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Fundamentals of Drug Delivery. Edition No. 1

  • Book

  • 576 Pages
  • December 2021
  • John Wiley and Sons Ltd
  • ID: 5838668
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.

Table of Contents

Preface xvii

List of Contributors xix

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
S. Narasimha Murthy, Shivakumar H.N, and Sarasija Suresh

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 37
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

5.4.6 Stability 85

5.4.7 Excipient Compatibility 86

5.4.8 Bulk Powder Properties 87

5.4.9 Drug Metabolism and Pharmacokinetic Modeling 88

5.5 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

6.1.3 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

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

6.2.3 Type C -Well Stirred Vehicle on Two Membranes in Series 145

6.3 Solution Methods 149

6.3.1 Separation of Variables Solutions 150

6.3.2 Laplace Transform Solutions 159

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, Lingyi 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

7.2.3 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

8.2.1.3 Expression of Drug Transporters in Different Intestinal Regions 197

8.2.2 Major Drug Transporters in the Liver 197

8.2.3 Major Drug Transporters in the Kidney 199

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

8.2.5 Major Drug Transporters in Other Tissues 202

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

Part II Challenges in Controlled Drug Delivery and Advanced Delivery Technologies 231

9 Advanced Drug Delivery Systems for Biologics 233
May Wenche Jøraholmen, Selenia Ternullo, Ann Mari Holsæter, Gøril Eide Flaten, and Nataša Škalko-Basnet

9.1 Introduction 233

9.2 Considerations in Biologics Product Development 234

9.2.1 Challenges Specific to the Route of Administration 234

9.2.2 Challenges Related to Parenteral Administration 234

9.2.3 Optimization of Dosage Regimens 234

9.3 Administration Routes for Biologics Delivery 235

9.3.1 Parenteral Route 235

9.3.2 Oral Route 236

9.3.3 Buccal Route 237

9.3.4 Sublingual Route 238

9.3.5 Pulmonary Route 238

9.3.6 Intranasal Route 239

9.3.7 Trans(dermal) Delivery 240

9.3.8 Dermal Delivery of Growth Hormones 243

9.3.9 Vaginal Route 247

9.4 Conclusion 251

References 251

10 Recent Advances in Cell-Mediated Drug Delivery Systems for Nanomedicine and Imaging 263
Li Li and Zhi Qi

10.1 Introduction 263

10.2 Cell Types and Modification for Therapeutic Agent Delivery 264

10.2.1 Cell Types 264

10.2.2 Cargo Loading Methods 269

10.3 Imaging and Tracking of Cell-Based Delivery Systems 270

10.3.1 MRI 271

10.3.2 PET 272

10.3.3 X-Ray Imaging 272

10.3.4 Multimodal Imaging Techniques 272

10.4 Cell-Mediated Drug Delivery Systems for Disease Treatment 272

10.4.1 Cancer Therapy 272

10.4.2 Immunotherapy 272

10.4.3 Brain-Related Diseases 274

10.4.4 Inflammatory Diseases 274

10.4.5 Theranostic Application 275

10.4.6 Others 275

10.5 The Mechanism of Cell-Mediated Delivery Systems for the Cell Therapies 275

10.5.1 Detoxification 276

10.5.2 Adhesive Mechanism 277

10.5.3 Homing Mechanism 278

10.6 The Administration Approach of Cell-Assist Drug Delivery System 278

10.7 Clinical Application of Cell-Based Delivery Systems 279

10.8 Conclusion and Outlook 279

References 280

11 Overcoming the Translational Gap - Nanotechnology in Dermal Drug Delivery 285
Christian Zoschke and Monika Schäfer-Korting

11.1 Nanotechnology - Failure or Future in Drug Delivery? 285

11.2 Identification of the Clinical Need 286

11.3 Nanoparticle Design and Physicochemical Characterization 289

11.4 Biomedical Studies 294

11.4.1 Atopic Dermatitis 294

11.4.2 Psoriasis 295

11.4.3 Ichthyosis 296

11.4.4 Wound Healing 297

11.4.5 Infections 297

11.4.6 Skin Cancer 298

11.4.7 Alopecia Areata 299

11.5 Approaches to Fill the Translational Gaps in Nanotechnology 299

References 303

12 Theranostic Nanoparticles for Imaging and Targeted Drug Delivery to the Liver 311
Haolu Wang, Haotian Yang, Qi Ruan, Michael S. Roberts, and Xiaowen Liang

12.1 Introduction 311

12.2 The Types of Theranostic NPs 312

12.2.1 Lipid- and Polymer-Based NPs 312

12.2.2 Mesoporous Silica NPs 312

12.2.3 Bio-nanocapsules 313

12.2.4 Iron Oxide NPs 313

12.3 Mechanisms of NPs Targeting the Liver 313

12.3.1 Passive Targeting to the Liver 313

12.3.2 Active Targeting to the Liver 314

12.3.3 Strategies for Combining Passive and Active Targeting 315

12.4 NPs in Liver Target Imaging 315

12.4.1 NP-Based Contrast Agents in Liver MRI 315

12.4.2 NP-Based Contrast Agents in Liver CT Imaging 316

12.4.3 NPs for Near-Infrared Fluorescence Imaging in Liver 316

12.5 NPs for Therapeutic and Drug Delivery in Liver Disease 316

12.5.1 NP Delivery System in HCC 316

12.5.2 NP Delivery System in Non-tumoral Liver Disease 318

12.6 Theranostic NPs in Liver Diseases 318

12.7 Conclusions 322

References 323

13 Toxicology and Safety of Nanoparticles in Drug Delivery System 329
Klintean Wunnapuk

13.1 Introduction 329

13.2 Lipid-Based Nanocarrier: Liposomes 329

13.3 Cellular Uptake Mechanism of Liposomes 330

13.4 Biodistribution, Clearance and Toxicity of Liposomes 331

13.4.1 Effect of Lipid Compositions on Liposome Distribution and Blood Circulation 331

13.4.2 Effect of Surface Charge on Liposome Distribution and Blood Circulation 333

13.4.3 Effect of Size on Liposome Distribution and Blood Circulation 333

13.5 Application of Liposomes in Drug Delivery 334

13.6 Inorganic Nanocarrier: Carbon Nanotubes 336

13.7 Cellular Uptake Mechanism of Carbon Nanotubes 337

13.8 Biodistribution, Clearance, and Toxicity of Carbon Nanotubes 337

13.9 Application of Carbon Nanotubes in Drug Delivery 342

13.10 Conclusion 342

References 342

Part III Administrative Routes for Controlled Drug Delivery 349

14 Controlled Drug Delivery via the Ocular Route 351
Peter W.J. Morrison and Vitaliy V. Khutoryanskiy

14.1 Introduction 351

14.2 Physiology of the Eye 352

14.2.1 Ocular Membranes; Conjunctiva, Cornea, and Sclera 353

14.2.2 Internal Ocular Structures 354

14.2.3 Anterior Chamber, Lens, and Vitreous Body 355

14.3 Ocular Disorders 355

14.3.1 Periocular Disorders 355

14.3.2 Intraocular Disorders 356

14.4 Controlled Drug Delivery Systems 357

14.4.1 Formulation Strategies 358

14.4.2 Mucoadhesive Systems 358

14.4.3 Solution to Gel In Situ Gelling Systems 359

14.4.4 Penetration Enhancers 361

14.4.5 Contact Lenses and Ocular Inserts 364

14.4.6 Intraocular Systems (Implants, Injectables, and Degradable Microparticles) 366

14.4.7 Phonophoresis and Ionophoresis 367

14.4.8 Topical Prodrugs 368

14.4.9 Microneedle Systems 368

14.5 Conclusions 369

References 370

15 Controlled Drug Delivery via the Otic Route 377
Jinsong Hao and S. Kevin Li

15.1 Introduction 377

15.2 Anatomy and Physiology of the Otic Route 377

15.2.1 Anatomy of the Otic Route 377

15.2.2 Barriers Relevant to Inner Ear Drug Delivery 378

15.3 Controlled Drug Delivery Systems 381

15.3.1 Intratympanic Administration 381

15.3.2 Trans-OvalWindow Administration 384

15.3.3 Intracochlear Administration 385

15.4 Conclusions 388

References 388

16 Controlled Drug Delivery via the Nasal Route 393
Barbara R. Conway and Muhammad U. Ghori

16.1 Introduction 393

16.2 Anatomy and Physiology of the Nose 393

16.3 Absorption from the Nasal Cavity 395

16.3.1 The Epithelial Barrier 395

16.3.2 Absorption 395

16.4 Mucus and Mucociliary Clearance 398

16.5 Drug Delivery Systems 399

16.5.1 Solutions and Suspensions 400

16.5.2 Mucoadhesive Polymers 401

16.5.3 The Nasal Route and the Blood-Brain Barrier 415

16.5.4 The Nasal Route for Vaccinations 419

16.5.5 In Vitro/in Vivo Models for Nasal Absorption 421

16.6 Conclusion 423

References 423

17 Controlled Drug Delivery via the Buccal and Sublingual Routes 433
Javier O. Morales, Parameswara R. Vuddanda, and Sitaram Velaga

17.1 Introduction 433

17.2 Buccal and Sublingual Physiology and Barriers to Drug Delivery 434

17.2.1 Saliva and Mucus 434

17.2.2 Buccal and Sublingual Epithelium and Permeation Barrier 434

17.3 Controlled Drug Delivery Systems 436

17.3.1 Tablets 436

17.3.2 Films 437

17.3.3 Gels, Ointments, and Liquid Formulations 438

17.3.4 Spray 438

17.3.5 Wafers 439

17.3.6 Lozenges 439

17.3.7 Advanced and Novel Drug Delivery Systems 439

17.4 Functional Excipients Used in Controlled Release Systems to Enhance Buccal and Sublingual Drug Bioavailability 440

17.4.1 Permeation Enhancers 440

17.4.2 Mucoadhesive Polymers 441

17.5 Conclusions 442

Acknowledgments 443

References 443

18 Controlled Drug Delivery via the Lung 449
María V. Ramírez-Rigo, Nazareth E. Ceschan, and Hugh D. C. Smyth

18.1 Introduction 449

18.2 The Relevant Physiology of the Route Including the Barriers to Drug Delivery 449

18.3 Controlled Drug Delivery Systems 451

18.3.1 Formulations 451

18.3.2 Devices 459

18.4 Conclusions 464

Acknowledgments 464

References 464

19 Controlled Drug Delivery via the Vaginal and Rectal Routes 471
José das Neves and Bruno Sarmento

19.1 Introduction 471

19.2 Biological Features of the Vagina and Colorectum 472

19.2.1 Vagina 472

19.2.2 Colorectum 473

19.3 Controlled Drug Delivery Systems 474

19.3.1 Vaginal Route 476

19.3.2 Rectal Route 489

19.4 Conclusions 494

Acknowledgments 494

References 494

20 Controlled Drug Delivery into and Through Skin 507
Adrian Williams

20.1 Introduction 507

20.1.1 Human Skin Structure and Function 507

20.1.2 Drug Transport Through Skin 512

20.2 Controlled Drug Delivery into and Through Skin 513

20.2.1 Skin Barrier Modulation 513

20.2.2 Controlled Release Transdermal and Topical Systems 515

20.2.2.5 Particles 520

20.2.3 Device-Based Controlled Delivery 522

20.3 Combination Approaches 528

20.4 Conclusions 528

References 529

Index 535

Authors

Heather A. E. Benson Curtin University, Australia. Michael S. Roberts University of South Australia; Therapeutics at The University of Queensland. Adrian C. Williams University of Reading, United Kingdom. Xiaowen Liang The University of Queensland Diamantina Institute, Australia.