Fundamentals of Drug Delivery

by Benson, Heather A. E.; Roberts, Michael S.; Williams, Adrian C.; Liang, Xiaowen

• ISBN13: 9781119769606
• ISBN10: 1119769604
• Edition: 1st
• Format: Hardcover
• Copyright: 2021-10-12
• Publisher: Wiley

Summary

A comprehensive guide to the current research, major challenges, and future prospects of controlled drug delivery systems

Controlled drug delivery has the potential to significantly improve therapeutic outcomes, increase clinical benefits, and enhance the safety of drugs in a wide range of diseases and health conditions. Fundamentals of Drug Delivery provides comprehensive and up-to-date coverage of the essential principles and processes of modern controlled drug delivery systems. Featuring contributions by respected researchers, clinicians, and pharmaceutical industry professionals, this edited volume reviews the latest research in the field and addresses the many issues central to the development of effective, controlled drug delivery.

Divided in three parts, the book begins by introducing the concept of drug delivery and discussing both challenges and opportunities within the rapidly evolving field. The second section presents an in-depth critique of the common administration routes for controlled drug delivery, including delivery through skin, the lungs, and via ocular, nasal, and otic routes. The concluding section summarizes the current state of the field and examines specific issues in drug delivery and advanced delivery technologies, such as the use of nanotechnology in dermal drug delivery and advanced drug delivery systems for biologics. This authoritative resource:

• Covers each main stage of the drug development process, including selecting pharmaceutical candidates and evaluating their physicochemical characteristics
• Describes the role and application of mathematical modelling and the influence of drug transporters in pharmacokinetics and drug disposition
• Details the physiology and barriers to drug delivery for each administration route
• Presents a historical perspective and a look into the possible future of advanced drug delivery systems
• Explores nanotechnology and cell-mediated drug delivery, including applications for targeted delivery and toxicological and safety issues
• Includes comprehensive references and links to the primary literature

Edited by a team of of internationally-recognized experts, Fundamentals of Drug Delivery is essential reading for researchers, industrial scientists, and advanced students in all areas of drug delivery including pharmaceutics, pharmaceutical sciences, biomedical engineering, polymer and materials science, and chemical and biochemical engineering.

Author Biography

Heather Benson, PhD, is an Associate Professor in the School of Pharmacy at Curtin University, Australia, where she leads the Skin Delivery Research Group.

Michael Roberts, PhD, is Professor of Therapeutics & Pharmaceutical Science at the University of South Australia and Professor of Clinical Pharmacology & Therapeutics at The University of Queensland.

Adrian Williams, PhD, is a Professor of Pharmaceutics at University of Reading where he also acts as the Research Dean.

Xiaowen Liang, PhD, is the UQ Development Fellow at The University of Queensland Diamantina Institute.

Table of Contents

Preface xvii

Part I Product Design, the Essence of Effective Therapeutics 1

1 Challenges and Innovations of Controlled Drug Delivery 3
Heather A.E. Benson and Michael S. Roberts

1.1 Background 3

1.2 Parenteral Dosage Forms 3

1.2.1 Intravenous Route (IV) 4

1.2.2 Intramuscular Route (IM) 5

1.2.3 Subcutaneous Route (SC) 5

1.2.4 Other Parenteral Routes 5

1.3 Oral Route and Delivery Systems 6

1.4 Nasal Drug Delivery 6

1.5 Pulmonary Drug Delivery 7

1.6 Transdermal Drug Delivery 7

1.7 Ocular Drug Delivery 9

1.8 Drug Delivery System Development Process 11

1.9 Conclusion 12

References 12

2 Challenges in Design of Drug Delivery Systems 15
Narasimha Murthy

2.1 Drug Properties to be Considered in Design of Controlled Release Products 19

2.2 Physicochemical Factors that Need to be Considered in Design of CRDDS 19

2.2.1 Dose Size 19

2.2.2 MolecularWeight/Size 19

2.2.3 Aqueous Solubility 21

2.2.4 Lipid Solubility and Partition Coefficient 25

2.2.5 Physicochemical Stability 26

2.3 Biopharmaceutical Properties that Deserve Consideration in Design of Controlled Release Products 26

2.3.1 Biological Half-life 26

2.3.2 Absorption 27

2.3.3 Metabolism 30

2.3.4 Presystemic Clearance 32

2.3.5 Margin of Safety 32

2.3.6 Adverse Effects 33

2.3.7 Therapeutic Need 33

2.3.8 Role of Circadian Rhythm 34

2.4 Conclusion 35

References 35

3 Drug Delivery of the Future (?) 39
Adrian Williams

3.1 Introduction 39

3.2 Therapeutic Indicators 40

3.3 Drugs of the Future 43

3.4 Delivering the Drugs of the Future 45

3.5 A View to the Longer Term? 47

3.6 Conclusion 50

References 50

4 The Pharmaceutical Drug Development Process: Selecting a Suitable Drug Candidate 53
Lionel Trottet

4.1 The Oral Drug Candidate: How to Get There and Questions to Answer 53

4.2 Challenges for Selecting a Topical Drug Candidate 55

4.3 Percutaneous Flux as a Surrogate Measurement of Skin Tissue Concentration 57

4.4 Learnings from Past Topical Drug Development of Factors Affecting Efficacy 58

4.5 Dermal Pharmacokinetics/Pharmacodynamics 62

4.6 Assessment of Systemic Exposure 63

4.7 Screening Cascade Approach to Select a Dermal Drug Candidate 64

4.7.1 Efficacy (Lack of Target Engagement) 64

4.7.2 Developability 65

4.7.3 Local Safety 65

4.7.4 Systemic Safety 65

4.8 Opportunities for Repurposing Molecules into Dermally Active Treatments for Cosmeceutical or Pharmaceutical Approaches 66

4.9 Conclusion 66

References 67

5 Preformulation and Physicochemical Characterization Underpinning the Development of Controlled Drug Delivery Systems 73
Ronak Savla and Julien Meissonnier

5.1 When Is a Controlled Drug Delivery System Needed? 73

5.2 Optimizing Drug Characteristics 74

5.3 Defining the Product Profile 75

5.4 Preformulation and Physicochemical Characterization Underpinning Development of CDD 77

5.4.1 Feasibility and Risk Assessment 78

5.4.2 Solubility and Dissolution Rate 79

5.4.3 Permeability 82

5.4.4 Drug and Drug Product Particle Sizes 83

5.4.5 Solid-State Chemistry 84

5.4.5.1 Crystallinity and Polymorphism 84

5.4.5.2 Salts 85

5.4.6 Stability 85

5.4.7 Excipient Compatibility 86

5.4.8 Bulk Powder Properties 87

5.4.9 Drug Metabolism and Pharmacokinetic Modeling 88

5.4.9.1 Guiding the Design of CDD Dosage Forms 88

5.4.9.2 Establishing In Vitro–In Vivo Correlation (IVIVC) 89

5.4.9.3 Physiologically Based Pharmacokinetic (PBPK) Modeling Tools 89

5.5 Conclusion 89

References 89

6 Mathematical Models Describing Kinetics Associated with Controlled Drug Delivery Across Membranes 95
Annette L. Bunge

6.1 Introduction 95

6.1.1 General Description 95

6.1.2 Governing Equations 98

6.1.2.1 Differential Equations 98

6.1.2.2 Dimensionless Differential Equations 98

6.1.2.3 Initial and Boundary Conditions 99

6.1.3 Other Derived Quantities 100

6.1.4 Dimensionless Variables and Groups 102

6.2 Model Solutions 104

6.2.1 Type A Models –Well-Stirred Vehicle on One Membrane 104

6.2.1.1 Model A1 104

6.2.1.2 Model A2 107

6.2.1.3 Model A3 112

6.2.1.4 Model A4 116

6.2.1.5 Model A5 120

6.2.1.6 Model A6 121

6.2.1.7 Model A7 123

6.2.1.8 Model A8 124

6.2.1.9 Model A9 125

6.2.1.10 Model A9a 128

6.2.1.11 Model A9b 130

6.2.1.12 Model A10 132

6.2.1.13 Model A11 136

6.2.1.14 Model A12 137

6.2.1.15 Model A13 138

6.2.2 Type B Models – Unstirred Semi-infinite Vehicle on One Membrane 140

6.2.2.1 Model B1 140

6.2.2.2 Model B2 143

6.2.3 Type C –Well Stirred Vehicle on Two Membranes 145

6.2.3.1 Model C1 145

6.3 Solution Methods 149

6.3.1 Separation of Variables Solutions 150

6.3.1.1 Separating the Partial Differential Equation of N Independent Variables into N Ordinary Differential Equations 150

6.3.1.2 Choosing the Sign (Positive or Negative) on the Separation Constant 151

6.3.1.3 Finding the Constants of Integration and the Eigenvalues 152

6.3.1.4 Superposition 153

6.3.1.5 Finding the Remaining Constants of Integration 153

6.3.1.6 Guidelines for Using Separation of Variable Methods to Solve Partial Differential Equations 155

6.3.1.7 Methods for Making a Nonhomogeneous Partial Differential Equation or Nonhomogeneous Boundary Conditions Homogeneous 156

6.3.1.8 Choosing the Index Starting Value on the Sum of All Solutions (i.e. should n = 1 or 0?) 158

6.3.2 Laplace Transform Solutions 159

6.3.2.1 Using Laplace Transforms to Determine Lag Times, Steady-state Values and Other Derived Quantities 159

6.3.2.2 Inversion of Laplace Transformed Functions to Time Domain Functions by Method of Residues 161

6.3.2.3 Example A – Model A1 161

6.3.2.4 Example B – Model A10 165

6.3.3 Useful Identities 169

References 169

7 Understanding Drug Delivery Outcomes: Progress in Microscopic Modeling of Skin Barrier Property, Permeation Pathway, Dermatopharmacokinetics, and Bioavailability 171
Guoping Lian, Tao Chen, Panayiotis Kattou, Senpei Yang, Linyi Li, and Lujia Han

7.1 Introduction 171

7.2 Governing Equation 172

7.2.1 Homogenized Model 172

7.2.2 Microscopic Model 174

7.2.2.1 Solute Diffusion in SC Lipid 174

7.2.2.2 Solute Diffusion in SC Corneocytes 175

7.2.2.3 Solute Diffusion in Appendages 175

7.2.3 Numerical Methods 175

7.3 Input Parameters 176

7.3.1 SC Microstructure 176

7.3.2 SC Lipid–Water Partition 177

7.3.3 Diffusivity in SC Lipids 177

7.3.4 Binding to Keratin 179

7.3.5 Diffusivity in Corneocytes 181

7.3.6 Solute Diffusivity and Partition in Sebum 181

7.4 Application 183

7.4.1 Steady-State 183

7.4.2 Dermatopharmacokinetics 184

7.4.3 Systemic Pharmacokinetics 184

7.4.4 Shunt Pathway 185

7.5 Perspective 186

References 188

8 Role of Membrane Transporters in Drug Disposition 193
Hong Yang and Yan Shu

8.1 Introduction 193

8.2 Distribution of Major Drug Transporters in Human Tissues 194

8.2.1 Major Drug Transporters in the Intestine 194

8.2.1.1 Drug Transporters Expressed in the Apical (Luminal) Membrane 194

8.2.1.2 Drug Transporters Expressed in the Basolateral Membrane 196

8.2.1.3 Expression of Drug Transporters in Different Intestinal Regions 197

8.2.2 Major Drug Transporters in the Liver 197

8.2.2.1 Drug Transporters Expressed in the Apical Membrane of Hepatocytes 197

8.2.2.2 Drug Transporters Expressed in the Basolateral (Sinusoidal) Membrane of Hepatocytes 199

8.2.2.3 Drug Transporters Expressed in the Bile Duct Epithelia (Cholangiocytes) 199

8.2.3 Major Drug Transporters in the Kidney 199

8.2.3.1 Drug Transporters Expressed in the Apical Membrane of Proximal Tubule Cells 200

8.2.3.2 Drug Transporters Expressed in the Basolateral Membrane of Proximal Tubule Cells 200

8.2.4 Major Drug Transporters in the Central Nervous System (CNS) 201

8.2.4.1 Drug Transporters Expressed in the Capillary Endothelial Cells of BBB 201

8.2.4.2 Drug Transporters Expressed in the Choroid Plexus Epithelial Cells of BCSFB 202

8.2.5 Major Drug Transporters in Other Tissues 202

8.2.5.1 Drug Transporters Expressed in Placenta Villi Epithelial Cells (Syncytiotrophoblasts) 203

8.2.5.2 Drug Transporters Expressed in Mammary Glands 203

8.2.5.3 Drug Transporters Expressed in the Blood–Testis-Barrier (BTB) 204

8.3 Role of Drug Transporters in Drug Disposition 205

8.3.1 Role of P-gp in Drug Disposition 206

8.3.2 Role of BCRP in Drug Disposition 207

8.3.3 Role of BSEP in Drug-Induced Cholestatic Liver Injury 214

8.3.4 Role of MRPs (MRP2, MRP3, and MRP4) in Drug Disposition 214

8.3.5 Role of OATPs (OATP1B1, OATP1B3, and OATP2B1) in Drug Disposition 215

8.3.6 Role of OATs (OAT1 and OAT3) in Drug Disposition 216

8.3.7 Role of OCTs (OCT1 and OCT2)/MATEs (MATE1 and MATE2-K) in Drug Disposition 217

8.4 Closing Remarks 218

References 219

9 Advanced Drug Delivery Systems for Biologics 231
May W. Jøraholmen, Selenia Ternullo, Ann M. Holsæter, Gøril E. Flaten, and Nataša Škalko-Basnet

9.1 Introduction 231

9.2 Considerations in Biologics Product Development 232

9.2.1 Challenges Specific to the Route of Administration 232

9.2.2 Challenges Related to Parenteral Administration 232

9.2.3 Optimization of Dosage Regimens 232

9.3 Administration Routes for Biologics Delivery 233

9.3.1 Parenteral Route 233

9.3.2 Oral Route 234

9.3.3 Buccal Route 235

9.3.4 Sublingual Route 236

9.3.5 Pulmonary Route 236

9.3.5.1 Additional Concerns in Pulmonary Delivery 237

9.3.6 Intranasal Route 237

9.3.7 Trans(dermal) Delivery 238

9.3.7.1 Gene Delivery 239

9.3.7.2 Vaccine Delivery 240

9.3.7.3 Protein Delivery 241

9.3.8 Dermal Delivery of Growth Hormones 241

9.3.9 Vaginal Route 245

9.4 Conclusion 249

References 249

10 Recent Advances in Cell-Mediated Drug Delivery Systems for Nanomedicine and Imaging 261
Li Li and Zhi Qi

10.1 Introduction 261

10.2 Cell Types and Modification for Therapeutic Agent Delivery 262

10.2.1 Cell Types 262

10.2.1.1 Blood Cells 262

10.2.1.2 Stem Cells 265

10.2.1.3 Antigen Presenting Cells (APCs) 266

10.2.1.4 Cell Membranes 266

10.2.2 Cargo Loading Methods 267

10.3 Imaging and Tracking of Cell-Based Delivery Systems 268

10.3.1 MRI 269

10.3.2 PET 270

10.3.3 X-Ray Imaging 270

10.3.4 Multimodal Imaging Techniques 270

10.4 Cell-Mediated Drug Delivery Systems for Disease Treatment 270

10.4.1 Cancer Therapy 270

10.4.2 Immunotherapy 270

10.4.3 Brain-Related Diseases 272

10.4.4 Inflammatory Diseases 272

10.4.5 Theranostic Application 273

10.4.6 Others 273

10.5 The Mechanism of Cell-Mediated Delivery Systems for the Cell Therapies 273

10.5.1 Detoxification 274

10.5.2 Adhesive Mechanism 275

10.5.3 Homing Mechanism 276

10.6 The Administration Approach of Cell-Assist Drug Delivery System 276

10.7 Clinical Application of Cell-Based Delivery Systems 277

10.8 Conclusion and Outlook 277

References 278

11 Overcoming the Translational Gap – Nanotechnology in Dermal Drug Delivery 283
Christian Zoschke and Monika Schäfer-Korting

11.1 Nanotechnology – Failure or Future in Drug Delivery? 283

11.2 Identification of the Clinical Need 284

11.3 Nanoparticle Design and Physicochemical Characterization 287

11.4 Biomedical Studies 292

11.4.1 Atopic Dermatitis 292

11.4.2 Psoriasis 293

11.4.3 Ichthyosis 294

11.4.4 Wound Healing 295

11.4.5 Infections 295

11.4.6 Skin Cancer 296

11.4.7 Alopecia Areata 297

11.5 Approaches to Fill the Translational Gaps in Nanotechnology 297

References 301

12 Theranostic Nanoparticles for Imaging and Targeted Drug Delivery to the Liver 309
Haolu Wang, Haotian Yang, Qi Ruan, Michael S. Roberts, and Xiaowen Liang

12.1 Introduction 309

12.2 The Types of Theranostic NPs 310

12.2.1 Lipid- and Polymer-Based NPs 310

12.2.2 Mesoporous Silica NPs 310

12.2.3 Bio-nanocapsules 311

12.2.4 Iron Oxide NPs 311

12.3 Mechanisms of NPs Targeting the Liver 311

12.3.1 Passive Targeting to the Liver 311

12.3.2 Active Targeting to the Liver 312

12.3.3 Strategies for Combining Passive and Active Targeting 313

12.4 NPs in Liver Target Imaging 313

12.4.1 NP-Based Contrast Agents in Liver MRI 313

12.4.2 NP-Based Contrast Agents in Liver CT Imaging 314

12.4.3 NPs for Near-Infrared Fluorescence Imaging in Liver 314

12.5 NPs for Therapeutic and Drug Delivery in Liver Disease 314

12.5.1 NP Delivery System in HCC 314

12.5.2 NP Delivery System in Non-tumoral Liver Disease 316

12.6 Theranostic NPs in Liver Diseases 316

12.7 Conclusions 320

References 321

13 Toxicology and Safety of Nanoparticles in Drug Delivery System 327
Klintean Wunnapuk

13.1 Introduction 327

13.2 Lipid-Based Nanocarrier: Liposomes 327

13.3 Cellular Uptake Mechanism of Liposomes 328

13.4 Biodistribution, Clearance and Toxicity of Liposomes 329

13.4.1 Effect of Lipid Compositions on Liposome Distribution and Blood Circulation 329

13.4.2 Effect of Surface Charge on Liposome Distribution and Blood Circulation 331

13.4.3 Effect of Size on Liposome Distribution and Blood Circulation 331

13.5 Application of Liposomes in Drug Delivery 332

13.6 Inorganic Nanocarrier: Carbon Nanotubes 334

13.7 Cellular Uptake Mechanism of Carbon Nanotubes 335

13.8 Biodistribution, Clearance, and Toxicity of Carbon Nanotubes 335

13.9 Application of Carbon Nanotubes in Drug Delivery 340

13.10 Conclusion 340

References 340

Part II Administrative Routes for Controlled Drug Delivery 347

14 Controlled Drug Delivery via the Ocular Route 349
Peter W.J. Morrison and Vitaliy V. Khutoryanskiy

14.1 Introduction 349

14.2 Physiology of the Eye 350

14.2.1 Ocular Membranes; Conjunctiva, Cornea, and Sclera 351

14.2.2 Internal Ocular Structures 352

14.2.3 Anterior Chamber, Lens, and Vitreous Body 353

14.3 Ocular Disorders 353

14.3.1 Periocular Disorders 353

14.3.2 Intraocular Disorders 354

14.4 Controlled Drug Delivery Systems 355

14.4.1 Formulation Strategies 356

14.4.2 Mucoadhesive Systems 356

14.4.3 Solution to Gel In Situ Gelling Systems 357

14.4.4 Penetration Enhancers 359

14.4.5 Contact Lenses and Ocular Inserts 362

14.4.6 Intraocular Systems (Implants, Injectables, and Degradable Microparticles) 364

14.4.7 Phonophoresis and Ionophoresis 365

14.4.8 Topical Prodrugs 366

14.4.9 Microneedle Systems 366

14.5 Conclusions 367

References 368

15 Controlled Drug Delivery via the Otic Route 375
Jinsong Hao and S. Kevin Li

15.1 Introduction 375

15.2 Anatomy and Physiology of the Otic Route 375

15.2.1 Anatomy of the Otic Route 375

15.2.2 Barriers Relevant to Inner Ear Drug Delivery 376

15.2.2.1 Blood Labyrinth Barrier 376

15.2.2.2 Round Window Membrane 378

15.2.2.3 Oval Window 378

15.2.2.4 Eustachian Tube 378

15.2.2.5 Tympanic Membrane 379

15.3 Controlled Drug Delivery Systems 379

15.3.1 Intratympanic Administration 379

15.3.1.1 Silverstein MicroWick 380

15.3.1.2 Round Window Microcatheter (μCath) 381

15.3.1.3 Gelfoam 381

15.3.1.4 Seprapack 381

15.3.1.5 Ozurdex as a RWM Implant 382

15.3.1.6 Propel Steroid-Eluting Stent 382

15.3.2 Trans-Oval Window Administration 382

15.3.3 Intracochlear Administration 383

15.3.3.1 Drug-Eluting Cochlear Implants 384

15.3.3.2 Microfluidic Reciprocating Reservoir 384

15.4 Conclusions 386

References 386

16 Controlled Drug Delivery via the Nasal Route 391
Barbara R. Conway and Muhammad U. Ghori

16.1 Introduction 391

16.2 Anatomy and Physiology of the Nose 391

16.3 Absorption from the Nasal Cavity 393

16.3.1 The Epithelial Barrier 393

16.3.2 Absorption 393

16.4 Mucus and Mucociliary Clearance 396

16.5 Drug Delivery Systems 397

16.5.1 Solutions and Suspensions 398

16.5.2 Mucoadhesive Polymers 399

16.5.2.1 In Situ Forming Nasal Gels 399

16.5.2.2 Nasal Inserts 407

16.5.2.3 Microspheres and Nanospheres 408

16.5.2.4 Liposomes 409

16.5.2.5 Microemulsions and Nanoemulsions 411

16.5.2.6 Combination/Hybrid Products and Others 411

16.5.3 The Nasal Route and the Blood–Brain Barrier 413

16.5.4 The Nasal Route for Vaccinations 417

16.5.5 In Vitro/in Vivo Models for Nasal Absorption 419

16.6 Conclusion 421

References 421

17 Controlled Drug Delivery via the Buccal and Sublingual Routes 431
Javier O. Morales, Parameswara R. Vuddanda, and Sitaram Velaga

17.1 Introduction 431

17.2 Buccal and Sublingual Physiology and Barriers to Drug Delivery 432

17.2.1 Saliva and Mucus 432

17.2.2 Buccal and Sublingual Epithelium and Permeation Barrier 432

17.3 Controlled Drug Delivery Systems 434

17.3.1 Tablets 434

17.3.2 Films 435

17.3.3 Gels, Ointments, and Liquid Formulations 436

17.3.4 Spray 436

17.3.5 Wafers 437

17.3.6 Lozenges 437

17.3.7 Advanced and Novel Drug Delivery Systems 437

17.4 Functional Excipients Used in Controlled Release Systems to Enhance Buccal and Sublingual Drug Bioavailability 438

17.4.1 Permeation Enhancers 438

17.4.2 Mucoadhesive Polymers 439

17.5 Conclusions 440

Acknowledgments 441

References 441

18 Controlled Drug Delivery via the Lung 447
María V. Ramírez-Rigo, Nazareth E. Ceschan, and Hugh D. C. Smyth

18.1 Introduction 447

18.2 The Relevant Physiology of the Route Including the Barriers to Drug Delivery 447

18.3 Controlled Drug Delivery Systems 449

18.3.1 Formulations 449

18.3.1.1 Dissolution Rate Controlled 449

18.3.1.2 Sustained Release Systems 449

18.3.1.3 Drug Complexes 453

18.3.1.4 Drug–Receptor Binding 454

18.3.1.5 Drug Conjugates 455

18.3.1.6 Drug–Polymer Matrix Particles 456

18.3.1.7 Large Porous Particles 457

18.3.1.8 Nanosystems 457

18.3.2 Devices 457

18.3.2.1 Controlling Lung Deposition Patterns 457

18.3.2.2 Nebulizers 458

18.3.2.3 Dry Powder Inhalers 459

18.3.2.4 Pressurized Metered-Dose Inhalers 460

18.4 Conclusions 462

Acknowledgments 462

References 462

19 Controlled Drug Delivery via the Vaginal and Rectal Routes 469
José das Neves and Bruno Sarmento

19.1 Introduction 469

19.2 Biological Features of the Vagina and Colorectum 470

19.2.1 Vagina 470

19.2.2 Colorectum 471

19.3 Controlled Drug Delivery Systems 472

19.3.1 Vaginal Route 474

19.3.1.1 Conventional Dosage Forms 474

19.3.1.2 Removable Drug Delivery Systems 481

19.3.1.3 Nanotechnology-based Drug Delivery Systems 484

19.3.2 Rectal Route 487

19.3.2.1 Dosage Forms 487

19.3.2.2 Nanotechnology-based Drug Delivery Systems 491

19.4 Conclusions 492

Acknowledgments 492

References 492

20 Controlled Drug Delivery into and Through Skin 505
Adrian Williams

20.1 Introduction 505

20.1.1 Human Skin Structure and Function 505

20.1.1.1 Biological Factors 505

20.1.1.2 Skin as a Physical Barrier 506

20.1.2 Drug Transport Through Skin 510

20.2 Controlled Drug Delivery into and Through Skin 511

20.2.1 Skin Barrier Modulation 511

20.2.1.1 Penetration Enhancers 512

20.2.1.2 Ablation 513

20.2.2 Controlled Release Transdermal and Topical Systems 513

20.2.2.1 Supersaturation 514

20.2.2.2 Reservoir Formation 516

20.2.2.3 Film Forming Systems 516

20.2.2.4 Vesicles 517

20.2.2.5 Particles 518

20.2.3 Device-Based Controlled Delivery 520

20.2.3.1 Iontophoresis 521

20.2.3.2 Sonophoresis 522

20.2.3.3 Electroporation 523

20.2.3.4 Microneedles 523

20.2.3.5 Heat 524

20.2.3.6 Other Devices 525

20.3 Combination Approaches 526

20.4 Conclusions 526

References 527

Index 533