Table Of ContentH. Schaefer· A. Zesch . G. Stllttgen
with collaboration of W. Schalla
Skin Permeability
With 139 Figures
Springer-Verlag
Berlin Heidelberg New York 1982
SCHAEFER, H., Prof. Dr., Centre International de Recherches Dermatologiques,
Sophia Antipolis, 06560 Valbonne, France
ZESCH, A., Prof. Dr., Institut fUr Arzneimittel des Gesundheitsamtes,
Stauffenbergstr. 13, D-IOOO Berlin 30
SruTTGEN, G., Prof. Dr., Hautklinik und -poliklinik der Freien Universitat Berlin
im Rudolf-Virchow-Krankenhaus, Augustenburger Platz 1, D-I000 Berlin 65
SCHALLA, W., Dr., Centre International de Recherches Dermatologiques,
Sophia Antipolis, 06560 Valbonne, France
This monograph comprises an article from Handbuch der Haut-und Geschlechtskrankheiten,
Erganzungswerk Erster Band/Vierter Teil B Normale und Pathologische Physiologie der Haut III
ISBN-13:978-3-540-11797-1 e-ISBN-13978-3-642-68734-1
DOl: 10.1007/978-3-642-68734-1
Library of Congress Cataloging in Publication Data. Schaefer, H. (Hans), 1935-. Skin permeability.
"Comprises an article from Handbuch der Haut- und Geschlechtskrankheiten, Erganzungswerk,
erster Band/vierter Teil B, Normale und patholPgische Physiologie der Haut III" - T. p. verso.
Bibliography: p. Includes index. 1. Skin - Permeability - Adresses, essays,. lectures. I. Zesch, A.
(Achim), 1938-. II. Stiittgen, Giinter. III. Title. QP88.5.s325 1982 615'.778 82-10571
This work is subject to copyright. All rights are reserved, whether the whole or part of the material
is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduc
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© Springer-Verlag Berlin Heidelberg 1982
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a
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Contents
Skin Penneability. By Prof. Dr. H. SCHAEFER, Valbonne/France, Prof. Dr. A ZESCH, Berlin, and
Prof. Dr. G. STlJTTGEN, Berlin (With 119 Figures) . 541
I. Introduction . . . 541
1. To the Reader . 542
2. Definitions . . . 543
II. Morphologic Basis of Absorption by Human Skin .545
1. Skin Surface .545
2. Horny Layer . . .545
3. Epidermis . . . .548
4. Dermis (Corium) .549
5. Subcutis . . . . .550
III. Methods for Measurement of Absorption 55(J
1. Animal Experiments . . . . . . . 550
2. In Vitro Methods . . . . . . . . . 554
a) Disappearance Measurements 555
b) Penetration Into the Isolated Horny Layer 556
c) Diffusion Through Horny Layer and Epidermis Into Dermis 556
d) Diffusion Through Horny Layer and Epidermis . 556
e) Diffusion Through the Total Skin Specimen . 557
t) Penetration Into Single Layers of the Skin . 557
g) Inverse Penetration . 559
3. In Vivo Methods ........ . 559
a) Disappearance Measurements . 559
b) Measurement in the Horny Layer 565
c) Appearance in the Skin and Inner Organs (Autoradiography) . 565
d) Measurement of Total Body Content . 566
e) Measurement of Skin Clearance . 566
t) Measurement in Exudates . . . . . . . . 566
g) Measurement of Appearance in the Serum . 567
h) Radioimmunoassay ......... . 567
i) Determination in the Urine ...... . 568
j) Determination of Concentration in the Horny Layer, Epidermis and Dermis . 568
k) Determination of Appearance in the Epidermis and Dermis by Secondary
Parameters . . . . . . . . . . . . 569
I) Determination of Skin Reactivity ......... . , . 569
m) Determination of Allergenic Potency . . . . . . . . . 569
n) Determination and Estimation of Therapeutic Efficiency . 570
0) Determination of Migration From the Vessels of the Underlying Tissue Into the
Skin and to the Skin Surface .. . . . . . . . . . . . 570
4. Prerequisites for the Measurement of Permeation Parameters
With Radioactively Labelled Substances 570
5. Comparison of in Vivo and in Vitro Permeability 571
6. Compartments of Skin Permeation 575
a) Skin Surface ............. . 575
b) Horny Layer ............. . 576
c) Percutaneous Resorption and Systemic Treatment 577
d) Binding to the Skin . 578
e) Transfollicular Absorption ......... . . 579
VI Contents
7. Transformation and Metabolism of Drugs in the Skin 579
a) Autodisintegration by Radiolysis 579
b) Chemical Decomposition 580
.c) Passive Metabolism 582
d) Microbial Transformation 583
e) Active Metabolism . . . · 583
t) CC)nclusions ..... · 587
IV. Quantitative and Qualitative Aspects of Absorption. · 588
1. Theoretic Aspects . . . . . . . . . . . . . . 588
a) Diffusion Through the Horny Layer · 588
b) Resulting Concentrations in the Epidermis and Dermis · 590
2. Kinetics of Penetration, Permeation, Resorption and Excretion ·590
a) Theoretic and Experimental Prerequisites . . . . . . . . ·590
b) Concepts of Optimal Permeation Kinetics in Topical Therapy · 593
c) Normal Kinetics ........ . · 598
d) Kinetics in the Horny Layer . . . . . ·598
e) Barrier Function of the Horny Layer ·599
t) Reservoir Function of the Horny Layer ·601
g) Shunt Diffusion ·604
h) Kinetics in the Epidermis . . . . . . ·605
i) Kinetics in the Dermis ..... . · 607
j) Percutaneous in Relation to Systemic Absorption · 608
k) Penetration Into the Subcutis . . . . . . . . · 614
I) Binding of Substances to Cutaneous Constituents · 616
m) Urinary Excretion ..... . .620
3. Chemical Structure and Absorption · 625
a) Homologous Series of Alcohols · 627
b) Transport Forms ..... . .628
c) Steroids ......... . · 628
4. The Horny Layer as Regulating and Limiting Factor .632
a) Barrier and Reservoir Function of the Individual Strata of the Horny Layer .632
b) Kinetics of Various Substances in the Horny Layer . . . . . . .634
c) Surface Fat and Barrier Effect . . . . . . . . . . . . . . . .634
d) Pathologic Alterations of the Barrier Function in Diseased Skin .634
e) Regeneration of Barrier Function. . . . . . . . . . . . . . .636
t) Alteration of the Barrier Function of the Horny Layer by "Chemical Stress" .637
g) Loss of Barrier Function of the Horny Layer Caused by Stripping .639
V. Pharmacy of Topical Drugs .. . . . . . . . . . . . 639
1. Pharmaceutical Problems of Externally Applied Drugs 640
2. Availability of Topically Applied Drugs ..... . 640
3. Drug Release Into the Stratum Corneum and Optimal Vehicle Properties 641
4. Vehicle Systems ................... . 642
a) Emulsifying Agents ................ . 643
b) Pharmaceutical Emulsifying Agents for External Application 644
c) Ointment Bases 645
IX) Hydrocarbons 645
P) Fats and Oils 645
y) Polyethylene Glycols 645
15) WIO Emulsion Ointments. 647
e) OjW Emulsion Ointments 647
C) HydrogelOintments . . . 648
d) Transparent Gels ..... 648
IX) Transparent Oleaginous Gels 648
P) Transparent Microemulsions ("Swinging Gels") 648
y) Transparent Hydrogels 648
e) Silicone Ointments . . . . . . . . . . . . . . 649
Contents VII
f) Powders ............................ 649
g) Solvents as Vehicles ....................... 649
IX) Penetration of Solvents and Surfactants - Enhancement of Penetration 652
fJ) Dimethylsulfoxide (DMSO) and Other "Accelerants" 653
y) Solvent Concentration and Particle Size 656
(j) Solvent Concentration in Nonvolatile Vehicles 657
5. Drug Release From Vehicles 660
a) In Vitro Release Rates 660
b) In Vivo Release 663
6. Intrinsic Activity of the Vehicle 664
a) Penetration of Vehicle Constituents 664
b) Skin Blanching by Vehicle Components 665
7. Drugs and the Accompanying "Appropriate" Vehicles 666
a) Partition Coefficient ............. 666
b) Concentration of the Applied Substance . . . . . 667
8. Kinetics of SUbstance Distribution in the Horny Layer 668
a) Shorter Penetration Periods 669
b) Intermediate Penetration Periods 670
c) Longer Penetration Periods 670
d) Horny Layer Kinetic Curves 671
IX) Phase I 671
fJ) Phase II 672
y) Phase III 672
(j) Phase IV 672
9. Kinetics of a Drug From Different Vehicles 672
a) Aqueous Hydrophilic Ointments 673
b) Vaseline ....... 673
c) Lipophilic W/O-Emulsion 674
d) Polyethylene Glycol 674
VI. Therapy and Preparation Form 674
1. Localization 674
2. Application Procedure 674
3. Application Frequency 676
4. Vehicle and Sebum 677
VII. The Choice of Vehicle in Skin Diseases 678
1. Acuity of a Dermatosis 679
2. Skin Type, Physiologic Skin Status 679
3. Localization of Dermatosis 680
4. Climatic Factors ....... . 680
5. Cosmetic Considerations . . . . . 680
VIII. Pharmacodynamic Activities of LocaIIy Applied Drugs to Normal and Diseased Skin . 681
1. Modification by the Dermatosis . . . . . . . . . . . . . . . . . . . .. . 681
2. Pharmacoanalysis . . . . . . . . . . . . . . . . . . . . . . . . . .. . 682
3. Primary Mode of Action of a Drug and Its Secondary Empiric Therapeutic Effects . 682
4. Site of Primary and Secondary Pharmacologic Effects . 682
5. Structure and Function in Relation to Pharmacologic Effects . 683
6. Antihistamines ................. . 688
7. Corticosteroids . . . . . . . . . ... . . . . . . . 689
8. "Vasoconstriction" Test as Bioassay for Corticosteroids . 690
a) Vasoconstriction and Antiinflammatory Activity . 691
b) Vasoconstriction (Blanching) as Measure for Penetration . 692
c) Vasoconstriction and Drug Interaction . 695
d) Vasoconstriction and Atrophy . . . . . . . . . 695
e) Mechanism of Steroid-Induced Vasoconstriction . 696
f) Further Vasoactive Drugs . 697
IX) Nicotinic Acid Esters . 697
fJ) Catecholamines . 697
VIII Contents
9. Caffeine · 698
10. Heparin · 699
11. Vitamins · 699
12. Sex Hormones · 700
IX. Special Cases and Modifying Factors Related to Topical Therapy . 700
1. Drug Interaction ................. . 700
2. Combinations with Salicyclic Acid and Derivatives . 701
3. State of Skin and Permeation (Childhood, Diseased Skin) . 707
4. Skin Permeability in Infants and Young Children . 709
5. Percutaneous Therapy of Systemic Diseases . 711
6. The Permeability of the Vessels of Human Skin . 712
7. Penetration From the Blood Into the S'kin . 714
8. Pharmacokinetics in the Skin (Local Versus Systemic Application) . 718
9. Penetration From the Undersurface ofthe Dermis into the Skin (Inverse Penetration) 720
10. Permeability of Mucosal Surfaces . 724
11. Permeability of Human Nails . . . . . 726
12. Permeability of the Cornea of the Eye . 727
X. Factors Influencing the Penetration · 731
1. Hydration of the Horny Layer · 731
2. Medicinal and Mineral Baths .732
3. Occlusion · 733
4. Stripping · 735
5. Temperature · 737
6. Depilatory Agents 738
7. pH Dependence 739
8. Surface Tension 740
9. Iontophoresis 740
10. Ultrasound (Phonophoresis) 741
XI. Toxicologic Aspects of Skin Permeability 742
1. Cytostatic Agents 742
2. Antibiotics . . . 742
3. Salicylic Acid . . 744
4. Hexachlorophene 745
5. Pesticides, Herbicides 746
6. Solvents 748
7. Mercury 748
8. Boron . 750
9. Lead 751
10. Contamination and Decontamination of the Skin 751
11. Surfactants, Soaps ........ . 754
XII. Special Problems Encountered in Penetration 755
1. Permeation of Gases 755
a) Permanent Gases 755
b) Nonpermanent Gases 756
2. Penetration of Solid Particles 758
3. Water Movement Through the Skin 764
4. Penetration of Electrolytes 766
5. Glucocorticosteroids ...... 770
a) Hydrocortisone ....... 774
b) Further Literature on Hydrocortisone (He) 779
c) Hydrocortisone-17-butyrate (HCB) . . . 779
d) Betamethasone-17-valerate, Bethamethasone 783
e) Desoximetasone (DOM) ........ 786
f) Fluocinolone (F), Fluocinolone Acetonide (FA), Fluocinolone Acetonide Acetate
(FAA) ................................ 791
Contents IX
g) Triamcinolone, Triamcinolone Acetonide (TA) · 795
h) Fluprednylidene-21-acetate .802
i) Corticosteroids: Conclusions .802
6. Mineralocorticoids ..... .804
7. Androgens, Antiandrogens and Estrogens .804
a) Androgens .804
b) Antiandrogens .805
c) Estrogens . . · 807
d) Conclusions .808
8. Vitamin A Acid and Derivatives · 808
9. Psoralens · 813
a) In Vitro Experiments . . . . · 813
IX) Effects of Different 8-MOP Concentrations on Penetration · 815
f3) Effects of Solvents on Penetration . . . . . · 816
y) Effects of UV Irradiation on 8-MOP Binding · 817
b) In Vivo Experiments · 819
IX) Oral Administration ......... . · 819
fJ) Topical Application ......... . · 819
y) Conclusions Concerning the Photochemotherapy With 8-MOP · 821
10. Dithranol (=Anthralin=Cignolin) .822
11. Methotrexate (MTX) .827
XIII. Flux ..... .829
XIV. General Rules · 831
XV. Substances Investigated in Penetration and Related Fields. .835
References . . .845
Subject Index .887
Skin Permeability
By
H. Schaefer, ValbonnejFrance, A. Zesch, Berlin, and G. StUttgen, Berlin
With 139 Figures
I. Introduction
The human skin is primarily an organ of excretion which behaves in part like
a holocrine gland. Sebum and sweat are actively excreted, and the epidermis is con
tinuously renewed for horny layer formation in a process termed molting which
takes place in 28-day cycles. Intake of substances by the skin is not necessary for
human existence and is in no way related to the physiologic development of homo
sapiens in the course of evolution. Due to the development of a "civilized environ
ment" which exposes the skin to innumerable substances, including those em
ployed for skin therapy, the investigation of skin permeability presently plays a
very important role. As is the case for other routes of administration drug safety
considerations in local therapy have become increasingly important.
This aspect which was sometimes neglected in the past, now plays an important
role in determining the choice of therapy of skin diseases.
The skin is a multilayered organ. The outermost layer, the stratum corneum,
together with the underlying epidermal matrix, from which the horny layer de
velops, functions as a protective organ preventing waterloss as well the absorption
offoreign matter. This function applies both for drugs and toxic agents and while
it is undesirable in the former it is vitally necessary in the latter case.
One of the most important function of the underlying dermis, "leather skin",
traversed by terminal vessels, is in temperature regulation. Heat radiation coupled
to sweating is a major factor in the regulation of body temperature. The film of
lipids on the skin surface formed by dissemination of sebum emanating from the
sebaceous glands can be regarded as a factor in skin protection under modern con
ditions of aggressive environmental chemicals. The original significance of this
film, however, is difficult to analyse. The sum of the various skin layers -.horny
layer, epidermis, and corium - with its vascular system constitutes a firm and du
rable envelope to which the underlying fatty tissue bestows form and degree of rig
idity.
The problems encountered historically in percutaneous absorption are those
concerned with toxic symptoms following skin contact with natural substances or
prepared extracts. Symptoms of skin irritation may develop after touching plants,
indicating that intake by the skin must have occurred. This led to the recognition
of the therapeutic possibility of therapy and, indeed, the application and "rubbing
in" of preparations on the skin was recommended at the time of GALEN (129-199
A. C.)
The first systematic investigation in skin permeability was undertaken by
SCHWENKENBECHER (1904) who summarized the knowledge accumulated on the
subject at that time. His observation, that lipid soluble substances permeate the
