Topical Drug Bioavailability,

Bioequivalence, and Penetration

Edited by

Vinod P. Shah
Food and Drug Administration
Rockvillc. Maryland

and

Howard I. Maibach
University of California
Sun Francisco. California

Plenum Press New York and London

Contents
Parti
Topical Drug Delivery
Chapter 1
Percutaneous Absorption
Ronald C. Wester and Howard I. Maibach
1.
2.
3.
4.
5.
6.

Introduction
Powdered Human Stratum Corneum
In Vitro Percutaneous Absorption Method
In Vitro Individual and Regional Variation
In Vitro Short-Term Skin Exposure
In Vivo Percutaneous Absorption Methods
6.1. Skin Stripping: Short-Term Exposure
6.2. Skin Flaps
6.3. Systemic Bioavailability (Blood and Excreta)
6.4. Surface Disappearance
6.5. Biological Response
References

3
4
5
7
9
10
10
11
12
13
13
14

Chapter 2
Transdermal Delivery Systems: A Medical Rationale
Gary W. Cleary
1.
2.
3.
4.

Introduction
Pharmacokinetic Interpretation
Selection of Suitable Drug Candidates
Pharmaceutics Considerations
4.1. Design of Transdermal Delivery Systems
4.2. Regulatory Considerations

17
21
28
30
30
34

ii

CONTENTS

5. Commercial Transdermal Drug Delivery Systems

5.1. Scopolamine Transdermal Systems
5.2. Nitroglycerin Transdermal Systems
5.3. Clonidine Transdermal Systems
5.4. Estradiol Transdermal Systems
5.5. Fentanyl Transdermal Systems
5.6. Nicotine Transdermal Systems
6. How Transdermal Drug Delivery Has Performed
6.1. Different Therapeutic Areas
6.2. Advantage over Current Dosage Forms
6.3. Different Ratios of Metabolites and Lipids: Estradiol Transdermal versus Oral
6.4. Drugs with Difficult-to-Formulate Properties
6.5. Different Blood-Level Profiles from Other Dosage Forms
6.6. Linear Relation of Blood Level to Area of System
6.7. Different Delivery and Wearing Time
6.8. Same Blood Levels with Different Designs
6.9. Same Blood Levels with Different Mechanisms
6.10. Other Drugs
6.11. Intermittent Delivery
6.12. Electrically Enhanced Permeation
References

35
35
37
44
47
50
52
57
57
57
58
58
58
59
59
59
59
60
61
62
63

Chapter 3
Prodrugs and Their Topical Use
Bradley D. Anderson
1. Introduction
2. Selectivity of the Stratum Corneum to Permeant Structure
2.1. Polar Pathway
2.2. Lipid Pathway
3. Design of Prodrugs to Optimize Maximum Flux
References

69
71
72
73
80
87

Chapter 4
Ultrasound-Mediated Transdermal Drug Delivery
Joseph Kost and Robert hanger
1. Introduction
2. Ultrasound Characteristics

91
92

CONTENTS

3.
4.
5.
6.
7.

xiii

2.1. Properties of the Ultrasound Beam

2.2. Nature of the Ultrasound Wave
2.3. Mass Density and Acoustic Impedance
2.4. Absorption and Penetration of Ultrasound
Clinical Studies
Nonhuman In Vivo Studies
Ultrasound for Transdermal Delivery Systems
Mechanism
Conclusions
References

93
93
93
94
94
96
96
98
101
101

Part II
In Vitro Methodology

Chapter 5
Practical Considerations in Developing a Quality Control (In Vitro
Release) Procedure for Topical Drug Products
Vinod P. Shah and Jerome P. Skelly
1.
2.
3.
4.

Introduction
In Vitro Release Methods for Transdermal Patches
In Vitro Release Method for Creams. Ointments, and Gels
Conclusions
References

107
109
110
115
115

Chapter 6
Diffusion Cell Design
Robert L. Bronaugh
1. Two-Chambered Cell
2. One-Chambered Cell
2.1. Static Diffusion Cell Design
2.2. Flow-Through Diffusion Cell Design
3. Validation of the Flow-Through Cell
4. Modifications
5. Conclusions
References

117
118
118
M9
122
123
124
124

CONTENTS

Part III
In Vivo Methodology
Chapter 7
Cutaneous Bioavailability, Bioequivalence, and Percutaneous
Absorption: In Vivo Methods, Problems, and Pitfalls
/. C. Jamoulle and H. Schaefer
1. Introduction
1.1. Definitions and Relationships between Cutaneous Bioavailability, Bioequivalence, and Percutaneous Absorption
1.2. Guidance and Definitions from Regulatory Publications . . .
2. In Vivo Strategy and Methodology: Problems and Pitfalls
2.1. In Vivo Methods in Animals
2.2. In Vivo Methods in Humans
3. Conclusion
References

129
129
130
132
133
138
141
I47

Chapter 8
The Human Skin Blanching Assay for Topical Corticosteroid
Bioavailability Assessment
Eric W. Smith, Eric Meyer, and John M. Haigh
1. Introduction
2. Blanching Trial Methodology
3. Observation of Results
3.1. Single versus Multiple Observations
3.2. Eye or Instrument Observations
3.3. Observer Training
4. Clinical Equivalency of Formulations
5. Conclusions
References

155
156
157
157
158
159
159
161
161

Chapter 9
Predictive Approaches I: The Stripping Technique
A. Rougier and C. Lotte
1. Introduction
2. In Vivo Relationship between Stratum Corneum Concentration and
Percutaneous Absorption

163
164

CONTENTS

3. Influence of Application Conditions on the Relationship between

Stratum Corneum Concentration and Percutaneous Absorption . .
3.1. Influence of Dose Applied
3.2. Influence of Vehicle
3.3. Influence of Application Time
3.4. Influence of Anatomical Location
4. Conclusion
References

xv

166
167
167
174
175
177
180

Chapter 10
Predictive Approaches II: Mass-Balance Procedure
Daniel A. W. Bucks
1. Introduction
2. Materials and Methods
3. Results
3.1. Percutaneous Absorption of Steroids in Humans
3.2. Percutaneous Absorption of Phenols in Humans
3.3. Relationships between Partitioning and Extent of Percutaneous
Absorption in Humans
3.4. Relationships between Partitioning and Amount ofCompound
Recovered by Surface Washing
3.5. Relationships between Penetrant Partitioning and Retention
in the Stratum Corneum
4. Discussion
References

183
184
186
186
186
189
189
190
192
194

Chapter 11
In Vivo Topical Bioavailability and Skin Decontamination:
Example Alachlor
Ronald C. Wester and Howard 1. Maihach
1. Introduction
2. Methods
2.1. Percutaneous Absorption
2.2. Skin Decontamination
2.3. Scintillation Counting
3. Results
4. Discussion
References

19?
198
198
199
199
200
204
206

xvj

CONTENTS

Chapter 12
Grafted Skin and Skin Flaps
J. Edmond Riviere
1. Introduction
2. Grafted Skin Models
2.1. Intact Rodent Models
2.2. The Rat/Human Skin Flap System (RHSFS)
3. The Isolated Perfused Porcine Skin Rap (IPPSF)
3.1. Procedure for Creating IPPSFs
3.2. Isolated Perfusion Protocols
3.3. Percutaneous Absorption Studies
3.4. In Vitro to In Vivo Predictions
3.5. Role of Isolated Tissue Systems in Dermatopharmacokinetics
4. Discussion
References

209
210
210
211
212
212
213
214
216
218
218
219

Part IV
Factors Influencing Percutaneous Transport
Chapter 13
In Vivo and In Vitro Skin Uptake and Permeation Studies: Critical
Considerations and Factors Which Affect Them
Charan R. Behl, Hing Char, Sunil B. Pate/, Deepak B. Mehta,
David Piemontese, and A. Waseem Malick
1. Introduction
2. Skin-Related Products: Definitions and Objectives
2.1. Transdermal Products
2.2. Dermatological Products
3. Development of Transdermal Products
3.1. Feasibility Studies
3.2. Formulation Studies
3.3. Design of Drug Delivery Systems (The "Hardware")
3.4. Clinical Studies
3.5. Optimization: Feedback Process
4. Development of Dermatological Products
4.1. Screening of Vehicles for Drug Uptake in the Skin
4.2. Formulation Studies
4.3. Clinical Studies
4.4. Optimization: Feedback Process

225
226
226
226
226
227
227
227
227
227
228
228
228
229
229

CONTENTS

5. Drug Uptake StudiesRationale and Objectives

6. In Vitro versus In Vivo Drug Uptake Studies: A Four-Prong
Approach
6.1. Transdermal Products
6.2. Dermatological Products
7. Models and Membranes for the Study of Drug Uptake and
Permeation in and through the Skin
7.1. Characteristics of Good Models: A Four-Prong Approach . .
7.2. Membranes
8. Role of Test Compounds in Studying Drug Uptake and
Permeation
9. Factors Which Affect Drug Uptake and Permeation
9.1. Hydration
9.2. Lipophilicity and Molecular Weight of Permeants
9.3. Drug Solubility and Concentration
9.4. Effects of Vehicle/Dosage Form
9.5. Site, Age, Gender, and Race
9.6. Enhancers
10. Recommendations
References

xvii

229
229
230
230
231
231
232
235
236
238
238
241
243
246
247
251
252

Chapter 14
Vehicle Effect: What Is an Enhancer?
B. W. Barry
1. Introduction
2. Nature of Dermatological Vehicles
2.1. Liquid Preparations
2.2. Simple Suspensions
2.3. Emulsions
2.4. Transdermal Drug Delivery Devices
3. Possible Effects of Vehicle on Stratum Corneum
3.1. Horny Layer UnmodifiedChemical Potential Adjustment
3.2. Horny Layer Modified
References

261
261
262
263
264
266
267
267
268
275

Chapter 15
The Dose Response of Percutaneous Absorption
Ronald C. Wester and Howard I. Maibach
1. Introduction
2. Accountability (Mass Balance)

277
279

CONTENTS

3.1.
3.2.
3.3.
3.4.
3.5.
4.

5.

6.

7.

Human Subject Population

Topical Drug Application
Analytical Methods
Skin Blanching Assay
Correlation between Amount of Topical Drug in the Human
Stratum Corneum and Skin Blanching Assay In Vivo
In Vitro Drug Uptake into Human Stratum Corneum
4.1. Skin Preparation
4.2. Topical Drug Application
4.3. In Vitro Results
In Vitro Drug Release across Synthetic Membranes
5.1. Methods
5.2. Drug Release from Ointment Formulations
5.3. Drug Release from Cream Formulations
In Vivo/In Vitro Comparisons of Drug Uptake and Release
6.1. Ointment Formulations
6.2. Cream Formulations
6.3. Comparison of Three Model Systems
Summary
References

353
354
355
356
357
358
358
358
359
359
359
360
361
362
362
363
363
364
365

Part VI
Biopharmaceutics and Clinical Assessment
Chapter 20
General Introduction and Conceptual Differentiation of Topical and
Transdermal Drug Delivery Systems: Differentiation with Respect to
Delivery Kinetics
Gordon L. Flynn
1. Fundamental Definitions: Topical and Transdermal Systems
2. Thermodynamic and Kinetic Factors of Topical Delivery
2.1. Kinetic Determinants of Delivery
2.2. Thermodynamic Determinants of Delivery
3. Summary
References

....

370
378
381
385
390
391

CONTENTS

xxi

Chapter 21
Bioequivalence of Topical Dermatological Products
Vinod P. Shah, Donald Hare, Shrikant V. Dighe,
and Roger L. Williams
1. Introduction
2. Generic Topical Dermatological Products: Regulatory History . . .
3. Pharmaceutical and Therapeutic Equivalence: Criteria for
Generic Substitution
4. Documentation of Bioequivalence: In Vitro Issues
4.1. Synthetic Membranes
4.2. Natural Membranes
5. Documentation of Bioequivalence: In Vivo Issues
5.1. Animal Models
5.2. Pharmacokinetic Methodology
5.3. Pharmacodynamic Studies
5.4. Clinical Trials
6. Conclusions and Recommendations
References

393
395
396
397
398
400
401
401
402
405
411
411
412

Chapter 22
Bioavailability and Bioequivalence of Transdermal Drug Delivery Systems:
Regulatory Considerations
Vinod P. Shah, Thomas M. Ludden, Shrikant V. Dighe,
Jerome P. Skelly, and Roger L. Williams
1. Introduction
2. New Drug Applications
2.1. Biopharmaceutics: General Issues
2.2. Pharmacokinetics: General Issues
2.3. Clinical Pharmacology: Considerations
2.4. Efficacy and Safety Requirements
2.5. Studies Required for Transdermal Drug Formulations
Approved for Other Routes of Administration
3. Abbreviated New Drug Applications
4. Conclusions
References

415
416
416
417
420
421
422
422
423
423

xxii

Chapter 23
Ethical and Clinical Considerations for Topical Drug Products
(Including Surgical Scrubs)
C. Carnot Evans, Jr.

CONTENTS

425

Chapter 24
Clinical Considerations of Transdermal Drugs
Solomon Sobel
1. Introduction
2. Current Progress
2.1. Estrogen Replacement Therapy
2.2. Testosterone Replacement
3. Conclusion

Index

431
432
432
435
436

437