Topical Drug Bioavailability, Bioequivalence, and Penetration (eBook)

John Jenner, Howard I. Maibach, Vinod P. Shah (Herausgeber)

eBook Download: PDF

2015 | 2nd ed. 2014
XIII, 402 Seiten
Springer New York (Verlag)
978-1-4939-1289-6 (ISBN)

Infos

This authoritative volume explores advances in the techniques used to measure percutaneous penetration of drugs and chemicals to assess bioavailability and bioequivalence and discusses how they have been used in clinical and scientific investigations.  Seven comprehensive sections examine topics including in vitro drug release, topical drugs products, clinical studies, and guidelines and workshop reports, among others. The book also describes how targeted transdermal drug delivery and more sophisticated mathematical modelling can aid in understanding the bioavailability of transdermal drugs.

 The first edition of this book was an important reference guide for researchers working to define the effectiveness and safety of drugs and chemicals that penetrated the skin. This second edition contains cutting-edge advances in the field and is a key resource to those seeking to define the bioavailability and bioequivalence of percutaneously active compounds to improve scientific and clinical investigation and regulation.

Vinod P. Shah is a pharmaceutical consultant. He was Scientific Secretary of International Pharmaceutical Federation (FIP) and is now Chair of Regulatory Sciences Special Interest Group of FIP. Dr. Shah has served at the U.S. Food and Drug Administration and has developed several regulatory guidances for the pharmaceutical industry in biopharmaceutics and topical drug products. Dr. Shah is a fellow of FIP as well as the American Association of Pharmaceutical Scientists (AAPS), where he served as president for a year. He is a recipient of an honorary doctorate from Semmelweis University, Budapest, Hungary.  

Howard I. Maibach is professor of dermatology at the University of California, San Francisco. He received his M.D. at Tulane University Medical School in New Orleans, Louisiana, and completed his residency and research fellowships at the University of Pennsylvania in Philadelphia, Pennsylvania. Professor Maibach is a leading authority in the fields of dermatotoxicology and dermatopharmacology, in which he has conducted research and written extensively. Prof. Maibach has served on the editorial boards of more than thirty scientific journals and is a member of many professional societies, including the American Academy of Dermatology and the International Commission on Occupational Health.

John Jenner is a principal scientist at The Defence Science and Technology Laboratory in the UK. He has a degree in pharmacology from the University of Manchester in Manchester, UK, and a Ph.D. from the University of Surrey, Guildford, UK. John has spent his career studying defense against and treatment of highly toxic chemicals. He has an enduring research interest in percutaneously active chemicals, whether toxic materials or drugs, and experience in the design and testing of transdermal formulations. His current interests include the translation of in vitro penetration measurements to in vivo using mathematical modelling.

Inhalt

Contents 5
About the Editors 8
List of Contributors 9
Part I 12
Percutaneous Absorption 12
Chapter-1 13
Percutaneous Absorption 13
1.1 Introduction 13
1.2 Powdered Human Stratum Corneum 14
1.3 In Vitro Percutaneous Absorption Method 16
1.4 In Vitro Individual and Regional Variation 17
1.5 In Vitro Short-Term Skin Exposure 20
1.6 In Vivo Percutaneous Absorption Methods 22
1.6.1 Skin Stripping: Short-Term Exposure 22
1.6.2 Skin Flaps 23
1.6.3 Systemic Bioavailability (Blood and Excreta) 24
1.6.4 Microdialysis 25
1.6.5 Surface Disappearance 25
1.6.6 Suction Blister 26
1.6.7 Biological Response (Pharmacodynamics) 26
1.6.8 Raman Spectroscopy 26
1.7 Other Methods to Examine Maturity of Stratum Corneum (The Major Barrier to Water Loss) 27
1.7.1 Quantitative Structure Activity Relationship (QSAR) 27
1.7.2 Transepidermal Water Loss 27
1.7.3 Skin Impedance 27
1.8 Concluding Remarks 28
References 28
Chapter-2 30
Animal Models for Percutaneous Absorption 30
2.1 Introduction 30
2.2 Monkeys: Rhesus/Squirrel 31
2.3 Pigs 31
2.4 Rats 33
2.5 Rabbits 35
2.6 Guinea Pigs 37
2.7 Hairless Rats/Hairless Mice/Hairless Guinea Pigs 37
2.7.1 Hairless Rats 38
2.7.2 Hairless Mice 38
2.7.3 Hairless Guinea Pigs (HGPs) 39
2.8 In Vitro Species Comparison and In Vitro/In Vivo Correlation 39
2.9 Alternative In Vitro Test Methods 42
2.9.1 Isolated Perfused Porcine Skin Flap (IPPSF) 42
2.9.2 Isolated Blood-Perfused Pig Ear 43
2.9.3 Isolated Normothermic Hemoperfused Porcine Forelimb 43
2.9.4 Mouse Dorsal Skin Fold Chamber Model 44
2.9.5 Isolated Bovine Udder 44
2.10 Human Skin Grafted onto Nude Mouse Model (HuSki Model) 44
2.11 Animal Skin: Physical and Chemical Parameters 46
2.12 Dose Response 46
2.13 Regional Variation in Animals 46
2.14 Summary 47
References 47
Chapter-3 50
Mitigating Dermal Exposure to Agrochemicals 50
3.1 Introduction 50
3.2 Agrochemicals 50
3.3 Dermal Absorption of Agrochemicals 52
3.3.1 Environmental Factors 52
3.3.2 Skin Condition 52
3.3.3 Adherence to Safe Working Practices 53
3.3.4 Exposure Scenarios and Environmental Decontamination 54
3.4 Skin Decontamination 54
3.4.1 Definition and Practice 54
3.4.2 Factors Affecting Decontamination 54
3.4.3 Experimental Methods to Assess Skin Decontamination 56
3.4.4 Consideration of Experimental Factors for Design of Decontamination Studies 59
3.4.5 Current Recommendations for Skin Decontamination of Agrochemicals 60
3.5 Summary 60
References 61
Part II 67
In Vitro Drug Release 67
Chapter-4 68
Importance of In Vitro Drug Release 68
4.1 Introduction 68
4.2 In Vitro Release Methods for Transdermal Systems 70
4.3 In Vitro Release Method for Semisolid Dosage Forms 71
4.4 Importance of In Vitro Drug Release 72
4.5 Conclusion 73
References 74
Chapter-5 75
Diffusion Cell Design 75
5.1 Introduction 75
5.2 Historical Perspective 76
5.3 Static Diffusion Cell 78
5.4 Flow-Through Diffusion Cell 81
5.5 Special Devices 82
5.5.1 Volatile Compounds 82
5.5.2 Solids and Powders 82
5.6 Bioequivalence Testing 83
References 84
Chapter-6 87
In Vitro Product Quality Tests and Product Performance Tests for Topical and Transdermal Drug Products 87
6.1 Introduction 87
6.2 Tests for Topical Dermatological Drug Products 88
6.2.1 Product Quality Tests 88
6.2.1.1 Particle Size 88
6.2.1.2 Viscosity 88
6.2.1.3 Container Uniformity 89
6.2.2 Product Performance Test 91
6.3 Application of In Vitro Drug Release 92
6.4 Tests for TDSs 93
6.4.1 Product Quality Tests 93
6.4.1.1 Adhesion Tests 93
6.4.1.2 Peel Adhesion Test 94
6.4.1.3 Release Liner Peel Test 94
6.4.1.4 Tack Test 94
6.4.1.5 Leak Test 94
6.4.2 Product Performance Test 94
References 95
Chapter-7 96
Safety and Efficacy Testing of Topical Products Practical Considerations
7.1 Introduction 96
7.2 Consumer Habits and Its Importance in Designing Safety and Efficacy Studies of Cosmetic Products 97
7.3 Mindset Issues: Testing for Claims vis-à-vis Claiming “What Tested” 97
7.4 Efficacy Results and Interpretations—Instrumental, Clinical, and Consumer Perceptions 98
7.5 Product Knowledge and Testing Methodology 99
7.6 How to Create a Value Proposition for the Sponsor and Consumer Through Safety and Efficacy Testing? 100
7.7 Ethical Issues in Study Design 101
7.8 Summary and Conclusion 102
References 102
Part III 103
Bioequivalence of Topical Drug Products 103
Chapter-8 104
Challenges in Evaluating Bioequivalence of Topical Dermatological Drug Products 104
8.1 Introduction 104
8.2 Regulatory History 105
8.3 Regulatory Requirements for BE 106
8.4 Topical Dermatologic Drug Products: BE Methods 106
8.4.1 BE for Topical Dermtologic Products: Accepted Methods 107
8.4.1.1 Pharmacodynamic Measurements 107
8.4.1.2 Comparative Clinical Trials 108
8.4.2 BE for Topical Dermatologic Products: Promising Approaches 108
8.4.2.1 Dermatopharmacokinetics 108
8.4.2.2 BE of Topical Dermatology Drug Products: In Vitro Studies 112
8.4.2.3 BE of Topical Dermatology Drug Products: Other Methods 113
8.4.2.4 BE of Topical Dermatology Drug Products: Case-By-Case Solutions 113
8.5 Conclusion 113
References 114
Chapter-9 116
Methods for the Assessment of Bioequivalence of Topical Dosage Forms: Correlations, Optimization Strategies, and Innovative Approaches 116
9.1 Introduction 116
9.2 Definitions and Types of Topical Dosage Forms 117
9.3 Methods 118
9.3.1 The Human Skin Blanching Assay (HSBA) also Known as the Vasoconstrictor Assay (VCA) for Topical Corticosteroids 119
9.3.2 Methods for the Evaluation of Skin Blanching 120
9.3.2.1 Visual Assessment 120
9.3.2.2 Chromameter Assessment 122
9.3.2.3 Study Designs 122
9.3.2.4 Comparison Between Visual and Chromameter Assessment 123
9.3.2.5 Assessment of Bioequivalence 124
9.3.3 Dermatopharmacokinetic (DPK) Methods or Tape Stripping (TS) 127
9.3.4 Microdialysis 136
9.3.4.1 Theoretical Principles 136
9.3.5 Dermal Microdialysis 136
9.3.5.1 Membrane Systems 137
9.3.5.2 Probe Calibration 138
9.3.5.3 Assessment of Probe Depth 139
9.3.5.4 Composition of Perfusates 139
9.3.5.5 Exposure and Trauma 139
9.3.5.6 Analytical Sensitivity Requirements 140
9.3.5.7 Advantages and Limitations 140
9.3.5.8 Bioavailability and Bioequivalence Applications 140
9.3.6 In Vitro Methods 143
9.3.7 Open Flow Microperfusion 146
9.3.7.1 Principles and Application of Open Flow Microperfusion to Study Drug Diffusion Through Skin 146
References 149
Chapter-10 155
Application of Microdialysis in Assessing Cutaneous Bioavailability 155
10.1 Introduction 155
10.2 The Methodology (Brief Description) 156
10.3 Planning an In Vivo Bioequivalence Study 156
10.3.1 Choice of Probe Type and Perfusate 156
10.3.2 Application Site 157
10.3.3 Insertion Procedure, Trauma, and Exclusion Criteria 157
10.4 Bioavailability 158
10.5 Bioequivalence 159
10.6 Sources of Variability 160
10.6.1 Skin Barrier Function 160
10.6.2 Microcirculation 161
10.6.3 Probe Depth in the Skin 161
10.7 Advantages and Limitations 162
10.7.1 Advantages 162
10.7.2 Limitations 162
10.8 Future Research 163
References 164
Part IV 168
Bioequivalence: Targeted Drug Delivery 168
Chapter-11 169
Follicular Drug Penetration 169
11.1 Introduction 169
11.2 Influence of Follicular Morphology, Density, and Activity Status on the Follicular Penetration Process 170
11.3 Measuring Methods for Investigating the Penetration of Topically Applied Substances into the Hair Follicles 171
11.4 Skin Models for the Analysis of Follicular Penetration 173
11.5 Particles, Follicular Penetration, and Safety Aspects 174
11.6 The Hair Follicle as a Long-Term Reservoir 176
11.7 Triggered Release from Particles in the Hair Follicles 176
11.8 Summary 177
Reference 177
Chapter-12 180
Development of Pilosebaceous Unit-Targeted Drug Products 180
12.1 Introduction 180
12.1.1 Rationale for Pilosebaceous Unit (PSU)-Targeted Drug Delivery 180
12.1.2 Properties of the PSU and Sebum 182
12.1.3 Potential Targets Within the PSU 182
12.1.4 Primary Approaches for PSU or Follicular Drug Delivery 183
12.2 Recent Development and Commercialization of PSU-Targeted Dermal Products 184
12.2.1 Particulate Carrier-Based Formulations 184
12.2.2 Recent Innovations in Follicular Drug Delivery 184
12.3 Research in Developing PSU-Targeted Formulations 187
12.3.1 Development of an Artificial Sebum Model 188
12.3.1.1 Hypothesis for Application of Artificial Sebum Model 188
12.3.1.2 Experimental Methods 188
12.3.2 In Vitro Methods for Quantifying Follicular Penetration 189
12.3.3 In Vivo Efficacy Models 190
12.3.4 Dosage Forms for Follicular Drug Delivery 191
12.3.5 Particulate Systems for Follicular Delivery 196
12.3.6 Characterization of Particulate Drug Delivery Systems 199
12.3.7 Stability Assessment 201
12.3.8 Safety and Tolerability 201
12.4 Discovery and Development Process for Topical Products Targeting Pilosebaceous Unit 204
12.4.1 Discovery and Early Stage Development Process 204
12.4.2 Late Stage Development or Reformulation Process 205
12.5 Conclusion 209
References 209
Chapter-13 215
Deep Percutaneous Penetration into Muscles and Joints: Update 215
13.1 Introduction 215
13.2 Drug Properties Affecting Distribution 216
13.2.1 Lipophilicity 216
13.2.2 Permeability 217
13.2.3 Molecular Weight 217
13.2.4 Fraction Unbound Drug in Viable Skin 217
13.2.5 Relative Importance of the Physicochemical Factors 218
13.3 Pharmacokinetic Models 218
13.3.1 Experimental Methods 219
13.3.2 Model Predictions 219
13.3.3 New Physiological Models 220
13.4 Distribution in Deeper Tissues 222
13.4.1 Direct Versus Indirect Penetration 222
13.4.2 Penetration Efficacy 222
13.5 Distribution into Joints and Surrounding Soft Tissues 224
13.5.1 Diclofenac Controversy 224
13.5.2 Salicylic Acid 225
13.6 Modes of Delivery 225
13.7 Transdermal Drug Delivery Enhancements 226
13.7.1 Transporter Proteins 226
13.7.1.1 Ultrasound Guided Percutaneous Drug Delivery 227
13.7.1.2 Combination of Iontophoresis, Terpene, and Hypothermia 227
13.7.2 Efficacy and Safety of Percutaneous Drug Delivery in Humans 227
13.8 New and Future Research Direction 228
13.8.1 Photoacoustic Spectroscopy 228
13.8.2 Compound Transdermal Patch 229
13.9 Improvements to Future Research 230
13.10 Conclusion 230
13.11 Declaration of Interest 230
References 231
Chapter-14 234
Efficacy and Toxicity of Microneedle-Based Devices 234
14.1 Introduction 234
14.2 Microneedle Fabrication 235
14.3 Microneedle Strategies for Drug Delivery 237
14.4 Transdermal Drug Delivery Applications 237
14.4.1 Hollow Microneedles 238
14.5 Safety of Microneedles 239
14.6 Pharmacokinetics and Pharmacodynamics 239
14.7 Conclusion 240
References 240
Part V 244
Transdermal Drugs and Modelling 244
Chapter-15 245
Mathematical Models for Topical and Transdermal Drug Products 245
15.1 Introduction 245
15.2 In Vitro Skin Diffusion Models in Percutaneous Absorption 246
15.2.1 In Vitro Skin Permeability Studies with a Constant Donor Concentration and Sink Receptor Conditions 249
15.2.2 Amount and Flux-Time Profiles on Removing the Donor Phase After Reaching the Steady State for Conditions Described in Section 15.1.1 254
15.2.3 In Vitro Permeability Studies with a Constant Donor Concentration and Finite Receptor Volume 257
15.2.4 In Vitro Permeability Studies with a Constant Donor Concentration or Defined Input Flux and Finite Clearance of Solute from the Epidermis 259
15.2.5 In Vitro Skin Permeability Studies with Finite Donor Volume and Receptor Sink Conditions 262
15.2.6 In Vitro Permeability Studies with a Finite Donor Volume and a Finite Clearance from the Epidermis into the Receptor 265
15.2.7 In Vitro Skin Permeability Studies with Diffusion Limited Finite Donor, and Sink Receptor Conditions 266
15.2.8 In Vitro Permeability Studies with Two Layer Diffusion Limitations in Transport 267
15.2.9 Desorption 269
15.2.10 SC Heterogeneity 270
15.3 Release Profiles from Topical Products 271
15.3.1 Diffusion Controlled Release 271
15.3.2 Release of a Suspended Drug by Diffusion 271
15.4 Compartmental Models as an Alternative to Diffusion Models in Percutaneous Absorption 272
15.5 Other Processes Affecting In Vitro Percutaneous Absorption 272
15.5.1 Concentration-Dependent Diffusive Transport Processes 272
15.5.2 Bioconversion/Metabolism of Solutes in the Skin 274
15.5.3 Solute–Vehicle, Vehicle–Skin and Solute–Skin Interactions 275
15.5.4 Effect of Surface Loss Through Processes Such as Evaporation and Adsorption to Skin Surface 276
15.5.5 Shunt Transport 277
15.5.6 Reservoir Effect 277
15.6 Simple In Vivo Models in Percutaneous Absorption 277
15.6.1 Compartmental Pharmacokinetic Models 277
15.6.2 Diffusion Pharmacokinetic Models 280
15.6.3 Physiologically-Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Models 281
15.6.4 Deconvolution Analysis in Pharmacokinetic Modelling 282
15.6.5 Penetration into Tissues Underlying Topical Application Site 283
15.6.6 Pharmacodynamic Modelling 284
15.7 Modelling-Facilitated Transdermal Delivery 285
15.7.1 Iontophoresis 285
15.7.2 Sonophoresis 286
15.8 Practical Issues in Applying Mathematical Models to Percutaneous Absorption Data 286
15.9 Conclusion 287
References 288
Chapter-16 295
Transdermal Patches: An Industrial Perspective on the Relevance of In Vitro Skin Permeation Studies and Approaches on Design of Manufacturing Processes 295
16.1 Introduction 295
16.2 Transdermal Drug Development: Skin Permeation Performance In Vitro and In Vivo 296
16.3 Transdermal Drug Development: Manufacturing Process Development 305
16.4 Conclusion 311
References 312
Chapter-17 315
Transdermal Drug Delivery Systems 315
17.1 Introduction 315
17.2 New Drug Applications 317
17.2.1 Biopharmaceutics: General Issues 317
17.2.2 Pharmacokinetics: General Issues 318
17.2.2.1 In Vivo Studies 319
17.2.2.2 In Vitro Studies 319
17.2.3 Clinical Pharmacology: Considerations 320
17.2.4 Efficacy and Safety Requirements 320
17.2.5 Studies Required for Transdermal Drug Formulations Approved for Other Routes of Administration 321
17.3 Abbreviated New Drug Applications 322
17.4 Looking into the Future 323
17.5 Conclusions 323
References 323
Part VI 325
Clinical Studies and Bioequivalence. 325
Chapter-18 326
Dermal Estradiol and Testosterone Transfer in Man: Existence, Models, and Strategies for Prevention 326
18.1 Introduction 326
18.2 Human Experiment Transfer Data: In Vivo 327
18.3 Standardization of Transfer Methods 336
18.4 Human Experiment Transfer Data: In Vitro 337
18.5 In Vitro Transfer Methodologies 337
18.6 Animal Experiment Transfer Data: In Vivo 337
18.7 Animal Experiment Transfer Data: In Vitro 337
18.8 Possible Excipient Effect and Quantification of Transdermal Transfer 337
18.9 Intrinsic Properties of Transdermal Hormones 338
18.10 Anatomic Effect 338
18.11 Absorption Properties of the Skin 339
18.12 Analytic Chemistry and Human Pharmocokinetics 340
18.13 Development and Optimization of Transfer Models 340
18.14 Conclusion 341
References 341
Chapter-19 346
Effects of Occlusion on Dermal Drug Delivery: Implications for Bioequivalence Measurement 346
19.1 Introduction 346
19.2 Effects of Occlusion on Skin Physiology and Chemistry 346
19.2.1 pH Changes 346
19.2.2 Carbon Dioxide Emission (pCO2) 347
19.2.3 Transepidermal Water Loss (TEWL) 347
19.2.4 Relative Skin Moisture, Hydration, and Skin Water Content (WC) 347
19.2.5 Histological Changes 349
19.2.6 Microbiological Changes 350
19.3 The Effect of Occlusion on Topical Drug Delivery 351
19.4 Effect of Occlusion on Healthy and Diseased Skin 352
19.5 Conclusion 353
References 353
Chapter-20 355
Challenges with Clinical Endpoints—Bioequivalence 355
A Brief Walk Through the History of Topical Bioequivalence 355
20.1 Introduction 355
20.2 Corticosteroid Vasoconstriction 356
20.3 Photography—Acne 357
20.4 Hair Weight—Hair Growth 357
20.5 Hair Photography 358
20.6 Paired Comparison Assay 358
20.7 Psoriasis Plaque Assay 358
20.8 Armitage Statistics 359
20.9 Placebo Response 359
20.10 Percutaneous Penetration 360
20.11 Skin Variability 361
20.12 Comparative Effectiveness 362
20.13 Conclusions 362
References 363
Chapter-21 365
Clinical Considerations of Bioequivalence for Topical Dermatologic Drugs 365
21.1 Introduction 365
21.2 Suction Blister Technique, Dermal Microdialysis, Skin Stripping, and In Vitro Release to Determine Bioequivalence 366
21.3 Reaching Clinical Endpoints in the Vasoconstrictor Assay with Chromametry, Digital Image Analysis, and Visual Inspection 367
21.4 Other Trials Using Visual Inspection to Reach Clinical Endpoints 368
21.4.1 Tretinoin and Adapalene 368
21.4.2 Psoriasis Small Plaque Bioassay 368
21.4.3 Assessing Acne Severity 368
21.4.4 Androgenetic Alopecia and Finasteride 369
21.5 Clinical Endpoints in BE 369
21.6 Conclusion 370
References 370
Part VII 372
Guidelines and Workshop Report 372
Chapter-22 373
OECD Test Guideline 428—A Method for In Vitro Percutaneous Absorption Measurement? 373
22.1 Introduction 373
22.2 The Contents of Guideline 428 374
22.2.1 Diffusion Cell Design 374
22.2.2 Choice of Receptor Fluid 375
22.2.3 Skin 375
22.2.4 Integrity Testing 376
22.2.5 Application of the Test Substance 376
22.2.6 Conditions During the Test 377
22.2.7 After the Test 378
22.2.8 Summary 378
22.3 Conclusion 378
References 379
Chapter-23 380
Bioequivalence, Quality, and Novel Assessment Technologies for Topical Products: Current Challenges and Future Prospects 380
23.1 Introduction 380
23.2 Characteristics of Topical Products 381
23.3 Topical Generic Products and Reference Product 381
23.4 Assessment of BE 382
23.4.1 Clinical Endpoint Studies 382
23.4.2 PK Studies 382
23.4.3 PD (Vasoconstriction Assay) 382
23.5 Alternative/Novel Methods to Assess BE 383
23.5.1 Dermatopharmacokinetics (DPK) 383
23.5.2 Microdialysis 383
23.5.3 Open Flow Microperfusion 384
23.5.4 Confocal Raman Spectroscopy 384
23.5.5 In Vitro Skin Permeation Studies 384
23.5.6 In Vitro Release Testing 385
23.6 Assessment of Quality and Performance of Topical Drug Products 385
23.7 Proposed Decision Tree for Assessment of Bioequivalence 386
23.8 BE of Topical Dermatology Drug Products: Case-By-Case Solutions 386
23.9 Looking Toward the Future 387
23.10 Conclusions 387
References 387
Index 390

Produkt-Details

• Erscheint lt. Verlag: 30.1.2015
• Zusatzinfo: XIII, 402 p. 64 illus., 16 illus. in color.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Pharmazie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik
• Themenwelt: Technik
• Schlagworte: Bioavailability • bioequivalence • Drug Release • Penetration • quality test • topical drugs
• ISBN-10: 1-4939-1289-5 / 1493912895
• ISBN-13: 978-1-4939-1289-6 / 9781493912896