Dermatopharmacology of Topical Preparations A Product

Development Oriented Approach, 1st Edition

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Dr. Bernard Gabard Univ.-Professor Dr. med. Peter Eisner
Abteilung Biopharmazie Klinikum der
Spirig AG, Pharmazeutische Präparate Friedrich Schiller-Universität Jena
4622 Egerkingen, Switzerland Klinik für Hautkrankheiten
Erfurter Straße 35
07740 Jena, Germany

Priv.-Doz. Dr. Christian Surber Dr. Pierre Treffel

Institut für Spital-Pharmazie Laboratoires Spirig SA
Universitätskliniken/Kantonspital Basel 109, Boulevard d'Haussonville
Spitalstraße 26 5400 Nancy, France
4031 Basel, Switzerland

ISBN 978-3-642-62960-0

Library of Congress Cataloging-in-Publication Data

Dermatopharmacology of topical preparations: a product development-oriented approach / B. Gabard ...
[et al] eds.
Includes bibliographical references and index.
I S B N 978-3-642-62960-0 I S B N 978-3-642-57145-9 (eBook)
D O I 10.1007/978-3-642-57145-9
1. Dermatopharmacology. 2. Dermatotoxicology. 3. Dermatologie agents - Testing. 4. Cosmetics - Testing.
I. Gabard, B. (Bernard), 1947-.
RL801.D48 1999 615'.778-dc21

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Verlag. Violations are liable for prosecution under the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 2000

Originally published by Springer-Verlag Berlin Heidelberg New York in 2000
Softcover reprint of the hardcover 1st edition 2000
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SPIN 10652613 22/3133 - 5 4 3 2 1 0 - Printed on acid-free paper

Preface

One of the founders of modern dermatology, Professor Albert Kligman, pre-

dicted that a blind man would someday be able to become a dermatologist
[1]. This vision is by far not realized at present, nor is it a desirable goal to
achieve, as good dermatological care always requires the ability to see the
patient. But it is true that modern technology has grown into the field of ex-
perimental dermatology. Bioengineering, or noninvasive biophysical methods
enabling the quantification of different skin parameters and/or functions are
now replacing or at least accompanying and confirming subjective judg-
ments. This triumphant advance shows that there has been a real need for
such techniques [2].
Besides boosting "organoleptic paleo dermatology" [1] onto third millen-
ium scientific level, these modern technologies have also changed the tradi-
tional product -development approaches. This is particularly true for the
manufacturers of cosmetics, who were quick to realize what enormous poten-
tial was offered by the use of suitable equipment for substantiating product
claims. Similarly, powerful methodologies have changed the way new drugs
are developed for skin diseases, not only because the disease itself (or the
corresponding experimental model) can be better appreciated, but also be-
cause the pharmacological activity of the drug under development may be
quantified in a far more precise fashion. Last, the most recent developments
in regulatory requirements or the newest cosmetic legislation foreseeing the
disappearance of animal experiments for cosmetic product development al-
most oblige the experimenter to use modern measuring devices.
The aim of this book is, in the light of these new approaches, not just to
summarize dermatopharmacological knowledge, but to bring together basic
experimental models useful for dermatological product development. We de-
liberately waived any separation between cosmetic or medical products, as
this distinction disappears as soon as one considers the experimental side of
the development. This is why a project for a product influencing skin hydra-
tion was considered just as important as a project for a topical antiphlogistic,
for example. Although we are aware of the fact that the developmental field
is evolving rapidly, we hope that this book will be useful for those engaged
in dermatological product development and as a source of new ideas and ex-
perimental approaches.
The book is divided into two parts. The first part deals with basic or gen-
eral rules on galenics, interaction of topical products with the skin, cell-cul-
ture testing and safety requirements. The special part is devoted to different
VI Preface

projects, each dealing with a particular pharmacological idea. Each chapter

has been written by specialists in their fields. We are most grateful to the
authors for their support, their enthusiasm and their constructive criticism.
We also particularly thank Professor Howard Maibach for his intellectual
support and his willingness to write an Introduction to our project. Finally,
we wish to thank Spirig Pharmaceuticals Ltd., Switzerland, and Hans Karrer
GmbH, Germany, for assistance and support.

The Editors

References

1. Leveque JL (1989) Cutaneous investigation in health and disease. Marcel Dekker, Inc.,
New York
2. Serup J, Jemec GBE (1995) Handbook of non-invasive methods and the skin. CRC Press,
Boca Raton
Contents

I Introduction I
H. 1. Maibach

General 3

2 The Vehicle: The Pharmaceutical Carrier of Dermatological

Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
C. Surber, E. Smith

3 The Absolute Fundamentals of Transdermal Permeation

(Drug Delivery for Dummies) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 23
E. Smith, C. Surber

4 Basics (Guidelines) on Cell Culture Testing for Topical!

Dermatological Drugs/Products and Cosmetics With Regard
to Efficacy and Safety of the Preparations. . . . . . . . . . . . . . . . . .. 37
E. Boelsma, M. Ponec

5 Guidelines and Methods on Safety Testing for Dermatics

and Cosmetics ................ . . . . . . . . . . . . . . . . . . . . . .. 59
T. Maurer

6 Basics on Clinical Safety Testing ........... , . . . . . . . . . . . . .. 79

P. J. Dykes, A. D. Pearse

Projects 95

7 Antimicrobials 97
P. Humbert

8 Topical Antifungal Agents .............................. 109

R. AIy, B. C. Brennan
VIII Contents

9 Hand Disinfection and Antiseptic of Skin, Mucous Membranes,

and Wounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 121
A. Kramer

10 Antivirals........................................... 135
P. Wutzler, R. K16cking

11 Dermatopharmacology of Antiparasitics and Insect Repellents ... 157

I. F. Burgess

12 Antiphlogistics (Dermocorticoids and topical

immunomodulators) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179
M. P. Schon, B. Homey, T. Ruzicka

13 Antiseborrheics...................................... 191
T. W. Fischer, C. U. Hipler, W. Wigger-Alberti, P. Elsner

14 a Principle of Drug Treatments for Itch 207

I.-J. Chen

14 b Methodological Approaches for Testing Anti-Itch

and Related Substances ................................ 231
G. Yosipovitch

15 Hair: Scalp Hair Growth Evaluation Methods ................ 241

G. Shaker, D. van Neste

16 Keratolytics 255
M. Loden

17 Dermatopharmacology of Topical Anti-Fungal Preparations

in Nail Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 281
R. Baran

18 Skin Care/Detergents 297

M. Paye, G. E. Pierard

19 Skin Hydration ...................................... 317

P. Treffel, B. Gabard

20 Efficacy of Skin Care Products and Different Mixtures of Lipids

on Barrier Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 329
1. Halkier-S0rensen

21 Project Sunscreen Protection ............................ 365

R. Stokes
 Contents IX

22 Photo aging - Retinoids, Alpha Hydroxy Acids,

and Antioxidants ..................................... 383
L. H. Kligman, A. M. Kligman

23 Antiperspirants 401
E. H6lzle

24 Wound Healing ...................................... 417

F. Gottrup, M. Agren, T. Karlsmark

25 Marketing of Pharmaceutical Products ..................... 443

H. Fuchs, H. Schlegel

Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 455

List of Contributors

M. Agren
Copenhagen Wound Healing Center
Bispebjerg Hospital
Bispebjerg Bakke 23
2400 Copenhagen NV, Denmark

Raza Aly
AC34
UCSF School of Medicine
Department of Dermatology
San Francisco, CA 94143-0517, USA
Phone: 001-415-476-4239
Fax: 001-415-476-8677 or 001-415-476-0414

Robert Baran
Nail Disease Center
42, rue des Serbes
06400 Cannes, France
Phone: +33-493-39-9966
Fax: +33-492-98-8030
e-mail: baranrmd@cote-dazur.com

Esther Boelsma
Skin Research Laboratory
Leiden University Medical Center
P. O. Box 9503
2300 RA Leiden, The Netherlands
Phone: +31-71-527-1900
Fax: +31-71-527-1910
e-mail: ponec@mail.medfac.leidenuniv.nl

Barbara C. Brennan
Director of Clinical Operations
Penederm Incorporated
Foster City, CA, USA
XII List of Contributors

Ian F. Burgess
Medical Entomology Centre
Cambridge Road
Fulbourn
Cambridge CB1 5EL, UK
Phone: +44-1223-414316
Fax: +44-1223-41-6171

Ing-Jun Chen
Department of Pharmacology
Institute of Medicine
Kaohsiung Medical College
100 Shih-Chuan 1st Road
Kaohsiung City 807, Taiwan, ROC
Phone: +886-7-323-4686
Fax: +886-7-321-8309
e-mail: ingjun@cc.kmc.edu.tw

Peter J. Dykes
CUTEST
174-178 Whitchurch Road, Heath
Cardiff CF4 3NB, UK
Phone: +44-1222-62-5686
Fax: +44-1222-61-4688

Peter Elsner
Klinik fur Hautkrankheiten
Friedrich -Schiller-Universitat
Erfurter Stra6e 35
07740 Jena, Germany
Phone: +49-3641-93-7370
Fax: +49-3641-93-7418
e-mail: elsner@derma.uni-jena-de

Tobias W. Fischer
Klinik fur Hautkrankheiten
Friedrich-Schiller-Universitat
Erfurter Stra6e 35
07740 Jena, Germany
Phone: +49-3641-93-7370
Fax: +49-3641-93-7343
e-mail: fischer@derma.uni-jena.de
 List of Contributors XIII

Heidi Fuchs
Dr. Schlegel Pharmamarketing AG
SennweidstraBe 46
6312 Steinhaus en, Switzerland
Phone: +41-41-748-7600
Fax: +41-41-748-7611
e-mail: h.fuchs@schlegelpharma.ch

Bernard Gabard
Abteilung Biopharmazie
Spirig AG, Pharmazeutische Pdiparate
4622 Egerkingen, Switzerland
Phone: +41-62-3982-461
Fax: +41-62-3982-468
e-mail: bernard.gabard@spirig.ch

Finn Gottrup
Copenhagen Wound Healing Center
Bispebjerg Hospital
Bispebjerg Bakke 23
2400 Copenhagen NY, Denmark
Phone: +45-3531-3721
Fax: +45-3531-3724
e-mail: fg02@bbh.hosp.dk

Lars Halkier-S0rensen
Hudklinikken
Marselisborg Hospital
P. P. 0rumsgade 11
8000 Aarhus C, Denmark
Phone: +45-8949-1854/1818
Fax: +45-8949-1870
e-mail: akh.grp03s.bij@aaa.dk

Christina Uta Hipler

Klinik fUr Hautkrankheiten
Friedrich -Schiller-Universitat
Erfurter StraBe 35
07740 Jena, Germany
Phone: +41-3641-93-7370
Fax: +41-3641-93-7343
e-mail: chip@derma.uni-jena.de
XIV List of Contributors

Erhard Holzle
Klinik fur Dermatologie und Allergologie
Stadtische Kliniken Oldenburg
Dr.-Eden-Stra6e 10
26133 Oldenburg, Germany
Phone: +49-441-403-2850
Fax: +49-441-403-2852

Bernhard Homey
Hautklinik
Medizinische Einrichtungen
Heinrich -Heine-Universitat Dusseldorf
Moorenstra6e 5
40225 Dusseldorf, Germany

Philippe Humbert
Service de Dermatologie I
Hopital Saint -Jacques
2, Place Saint -Jacques
25030 Besans:on Cedex, France
Phone: +33-381-218710
Fax: +33-381-218163
e-mail: philippe.humbert@univ-fcomte.fr

T. Karlsmark
Copenhagen Wound Healing Center
Bispebjerg Hospital
Bispebjerg Bakke 23
2400 Copenhagen NV, Denmark

Albert Kligman
Department of Dermatology
University of Pennsylvania
226 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6142, USA

Lorraine H. Kligman
Department of Dermatology
University of Pennsylvania
226 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6142, USA
Phone: 001-215-898-3234
Fax: 001-215-573-2116
e-mail: lkligman@mail.med.upenn.edu
 List of Contributors XV

Renate KlOcking
Institut fur Antivirale Chemotherapie
Medizinische Mikrobiologie und Virologie
Friedrich -Schiller -Universi tat Jena
Nordhauser Stra6e 78
99089 Erfurt, Germany
Phone: +49-361-741-1482
Fax: +49-361-741-1114
e-mail: rkloeck@zmkh.ef.uni-jena.de

Axel Kramer
Institut fur Hygiene und Umweltmedizin
Ernst -Moritz-Arndt -Universitat
Hainstra6e 26
17487 Greifswald/Eldena, Germany
Phone: +49-3834-84-1021/1022
Fax: +49-3834-84-1023
e-mail: kramer@rz.uni-greifswald.de

Marie Loden
ACO HUDAB
P.O. Box 542
18215 Danderyd, Sweden
Phone: +46-8-622-3651
Fax: +46-8-753-4020
e-mail: marie.loden@acohud.se

Howard I. Maibach
University of California School of Medicine
Department of Dermatology
Box 0989, Surge 110
San Francisco, CA 94143-0989, USA
Phone: 001-415-476-4997
Fax: 001-415-753-5304
e-mail: himjlm@itsa.ucsf.edu

Thomas Maurer
MTC Maurer Toxicology Consulting
Biederthalstra6e 39
4118 Rodersdorf, Switzerland
Phone: +41-61-733-9393
Fax: +41-61-733-9390
e-mail: tcmaurer@datacomm.ch
XVI List of Contributors

Marc Paye
Colgate-Palmolive R&D
Avenue du Parc Industriel
4041 Milmort, Belgium
Phone: +32-4-278-9411
Fax: +32-4-278-9575
e-mail: marc_paye@colpal.com

Anthony D. Pearse
CUTEST
174-178 Whitchurch Road, Heath
Cardiff, CF4 3NB, UK
Phone: +44-1222-62-5686
Fax: +44-1222-61-4688

Gerald E. Pierard
Belgian SSTC Research Center, 5596
University Medical Hospital Sart Tilman-B 35
4000 Liege, Belgium
Phone: +32-4-366-2408/2407
Fax: +32-4-366-2976
e-mail: gerald.pierard@ulg.ac.be

Maria Ponec
Skin Research Laboratory
Leiden University Medical Center
P. O. Box 9503
2300 Leiden, The Netherlands
Phone: +31-71-527-1900
Fax: +31-71-527-1910
e-mail: ponec@mail.medfac.leidenuniv.nl

Thomas Ruzicka
Hautklinik
Medizinische Einrichtungen
Heinrich -Heine-Universitat Dusseldorf
MoorenstraBe 5
40225 Dusseldorf, Germany
Phone: +49-221-8117600
Fax: +49-221-8117316

Hansjorg Schlegel
Dr. Schlegel Pharmamarketing AG
SennweidstraBe 46
6312 Steinhausen, Switzerland
Phone: +41-41-748-7600
Fax: +41-41-748-7611
e-mail: h.j.schlegel@schlegelpharma.ch
 List of Contributors XVII

Michael P. Schon
Hautklinik
Medizinische Einrichtungen
Heinrich -Heine-Universitat Dusseldorf
Moorenstra:Ge 5
40225 Dusseldorf, Germany
Phone: +49-211-81-18224
Fax: +49-211-81-16173

Ghassan Shaker
Skinterface sprl
9, rue du Sondart
7500 Tournai, Belgium
Phone: +32-69-22-0740
Fax: +32-69-21-5379
e-mail: skinterface@unicall.be

Eric Smith
College of Pharmacy
Ohio Northern University
Ada, OH 45810 USA
Phone: 001-419-772-2283
Fax: 001-419-772-1917
e-mail: e-smith3@onu.edu

Roger Stokes
Regional Medical Physics Department
Durham Unit
Dryburn Hospital
Durham DH1 5TW, UK
Phone: +44-191-333-2216
Fax: +44-191-386-5695

Christian Surber
Institut fUr Spital-Pharmazie
Dermatologische Universitatsklinik
Departement Pharmazie
Universitatskliniken/Kantonsspital Basel
Spitalstra:Ge 26
4031 Basel, Switzerland
Phone: +41-61-265-2905
Fax: +41-61-265-3275
e-mail: csurber@swissonline.ch
XVIII List of Contributors

Pierre Treffel
Laboratoires Spirig SA
109, Boulevard d'Haussonville
54000 Nanc~ France
Phone: +33-383-400981
Fax: +33-383-401335

Dominique Van Neste

Skinterface sprl
9, rue du Sondart
7500 Tournai, Belgium
Phone: +32-69-22-0740
Fax: +32-69-21-5379
e-mail: skinterface@unicall.be

Walter Wigger-Alberti
Klinik fur Hautkrankheiten
Friedrich -Schiller-Universitat
Erfurter StraBe 35
07740 Jena, Germany
Phone: +49-3641-93-7370
Fax: +49-3641-93-7343
e-mail: wigger@derma.uni-jena.de

Peter Wutzler
Institut fur Antivirale Chemotherapie
Medizinische Mikrobio1ogie und Viro1ogie
Friedrich -Schiller-Universitat Jena
Nordhiiuser StraBe 78
99089 Erfurt, Germany
Phone: +49-361-741-1314
Fax: +49-361-741-1114
e-mail: wutzler@zmkh.ef.uni-jena.de

Gil Yosipovitch
National Skin Centre
1, Mandalay Road
Singapore 308205
Phone: +65-25-34-455
Fax: +65-25-33-225
e-mail: gil@nsc.gov.sg