Drug Delivery

List of Contributors xvii Preface xxi 1 Factors that Impact the Developability of Drug Candidates 1 Chao Han and Binghe Wang 1.1 Challenges Facing the Pharmaceutical Industry 1 1.2 Factors that Impact Developability 5 1.3 Remarks on Developability 12 1.4 Drug Delivery Factors that Impact Developability 13 References 15 2 Physiological, Biochemical, and Chemical Barriers to Oral Drug Delivery 19 Paul Kiptoo, Anna M. Calcagno, and Teruna J. Siahaan 2.1 Introduction 19 2.2 Physiological Barriers to Drug Delivery 20 2.3 Biochemical Barriers to Drug Delivery 25 2.4 Chemical Barriers to Drug Delivery 28 2.5 Drug Modifications to Enhance Transport Across Biological Barriers 29 2.6 Conclusions 31 Acknowledgment 31 References 31 3 Physicochemical Properties, Formulation, and Drug Delivery 35 Dewey H. Barich, Mark T. Zell, and Eric J. Munson 3.1 Introduction 35 3.2 Physicochemical Properties 36 3.3 Formulations 42 3.4 Drug Delivery 43 3.5 Conclusion 47 References 47 4 Targeted Bioavailability: A Fresh Look at Pharmacokinetic and Pharmacodynamic Issues in Drug Discovery and Development 49 Christine Xu 4.1 Introduction 49 4.2 Target Bioavailability 50 4.3 Drug Delivery Trends and Targets Related to PK and PD 51 4.4 PK-PD in Drug Discovery and Development 51 4.5 Source of Variability of Drug Response 55 4.6 Recent Development and Issues of Bio?]Analytical Methodology 57 4.7 Mechanistic PK-PD Models 58 4.8 Summary 60 References 60 5 The Role of Transporters in Drug Delivery and Excretion 62 Marilyn E. Morris and Xiaowen Guan 5.1 Introduction 62 5.2 Drug Transport in Absorption and Excretion 63 5.3 ABC (ATP?]Binding Cassette) Transporter Family 67 5.4 SlC (Solute Carrier) Transporter Family 76 5.5 Conclusions 88 Acknowledgment 88 References 89 6 Intracellular Delivery and Disposition of Small?]Molecular?]Weight Drugs 103 Jeffrey P. Krise 6.1 Introduction 103 6.2 The Relationship between the Intracellular Distribution of a Drug and its Activity 104 6.3 The Relationship between the Intracellular Distribution of a Drug and its Pharmacokinetic Properties 104 6.4 Overview of Approaches to Study Intracellular Drug Disposition 105 6.5 The Accumulation of Drugs in Mitochondria, Lysosomes, and Nuclei 108 6.6 Summary and Future Directions 123 References 124 7 Cell Culture Models for Drug Transport Studies 131 Irina Kalashnikova, Norah Albekairi, Shariq Ali, Sanaalarab Al Enazy, and Erik Rytting 7.1 Introduction 131 7.2 General Considerations 132 7.3 Intestinal Epithelium 133 7.4 The Blood-Brain Barrier 135 7.5 Nasal and Pulmonary Epithelium 137 7.6 The Ocular Epithelial and Endothelial Barriers 141 7.7 The Placental Barrier 142 7.8 The Renal Epithelium 143 7.9 3D In Vitro Models 145 7.10 Conclusions 146 References 146 8 Intellectual Property and Regulatory Issues in Drug Delivery Research 152 Shahnam Sharareh and Wansheng Jerry Liu 8.1 Introduction 152 8.2 Pharmaceutical Patents 153 8.3 Statutory Requirements for Obtaining a Patent 154 8.4 Patent Procurement Strategies 157 8.5 Regulatory Regime 158 8.6 FDA Market Exclusivities 160 8.7 Regulatory and Patent Law Linkage 162 References 162 9 Presystemic and First?]Pass Metabolism 164 Qingping Wang and Meng Li 9.1 Introduction 164 9.2 Hepatic First?]Pass Metabolism 165 9.3 Intestinal First?]Pass Metabolism 170 9.4 Prediction of First?]Pass Metabolism 174 9.5 S trategies for Optimization of Oral Bioavailability 178 9.6 Summary 179 References 180 10 Pulmonary Drug Delivery: Pharmaceutical Chemistry and Aerosol Technology 186 Anthony J. Hickey 10.1 Introduction 186 10.2 Aerosol Technology 187 10.3 Disease Therapy 190 10.4 Formulation Variables 196 10.5 Regulatory Considerations 200 10.6 Future Developments 201 10.7 Conclusion 201 References 202 11 Transdermal Delivery of Drugs Using Patches and Patchless Delivery Systems 207 Tannaz Ramezanli, Krizia Karry, Zheng Zhang, Kishore Shah, and Bozena Michniak?]Kohn 11.1 Introduction 207 11.2 Transdermal Patch Delivery Systems 208 11.3 Patchless Transdermal Drug Delivery Systems 211 11.4 Recent Advances in Transdermal Drug Delivery 216 11.5 Summary 221 References 222 12 Prodrug Approaches to Drug Delivery 227 Longqin Hu 12.1 Introduction 227 12.2 Basic Concepts: Definition and Applications 228 12.3 Prodrug Design Considerations 238 12.4 Prodrugs of Various Functional Groups 241 12.5 Drug Release and Activation Mechanisms 258 12.6 Prodrugs and Intellectual Property Rights--Two Court Cases 266 References 268 13 Liposomes as Drug Delivery Vehicles 272 Guijun Wang 13.1 Introduction 272 13.2 Currently Approved Liposomal Drugs in Clinical Applications 273 13.3 Conventional and Stealth Liposomes 276 13.4 Stimuli?]Responsive Liposomes or Triggered?]Release Liposomes 277 13.5 Targeted Liposomal Delivery 289 13.6 Hybrid Liposome Drug Delivery System 291 13.7 Conclusions and Future Perspectives 293 References 293 14 Nanoparticles as Drug Delivery Vehicles 299 Dan Menasco and Qian Wang 14.1 Introduction 299 14.2 O rganic DDVs 308 14.3 Inorganic DDVs: Metal?] and Silica?]Based Systems 320 14.4 Conclusion 330 References 330 15 Evolution of Controlled Drug Delivery Systems 336 Krishnaveni Janapareddi, Bhaskara R. Jasti, and Xiaoling Li 15.1 Introduction 336 15.2 Biopharmaceutics and Pharmacokinetics 337 15.3 Material Science 341 15.4 Proteins, Peptides and Nucleic Acids 343 15.5 Discovery of New Molecular Targets--Targeted Drug Delivery 345 15.6 Microelectronics and Microfabrication Technologies 347 15.7 Conclusion 349 References 349 16 Pathways for Drug Delivery to the Central Nervous System 353 Ngoc H. On, Vinith Yathindranath, Zhizhi Sun, and Donald W. Miller 16.1 Introduction 353 16.2 Circumventing the CNS Barriers 356 16.3 Transient BBB Disruption 359 16.4 Transcellular Delivery Routes 364 16.5 Conclusions 375 References 375 17 Metabolic Activation and Drug Targeting 383 Xiangming Guan 17.1 Introduction 383 17.2 Anticancer Prodrugs and their Biochemical Basis 384 17.3 Antibody?] and Gene?]Directed Enzyme Prodrug Therapy 420 17.4 Summary 429 References 429 18 Targeted Delivery of Drugs to the Colon 435 Anil K. Philip and Sarah K. Zingales 18.1 Introduction 435 18.2 Microbially Triggered Release 437 18.3 pH?]Sensitive Polymers for Time?]Dependent Release 442 18.4 Osmotic Release 443 18.5 Pressure?]Controlled Delivery 443 18.6 Nanoparticle Approaches 444 18.7 Conclusion 446 Acknowledgment 446 References 447 19 Receptor?]Mediated Drug Delivery 451 Chris V. Galliford and Philip S. Low 19.1 Introduction 451 19.2 Selection of a Receptor for Drug Delivery 454 19.3 Design of a Ligand-Drug Conjugate 455 19.4 Folate?]Mediated Drug Delivery 458 19.5 Conclusions 467 Acknowledgments 467 References 467 20 Protein and Peptide Conjugates for Targeting Therapeutics and Diagnostics to Specific Cells 475 Barlas Büyüktimkin, John Stewart, Jr., Kayann Tabanor, Paul Kiptoo, and Teruna J. Siahaan 20.1 Introduction 475 20.2 Radiolabeled Antibodies for Cancer Treatment 479 20.3 Antibody-Drug Conjugate 480 20.4 Non?]Antibody?]Based Protein-Drug Conjugates 486 20.5 Peptibody 488 20.6 Protein Conjugates for Diagnostics 489 20.7 Peptide-Drug Conjugates 491 20.8 Challenges in Analyzing Conjugates 494 20.9 Conclusions 497 References 497 21 Drug Delivery to the Lymphatic System 503 Qiuhong Yang and Laird Forrest 21.1 Introduction 503 21.2 Anatomy and Physiology of the Lymphatic System 504 21.3 Influence of Physicochemical Characteristics of Drug Carriers on Lymphatic Uptake and Transport 509 21.4 Carriers for Lymphatic Drug Delivery 513 21.5 Administration Routes for Lymphatic Delivery 528 21.6 Lymphatic?]Targeting Vaccination 536 21.7 Conclusions 538 References 539 22 The Development of Cancer Theranostics: A New Emerging Tool Toward Personalized Medicine 549 Hongying Su, Yun Zeng, Gang Liu, and Xiaoyuan Chen 22.1 Introduction 549 22.2 Imaging?]Guided Drug Delivery and Therapy 551 22.3 Optical Imaging-Based Theranostics 553 22.4 MRI?]Based Theranostics 558 22.5 Nuclear Imaging-Based Theranostics 559 22.6 Ultrasound?]Based Theranostic Platform 563 22.7 Multimodality Imaging-Based Theranostic Platform 564 22.8 Conclusion and Future Perspectives 567 Acknowledgments 569 References 569 23 Intracellular Delivery of Proteins and Peptides 576 Can Sarisozen and Vladimir P. Torchilin 23.1 Introduction 576 23.2 Intracellular Delivery Strategies of Peptides and Proteins 579 23.3 Concepts in Intracellular Peptide and Protein Delivery 580 23.4 Peptide and Protein Delivery to Lysosomes 589 23.5 Receptor?]Mediated Intracellular Delivery of Peptides and Proteins 590 23.6 Transmembrane Delivery of Peptides and Proteins 595 23.7 Conclusion 602 References 602 24 Vaccine Delivery: Current Routes of Administration and Novel Approaches 623 Neha Sahni, Yuan Cheng, C. Russell Middaugh, and David B. Volkin 24.1 Introduction 623 24.2 Parenteral Administration of Vaccines 625 24.3 Oral Delivery of Vaccines 634 24.4 Nasal and Aerosol Delivery of Vaccines 639 24.5 Conclusions 643 References 644 25 Delivery of Genes and Oligonucleotides 655 Charles M. Roth 25.1 Introduction 655 25.2 Systemic Delivery Barriers 656 25.3 Cellular Delivery Barriers 663 25.4 Current and Future Approaches to Nucleic Acid Delivery 666 25.5 Summary and Future Directions 668 References 668 Index 674