Transdermal Drug Delivery

Technologies, Companies & Markets

By

Prof. K. K. Jain

MD, FRACS, FFPM

Jain PharmaBiotech Basel, Switzerland

April 2018

A Jain PharmaBiotech Report

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A B O U T T H E A U T H O R

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in the biotechnology/biopharmaceuticals industry for several years. He received graduate training in both Europe and USA, has held academic positions in several countries and is a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of UK. Currently he is a consultant at Jain PharmaBiotech. Prof. Jain’s 476 publications include 30 books (6 as editor + 24 as author) and 50 special reports, which have covered important areas in biotechnology, gene therapy and biopharmaceuticals.

Prof. Jain has edited "Drug Delivery Systems" (1st ed 2008, 2nd ed 2014, 3rd edn 2019, in preparation) and Drug Delivery to the Central Nervous System (2010), both published by Humana/Springer. His other recent books include "Handbook of Nanomedicine" (Springer/Humana 2008; Chinese ed, Peking University Press 2011, 2nd ed Springer 2012, 3rd ed 2017), “Textbook of Personalized Medicine (Springer 2009; Japanese ed 2012; 2nd ed Springer, 2015), "Handbook of Biomarkers" (Springer 2010; Chinese edition, Chemical Industry Press 2016, 2nd ed Springer 2017), “Application of Biotechnology in Cardiovascular Therapeutics” (Springer 2011), “Application of Biotechnology in Neurology” (Springer 2013), and “Application of Biotechnology in Oncology” (Springer 2014)

A B O U T T H I S R E P O R T

The original report on Transdermal Drug Delivery appeared as a section in the author's Drug Delivery Systems published by Decision Resources Inc in 1998. The second edition was published by Informa Pharmaceuticals after detaching Cancer Drug Delivery and Central Nervous System Drug Delivery as separate reports in 2000. In 2002, Transdermal Drug Delivery was also detached, expanded and updated to be issued as separate publications by Jain PharmaBiotech. The report was regularly updated since 2002, enlarged and rewritten for 2017 edition.

April 2018 Copyright 2018 by

Jain PharmaBiotech Bläsiring 7 CH-4057 Basel Switzerland

Tel & Fax: +4161-6924461 Email: info@pharmabiotech.ch Web site: http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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T A B L E O F C O N T E N T S

0. Executive Summary .............................................................................. 10

1. Basics of Transdermal Drug Delivery .................................................... 12 Introduction ...................................................................................................................... 12

Historical landmarks in transdermal drug delivery ................................................................ 12 Anatomy and physiology of skin ........................................................................................ 13

Skin metabolomics and transcutaneous passage of drugs...................................................... 13 Transcutaneous absorption ............................................................................................... 14

Transdermal versus other methods of drug delivery .......................................................... 14 Advantages of transdermal drug delivery ............................................................................ 14

First-Pass Effect .......................................................................................................... 14 Drawbacks of transdermal delivery..................................................................................... 14

Factors that influence transdermal drug delivery .............................................................. 15 Rate of permeation across the skin .................................................................................... 15 Properties of the skin ....................................................................................................... 16 Properties of drugs ........................................................................................................... 16

The role of pH and pharmacokinetics ............................................................................. 17 Intradermal disposition of drugs after topical application .................................................. 17

Role of nanobiotechnology in understanding basis of transdermal delivery .............................. 17

2. Transdermal Drug Delivery Technologies ............................................. 20 Introduction ...................................................................................................................... 20 Local application formulations ........................................................................................... 21

Crystalline topical formulations .......................................................................................... 21 Microemulsions for transdermal drug delivery ...................................................................... 21 Nanoemulsions for transdermal drug delivery ...................................................................... 22 Transdermal gel technology .............................................................................................. 22 Biphasix system ............................................................................................................... 24

Penetration enhancers ....................................................................................................... 24 Chemical enhancers ......................................................................................................... 24

Nitric oxide-based transdermal drug delivery .................................................................. 26 Ionic liquids for transdermal delivery of drugs against bacterial biofilms on skin ...................... 27 Vesicular transdermal carriers ........................................................................................... 27

Liposomes .................................................................................................................. 27 Transfersomes ............................................................................................................ 28 Ethosomes ................................................................................................................. 28 Elastic vesicles for transdermal drug delivery ................................................................. 29 Nanovesicles for transdermal drug delivery .................................................................... 29

Transdermal patches ......................................................................................................... 30 Adhesives for transdermal patches ..................................................................................... 31 Commercial development of transdermal patches ................................................................ 32 Innovations in transdermal patches .................................................................................... 32

e-Patch™ controlled release micropump system .............................................................. 33 Patchless Transdermal Delivery System ......................................................................... 33 Metered-dose transdermal system ................................................................................ 34

Polymers for transdermal drug delivery............................................................................. 34 Polymer membranes in transdermal patches ....................................................................... 35 Film forming polymeric solutions ........................................................................................ 36 Crystal Reservoir System of Nitto Denko ............................................................................. 36

Use of physical modalities to facilitate transdermal transport ........................................... 37 Transdermal electrotransport ............................................................................................ 37 Electroporation ................................................................................................................ 37

Drug delivery by electroporation ................................................................................... 38 Cryoelectrophoresis .......................................................................................................... 39 Iontophoresis .................................................................................................................. 40

Iontophoresis compared with electrophoresis ................................................................. 40 Application of iontophoresis for drug delivery ................................................................. 40 Patents in iontophoresis ............................................................................................... 42 Companies with technologies for drug delivery by iontophoresis ....................................... 42

Combination of electrophoresis and iontophoresis ................................................................ 43 Dermaportation .......................................................................................................... 43

Radiofrequency-driven transdermal delivery ........................................................................ 44 Microporation .................................................................................................................. 44 Transcutaneous drug delivery by electropulsation ................................................................ 44 Companies involved in electroporation-based drug delivery ................................................... 45 Electrode Scanning System ............................................................................................... 45 Use of electrostatic force in skin patch technology ................................................................ 46

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Multiple Absorption Kinetic System ..................................................................................... 46 Transdermal drug delivery facilitated by heat ...................................................................... 46

Controlled, heat-aided drug delivery .............................................................................. 46 Ultrasound ...................................................................................................................... 47 Magnetophoresis .............................................................................................................. 48 Use of lasers for transdermal drug delivery ......................................................................... 49

Laser-induced microporation ........................................................................................ 49 Transdermal drug delivery by laser-induced pressure waves............................................. 49 Transdermal drug delivery by laser-assisted changes in skin ............................................ 50

Transdermal delivery by gas under pressure ....................................................................... 50 Transdermal delivery with PowderJect gas gun ............................................................... 50 Microscission induced by gas ........................................................................................ 51

Role of microelectronics in transdermal drug delivery ....................................................... 51 Microneedles and dermal microinjection technologies ....................................................... 52

Applications of microneedles ............................................................................................. 53 AdminPatch® microneedle array ........................................................................................ 54 Biodegradable microneedles .............................................................................................. 54 Ceramic microneedle arrays .............................................................................................. 55 Dissolvable microneedle patches ........................................................................................ 55 MicorCor ......................................................................................................................... 55 Microneedle arrays for drug delivery ................................................................................... 56 Microneedle patch ............................................................................................................ 57 MicroPyramid™ microneedles ............................................................................................ 57 Microstructured Transdermal Systems ................................................................................ 58 Microneedle Array Patch technology ................................................................................... 58 Microneedle transdermal chip ............................................................................................ 59 Microneedle applicator device ............................................................................................ 59 Nanoject™ microneedle technology .................................................................................... 59 PatchPump ...................................................................................................................... 60 Polymer microneedles ...................................................................................................... 60 Silk microneedles ............................................................................................................. 61 Tattooing for drug delivery ................................................................................................ 61 ZP Patch microprojections technology ................................................................................. 62 Companies developing microneedles for transdermal drug delivery ........................................ 62

Needlefree injections ......................................................................................................... 63 Glide SDI® solid dose injector ........................................................................................... 63 Jet injection .................................................................................................................... 63 Mini-Ject needlefree delivery system .................................................................................. 63 MicroJet for painless injections .......................................................................................... 64 Nanoliter-volume pulsed microjets ..................................................................................... 64 SUMAVEL™ DosePro™ needle-less injection ........................................................................ 64

Skin ablation or abrasion for drug delivery ........................................................................ 65 Nanotechnology-based transdermal drug delivery ............................................................. 65

Delivery of nanostructured drugs from transdermal patches .................................................. 65 Effect of mechanical flexion on penetration of bucky balls through the skin ............................. 66 Nanobiotechnology for transdermal application .................................................................... 66

Nanoparticles and nanoemulsions for skin disorders ........................................................ 66 Nanopatches .............................................................................................................. 67 Inocyte™ epidermal drug delivery system ...................................................................... 67 Ionic nanoparticle technology ....................................................................................... 67 SLN gel for treatment of skin disorders .......................................................................... 68 Topical delivery of siRNA- nanoparticle conjugates .......................................................... 68 Transdermal nanoparticle preparations for systemic effect ............................................... 68 Transferosomes for transdermal drug delivery ................................................................ 69 Transdermal administration of nanocarriers .................................................................... 69

Nanotechnology-based transdermal vaccination and immunotherapy ...................................... 70 Safety issues of applications of nanomaterial carriers on the skin ........................................... 70

Comparison of transdermal drug delivery systems ............................................................ 70 Transdermal drug design ................................................................................................... 71 In vitro testing of transdermal drug delivery systems ....................................................... 71

Commercially available skin models for transdermal drug testing ...................................... 72 FDA guidelines for post-approval changes in semisold topical drugs................................... 72

In vivo testing of drug delivery systems ............................................................................ 73 Infrared spectroscopy for evaluation of transdermal drug delivery .......................................... 73

Modeling of transport through the skin.............................................................................. 73 Concluding remarks on transdermal drug delivery technologies ........................................ 74 Future developments in transdermal drug delivery ........................................................... 74

3. Transdermal Therapeutics .................................................................... 76 Introduction ...................................................................................................................... 76 Drugs that can be administered transdermally .................................................................. 76

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Approved transdermal products ......................................................................................... 76 Drugs in clinical trials ....................................................................................................... 78

Skin disorders .................................................................................................................... 79 Cutaneous leishmaniasis ................................................................................................... 79 Hair loss ......................................................................................................................... 79 Iontophoretic drug delivery for nail disorders ....................................................................... 80 Psoriasis ......................................................................................................................... 80

Nanoemulsions for paclitaxel delivery in psoriasis............................................................ 80 Iontophoresis for treatment of psoriasis ......................................................................... 80

Cardiovascular disorders ................................................................................................... 81 Transdermal estrogen for prevention of atherosclerotic cardiovascular disease ........................ 81 Transdermal drug delivery for angina pectoris ..................................................................... 81 Transdermal drug delivery for hypertension ........................................................................ 82

Transdermal clonidine ................................................................................................. 83 Transdermal delivery of β-blockers for hypertension ........................................................ 83 Transdermal delivery of calcium channel blockers for hypertension ................................... 84

Transdermal drug delivery for congestive heart failure .......................................................... 84 Transdermal beta blockers ................................................................................................ 84 Transdermal anticoagulants .............................................................................................. 85

Respiratory diseases .......................................................................................................... 85 Asthma ........................................................................................................................... 85 Chronic obstructive pulmonary disease ............................................................................... 86

Neurological and psychiatric disorders .............................................................................. 87 Parkinson's disease .......................................................................................................... 87

Transdermal drug delivery for Parkinson's disease .......................................................... 87 Transdermal levodopa delivery systems ......................................................................... 87 Transdermal dopamine agonists for Parkinson's disease ................................................... 88 Rotigotine for Parkinson disease ................................................................................... 89 Rotigotine for restless legs syndrome ............................................................................ 91 Transdermal administration of other drugs for Parkinson disease ...................................... 91

Depression ...................................................................................................................... 91 Antidepressants .......................................................................................................... 92 Selective serotonin-reuptake inhibitors .......................................................................... 92 Transdermal fluoxetine ................................................................................................ 92 Monoamine oxidase inhibitors ....................................................................................... 93 Transdermal selegiline ................................................................................................. 93 Trazodone hydrochloride .............................................................................................. 94 Venlafaxine ................................................................................................................ 94 Bupropion .................................................................................................................. 94

Bipolar disorder ............................................................................................................... 95 Transdermal lithium .................................................................................................... 95

Schizophrenia .................................................................................................................. 96 Transdermal haloperidol .............................................................................................. 96 Transdermal risperidone for treatment of schizophrenia ................................................... 96 Transdermal blonanserin for treatment of schizophrenia .................................................. 96

Restless legs syndrome .................................................................................................... 97 Alzheimer's disease .......................................................................................................... 97

Transdermal rivastigmine ............................................................................................. 97 Transdermal donepezil ................................................................................................. 98 Transdermal galantamine ............................................................................................. 98 Transdermal arecoline ................................................................................................. 99

Transdermal nicotine for Tourette syndrome ....................................................................... 99 Attention deficit hyperactivity disorder ................................................................................ 99

Transdermal methylphenidate ...................................................................................... 99 Migraine ....................................................................................................................... 100

Transdermal sumatriptan ........................................................................................... 100 Transdermal zolmitriptan ........................................................................................... 101 Transdermal dihydroergotamine ................................................................................. 101

Epilepsy ........................................................................................................................ 102 Tinnitus/Vertigo ............................................................................................................. 102 Transdermal nitroglycerin for vasospasm due to subarachnoid hemorrhage ........................... 102

Musculoskeletal disorders ................................................................................................ 102 Osteoporosis ................................................................................................................. 102

Transdermal alendronate ........................................................................................... 103 Transdermal estrogen ................................................................................................ 103 Transdermal human parathyroid hormone .................................................................... 103

Osteoarthritis ................................................................................................................ 104 Transdermal therapy of diabetes ..................................................................................... 104

Insulin delivery in diabetes by transdermal patches ............................................................ 104 Microneedle patch for glucose-responsive insulin delivery ................................................... 105 Patch monitoring system for insulin delivery ...................................................................... 105

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Sonic Applicator & Control Device for TDD of insulin ........................................................... 106 V-Go® disposable insulin delivery device .......................................................................... 106 ViaDor System for TDD of insulin ..................................................................................... 106 Companies developing devices for transdermal insulin delivery ............................................ 107 Transdermal therapy of oral antidiabetic agents ................................................................. 107

Transdermal antidiabetic agents other than insulin ........................................................ 108 Male disorders ................................................................................................................. 108

Erectile dysfunction ........................................................................................................ 108 Topical and transdermal preparation for erectile dysfunction .......................................... 108

Hypogonadism in the male .............................................................................................. 109 Topical testosterone .................................................................................................. 109

Benign prostatic hypertrophy........................................................................................... 111 Tamsulosin TDS ........................................................................................................ 111

Women's health ............................................................................................................... 111 Female sexual arousal disorder ........................................................................................ 111 Menopause.................................................................................................................... 112

Hormone replacement therapy for menopause .............................................................. 112 Effect of transdermal estradiol on bone density ............................................................. 114 Transdermal PTH for postmenopausal osteoporosis ....................................................... 114 Transdermal testosterone for low libido in postmenopausal women ................................. 114

Breast disorders ............................................................................................................ 115 Dysmenorrhea ............................................................................................................... 115 Female infertility ............................................................................................................ 115

Contraception .................................................................................................................. 116 Female contraception ..................................................................................................... 116

Ortho Evra™ ............................................................................................................ 116 AG200-15 ................................................................................................................ 117 BAY86-5016 ............................................................................................................. 117 Desogestrel .............................................................................................................. 117

Male contraception ......................................................................................................... 118 Transdermal progestin plus testosterone ...................................................................... 118

Cancer ............................................................................................................................. 118 Delivery of the photosensitizer drug δ-amino levulinic acid .................................................. 118 Intradermal delivery of cancer vaccines by adenoviral vectors ............................................. 119 Nanoemulsion-based delivery of caffeine for skin cancer ..................................................... 119 Topical interferon α2b for cervical cancer and precancerous lesions ...................................... 119 Transcutaneous electroporation for delivery of anticancer drugs .......................................... 120 Transdermal delivery of peptide cancer vaccines ................................................................ 120 Transdermal drug delivery for prostate cancer ................................................................... 120

Transdermal nitroglycerine for prostate cancer ............................................................. 120 Transdermal estradiol gel for prostate cancer ............................................................... 121 Transdermal leuprolide acetate for prostate cancer ....................................................... 121

Transdermal drug delivery for breast cancer ...................................................................... 121 Afimoxifene topical gel for breast cancer ...................................................................... 121

Pain ................................................................................................................................. 121 Relief of pain associated with minor medical procedures ..................................................... 121 Transdermal lidocaine relief of postherpectic neuralgia ....................................................... 122

Lidoderm ............................................................................................................... 122 Lidopat® ................................................................................................................. 122 ZTlido ...................................................................................................................... 122

Transdermal capsaicin for relief of pain ............................................................................. 122 Nonsteroidal antiinflammatory drugs ................................................................................ 123

Topical NSAIDs ......................................................................................................... 123 Transdermal ketoprofen ............................................................................................. 124 Topical opioids .......................................................................................................... 125

Cancer pain ................................................................................................................... 125 Transdermal fentanyl................................................................................................. 125 Transdermal nitroglycerine as an adjuvant to opioids .................................................... 126 Transdermal buprenorphine ....................................................................................... 126

Chronic pain of non-malignant origin ................................................................................ 127 Transdermal local anesthetics .......................................................................................... 127 Postoperative pain ......................................................................................................... 127

Transdermal fentanyl for the management of postoperative pain .................................... 127 Fibromyalgia ............................................................................................................ 128

Nanotechnology-based approved transdermal analgesic preparations ................................... 128 Nausea and vomiting ....................................................................................................... 128

Motion sickness ............................................................................................................. 128 Postoperative vomiting ................................................................................................... 128 Chemotherapy-induced nausea and vomiting .................................................................... 129

Antiaging strategies ........................................................................................................ 129 Smoking cessation ........................................................................................................... 129

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Transdermal nicotine replacement .................................................................................... 129 Use of nicotine patch for smoking cessation in pregnancy ................................................... 130 Other methods of nicotine replacement ............................................................................ 131 Other treatments for smoking cessation............................................................................ 131

Miscellaneous uses of transdermal drug delivery............................................................. 131 Allergic rhinitis............................................................................................................... 131 Chronic fatigue syndrome ............................................................................................... 132 Overactive bladder and urinary incontinence ..................................................................... 132

Transdermal oxybutynin ............................................................................................ 132 Viral infections ............................................................................................................... 133

Transdermal nanoparticles for immune enhancement in HIV........................................... 133 Transdermal IQP-0410 for HIV/AIDS ........................................................................... 134

Wound healing and ulcers ............................................................................................... 134 Transdermal gene therapy ............................................................................................... 135

Transdermal delivery of plasmid DNA by electroporation ..................................................... 135 Transdermal antisense therapy ....................................................................................... 135 Transdermal vaccination .................................................................................................. 136

The skin as an immune organ .......................................................................................... 136 Technologies for transdermal vaccination .......................................................................... 136

Dissolvable microneedle array for vaccine delivery ........................................................ 136 Electroporation for administering DNA vaccines ............................................................ 137 Microneedles for transdermal delivery of vaccines ......................................................... 138 Needle-free delivery of vaccines .................................................................................. 139 Transcutaneous immunotherapy using nanodispersions ................................................. 140

Applications of transdermal vaccination ............................................................................ 141 HIV/AIDS vaccination by topical application .................................................................. 141 Transdermal DNA influenza vaccine ............................................................................. 141 Transdermal Aβ vaccination for Alzheimer’s disease ...................................................... 142 Transdermal vaccination for traveller’s diarrhoea .......................................................... 142

Transdermal nutraceuticals ............................................................................................. 142 Complications of transdermal therapy ............................................................................. 143

Adverse effects of drugs ................................................................................................. 143 Overdose effect ............................................................................................................. 143 Skin complications ......................................................................................................... 144

MRI-induced skin burns from transdermal patches ........................................................ 144

4. Markets for Transdermal Drug Delivery .............................................. 146 Introduction .................................................................................................................... 146 Global markets for drug delivery ..................................................................................... 146 Geographical distribution of transdermal drug delivery markets ..................................... 147

Emerging transdermal drug delivery markets in Asia .......................................................... 147 Transdermal technology markets in therapeutic areas .................................................... 147

Angina pectoris .............................................................................................................. 148 Attention deficit hyperactivity disorder .............................................................................. 148 Erectile dysfunction ........................................................................................................ 149 Hypertension ................................................................................................................. 149 Osteoporosis ................................................................................................................. 149 Pain therapeutics ........................................................................................................... 149 Parkinson's disease ........................................................................................................ 149 Smoking cessation ......................................................................................................... 150 Transdermal hormone replacement therapy for menopause ................................................ 150 Transdermal testosterone replacement therapy for hypogonadism in the male ...................... 150 Transdermal contraceptive market ................................................................................... 150

Markets according to transdermal technologies............................................................... 151 Markets for microneedle-based transdermal drug delivery ................................................... 151

Marketing strategies for transdermal drug delivery ......................................................... 151 Marketing advantages of transdermal drug delivery ........................................................ 152 Unmet needs in transdermal drug delivery ...................................................................... 152 Regulatory aspects that affect transdermal drug delivery markets .................................. 153 Future prospects of transdermal drug delivery ................................................................ 154

Growth of new technologies used in transdermal drug delivery ............................................ 154 Prospects of transdermal delivery for drugs coming off patents ............................................ 154 Transdermal delivery of biologicals ................................................................................... 155 Transdermal delivery of cosmetics ................................................................................... 155

5. Companies involved in transdermal drug delivery .............................. 156 Profiles of companies....................................................................................................... 156

Top companies in transdermal drug delivery...................................................................... 156 Collaborations .................................................................................................................. 284

6. References .......................................................................................... 288

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Tables

Table 1-1: Historical landmarks in the development of transdermal drug delivery .............................. 12 Table 1-2: Transdermal vs oral and intravenous drug delivery ......................................................... 14 Table 1-3: Size ranges of molecules that can be delivered by transdermal route ................................ 17 Table 2-1: Technologies for transdermal drug delivery ................................................................... 20 Table 2-2: Chemical enhancers of skin penetration ........................................................................ 25 Table 2-3: Drug-in-adhesive versus reservoir type of transdermal patch ........................................... 30 Table 2-4: Companies with transdermal patches for drug delivery.................................................... 32 Table 2-5: Companies with technologies for drug delivery by iontophoresis ....................................... 42 Table 2-6: Companies involved in electroporation-based drug delivery ............................................. 45 Table 2-7: Companies developing microneedles for transdermal drug delivery ................................... 62 Table 2-8: Comparison of transdermal drug delivery systems .......................................................... 71 Table 3-1: Approved transdermal products ................................................................................... 76 Table 3-2: Transdermal drugs in clinical trials or approval process ................................................... 78 Table 3-3: Companies developing devices for transdermal insulin delivery ...................................... 107 Table 3-4: Selected transdermal systems GLP-1 antidiabetic agents ............................................... 108 Table 4-1: Worldwide drug delivery market growth 2017 to 2027 .................................................. 146 Table 4-2: Transdermal drug delivery markets for geographical regions 2017 to 2027 ...................... 147 Table 4-3: Markets for transdermal products for therapeutic areas 2017-2027 ................................ 148 Table 4-4: Markets according to transdermal technologies 2017-2027 ............................................ 151 Table 4-5: Marketing strategies based on transdermal drug delivery technologies ............................ 151 Table 5-1: Top ten companies in transdermal drug delivery .......................................................... 156 Table 5-2: Collaborations in transdermal drug delivery ................................................................. 284

Figures

Figure 1-1: Basic structure of the skin .......................................................................................... 13 Figure 1-2: Events governing transcutaneous drug absorption ........................................................ 15 Figure 2-1: Basic structure and function of transdermal drug delivery systems .................................. 30 Figure 2-2: Transdermal system for delivery of liquid drugs ............................................................ 31 Figure 2-3: Crystal Reservoir System of Nitto Denko ...................................................................... 36 Figure 2-4: A schematic view of electroporation............................................................................. 37 Figure 2-5: Depiction of breakdown of the stratum corneum during electroporation ........................... 39 Figure 2-6: A schematic drawing of Iontophoresis .......................................................................... 40 Figure 2-7: SonoPrep ultrasonic skin permeation ........................................................................... 48 Figure 2-8: A a schematic sketch of PowderJect gas gun................................................................. 51 Figure 2-9: Drug delivery using different types of microneedles (MN) ............................................... 52 Figure 2-10: A schematic drawing of the microneedle patch ............................................................ 57 Figure 2-11: Preparation of solid-in-oil nanodispersion for transdermal application ............................. 66 Figure 3-1: Oral versus transdermal administration of a drug in Parkinson's disease .......................... 90 Figure 3-2: Control functions and user interface of insulin patch monitoring system ......................... 106 Figure 3-3: Transcutaneous immunotherapy using nanodispersions ............................................... 140 Figure 4-1: Unmet needs in transdermal drug delivery ................................................................. 153