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 Nataa kalko-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
