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C M Y CM MY CY CMY K
T
RANSDERMAL AND
I D
NTRADERMAL ELIVERY
T
OF HERAPEUTIC
A
GENTS
A P T
PPLICATION OF HYSICAL ECHNOLOGIES
CRC Press
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© 2011 by Taylor and Francis Group, LLC
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Dedication
This book is dedicated to my wife, Saveta, and my
children, Manisha and Anshul, for their support and
understanding during the preparation of this book.
© 2011 by Taylor & Francis Group, LLC
Contents
Preface....................................................................................................................xiii
About the Author .....................................................................................................xv
Chapter 1 Percutaneous Absorption and Enhancement Strategies .......................1
1.1 Introduction ...............................................................................1
1.2 Structure and Enzymatic Activity of the Skin ..........................5
1.2.1 Skin Structure...............................................................5
1.2.1.1 Hair Follicles in the Skin ..............................7
1.2.2 Enzymatic Activity of the Skin ....................................8
1.3 Percutaneous Absorption ...........................................................8
1.3.1 Mechanisms of Percutaneous Absorption ....................8
1.3.2 Theoretical Basis of Percutaneous Absorption ............9
1.4 Passive Permeation Enhancement Strategies ..........................10
1.4.1 Chemical Penetration Enhancers ...............................10
1.4.2 Prodrugs .....................................................................12
1.4.3 Nanocarriers for Intradermal or Transdermal
Delivery ......................................................................13
1.4.4 Microemulsions ..........................................................13
1.4.5 Liposomes ..................................................................13
1.4.6 Cyclodextrins..............................................................15
1.5 Active Enhancement Strategies for Percutaneous
Absorption ...............................................................................15
1.5.1 Microporation .............................................................16
1.5.2 Iontophoresis ..............................................................16
1.5.3 Sonophoresis...............................................................17
1.5.4 Microdermabrasion ....................................................17
1.6 Applications in Veterinary Medicine ......................................18
References ..........................................................................................19
Chapter 2 Experimental Methods and Tools for Transdermal Delivery by
Physical Enhancement Methods .........................................................27
2.1 Introduction .............................................................................27
2.2 Considerations in Selecting the Skin Model ...........................27
2.2.1 Animal Models for Transdermal Delivery .................27
2.2.2 Use of Human Skin ....................................................29
2.2.3 Isolated Perfused Porcine Skin Flap Model ...............30
2.2.4 Artificial Skin Equivalents .........................................31
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viii Contents
2.2.5 Skin Treatment ...........................................................31
2.2.6 Use of Synthetic Membranes .....................................32
2.3 Transdermal Studies ................................................................33
2.3.1 Diffusion Cells: Vertical Configuration .....................33
2.3.2 Diffusion Cells: Horizontal Configuration .................35
2.3.3 Devices Used with Skin Enhancement
Techniques ..................................................................35
2.3.4 Typical Experimental Setup .......................................36
2.3.5 Variability of Percutaneous Absorption .....................37
2.4 Analysis ...................................................................................38
2.4.1 Tape Stripping ............................................................39
2.4.2 Microdialysis ..............................................................40
2.5 Instrumental Tools Used to Characterize Transdermal
Transport..................................................................................41
References ..........................................................................................44
Chapter 3 Microporation-Mediated Transdermal Drug Delivery ......................53
3.1 Introduction .............................................................................53
3.2 Skin Microporation by Microneedles ......................................53
3.2.1 Potential Advantages of a Microneedle Patch ............53
3.2.2 Fabrication of Microneedles .......................................54
3.2.3 Mechanisms of Delivery and Type of
Microneedles ..............................................................56
3.2.3.1 Solid Microneedles .....................................56
3.2.3.2 Hollow Microneedles ..................................59
3.2.4 Factors Influencing Microneedle Insertion ................61
3.2.4.1 Insertion Kinetics .......................................61
3.2.4.2 Microneedle Length and Density ...............62
3.2.4.3 Microneedle Geometry ...............................63
3.2.4.4 Depth of Insertion and Pain ........................63
3.2.5 Pore Closure and Safety Following
Microporation .............................................................64
3.2.6 Delivery of Particulates through Hair Follicles
and through Microporated Skin .................................65
3.3 Skin Microporation by Other Approaches ..............................66
3.3.1 Thermal Ablation .......................................................66
3.3.2 Laser Microporation ...................................................67
3.3.3 Radio-Frequency Ablation .........................................68
3.3.4 Other Means of Skin Microporation ..........................70
3.4 Combination Approaches ........................................................70
3.5 Applications of Microporation ................................................71
3.5.1 Delivery of Small Drug Molecules ............................71
3.5.2 Photodynamic Therapy ..............................................71
3.5.3 Delivery of Lipophilic Drugs .....................................72
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Contents ix
3.5.4 Delivery of Macromolecules ......................................72
3.5.5 Diagnostic and Other Applications ............................72
References ..........................................................................................73
Chapter 4 Iontophoretic Intradermal and Transdermal Drug Delivery ..............81
4.1 Introduction .............................................................................81
4.1.1 Historical Origin of Iontophoresis .............................81
4.2 Electrical Properties of Skin ...................................................82
4.3 Pathways of Iontophoretic Drug Delivery ...............................83
4.4 Theoretical Basis of Iontophoresis ..........................................85
4.5 Factors Affecting Iontophoretic Delivery ................................87
4.5.1 Electric Current ..........................................................87
4.5.2 Modality of Current ...................................................89
4.5.3 Physicochemical Properties of the Drug ....................90
4.5.4 Formulation Factors ...................................................92
4.5.5 Biological Factors .......................................................93
4.6 pH Control in Iontophoresis Research .....................................93
4.6.1 Selection of Electrode Material ..................................93
4.6.2 Silver/Silver Chloride Electrodes ...............................94
4.6.3 Preparation and Care of Silver/Silver Chloride
Electrodes ...................................................................95
4.6.4 Alternative Methods for pH Control ..........................96
4.7 Electroosmotic Flow ................................................................97
4.7.1 Theoretical Treatment of Electroosmotic Flow .........99
4.8 Reverse Iontophoresis ..............................................................99
4.9 Treatment Protocols and Formulations .................................101
4.10 Combined Use of Iontophoresis and Other
Enhancement Techniques ......................................................102
4.11 Applications of Iontophoresis ................................................102
4.11.1 Iontophoretic Delivery to the Nail............................102
4.11.2 Nicotine ....................................................................103
4.11.3 Synthetic Narcotics: Sufentanil ................................104
4.11.4 Iontophoretic Delivery of Dopamine Agonists ........104
4.11.5 Miscellaneous ...........................................................105
4.11.6 Alternate Applications for Iontophoresis .................106
4.12 Clinical Applications of Iontophoresis for Intradermal
Delivery .................................................................................106
4.12.1 Delivery of Dexamethasone .....................................107
4.12.2 Delivery of Other Steroids .......................................109
4.12.3 Treatment of Hyperhidrosis ......................................109
4.12.4 Diagnosis of Cystic Fibrosis .....................................110
4.12.5 Iontophoresis of Histamine and
Antihistamines .........................................................112
4.12.6 Delivery of Antiviral Agents ....................................112
© 2011 by Taylor & Francis Group, LLC
