Fundamentals of Drug Delivery

Heather A.E. Benson, PhD is an Associate Professor at the Curtin Medical School, Curtin University, Australia, where she leads the Skin Delivery Research Group.Michael S. Roberts, PhD is Professor of Therapeutics and Pharmaceutical Science at the University of South Australia, and a Professor of Clinical Pharmacology and Therapeutics at the University of Queensland, Australia. Adrian C. Williams, PhD is Professor of Pharmaceutics and Research Dean at University of Reading, England, UK. Xiaowen Liang, PhD is the UQ Development Fellow at The University of Queensland, Australia.

• Preface xviiList of Contributors xixPart I Product Design, the Essence of Effective Therapeutics 11 Challenges and Innovations of Controlled Drug Delivery 3Heather A.E. Benson and Michael S. Roberts1.1 Background 31.2 Parenteral Dosage Forms 31.2.1 Intravenous Route (IV) 41.2.2 Intramuscular Route (IM) 51.2.3 Subcutaneous Route (SC) 51.2.4 Other Parenteral Routes 51.3 Oral Route and Delivery Systems 61.4 Nasal Drug Delivery 61.5 Pulmonary Drug Delivery 71.6 Transdermal Drug Delivery 71.7 Ocular Drug Delivery 91.8 Drug Delivery System Development Process 111.9 Conclusion 12References 122 Challenges in Design of Drug Delivery Systems 15S. Narasimha Murthy, Shivakumar H.N, and Sarasija Suresh2.1 Drug Properties to be Considered in Design of Controlled Release Products 192.2 Physicochemical Factors that Need to be Considered in Design of CRDDS 192.2.1 Dose Size 192.2.2 MolecularWeight/Size 192.2.3 Aqueous Solubility 212.2.4 Lipid Solubility and Partition Coefficient 252.2.5 Physicochemical Stability 262.3 Biopharmaceutical Properties that Deserve Consideration in Design of Controlled Release Products 262.3.1 Biological Half-life 262.3.2 Absorption 272.3.3 Metabolism 302.3.4 Presystemic Clearance 322.3.5 Margin of Safety 322.3.6 Adverse Effects 332.3.7 Therapeutic Need 332.3.8 Role of Circadian Rhythm 342.4 Conclusion 35References 353 Drug Delivery of the Future (?) 39Adrian Williams3.1 Introduction 393.2 Therapeutic Indicators 403.3 Drugs of the Future 433.4 Delivering the Drugs of the Future 453.5 A View to the Longer Term? 473.6 Conclusion 50References 504 The Pharmaceutical Drug Development Process: Selecting a Suitable Drug Candidate 37Lionel Trottet4.1 The Oral Drug Candidate: How to Get There and Questions to Answer 534.2 Challenges for Selecting a Topical Drug Candidate 554.3 Percutaneous Flux as a Surrogate Measurement of Skin Tissue Concentration 574.4 Learnings from Past Topical Drug Development of Factors Affecting Efficacy 584.5 Dermal Pharmacokinetics/Pharmacodynamics 624.6 Assessment of Systemic Exposure 634.7 Screening Cascade Approach to Select a Dermal Drug Candidate 644.7.1 Efficacy (Lack of Target Engagement) 644.7.2 Developability 654.7.3 Local Safety 654.7.4 Systemic Safety 654.8 Opportunities for Repurposing Molecules into Dermally Active Treatments for Cosmeceutical or Pharmaceutical Approaches 664.9 Conclusion 66References 675 Preformulation and Physicochemical Characterization Underpinning the Development of Controlled Drug Delivery Systems 73Ronak Savla and Julien Meissonnier5.1 When Is a Controlled Drug Delivery System Needed? 735.2 Optimizing Drug Characteristics 745.3 Defining the Product Profile 755.4 Preformulation and Physicochemical Characterization Underpinning Development of CDD 775.4.1 Feasibility and Risk Assessment 785.4.2 Solubility and Dissolution Rate 795.4.3 Permeability 825.4.4 Drug and Drug Product Particle Sizes 835.4.5 Solid-State Chemistry 845.4.6 Stability 855.4.7 Excipient Compatibility 865.4.8 Bulk Powder Properties 875.4.9 Drug Metabolism and Pharmacokinetic Modeling 885.5 Conclusion 89References 896 Mathematical Models Describing Kinetics Associated with Controlled Drug Delivery Across Membranes 95Annette L. Bunge6.1 Introduction 956.1.1 General Description 956.1.2 Governing Equations 986.1.3 Other Derived Quantities 1006.1.4 Dimensionless Variables and Groups 1026.2 Model Solutions 1046.2.1 Type A Models –Well-Stirred Vehicle on One Membrane 1046.2.2 Type B Models – Unstirred Semi-infinite Vehicle on One Membrane 1406.2.3 Type C –Well Stirred Vehicle on Two Membranes in Series 1456.3 Solution Methods 1496.3.1 Separation of Variables Solutions 1506.3.2 Laplace Transform Solutions 1596.3.3 Useful Identities 169References 1697 Understanding Drug Delivery Outcomes: Progress in Microscopic Modeling of Skin Barrier Property, Permeation Pathway, Dermatopharmacokinetics, and Bioavailability 171Guoping Lian, Tao Chen, Panayiotis Kattou, Senpei Yang, Lingyi Li, and Lujia Han7.1 Introduction 1717.2 Governing Equation 1727.2.1 Homogenized Model 1727.2.2 Microscopic Model 1747.2.3 Numerical Methods 1757.3 Input Parameters 1767.3.1 SC Microstructure 1767.3.2 SC Lipid–Water Partition 1777.3.3 Diffusivity in SC Lipids 1777.3.4 Binding to Keratin 1797.3.5 Diffusivity in Corneocytes 1817.3.6 Solute Diffusivity and Partition in Sebum 1817.4 Application 1837.4.1 Steady-State 1837.4.2 Dermatopharmacokinetics 1847.4.3 Systemic Pharmacokinetics 1847.4.4 Shunt Pathway 1857.5 Perspective 186References 1888 Role of Membrane Transporters in Drug Disposition 193Hong Yang and Yan Shu8.1 Introduction 1938.2 Distribution of Major Drug Transporters in Human Tissues 1948.2.1 Major Drug Transporters in the Intestine 1948.2.1.3 Expression of Drug Transporters in Different Intestinal Regions 1978.2.2 Major Drug Transporters in the Liver 1978.2.3 Major Drug Transporters in the Kidney 1998.2.4 Major Drug Transporters in the Central Nervous System (CNS) 2018.2.5 Major Drug Transporters in Other Tissues 2028.3 Role of Drug Transporters in Drug Disposition 2058.3.1 Role of P-gp in Drug Disposition 2068.3.2 Role of BCRP in Drug Disposition 2078.3.3 Role of BSEP in Drug-Induced Cholestatic Liver Injury 2148.3.4 Role of MRPs (MRP2, MRP3, and MRP4) in Drug Disposition 2148.3.5 Role of OATPs (OATP1B1, OATP1B3, and OATP2B1) in Drug Disposition 2158.3.6 Role of OATs (OAT1 and OAT3) in Drug Disposition 2168.3.7 Role of OCTs (OCT1 and OCT2)/MATEs (MATE1 and MATE2-K) in Drug Disposition 2178.4 Closing Remarks 218References 219Part II Challenges in Controlled Drug Delivery and Advanced Delivery Technologies 2319 Advanced Drug Delivery Systems for Biologics 233May Wenche Jøraholmen, Selenia Ternullo, Ann Mari Holsæter, Gøril Eide Flaten, and Nataša Škalko-Basnet9.1 Introduction 2339.2 Considerations in Biologics Product Development 2349.2.1 Challenges Specific to the Route of Administration 2349.2.2 Challenges Related to Parenteral Administration 2349.2.3 Optimization of Dosage Regimens 2349.3 Administration Routes for Biologics Delivery 2359.3.1 Parenteral Route 2359.3.2 Oral Route 2369.3.3 Buccal Route 2379.3.4 Sublingual Route 2389.3.5 Pulmonary Route 2389.3.6 Intranasal Route 2399.3.7 Trans(dermal) Delivery 2409.3.8 Dermal Delivery of Growth Hormones 2439.3.9 Vaginal Route 2479.4 Conclusion 251References 25110 Recent Advances in Cell-Mediated Drug Delivery Systems for Nanomedicine and Imaging 263Li Li and Zhi Qi10.1 Introduction 26310.2 Cell Types and Modification for Therapeutic Agent Delivery 26410.2.1 Cell Types 26410.2.2 Cargo Loading Methods 26910.3 Imaging and Tracking of Cell-Based Delivery Systems 27010.3.1 MRI 27110.3.2 PET 27210.3.3 X-Ray Imaging 27210.3.4 Multimodal Imaging Techniques 27210.4 Cell-Mediated Drug Delivery Systems for Disease Treatment 27210.4.1 Cancer Therapy 27210.4.2 Immunotherapy 27210.4.3 Brain-Related Diseases 27410.4.4 Inflammatory Diseases 27410.4.5 Theranostic Application 27510.4.6 Others 27510.5 The Mechanism of Cell-Mediated Delivery Systems for the Cell Therapies 27510.5.1 Detoxification 27610.5.2 Adhesive Mechanism 27710.5.3 Homing Mechanism 27810.6 The Administration Approach of Cell-Assist Drug Delivery System 27810.7 Clinical Application of Cell-Based Delivery Systems 27910.8 Conclusion and Outlook 279References 28011 Overcoming the Translational Gap – Nanotechnology in Dermal Drug Delivery 285Christian Zoschke and Monika Schäfer-Korting11.1 Nanotechnology – Failure or Future in Drug Delivery? 28511.2 Identification of the Clinical Need 28611.3 Nanoparticle Design and Physicochemical Characterization 28911.4 Biomedical Studies 29411.4.1 Atopic Dermatitis 29411.4.2 Psoriasis 29511.4.3 Ichthyosis 29611.4.4 Wound Healing 29711.4.5 Infections 29711.4.6 Skin Cancer 29811.4.7 Alopecia Areata 29911.5 Approaches to Fill the Translational Gaps in Nanotechnology 299References 30312 Theranostic Nanoparticles for Imaging and Targeted Drug Delivery to the Liver 311Haolu Wang, Haotian Yang, Qi Ruan, Michael S. Roberts, and Xiaowen Liang12.1 Introduction 31112.2 The Types of Theranostic NPs 31212.2.1 Lipid- and Polymer-Based NPs 31212.2.2 Mesoporous Silica NPs 31212.2.3 Bio-nanocapsules 31312.2.4 Iron Oxide NPs 31312.3 Mechanisms of NPs Targeting the Liver 31312.3.1 Passive Targeting to the Liver 31312.3.2 Active Targeting to the Liver 31412.3.3 Strategies for Combining Passive and Active Targeting 31512.4 NPs in Liver Target Imaging 31512.4.1 NP-Based Contrast Agents in Liver MRI 31512.4.2 NP-Based Contrast Agents in Liver CT Imaging 31612.4.3 NPs for Near-Infrared Fluorescence Imaging in Liver 31612.5 NPs for Therapeutic and Drug Delivery in Liver Disease 31612.5.1 NP Delivery System in HCC 31612.5.2 NP Delivery System in Non-tumoral Liver Disease 31812.6 Theranostic NPs in Liver Diseases 31812.7 Conclusions 322References 32313 Toxicology and Safety of Nanoparticles in Drug Delivery System 329Klintean Wunnapuk13.1 Introduction 32913.2 Lipid-Based Nanocarrier: Liposomes 32913.3 Cellular Uptake Mechanism of Liposomes 33013.4 Biodistribution, Clearance and Toxicity of Liposomes 33113.4.1 Effect of Lipid Compositions on Liposome Distribution and Blood Circulation 33113.4.2 Effect of Surface Charge on Liposome Distribution and Blood Circulation 33313.4.3 Effect of Size on Liposome Distribution and Blood Circulation 33313.5 Application of Liposomes in Drug Delivery 33413.6 Inorganic Nanocarrier: Carbon Nanotubes 33613.7 Cellular Uptake Mechanism of Carbon Nanotubes 33713.8 Biodistribution, Clearance, and Toxicity of Carbon Nanotubes 33713.9 Application of Carbon Nanotubes in Drug Delivery 34213.10 Conclusion 342References 342Part III Administrative Routes for Controlled Drug Delivery 34914 Controlled Drug Delivery via the Ocular Route 351Peter W.J. Morrison and Vitaliy V. Khutoryanskiy14.1 Introduction 35114.2 Physiology of the Eye 35214.2.1 Ocular Membranes; Conjunctiva, Cornea, and Sclera 35314.2.2 Internal Ocular Structures 35414.2.3 Anterior Chamber, Lens, and Vitreous Body 35514.3 Ocular Disorders 35514.3.1 Periocular Disorders 35514.3.2 Intraocular Disorders 35614.4 Controlled Drug Delivery Systems 35714.4.1 Formulation Strategies 35814.4.2 Mucoadhesive Systems 35814.4.3 Solution to Gel In Situ Gelling Systems 35914.4.4 Penetration Enhancers 36114.4.5 Contact Lenses and Ocular Inserts 36414.4.6 Intraocular Systems (Implants, Injectables, and Degradable Microparticles) 36614.4.7 Phonophoresis and Ionophoresis 36714.4.8 Topical Prodrugs 36814.4.9 Microneedle Systems 36814.5 Conclusions 369References 37015 Controlled Drug Delivery via the Otic Route 377Jinsong Hao and S. Kevin Li15.1 Introduction 37715.2 Anatomy and Physiology of the Otic Route 37715.2.1 Anatomy of the Otic Route 37715.2.2 Barriers Relevant to Inner Ear Drug Delivery 37815.3 Controlled Drug Delivery Systems 38115.3.1 Intratympanic Administration 38115.3.2 Trans-OvalWindow Administration 38415.3.3 Intracochlear Administration 38515.4 Conclusions 388References 38816 Controlled Drug Delivery via the Nasal Route 393Barbara R. Conway and Muhammad U. Ghori16.1 Introduction 39316.2 Anatomy and Physiology of the Nose 39316.3 Absorption from the Nasal Cavity 39516.3.1 The Epithelial Barrier 39516.3.2 Absorption 39516.4 Mucus and Mucociliary Clearance 39816.5 Drug Delivery Systems 39916.5.1 Solutions and Suspensions 40016.5.2 Mucoadhesive Polymers 40116.5.3 The Nasal Route and the Blood–Brain Barrier 41516.5.4 The Nasal Route for Vaccinations 41916.5.5 In Vitro/in Vivo Models for Nasal Absorption 42116.6 Conclusion 423References 42317 Controlled Drug Delivery via the Buccal and Sublingual Routes 433Javier O. Morales, Parameswara R. Vuddanda, and Sitaram Velaga17.1 Introduction 43317.2 Buccal and Sublingual Physiology and Barriers to Drug Delivery 43417.2.1 Saliva and Mucus 43417.2.2 Buccal and Sublingual Epithelium and Permeation Barrier 43417.3 Controlled Drug Delivery Systems 43617.3.1 Tablets 43617.3.2 Films 43717.3.3 Gels, Ointments, and Liquid Formulations 43817.3.4 Spray 43817.3.5 Wafers 43917.3.6 Lozenges 43917.3.7 Advanced and Novel Drug Delivery Systems 43917.4 Functional Excipients Used in Controlled Release Systems to Enhance Buccal and Sublingual Drug Bioavailability 44017.4.1 Permeation Enhancers 44017.4.2 Mucoadhesive Polymers 44117.5 Conclusions 442Acknowledgments 443References 44318 Controlled Drug Delivery via the Lung 449María V. Ramírez-Rigo, Nazareth E. Ceschan, and Hugh D. C. Smyth18.1 Introduction 44918.2 The Relevant Physiology of the Route Including the Barriers to Drug Delivery 44918.3 Controlled Drug Delivery Systems 45118.3.1 Formulations 45118.3.2 Devices 45918.4 Conclusions 464Acknowledgments 464References 46419 Controlled Drug Delivery via the Vaginal and Rectal Routes 471José das Neves and Bruno Sarmento19.1 Introduction 47119.2 Biological Features of the Vagina and Colorectum 47219.2.1 Vagina 47219.2.2 Colorectum 47319.3 Controlled Drug Delivery Systems 47419.3.1 Vaginal Route 47619.3.2 Rectal Route 48919.4 Conclusions 494Acknowledgments 494References 49420 Controlled Drug Delivery into and Through Skin 507Adrian Williams20.1 Introduction 50720.1.1 Human Skin Structure and Function 50720.1.2 Drug Transport Through Skin 51220.2 Controlled Drug Delivery into and Through Skin 51320.2.1 Skin Barrier Modulation 51320.2.2 Controlled Release Transdermal and Topical Systems 51520.2.2.5 Particles 52020.2.3 Device-Based Controlled Delivery 52220.3 Combination Approaches 52820.4 Conclusions 528References 529Index 535