Topical Absorption of Dermatological Products

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Topical Absorption of Dermatological Products edited by Robert L Bronaugh U.S Food and Drug Administration Laurel, Maryland Howard I Maibach University of California School of Medicine San Francisco, California Marcel Dekker, Inc New York Basel TM Copyright â 2001 by Marcel Dekker, Inc All Rights Reserved Portions reprinted from first, second, and third editions of Percutaneous Absorption: Drugs—Cosmetics—Mechanisms—Methodology ISBN: 0-8247-0626-9 This book is printed on acid-free paper Headquarters Marcel Dekker, Inc 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities For more information, write to Special Sales/Professional Marketing at the headquarters address above Copyright © 2002 by Marcel Dekker, Inc All Rights Reserved Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher Current printing (last digit): 10 PRINTED IN THE UNITED STATES OF AMERICA Series Introduction Over the past decade, there has been a vast explosion in new information relating to the art and science of dermatology as well as fundamental cutaneous biology Furthermore, this information is no longer of interest only to the small but growing specialty of dermatology Scientists from a wide variety of disciplines have come to recognize both the importance of skin in fundamental biological processes and the broad implications of understanding the pathogenesis of skin disease As a result, there is now a multidisciplinary and worldwide interest in the progress of dermatology With these factors in mind, we have undertaken to develop this series of books specifically oriented to dermatology The scope of the series is purposely broad, with books ranging from pure basic science to practical, applied clinical dermatology Thus, while there is something for everyone, all volumes in the series will ultimately prove to be valuable additions to the dermatologist’s library The latest addition to the series by Larry E Millikan is both timely and pertinent The authors are well known authorities in the fields of cutaneous microbiology and clinical skin infections We trust that this volume will be of broad interest to scientists and clinicians alike Alan R Shalita SUNY Health Science Center Brooklyn, New York iii BASIC AND CLINICAL DERMATOLOGY Series Editors ALAN R SHALITA, M.D Distinguished Teaching Professor and Chairman Department of Dermatology State University of New York Health Science Center at Brooklyn Brooklyn, New York DAVID A NORRIS, M.D Director of Research Professor of Dermatology The University of Colorado Health Sciences Center Denver, Colorado Cutaneous Investigation in Health and Disease: Noninvasive Methods and Instrumentation, edited by Jean-Luc Lévêque Irritant Contact Dermatitis, edited by Edward M Jackson and Ronald Goldner Fundamentals of Dermatology: A Study Guide, Franklin S Glickman and Alan R Shalita Aging Skin: Properties and Functional Changes, edited by Jean-Luc Lévêque and Pierre G Agache Retinoids: Progress in Research and Clinical Applications, edited by Maria A Livrea and Lester Packer Clinical Photomedicine, edited by Henry W Lim and Nicholas A Soter Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice and Development, edited by John W Rippon and Robert A Fromtling Oxidative Stress in Dermatology, edited by Jürgen Fuchs and Lester Packer Connective Tissue Diseases of the Skin, edited by Charles M Lapière and Thomas Krieg 10 Epidermal Growth Factors and Cytokines, edited by Thomas A Luger and Thomas Schwarz 11 Skin Changes and Diseases in Pregnancy, edited by Marwali Harahap and Robert C Wallach 12 Fungal Disease: Biology, Immunology, and Diagnosis, edited by Paul H Jacobs and Lexie Nall 13 Immunomodulatory and Cytotoxic Agents in Dermatology, edited by Charles J McDonald 14 Cutaneous Infection and Therapy, edited by Raza Aly, Karl R Beutner, and Howard I Maibach 15 Tissue Augmentation in Clinical Practice: Procedures and Techniques, edited by Arnold William Klein 16 Psoriasis: Third Edition, Revised and Expanded, edited by Henry H Roenigk, Jr., and Howard I Maibach 17 Surgical Techniques for Cutaneous Scar Revision, edited by Marwali Harahap 18 Drug Therapy in Dermatology, edited by Larry E Millikan 19 Scarless Wound Healing, edited by Hari G Garg and Michael T Longaker 20 Cosmetic Surgery: An Interdisciplinary Approach, edited by Rhoda S Narins 21 Topical Absorption of Dermatological Products, edited by Robert L Bronaugh and Howard I Maibach 22 Glycolic Acid Peels, edited by Ronald Moy, Debra Luftman, and Lenore S Kakita 23 Innovative Techniques in Skin Surgery, edited by Marwali Harahap ADDITIONAL VOLUMES IN PREPARATION Safe Liposuction, edited by Rhoda S Narins Preface This book is based on Bronaugh and Maibach’s Percutaneous Absorption: Third Edition and In Vitro Percutaneous Absorption (Marcel Dekker, Inc.) It is a condensed entry into this complex area geared toward dermatologists, pharmacists, toxicologists, cosmetic chemists working in the area of transdermal drug absorption, and others concerned with clinical treatment and studies involving the skin The chapters are divided into three parts “Mechanisms of Absorption” contains chapters that discuss the effects of skin metabolism, hair follicles, occlusion, and other factors on skin absorption Chapters in the “Methodology” part discuss the various issues involved in measuring percutaneous absorption such as in vivo and in vitro methodology, single versus multiple dosing, the relationship of blood flow to absorption, and the significance of drug concentrations in the different layers of skin In “Drug and Cosmetic Absorption,” many updated and new chapters have been added on topical dermatological products We would like to thank the authors for preparing outstanding chapters and Sandra Beberman and Barbara Mathieu of Marcel Dekker, Inc., for their expert editorial guidance Robert L Bronaugh Howard I Maibach v Contents Series Introduction Preface Contributors Alan R Shalita iii v xi Mechanisms of Absorption Cutaneous Metabolism During In Vitro Percutaneous Absorption Robert L Bronaugh, Margaret E K Kraeling, Jeffrey J Yourick, and Harolyn L Hood Occlusion Does Not Uniformly Enhance Penetration In Vivo Daniel A W Bucks and Howard I Maibach Regional Variation in Percutaneous Absorption Ronald C Wester and Howard I Maibach 33 The Development of Skin Barrier Function in the Neonate Lourdes B Nonato, Yogeshvar N Kalia, Aarti Naik, Carolyn H Lund, and Richard H Guy 43 Cutaneous Metabolism of Xenobiotics Saqib J Bashir and Howard I Maibach 77 Percutaneous Drug Delivery to the Hair Follicle Andrea C Lauer 93 In Vivo Relationship Between Percutaneous Absorption and Transepidermal Water Loss André Rougier, Claire Lotte, and Howard I Maibach 115 vii viii Contents Dermal Decontamination and Percutaneous Absorption Ronald C Wester and Howard I Maibach 129 Methodology 10 In Vivo Methods for Percutaneous Absorption Measurement Ronald C Wester and Howard I Maibach Determination of Percutaneous Absorption by In Vitro Techniques Robert L Bronaugh, Harolyn L Hood, Margaret E K Kraeling, and Jeffrey J Yourick 145 157 11 Systemic Absorption of Cutaneous Material Robert L Bronaugh and Harolyn L Hood 12 Interrelationships in the Dose-Response of Percutaneous Absorption Ronald C Wester and Howard I Maibach 169 Effect of Single Versus Multiple Dosing in Percutaneous Absorption Ronald C Wester and Howard I Maibach 185 13 14 Blood Flow as a Technology in Percutaneous Absorption: The Assessment of the Cutaneous Microcirculation by Laser Doppler and Photoplethysmographic Techniques Ethel Tur 15 Drug Concentration in the Skin Christian Surber, Eric W Smith, Fabian P Schwarb, Tatiana Tassopoulos, and Howard I Maibach 16 Stripping Method for Measuring Percutaneous Absorption In Vivo André Rougier, Didier Dupuis, Claire Lotte, and Howard I Maibach 17 18 Interference with Stratum Corneum Lipid Biogenesis: An Approach to Enhance Transdermal Drug Delivery Peter M Elias, Vivien Mak, Carl Thornfeldt, and Kenneth R Feingold Methods for the Assessment of Topical Corticosteroid-Induced Skin Blanching John M Haigh, Eric W Smith, Carryn H Purdon, and Howard I Maibach 163 195 227 241 261 275 Alternative Therapies Fluffy Tannic Acid Bentonite Kaolin aa q.s ad 509 60.0 (Dispense in a sifter-top can.) Indications: Hyperhidrosis and contact dermatitis of the feet Directions: Dust into shoes and socks daily * Zeasorb Powder Indications: Hyperhidrosis of the feet and contact dermatitis of the feet due to shoe contactants Directions: Dust into shoes and socks daily XI MISCELLANEOUS * Balneol Indications: A fine anal cleanser for patients with pruritus ani Can also be used for pruritus vulvae * Lamb’s Wool Indications: To keep toes separated in conditions such as acute tinea pedis and acute contact dermatitis of the feet and toe webs (Note: Do not use cotton batting for these purposes.) * Dermal Gloves Indications: To be used at all times inside rubber or cotton-lined rubber gloves in cases of hand eczemas * Yogurt Indications: For acute vulvitis, contact dermatitis and extensive herpes simplex of the vulva, and vulvar pruritus due to candidiasis Directions: Apply liberally and cover with a soft handkerchief or sanitary napkin Also, tablespoonfuls of plain yogurt eaten once daily may prevent the recurrence of canker sores * Tea Bags Indications: A wet tea bag applied to a fresh canker sore will afford pleasant and surprising relief Tea bags can also used for hyperhidrosis and bromhidrosis of the feet 510 Litt * Johnson’s Baby Shampoo Indications: Useful for pediculosis of the eyelashes and blepharitis marginalis Directions: Apply gently to affected areas times daily * Adhesive Tape, Elastoplast, or Duct Tape Indications: This is a painless, safe, nonscarring, inexpensive, and effective method for treating periungual and subungual warts.10 Treat only one digit at a time Directions: Apply as noted in the diagram and leave on for days Remove, and let patient re-apply 12 h later Continue this regimen until the wart grows smaller; then disappears Every or weeks, in your office, apply liquefied phenol, let dry, and follow with fuming nitric acid to the warts(s) (Nota bene: take care in applying these!) 1_ 10 See article: Don’t Excise—Exorcise (Treatment for Subungual and Periungual Warts) Cutis 22:673–676, December 1978 35 Ointments, Creams, and Lotions Used as Topical Drug Delivery Vehicles Christian Surber and Tatiana Tassopoulos University Hospital, Basel, Switzerland Eric W Smith Ohio Northern University, Ada, Ohio I INTRODUCTION In dermatological treatment, patients rarely apply the drug to the skin in the form of a pure chemical; the active ingredient is normally incorporated into a topical carrier system—the vehicle Classically, these vehicles have been either lotion, cream, or ointment formulations, which vary markedly in their physicochemical nature, effect on the skin, and drug delivery potential Modern vehicles are frequently tailor-made and researched as carefully as the drug that they are intended to deliver Classically, formulators have developed preparations in terms of stability, compatibility, and patient or consumer acceptability of the vehicle More recently, clinical and research observations that the type of vehicle or the spectrum of excipients can markedly affect the percutaneous absorption of a drug, added another dimension to the formulation development process Many of the early studies in this regard involved the percutaneous absorption of corticosteroids These studies have yielded valuable information on vehicle effects in topical drug availability (1–4) Thus, modern pharmaceutical (and cosmetic) formulation development is based upon the stability and compatibility of excipients and active agents(s), cosmetic acceptability by the user, usage criteria of the vehicle, and the required topical drug availability of the actives 511 512 Surber et al No uniform and comprehensive classification of topical vehicles is currently available A simple pharmaceutical classification for the topical preparation is based on liquid, semi-solid or solid (powder) systems, that may further be defined as monophasic, diphasic, or tri(multi)phasic matrices A formulation may be classified by its pharmacopoeial nomenclature: cream, ointment, gel, paste; by the pharmaceutical principle of the structural matrix (emulsion, liposome, gel, suspension, transdermal patch); or by the formulation appearance (paint, milk, foam, shake) In a clinical setting, a further approach is defined by clinicians: the expected “in-use” effect (hydrating, lubricating, protecting, or drying) With this multitude of classification systems, it is often difficult to define a vehicle exactly in terms of the formulator, patient, and clinician perspectives In addition, despite the fact that the “ideal” vehicle should be “inert,” both prescribers and consumers expect the topical formulation to provide several (ancillary) therapeutic effects in addition to the release of the drug for the primary therapeutic effect These anticipated, additional vehicle effects may include cleansing, protecting, lubricating or hydrating/drying actions that result from both on the physical (matrix) and from the chemical (pharmacological) properties of the formulation ingredients (5–8) II CLASSIFICATION OF TOPICAL SEMISOLIDS A Creams and Lotions Creams are viscous semisolids and are usually oil-in-water emulsions (aqueous creams) or water-in-oil emulsions (oily creams) The type of cream used will depend on the solubility of the drug Water-soluble drugs are dispersed in oil-in-water emulsions while lipid soluble drugs are often dispersed in water-in-oil emulsions (drug dissolves in the continuous phase of the emulsion) Creams are used to apply solutions or dispersions of medications to the skin for therapeutic or prophylactic purposes where a highly occlusive effect is not necessary Bland creams may also be applied for their emollient, cooling, or moistening effects on the skin Creams are frequently chosen for wet and weepy skin conditions because they are able to emulsify with the serous exudate of the dermatitis They are desirable to the user because they have an elegant appearance, are more readily spread on the skin, are less greasy and they rub into the skin leaving little or no trace of their presence Creams and lotions are inherently less occlusive in nature (generally lower drug delivery potential without additional occlusion), and undergo more substantial metamorphosis of the vehicle after application (evaporation of water and other volatile formulation constituents) B Ointments Ointments are semisolid preparations intended to adhere to the skin or certain mucous membranes; they are usually solutions or dispersions of one or more medica- Ointments, Creams, and Lotions 513 ments in nonaqueous bases There is a greater emphasis on the emollient and protective functions of ointments because of their highly occlusive nature Ointments prevent water loss from the surface of the stratum corneum resulting in increased skin hydration and therefore a marked increase in drug permeability Due to the presence of a lipophilic continuous phase, ointments are particularly suitable for chronic dry skin lesions and disadvantageous in moist skin conditions Occlusion of application sites seems to increase the drug delivery from most vehicle types This increase may either be desirable or undesirable depending on the clinical condition Drug delivery from ointment-type formulations appears to be least affected by additional external occlusion of the formulation application sites, probably because the vehicle is essentially nonaqueous in nature and hence cannot deliver additional moisture to hydrate the skin, or the drug partitioning environment is little affected by the evaporation of the formulation components Additionally, ointment formulations are inherently occlusive in nature an will limit endogenous water evaporation from the application sites, causing some degree of stratum corneum hydration with concomitantly higher skin permeation In clinical practice, the question is often raised whether creams, lotions, or ointments are better in delivering a drug to the skin Drug delivery to the skin is controlled by the vehicle excipients as these affect partitioning into and diffusion through the stratum corneum Any component of the vehicle that will affect the dissolution of the active ingredient in the skin, or affect the rate at which the active ingredient is able to diffuse through the barrier layer, will markedly affect the therapeutic outcome of formulation application However, it remains speculative as to whether one can assign a specific effect to a particular chemical or structural features of a vehicle, keeping in mind that volatile formulation components evaporate and the structural matrix usually changes markedly once the formulation is applied to the skin Additionally, certain cosmetic aspects of the formulation (e.g., spreadability, greasiness) may have an influence on patient compliance and are, therefore, of clinical relevance The potential for large differences in the extent of drug delivery between topical formulations is due to the complex interactions between the drug, the vehicle, and the skin Factors that control partitioning into and diffusion through the stratum corneum are Vehicle-drug interactions include the thermodynamic activity of the drug in the vehicle, which is related to solute drug concentration in the vehicle Vehicle–skin interactions include the broad spectrum of permeation/penetration enhancers Basically, these are vehicle components that reduce the diffusive resistance of the stratum corneum or alter its solvent potential, enhancing drug solubility or drug diffusion, or both Drug–skin interactions include drug metabolism in the skin and binding of the drug by the skin (reservoir effect) 514 Surber et al Any formulation component will usually influence all aspects of the drug delivery process: increasing the solubility of the active ingredient in the vehicle (vehicle–drug interaction); reducing the skin barrier function (vehicle–skin interaction); influencing the partitioning of the drug from the vehicle into the stratum corneum (vehicle–skin interaction); and affecting the magnitude of the reservoir formed in the stratum corneum (drug–skin effect) III GUIDELINES FOR VEHICLE SELECTION The foregoing discussion suggests that the effects of the vehicles in delivering the drug are probably as important for the medical practitioner as the choice of which drug to use The choice of vehicle for topical drug delivery depends on the patient, the type and site of the dermatological lesion, and the extent of drug delivery desired by the practitioner It must be borne in mind that the effects of topical drug administration depend on several factors, including: The anatomical site of application—the absorption of most topically-administered drugs is greater when applied to certain anatomical areas such as the face, scrotum, vulva, or intertriginous areas The dermatological condition being treated—applications to diseased/damaged areas or to hydrated moist skin may increase the total drug absorption at these sites Individual patient variations—children and certain classes of patients are more susceptible to serious side effects from topically-administered drugs; weaker preparations should preferably be used in these patients The elderly often have thinner and drier skin and are more likely to develop adverse side effects (e.g., atrophy and telangiectasia in topical corticosteroid administration) Topical drug delivery can also be increased by the use of occlusive dressings or by the selection of a particular delivery vehicle type It has become evident that incorporating identical concentrations of the same drug into two or more different topical vehicles (chemical equivalency) does not necessarily produce dosage forms that will deliver the active drug to the skin at the same rate or to the same extent (9) Occlusion of the skin (preventing endogenous water loss), solvation of the skin strata by exogenous liquids from the formulation, or evaporation of components from the occluded formulations (metamorphosis of the delivery vehicle) may alter the drug solubilizing and partitioning environment markedly Ointments, Creams, and Lotions 515 IV THE CLINICAL CHOICE OF VEHICLE TYPE A Acuity and Type of the Disease It is a basic dermatological precept that the more acute the dermatosis, the blander the treatment should be The application of cooling vehicles and the use of frequent wet compresses, with or without drugs, remain an indispensable part of the management of acute or exudative dermatoses The principle of “wet on wet” and the use of occlusive ointments for dry or chronic dermatoses has become commonplace B Skin Type or Skin Status Clinicians try to select an appropriate vehicle in terms of the skin type or skin status of the patient Vehicles alter the physical or chemical state of the skin because of their influence on the lipid and water content or composition of the skin (8,10,11) Vehicles with hydrophilic properties are suitable for oily and normal skin conditions, whereas vehicles with lipophilic properties are more suitable for dry skin conditions C Localization of the Disease Chemicals applied to different anatomical regions of the body permeate the skin to a varying extents and the clinical reactivity of the same dermatosis at different locations may vary markedly D Cosmetic Consideration The pharmaceutical character of the topical preparation (ointment, cream, or lotion) is often associated with the expected clinical effectiveness, with the severity of the disease, or with the appearance of the formulation on the skin Ointments are often associated with oiliness/adhesiveness and are used for more severe diseases; creams and lotions rub into the skin easily and are generally used in less severe diseases E Metamorphosis of the Vehicle In clinical and experimental situations most dermatological vehicles undergo considerable changes (structurally and chemically) after they are removed from the primary container and are applied to the skin Subsequently, the initial structural matrix of the vehicle will most likely change during and after the mechanical agitation/friction associated with application of the product (e.g., inunction), and/or 516 Surber et al evaporation of ingredients (phase inversion) As a consequence, the thermodynamic activity (delivery potential) of the drug within the formulation will also change The maximum drug transfer into the skin takes place when the drug is at saturated concentration in the delivery matrix, at the vehicle–skin interface Otherwise, the rate of drug transfer across the interface is proportional to its degree of saturation (concentration/solubility) Rapid evaporation of the volatile components of some vehicles may have several effects on drug delivery Initially, there may be an appreciable increase in drug concentration in the vehicle, improving the potential for drug delivery to the skin Continued evaporative concentration eventually leads to drug saturation in the vehicle (maximal thermodynamic activity), and may subsequently produce a situation of supersaturation that, although generally a transient condition, results in drug delivery exceeding that achievable with a saturated solution (12,13) Finally, continued evaporation (removal of solvent components) may force the drug out of the solution (precipitation) and superimpose a crystal dissolution dependency in the subsequent drug delivery rate Thus the metamorphosis of the vehicle after application to the skin may have a profound and changing effect on the rate and extent of drug delivery Many formulators and clinicians are still of the perception that the rate of drug delivery to the stratum corneum is constant after formulation application—this is clearly incorrect in the light of modern discoveries in this field It should, therefore, also be obvious why creams and lotions (with their greater volatile component fraction) would undergo much more extensive metamorphosis than would an lipophilic ointment formulation The potential for alteration of the drug delivery pattern with time is therefore much greater with the more hydrous formulations Precipitation of a drug from solution, for example, will result in lower overall drug delivery compared with a situation where a drug is held in solution at a much higher, saturated concentration V CONCLUSIONS Despite the wishes of many formulators, there is no universal topical drug delivery vehicle that meets the requirements of all clinical situations Each drug, at each concentration, requires a different, precisely formulated, vehicle (structural matrix and/or formulation ingredients) for optimized therapy Issues of stability and compatibility of excipients and active agents together with local and systemic safety of all components must be counter-balanced with adequate drug delivery potential and user acceptability It is primarily important for the clinician to distinguish between vehicles with predominantly hydrophilic or lipophilic features so that an appropriate choice may be made for the dermatological condition Medical practitioners should not presume that different formulation types with the Ointments, Creams, and Lotions 517 same label concentration of the same drug will show similar topical drug availability Furthermore, substitution of one formulation ingredient for another or any dilution of the proprietary product would almost certainly alter the drug delivery from, and clinical performance of, the dosage form Finally, metamorphosis of the vehicle after application to the skin is worthy of consideration in terms of the drug reservoir formed in the stratum corneum and in terms of the extent and period of drug delivery desired REFERENCES 10 11 12 13 FDA, Center of Drug Evaluation and Research Guidance: Topical dermatologic corticosteroids: In vivo bioequivalence Division of Bioequivalence, Rockville, MD, 1995 European Comission: CPMP Efficacy Working Party Clinical requirements for locally applied, locally acting products, containing known constituents CPMP/EWP/ 239/95, Final 1995 Bundesgesundheitsamt, Berlin Bekanntmachung über die Zulassung und Registrierung und über die Verlängerung der Zulassung von Arzneimitteln nach Artikel & des Gesetzes zur Neuordnung des Arzneimittelrechts (Besonderheiten zu topischen Arzneimitteln), 1992 Bundesgesundheitsamt, Berlin Diskussionspapier zur Bewertung topischer Antirheumatika Bundesgesundhbl 1991; 2:78 Juch, R D., Rufli, T., Surber, C Pastes: what they contain? How they work? Dermatology 189:373–377, 1994 Wolf, R Has mildness replaced cleanliness next to godliness? Dermatology 189: 217–221 1994 Hills, R J., Unsworth, A., Ive, F A A comparative study of the frictional properties of emollient bath additives using procine skin Br J Dermatol 130:37–41, 1994 Gabard, B Testing the efficacy of moisturizers In: Elsner, P., Berardesca, E., Maibach, H I., eds Bioengineering of the Skin: Water and Stratum Corneum Boca Raton: CRC Press, 1994, pp 147–170 Smith, E W., Meyer, E., Haigh, J M Blanching activities of betamethasone formulations Arzneim-Forsch/Drug Res 40(5):618–621, 1990 Lodén, M The increase in skin hydration after application of emollients with different amounts of lipids Acta Derm Venereol (Stockh) 72:327–330, 1992 Choudhury, T H., Marty, J P., Orecchini, A M., Seiller, M., Wepierre, J Factors in the occlusivity of aqueous emulsions Influence of humectants J Soc Cosmet Chem 36:255–269, 1985 Chiang, C M., Flynn, G L., Weiner, N D., Szpunar, G J Bioavailability assessment of topical delivery systems: effect of vehicle evaporation upon in vitro delivery of minoxidil from solution formulations Int J Pharm 55:229–236, 1989 Davis, A F., Hadgraft, J Effect of supersaturation on membrane transport: Hydrocortisone acetate Int J Pharm 76:1–8, 1991 Index Abdomen, 34, 116, 130, 254, 263 Absorption: definition, 157, 164 effect of pH on, 416, 422 Age, 119, 203, 380 Alachlor, 130 Alpha hydroxy acids (AHAs), 415–428 Alternative therapies, 495–510 p-amino benzoic acid, 2, 467–468, 475 Anatomical site, 116, 253–256, 312–314, 514 Animal models, 96–102, 193 Antifungal drugs, 437–455 Appendages, 360–361 Application: duration, 247 frequency, 180–181 Autoradiography, 231 Barrier integrity, 418 Baths, medicated, 497–498 Benzo(a)pyrene, 2, 9, 135, 166 Benzocaine, Benzoic acid, 2, 38, 81, 116–118, 175, 243, 390 Benzophenone, 12, 465 Benzyl alcohol, 5, 12 Betamethasone 17-valerate, 82–83 Bioavailability, 228, 235, 283, 410 Bioequivalence, 228, 235, 283, 295–296 Blood flow, 195–225 (See also Laser Doppler) Blood levels, 299 Body surface area, 469 Breath analysis, 300–301 Caffeine, 123–124, 244 Ceramides, 48, 263, 265 Cholesterol, 48, 49, 96, 108, 263–264, 488 Cholesterol sulfate, 49 Chromameter, 277 Cinnamic alcohol, 12, 389, 396 Collagen, 495 Colloidal drug carrier systems, 483–493 Conjugation: glutathione, 87 glycine, 81 Contact dermatitis, 201, 495, 499, 501 Corneocytes, 26, 235 Corticosteroids, 10, 282, 289–294, 495 Cosmetic ingredients, 377–388 Cosmetics, 397, 459, 465, 511 Coumarin, 392 519 520 Creams, 501–502, 511–517 Cytochrome P-450, 78 Decontamination, 129–143, 152–153 Dermatitis, 203 Dermatological vehicles, 457–463 (See also Vehicles) Dermatome, 2, 418 Dermis, 120, 321, 490 Diffusion, 344, 513 Diffusion cell, 133 Diffusion cell type: flow, 1, 158, 396, 418 static, 158 Diffusivity, 359 Dinoseb, 173–174 Dose-response, 169–184 Epidermis, 471, 488, 490 Estradiol, 2, 15, 39, 98, 186–187, 317 Evaporation, 514, 516 Exposure estimate, 311–315, 378–379 Finn chamber, 433 Flow-through diffusion cell, 1, 158, 396, 418 Fluorescence microscopy, 103 Follicular permeation, 93–114, 255 Forearm, 34, 106, 116, 276, 411 Forehead, 34, 106, 116, 254 Fourier transform infrared spectroscopy, 45, 58 Fragrances, 11, 377, 389–399 Gentian violet, 506 Glycolic acid, 416 Guinea pig, 10, 99, 432 Hair dyes, 401–413 Hair follicles, 93–114, 469 percutaneous drug delivery to, 93–114 Hairless guinea pig, 2, 99, 165, 394 Hairless mouse, 489 Hairless rat, 96–98 Index Head, 36–37 Heat separation, 471 Hill-top chambers, 430 Human, 2, 20, 33, 165, 187–194, 299–309, 312–414, 355, 392, 395, 402, 466 Hydrocortisone, 10, 13, 34, 97, 98, 175, 186–187, 244, 312, 322, 340, 489 Hydroquinone, 147–148 Infinite dose, 470 In vitro absorption, 155, 157–161 In vitro release, 283–297 In vivo absorption, 145–156 blood, 147 excreta, 146 In vivo/in vitro comparison, 154, 165, 368–369 Iontophoresis, 326–330, 353–376 current, 355, 362 flux, 94, 355, 359 molecular size, 364–365 pathways of ion transport, 360–361 Lactic acid, 416 Lamellar body, 53, 265–266 Laser Doppler, 105–106 (See also Blood flow) Laser Doppler flowmetry, 195–225 Lindane, 175 Lipid biosynthesis, 263–266 Lipophilic compounds, 28, 397, 478 Liposomes, 94, 107–108 Lotions, 499–501, 511–517 Malathion, 34–37, 135, 179, 185–187, 322 Mannitol, 109–110, 244, 365 Mass balance, 173 Mathematical models, 324, 474–478 Metabolism, skin, 1–8 Miconazole, 452 Microdialysis, 231 Microemulsions, 483 Minoxidil, 172 Molecular weight, 447, 478 Index Monkey, 11, 40, 101, 129, 173, 394, 402 Monte Carlo simulation, 383–386 Mouse, 2, 393 Multiple dosing, 179, 185–194 Muscle, 318 Musk xylol, 165, 382–387, 391, 393–394 Nail penetration, 437–455 Nail plate, 437–439 Neonatal skin, 43–75 development of barrier function in, 43–75 morphological changes in, 53–57 stratum corneum lipids in, 47–53 Nitroglycerin, 177 Occlusion, 9–32, 135, 177, 380, 391, 396–397, 430, 469, 495–496, 513, 514 Octanol/water partition, 13, 407, 469, 477–478 Octyl salicylate, 465, 468, 470, 475 Ointments, 502–504, 511–517 Oleic acid, 488 Parathion, 34–37, 139, 175, 322 Patch test absorption, 429–436 PCBs, 133 PEG20 oleyl ether (Volpo 20), 164, 472 Penetration enhancers, 335 Penetration pathways, 344 Permeability coefficient, 488 Pesticides, 86, 312 Pharmacokinetic models, 301–303 Phenol, 21, 24–25 p-phenylenediame, 10, 403, 405–406, 431–435 Phonophoresis, 335–351 Phospholipases, 51 Pig, 355, 391 Polar pathway, 490–491 Postauricular, 33, 254 Prediction of absorption, 477–478 Progesterone, 16, 98, 322 521 Rat, 40, 96, 173, 177, 242, 305, 317, 329, 355, 392 Receptor fluid, 159–160, 163–164, 288, 393, 470 Recovery, 160 Regional variation, 33–42, 119, 263 Reservoir, 236, 164, 167, 233, 241, 410, 427, 489, 513, 514 Retinyl palmitate, Risk assessment, 377, 472, 479 Safety assessments, 377–388 Safrole, 79, 394–395 Salicylic acid, 5, 177, 243, 322, 442, 499, 502 Scrotum, 34 Sebaceous glands, 93, 96 Sebum, 95, 255 Skin: biopsy, 229 drug concentration in, 227–240 pH, 268, 419 preparation, 159, 418 source of, 158–159 structure, 415 viability, 1, 145, 159, 164, 192, 393, 418 Skin barrier function, 43–75 Skin barrier integrity, 419 Skin blanching, 275–282 Skin diseases, 202 Skin layers, separation of, 145 Skin metabolism, 1–8, 77–92 Skin stripping, 149, 241–259, 408–409 (See also Tape stripping) Soaks, wet dressings, 498–499 Sonophoresis, 335 Steady-state flux, 476 Steroids, 186 Stratum corneum, 28, 44–75, 103, 119, 236, 242, 404, 471 barrier, 245, 262, 490 corneocytes, 119, 235 lipids, 28, 58, 120, 261–274, 344 powdered, 134 522 [Stratum corneum] reservoir (depot), 120, 256, 487 thickness, 120 Subcutaneous, 319 Substantivity, 474 Suction blister, 228 Sunburn, 499 Sunscreens, 465–481 Surfactants, 160, 180, 483 Systemic absorption, 163–167 Tape stripping, 102, 148, 233–235, 424, 434, 468–469 (See also Skin stripping) Testosterone, 2, 17, 39–41, 175, 187, 244, 317, 322 Theophylline, 34–35, 247 Index Transdermal delivery, 269–271, 317, 347, 461, 483 Transepidermal water loss (TEWL), 45, 54, 115–128, 262, 439 Trichloroethane, 170 Trichloroethylene, 305 Underlying tissue, 317–333 Vasoactive chemicals, 326 Vehicles, 106, 124, 251, 468, 470, 487, 511 (See also Dermatological vehicles) Volatile, 10 Wash (or rinse), 129–143, 434, 474 Water, 118 Zinc oxide paste, 504 About the Editors ROBERT L BRONAUGH is Chief, Skin Absorption and Metabolism Section, U.S Food and Drug Administration, Laurel, Maryland The author or coauthor of nearly 200 publications, including Percutaneous Absorption: Third Edition (Marcel Dekker, Inc.), he is a Fellow of the Academy of Toxicological Sciences and a member of the Society of Toxicology and the Society of Cosmetic Chemists The recipient of the Scientific Achievement Award from the FDA, Dr Bronaugh serves on the editorial boards of the journal Toxicology and Applied Pharmacology and the Journal of Toxicology–Cutaneous and Ocular Toxicology (Marcel Dekker, Inc.) Dr Bronaugh received the Ph.D degree (1972) in pharmacology from the University of Colorado, Boulder HOWARD I MAIBACH is Professor of Dermatology at the University of California School of Medicine, San Francisco The author of over 1600 professional papers, he is the coeditor of Cosmeceuticals; Cutaneous Infection and Therapy; Cutaneous Infestations and Insect Bites; the Handbook of Cosmetic Science and Technology; Neonatal Skin; Percutaneous Absorption: Third Edition; and Psoriasis: Third Edition (all titles, Marcel Dekker, Inc.) Dr Maibach serves on the editorial boards of the International Journal of Dermatology and Excerpta Medica, among others, and is a Fellow of the American College of Physicians, as well as a member of the American Academy of Dermatology, the Society for Investigative Dermatology, the American Federation for Clinical Research, and the American Dermatological Association Dr Maibach received the A.B (1950) and M.D (1955) degrees from Tulane University, New Orleans, Louisiana
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