reformatted by Knovel to provide easier navigation.

610

644

691

1037

Index terms

Links

Random units (RU)

379

Rate of degradation

864

Rate of diffusion

103

Rate of dissolution

838

Rate-limiting barrier Raw materials

Index terms cell

Links 79

Reproducibility lack of

445

Reproductive material

121

104

Reproductive process

121

935

Reservoir effect

278

745

Residue

278

Rest phase

921

541

Rete pegs

78

Reaction mixtures

521

Rete ridges

78

Reactive oxygen species (ROS)

863

Reticulated foam

Receptor agonist

107

Reticulation agents

Receptor compartment

809

formaledehyde

803

412

glutaraldehyde

803

695

Reticulation step

803

Reticuloendothelial system

279

Retinal Retinoic acid

renewable sources

839

Rays ordinary and extraordinary

volume Receptor fluid Recessive X-linked ichthyosis Redox cycle

81 862

Refraction

517

518

519

221

766

863

221

590

863

766 854

767

188

221

277

341 344 863

342 675 873

343 861

297

865

541

chitosan-entrapped

275

Regulatory oversight

913

irritation

274

Rehydration-processed MLV

141

Relative fraction of starch

608

Relative polarity index (RPI)

425

double

example of use

428

expression

427

impact of using RPI

430

typical values of emollients

428

visualization

425

Release

192

benefits of encapsulation

203

controlled

216

of irritating actives

274

mechanisms

189

profile

109

triggers

188

Release agent

835

Release rate

106

Repeat application patch test

924

Repeat Insult Patch Test (RIPT)

917

Replication

Retinoids 432

heat-sensitive actives

445

inherent instability

864

Retinol

233

195

195 921

809

324

450 770

See also Vitamin A decomposition

863

encapsulating

864

entrapment

343

penetration

109

progressive and mild delivery

810

properties

277

quantity

809

stability

277

Retinol acetate

863

Retinol palmitate

221

loading

This page has been reformatted by Knovel to provide easier navigation.

230

226

1038

Index terms

Links

Index terms polymers

Retinol palmitate (Continued) protection factor

230

stability

226

Links 623

Ruthenium tetroxide 231

233

post-fixative

82

Retinol propionate

863

Retinyl palmitate

590

863

S

Retrogradation

745

746

Safety

Reverse hexagonal phase formation

610

Reverse loading

292

Safety expert

927

Reverse-phase evaporation

591

Safety protocols

919

Safety testing

913

delivery system

Rewetting

172

640

oral, dermal, or inhalation

917

Rheologically modified oils

622

predictive

912

Rheology

452

program

915

analyses

476

Safety-in-use

917

emulsions

554

measurements

541

profile

440

S4 formulations

541

Rheology modifiers

231 625 865

hair

sodium stearyl phthalamate

765

phototoxicity Salicylic acid

559 744

Rheopectic 626

Rhone-Poulenc’s Jaguar® C162

691

Rifampicin bioavailability

163

gastrointestinal absorption

165

with piperine

159

piperine enhanced

163

Rigid liposomes

108

Rosmarinus (phyosterols)

777

Rotigotine

107

Rouge

837

Routes of exposure

917

Rovisomes

596

Rubout properties

203

Rupture

195

mechanism

193

microcapsules

324

924

343 590 810 876

356 675 854

113

878

irritation, sensitization, and

548

viscosity

923

621 753

923 341 359 703 873

acid functionality

877

for acne

109

cyclodextrin complexes

875

delivery systems

874

keratolytic properties

874

solubility

875

Salisomes

875

Salmon calcitonin delivery

93

Salt concentration

108

Salt forms

885

Salting-out technique

219

Sandwich model

86

SanoSeal gel

776

Saw palmetto

837

SBS transparent 203

625

Scanning electron microscopy (SEM) 339 thixogel systems Schiff base

This page has been reformatted by Knovel to provide easier navigation.

764 671

889

1039

Index terms

Links

Science of Delivery Systems Sclerotium gum

Index terms Shampoos

4 452

Scopolamine transdermal

89

Links 509

coacervation

502

dilution

503

evaluated for

691

Scotchpak® release liner

695

haziness

503

Scratch-and-sniff

324

undergoing dilution

502

SDS-micelles

369

Sea buckthorn oil

770

777

Sebaceous glands

91

113

Seborrheic dermatitis

874

Sebum

111

Shape-matching

161

337

of shampoo

509

Shear foaming

503

Shear forces

81

Shear plane

108

Shear rates

199

802

liposomes

808

809

Shear stability

622

Secondary emollient

428

432

Shear thinning

554

Sedimentation

108

Shelf life

192

benefits of encapsulation

Selenium Self-assembled microstructures

288

Semi-encapsulated actives

308

Semisynthetic materials

186

Sensitive skin

438

Sensitive teeth

838

Sensitization

921

testing

Shell material

934

Sensory profile analysis

934

938

949

Sensory profiles

687

940

941

Sensory test

939

Sequesterant sodium polyphosphate

202

Serine proteases

81

Set/melt points

851

Sex glands

161

Sexual reproduction

121

of microencapsules

217

plasticizers

195

solubility

195

Shunt pathways

938

221

326 324

thermogenic effect

Sensory evaluations

of capsules

564

324

187

Shogaol

916

Separation

509

203

of microcapsules

“Shock-cooling”

Sensory analysis definitions

504

123

drug delivery system

165

725

Shear

Second generation

gastrointestinal absorption

691

162 88

Side effects

314

Sierpinski-Menger sponge

399

Silanol endblocked polymers

724

hydroxyl groups

718

Silica

717

Silicates

717

Silicic-acid esters

671

Silicon

717

Silicon and oxygen atoms

717

Silicon-chlorine bonds

718

Silicone backbone

669

backbone chain length

687

This page has been reformatted by Knovel to provide easier navigation.

401

1040

Index terms

Links

Index terms formation

Silicone (Continued) copolyols stabilization

692

crosslinked structure

695

delivery systems

668

685

deposition on hair

503

510

derivatives

447

early 1990s

693

elastomers

693

expanding use

684

fragrance technology

668

gel matrix

694

hydrophilic/hydrophobic vesicles

698

oils

225

polar and non-polar oils

687

polyethers

690

Single gel phase model 686

779 693

684

resins

668

725

surfactant

693

698

three-dimensional

694

toxicological effects

716

umbrella term

684

vesicles

695

wax copolymers

689

active delivery systems

700

Silicone-based substrates

677

697

698

Silicone-based technologies enhance and/or deliver actives

86

Single-molecule encapsulation

130

Single-tail surfactants

591

Sink condition

103

Site of action

110

Size exclusion chromatography

698

aging

112

animal vs. human

413

barrier

polymers

357

493

Skin

See also Dimethicone copolyols

Silicone-based formulations

Links

bioavailability

798

biochemistry

440

conditions affect delivery

107

cubic phase systems

611

defense against exposure

915

functions

139

hydration

93

imperfections

91

impermeability

140

increased storage capacity

810

largest organ

160

layers

103

metabolic system

160

mimic

144

moisturization

558

occlusion

93

pH

91

685

physiology

Silicone-modified materials

637

pliability

Silicones

716

823

941

85

protectant features

450

saturation capacity

379

Siloxane backbone

684

secretions

109

structure

78

693

tumor cells

112

Silyl hydrides

668

uneven pigmentation

438

Simple lipids

285

water-related properties

612

Simultaneous delivery systems

822

Single delivery systems

818

824

825

Skin biopsy

809

Skin cancer

824

Single emulsions

This page has been reformatted by Knovel to provide easier navigation.

114

855

111

85

718

lightly cross-linked

571

410

raw materials Siloxane chains

448

139

811

1041

Index terms

Links

Skin care

413

821

Skin permeation

161

863

Skin protectant

337

body powders

335

327

725 active ingredients

700

billon dollar industry

881

foam products

517

formulations

173

longer-lasting action

823

market

823

silicones

684

605

852

Skin care products

818

850

Skin care treatments

334 826

818 852

825

314

Skin cells

161

837

Skin disorder treatment

404 431

Skin feel

554

Skin gel

228

Skin irritation

93 554 873

Skin lipid barrier

577

Skin lipid replenishment system

572

Skin moisturization

359

Skin oiliness

343

Skin penetration

297

694

Skin smoothing

675

Skin surface temperature

262

Skin tone

173

Slack skin

438

Slimming liposomes

297 813

of irritating actives

274

system

123

938 173 615

276 697

microcapsules

194

Small particle size

367

Small unilamellar vesicles (SUV)

286

Smoking incense

125

SnapPack

821

construction

825

design

819

systems

822

fatty acid

622

making

438

Sodium alginate gelation

610

865

Sodium chlorite

747

923

Sodium cholate

610

in vivo measurement

413

Sodium dodecyl sulfate

measuring

412

novel measurement methods

414

368 476 496

pigskin model for human

414

routes

298

104

in vitro measurement

415

in vitro methods

823

824

106

808

absence of

368

addition of

368

Sodium fluorescein

This page has been reformatted by Knovel to provide easier navigation.

803

219

Sodium ascorbyl phosphate (SAP)

enhancers

199

Soaps

865

308

855

80

Sodium ascorbate

beneficial actives

762

Slurry

Skin distribution influence of emulsifier on

Skin sensitivity

165

Slow release

294

Skin cosmetics

337

Slow delivery

Skin ceramides transition temperature

Skin scrubs

Sloughing process

850

Skin cell membranes

Links

tracer studies

232

without water

Index terms

698

370 487

475 493

1042

Index terms

Links

Sodium hyaluronate

358

Sodium hydroxide

885

Sodium hypochlorite

747

Sodium lauryl ether sulfate

476

485

489 503

493

88 640 886

161 762

Sodium lauryl sulfate

Sodium oleate

886

Index terms

Links

dichloromethane

220

enhancers

161

high concentrations

232

487

non-chlorinated

220

494

penetration enhancers

161

889

as permeability enhancers 636 770

610

Sodium polyphosphate

supercritical carbon dioxide Sonophoresis

89 186 91

106

Sorbitan stearate

316

431

Sorbitol plasticizer

195

Sore throat

159

sequesterant

202

Sorption-desorption test

612

Sodium soaps

622

Sound waves

125

Soybean oil

475

Sodium stearate molecular modelling

550

Sodium stearoyl lactylate

316

Sodium stearyl phthalamate

548

emulsifying system

556

mildness

555

molecular weight

556

sprayable lotions

564

toxicological profile

554

Sol-gels

188

Solid anhydrous formulation

850

Solid lipid nanoparticles (SLN)

187

551

multiple emulsion

615 494

474

Spacing 559

563

repeat

538

Sparteine bioavailability Spectrophotometric methods

912

SPF enhancement

559

Spheres

186

alginate-based

201

matrices

200

Spherical particles

Solubility

163

217

201

337

Spherical vesicles

of penetrant in stratum corneum

426

uncontrolled interaction

594

requirements

411

Spherulitic lamellar phase

536

537

Sphingolipids

143

285

Solubility group opposites

636

Soluble carbohydrate

536

538

sphingosomes

277

Solvent evaporation

219

801

transition temperature

294

loading of liposomes Solvent removal technology

292

Sphingomyelin

233

Sphingosine

Solvent/gel transition temperature

217

800

Solvents alcoholic

516

for block polymers

625

chlorinated

219

chloroform

220

316 79

tails

82

Spices

158

thermogenic effect

162

trade route

158

Spinning drop tensiometer

552

Spinous layer

78

Splenomegaly

159

This page has been reformatted by Knovel to provide easier navigation.

84

410

296

1043

Index terms

Links

Index terms

Links

Stable anhydrous solid

Spoilage microbial

water-activated

538

851

Stable combination formulations

Sponge

single products

818

collagen

109

contraceptive

524

Stable double emulsion w1/o/w2

474

technology

186

Stable gel emulsions

765

Spray coating

186

Stable water-oil emulsion

476

Spray drying

186 608

Staphylococcus

776

acne lesions

802

Star polymers

396

Starch

186

hydrotrope effect

608

liquid feed

608

219 752

607

Sprayable emulsion system

577

bioadhesive enhancer

278

Sprayable lotions

564

delivery systems

743

encapsulation material

109

525

focus for use

747

Spun bonding

840

gel matrix

779

Squalene

142

mixed with oil

762

162

modification technology

744

381

molecules

768

retrogradation

743

slurry

765

solution

745

ubiquitous excipient

769

viscosity concentration

765

Spreader bar for cream state mixture

delivery vehicles Squalene hydroperoxide (SQOOH)

381

Squalene peroxidation UV-A-induced

381

Squamous epithelium

78

Square cavities

399

Stability

Starch granule

742

effect of pH

224

encapsulation

203

aqueous dispersion

745

in high pH media

231

physical structure

749

liposomes

187

295

Starch-based systems

741

retinol palmitate

230

231

vitamins

223

224

hydrophilic polyurethane

273

760

226

Stability testing

233

Starch Conversion Technology

active ingredients

new 225

SEM photographs

822

Starch-in-oil dispersions prepare

Stabilization

770 763

296

Starch-to-oil ratio

764

use of non-chlorinated solvents

220

Starch:monoolein ratio

608

Stabilized starches

747

Static pendant drop

480

Stabilizers

146

Statistical analysis criteria

939

107

Stealth liposomes

286

of liposomal vesicles

742

608

liposomes

753

743

754

Starch-oil dispersions

This page has been reformatted by Knovel to provide easier navigation.

741

746

Starch-encapsulated monoolein

226 516

216

764

593

748

1044

Index terms

Links

Index terms

Links

lipids

549

642

microsponge

340

Steareth-21/steareth-2 system

431

oil-in-water emulsion

577

Stearic acid

573

ProLipid

151

Stearyl alcohol

573

675

repair and enhancement

575

Stearyl dimethicone

688

689

resistance to penetration

89

Stearalkonium chloride

636

Stem cells

309

Steric stabilization

593

Sterical vesicle stabilization

593

Steripak

396

Steroids hormones Stigma

640

skin layer

79

Steric hindrance

fractal polymers

639

structural proteins

161 122 110 885

Stingers

885

Stinging

882

Storage of microcapsules

233

Stratum basale

160

Stratum corneum

79 104 160 410 611 765 874

103

thickness

411

enzyme (SCCE)

854

Sting testing results

83

93

Stratum corneum chymotrypsic

403

Stimuli skin

80 139 359 590 697 773 882

89 142 379 596 716 779

802

Stratum corneum trypsic enzyme (SCTE)

802

Stratum granulosum

111

Stratum lucidum

161

Stratum spinosum

161

Stressors

260

Stridex®

823

Structurants

536

Structure-Activity Relationship (SAR)

919

Structured surfactant systems

536

sugar

538

Structured surfactants

537

Styrene

338

Styrene-butadiene block copolymers

624

Styrene-butadiene-styrene (SBS)

624

Styrenic block copolymers

625

AHA product benefits

887

Styrenic blocks

629

corneocytes

111

Subcutaneous fat

139

dead cell layer

375

Substance P

diffusion

94

enhanced cell turnover

881

enhanced permeation

366

enzymes

112

hydrated vs. dry hydration intercellular space

neurotransmitter

93 556 85

575

103

structure water content

571

766

162

Substantivity

873

Substituted starches

746

Sucrose cocoate

431

Sugar structured surfactant systems

This page has been reformatted by Knovel to provide easier navigation.

538

161

538

1045

Index terms

Links

Index terms Support layers

Sulfoxides as permeability enhancers

suitable materials

89

Surface active agents

Sulfur crosslinking agent

691

Sumerian tale

124 689

oil-in-water

689

water-in-oil

689

842 440

444

616

See also Surfactants

Sun care formulations cost and potential irritancy

842

691

624

Sulphosuccinates

Links

Surface electrical capacitance

612

Surface isotherm

484

Surface potentials

479

isotherm

Sun care products

483

Surface pressures

479

Surface tension

145

alkylmethylsiloxanes

687

Surfactant-free dispersions

452

creams and lotions

725

Surfactant-free formulating

454

Surfactant-induced particle shrinkage

371

Sun protection

232

576

Sun protection factor (SPF)

453

575

Surfactant-solubilized actives

382

Sun screen agents

232

Surfactant-starch colloidal gel

764

Sun sprays

592

Surfactants

146

187

296

Sunburn

438

Sunscreens

326

443 539

509 610

actives

675

438 536 695

agents

559

delivery systems

114

carbon-based

637

encapsulation

686

chemistry

442

formulations

559

561

concentration

108

inorganic

559

563

delivery system without

276

inorganic/organics combinations

560

561

foam products

517

key requirements

689

Gemini-type

551

organic

559

high concentrations

232

physical

559

interactions

491

186

lamellar phases

548

and liposomes

295

micelles

368

mixed

636

monomeric

217

Supercritical carbon dioxide Superficial dryness amelioration

438

Superior spreadability properties

725

Supernatant

324

Supernutrient

163

Supersaturation of active

166

as permeation enhancer

94

permeability enhancer

93

Supplier Companies

4

496

687

824 See also Surface active agents

836

560

561

as permeability enhancers

89

physical-chemical properties

475

self-assembled

605

silicone

637

skin irritation

554

structured

536

surface active

446

This page has been reformatted by Knovel to provide easier navigation.

1046

Index terms

Links

Index terms

Links

Surveillance system

927

Tartar

838

Suspended actives

540

Tartaric acid

703

Tasselin

771

538

Taste-masking

192

Suspending solid particles

536

Tea tree oil

771

Suspension aid

231

Tear fluid

297

Suspension vehicles

627

Tear strength

626

Sustained delivery systems

809

Technological delivery systems

122

Suspending power lamellar structured surfactants

Sweat glands

88

Sweet birch bark

873

Syneresis

745

Synergistic effects

310

Synthetic polymers

200

System 3™

439

Systemic absorption

91

Technology

753

resulting misuse

912

Technology transfer

308

Teeth whitening prolonged

838

Temperature-jump experiments

609

923

Temperature-sensitive actives

327

Systemic distribution

923

Temperatures

Systemic sensitization

921

452

454

T Tactile properties

325

Tail of molecule Talc suspended TanDerm

287

aqueous and prepolymer phases

523

for esters

629

good control

765

for hydrocarbon oils

629

phase-transition

548

production

233

336

Tensiometer measurements

552

540

Teratogenicity

919

822

823

827

Terazosin hydrochloride

92

manufacturing

824

Ternary phase diagram

606

packette

819

Ternary surfactant system

595

system

822

825

430

809

Tape stripping

Terpenes

stratum corneum distribution profiles 419 Target age group

915

Target consumers

915

size of studies

916

Targeted delivery

123

Targeted liposomes

286

Targeted treatment delivery skin conditions Targeting

89

as permeability enhancers

90

ethanol

95

propylene glycol

95

hair 915

641 ®

558

Testing drug products

916

Testing on animals

918

Testing on humans

918

Testosterone

90 419

”Scotch tape” 805

873

837 305

553

Test methods

Target population identifying

743

transdermal

This page has been reformatted by Knovel to provide easier navigation.

89

414

417

1047

Index terms

Links

Index terms

Links

Tethers

610

of personal care products

262

Tetraglycerols

484

Thermal gravimetric analysis

609

Thermal phase behavior

Tetrahydrocurcumin bioavailability Tetrahydrocurcuminoids permeation

168

170

170

173

lipids

158

of PCMs 160

165

Thermal reversibility

262 625

absorbance

169

bioavailability enhancer

168

hydrophilic polyurethane

516

bioenhancing mechanism

166

structured surfactants

542

chemistry

166

Thermedics

354

permeation enhancer

173

Thermodynamic activity

418

safety

165

Thermodynamic constraints

609

Thermogenesis

163

Textile fabrics

Thermal stability

521

®

Thalasphere

805

collagen-based

277

nano-

806

Thalidomide disaster early 1960s

912

The British Medical Journal

159

The Economist

396

Theophylline bioavailability

163

gastrointestinal absorption

165

with piperine

159

piperine enhanced

163

Theory of relativity

396

Therapeutic agents biological and botanical

445

lack of specificity

440

806

813

424

Thermogenic action of pepper

162

Thermogenic effect of piperine

162

Thermonutrient

158

163

Thermoplastic block copolymers

623

624

rheological properties

629

626

Thermoplastic carriers

839

Thermoplastic elastomers

622

Thermoplastic gels

626

Thermoreceptors

162

624

Thermoregulation by piperine Thickeners

162 629

anhydrous systems

627

nonaqueous phase

621

oil-based systems

621

polyacrylates

639

Therapeutic dose

106

Therapeutic effect

440

Therapeutic efficacy

439

Thin-film coatings

Therapeutic index

110

manufacturing

Therapeutic ingredients

141

Therapeutic moisturizing cream

558

Therapeutic molecules

161

Therapeutic petrolatum

556

Third generation drug delivery systems

802

Thermal bonding

840

Thixogel

763

Thermal effects

294

Thermal regulating effect

165

Tetrahydropiperine

293

525

Thioglycolate penetration enhancers

emulsions This page has been reformatted by Knovel to provide easier navigation.

161

780

764

767

1048

Index terms

Links

Index terms

Thixogel (Continued)

Links

Toothache pain

838

extract of corn tassels

771

Top-to-bottom construction

401

hydrophobic

779

Topical active agents

334

kinetic release curves

775

Topical anesthetics

496

preparation

767

Topical anti-inflammatories

304

two-step process

763

Topical antifungal delivery devices

354

Topical antiseptic creams

404

Topical application

102

Topical bioactives

166

Topical bioavailabilty

874

Topical cosmetic formulations

304

Topical delivery

140 440

medicinals

121

Thixogel formulations

765

anti-bacterial agent

776

key ingredient

769

skin-protecting effect

774

starch

771

Thixotropy

452

of emulsions

554

values

688

622

THP. See Tetrahydropiperine Three-layer sandwich structure

825

Thyme (thymol)

777

Thymol (thyme)

777

Thyroid gland

163

Tiamenidine permeation

88

Timolol maleate

610

Tinoderm™ A

373

Tinoderm™ E

375

Tinoderm™ P

379

Titanium dioxide

560 559

Tocopherol

577

689

862

865

See also Vitamin E sodium ascorbate system

225

vitamin E

779

Tocopherols

162

vitamin E

771

Tocopheryl acetate TOFA

865 90

Toluene diisocyanate (TDI)

515

Toner

877

Tonofilaments

81

Topical medicinals

308

Topical permeation

158

Topical products

334

Topical vehicles

308

Total porosity

339

Toxic dose

106

of active ingredients

273

chlorinated solvents

220

Toxicity tests

276

Toxicological testing

716

Toxicologists

915

226

122 695

304 873

554

450

919

Trademarks liquid

865

α-Tocopherol

120 353

410

Toxicity

381

See also Inorganic sunscreen sunscreen

Topical delivery systems

273

541

Traditional emulsion systems

452

Traditional medicine

126

Ayurveda

126

Chinese

127

Navajo

126

159

Trans fatty acids penetration enhancers Transacylation Transcellular pathway

This page has been reformatted by Knovel to provide easier navigation.

161 805 87

104

1049

Index terms

Links

Transcellular penetration

161

Transcellular route

298

Transdermal absorption

94

Index terms rate of

95

Transdermal and dermal delivery inverse correlation?

421

inversely correlated?

423

Transdermal applications

89

Transdermal delivery

309 611

function of polarity

417

vehicles

314

Transdermal drugs

416

344

occlusive nature

93

Transdermal penetration systems Transdermal permeation enhancement

Tretinoin

341

Triacetin®

108 612

139 615

110 107

Transformation process

122 1

80

Transition liquid crystalline gel

548

order-disorder

548

Transition temperature

293

553

Transmission electron microscopy (TEM)

293

571

Transmucosal delivery

278

Transparency

540

Transparent lamellar

538

Transparent quartz cell

480

Transport pathways 93 122

863

595

625

305

90

Tricaprylin

228 228

Triclosan

702

Triethanolamine (TEA)

444 195

Triethylhexanoin

429

Triggered release

188

osmotic pressure

802 802

Triglycerides

86

Triglycerols

142

484

Trikatu

158

159

Trimethylchlorosilane

718

Trimethylsilyl derivatives

675

Triton X-100

770

Trough electrode

479

Trypsin

112

sensitivity to degradation Trypsin-like protease 809

769 593 626

Triggering mechanism

668

Transferosomes

343

342

Triblock copolymers

as plasticizer

Transfection

Transportation

941

plasticizer

105 557 628

pores

Trendy actives

Triethyl citrate

Transepidermal water loss (TEWL)

Transglutaminase

770

90 479

of DNA

Trehalose

189

Transducer-amplifier

Transesterification reactions

877

Triacylglycerol hydrolase

94

Transdermal patches

Treatment lotion

minimize skin irritation

421 418

103

See also All trans retinoic acid

120

as a function of formulation

Links

Tumeric root

813 81 165

168

170

173 Turbidity measurements

368

Turtle head encapsulation

308

Twentieth century milestones

396

TwinDerm packette

825

back-to-back design

827

candidates

826

delivery system

825

This page has been reformatted by Knovel to provide easier navigation.

371

826

827

1050

Index terms

Links

Index terms

TwinDerm packette (Continued)

Links

Urea-formaldehyde membrane

188

marketing benefits

826

Urethane foams

517

portability

826

Urethane groups

514

Urethane prepolymers

514

Urethanes

624

Two preliminary studies general conclusions

615

Two-compartment model

85 608

Two-phase formula

108

US FDA

Two-phase system

440

USD. See Dispensatory of the United

Tyrosinase enzyme

112

Tyrosinase inhibition

808

Tyrosine protein kinases

779

in corneocytes

927

USP. See United States Pharmacopoeia (USP) UV absorbent ingredients

516

UV filters

596

687 563

Ultra-Turrax mixer

476

in sunscreens

561

UltraDerm

780

UV irradiation

675

777

UV light

114

UV protection

173

UV radiation

561

Ultrasound 91

Ultraviolet (UV) imaging

912

Ultraviolet light-initiated polymerization

922 absorption

917

protection

559

UV-B dose

575

UV-induced cellular processes

863

356

Unconscious Technology Transfer Conduit

5

Unilamellar liposomes

288

Unilamellar vesicles (ULV)

286 595

Unilever

877

United States Department of Agriculture (USDA)

762

United States Pharmacopoeia (USP)

127

UV-irradiated site 590 696

593

decreased microcirculation

380

V Vaccine delivery systems liposomes

287

Validation

Unmodified starch

of profile analysis

949

corn

745

Van der Waal’s forces

570

deficiencies

746

Van Koch Method

399

solutions

745

Vapor permeability

615

596

Variable perimeter

397

Variegated compositions

540

Variegation

540

Vasicine

163

Unsaturated fatty acids Urea as permeability enhancer

89

penetration enhancers

161

Urea-formaldehyde encapsulation

198

805

111

States (USD)

U

enhance drug delivery

853

Urocanic acid

Two-phase emulsion

best delivery system

521

90

bioavailability

This page has been reformatted by Knovel to provide easier navigation.

163

687

863

1051

Index terms

Links

Index terms

Links

Video microscopic observations

495

165

Video microscopy

476

Vectorization

813

Vinyl-based polymers

216

Vectors of penetration

808

Virtual pores

105

Vasicine (Continued) gastrointestinal absorption

Vegetable oil

Viscoelastic behavior

thickeners

629

emulsions

554

Vegetable-derived materials

200

Viscosity

Vehicle development

130

change

491

delivery systems

439

dilatant

626

Vehicle performance

308

effect on stability

224

film coating

522

rheopectic

626

thermoplastic gels

626

Viscosity index (VI)

622

Vehicles aesthetic properties

440

Verbatim responses spontaneous perceptions

936

Vesicle bilayer membrane

588

Vesicle dispersions

595

Vesicle gel formation

595

596

Vesicles

187 588

325

classified

286

configuration

698

elastic

105

formation mechanism

590

595

Visual effects variegated

366

540

Visual observation

476

Vitamin A

121 314 863 165

591

derivatives

766

formulation

590

penetration of

809

particle size results

699

Vitamin A acetate (VAA)

694

reduced fusion

597

Vitamin A palmitate

373

rigid and elastic

107

size 591

594

size controls

697

bioavailability

165

specific type

697

with Bioperine

160

suspension

699

gastrointestinal absorption

165

synthetic

106

106

107

bioconversion Vitamin B6

596

Vesicular carriers 594

Vesicular systems

439

lamellar

107

Vesisomes

596

Viable epidermis

410

Video enhanced optical microscopy

698

277 770

440

444

160

803

Vitamin C

160 576 862

See also Ascorbic acid ascorbic acid

779

bioavailability

165

with Bioperine

160

gastrointestinal absorption

165

This page has been reformatted by Knovel to provide easier navigation.

376

376

Vitamin bioavailability

106

Vesicular phospholipid gels (VPGs)

226 367

See also Retinol bioavailability

penetration enhancers

225

310 838

344 839

1052

Index terms

Links

Vitamin complexes

850

Vitamin E

221 375 839

310 450 862

Index terms 367 770

Links

definition of

719

of mixtures

722

Volume fraction ratios

369

Vulcanization process

624

See also Tocopherol oxidation of

694

W

photo-protective effect

771

Wall-forming material

217

a-tocopherol

779

Walnut (juglone)

777

Vitamin E acetate

367 381

373 694

Wash off resistance

687

bioconversion

375

376

carriers

377

cleavage

375

Nanotopes-encapsulated

381

375

Water active ingredient flux

Vitamin F

222

228

Vitamin K

343

344

770

Vitamin oils

748

Vitamins

192 854

326

703

benefits of encapsulation

203

in cosmetic formulations

222

encapsulation of

222

in Chitospheres™

279

microcapsules

226

microencapsulated

222

microencapsulation

233

stability

223

VOC legislation

717

Void volume

339

Volatile actives

354

Volatile dimethicones

725

use

general properties

723

396

resistance

576

sensitivity

851

solubility

609

Water miscible dispersion

447

Water phase

696

desired rheological properties

443

lower interfacial tension

494

gradient

615

permeability

612

225

negative control

853

Water-based emulsions

404

Water-based formulation insoluble ingredients

850

Water-based fractions

404

Water-dispersible adhesive

835

Water-dispersible carrier

718

Volatile organic compound (VOC)

716

Volatility

716

556

885

Water-activated formulas

film, fabric, or tape

835

Water-in-oil emulsions

224 373 687

Volatile linear silicones process of manufacturing

93

Water vehicle

Volatile linear dimethicones 723

82

Water vapor

716

different

522

purification

in stratum corneum

724

Volatile fluids

219

thickening 721

627

Water-in-oil-in-water

219

Water-in-silicone emulsions

226

This page has been reformatted by Knovel to provide easier navigation.

225 377 865

700

228 622

1053

Index terms

Links

Water-in-water emulsion technique

217

Water-insoluble actives

193 836

Index terms Watertight skin

198

698

encapsulation

222

161

Waxes

450

354

Water-permeable capsules

219

Waxy cornstarch

Water-removable masks

841

Wet cake

Water-soluble actives

194 357 836

encapsulation

encapsulation material

356 698

199

Water-soluble adhesive

microcapsules

pigmented

838

769 194 840

Wet tissues

232

Whitening effect of physical sunscreens

Water-soluble carriers 835

109

Wet laying

835

film, fabirc, or tape

262

Wax glands

Water-miscible actives

326 610

81

Wax encapsulated

Water-insoluble compounds

Links

Water-soluble delivery

744

835

Water-soluble ingredients

314

Water-soluble materials

611

636

Water-soluble polymers

598

750

563

Willow bark

873

Wintergreen leaves

873

Wipe-on application technique

823

Wipe/towelette form dry, water-activated

853

Wipes cleansing

514

hydrophobically modified

595

nonwoven

523

rheological properties

489

pre-moistened

519

Water-soluble polysaccharide

610

Wood’s lamp

887

Water-soluble wound dressings

836

Wound care

297

Wound care applications

762

Wound dressing

836

Woven textile fabrics

521

Wrinkles

222 855

Water/oil droplets decrease in size

487

fragmentation

493

Water/oil emulsion

687

Water/oil emulsions

480

oil-insoluble solute

488

487

Water/oil interface

481

Water/oil-water emulsions

701

X-ray analysis

698

Water/oil/water (w1/o/w2) emulsions

474

Xanthan gum

Water/oil/water emulsions

474

452 491 576 750

Xanthan gum-based thickeners

378

Xerotic (dry) skin

612

multiple

494

stability

475

Waterless hair shampoos

519

Waterproofing skin layer Waterproofing properties

487

837

476 493 594

489 573 744

X

475 491

314

494

161 560 This page has been reformatted by Knovel to provide easier navigation.

615

1054

Index terms

Links

Index terms

Y Yield stress

536

Z Zea Mays

745

Zeina B860

750

delivery films

751

film-forming properties

751

hydroxypropyl starch

750

starch film

751

Zeina™ hydroxypropyl starch

750

Zero surface

398

Zeta potential

107

Zinc oxide

561

sunscreen Zwitterionic molecules

751

752

108

559 92

This page has been reformatted by Knovel to provide easier navigation.

Links