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<p>Preface xvii</p> <p>List of Contributors xix</p> <p><b>Part I Product Design, the Essence of Effective Therapeutics </b><b>1</b></p> <p><b>1 Challenges and Innovations of Controlled Drug Delivery </b><b>3</b><i><br /> Heather A.E. Benson and Michael S. Roberts</i></p> <p>1.1 Background 3</p> <p>1.2 Parenteral Dosage Forms 3</p> <p>1.2.1 Intravenous Route (IV) 4</p> <p>1.2.2 Intramuscular Route (IM) 5</p> <p>1.2.3 Subcutaneous Route (SC) 5</p> <p>1.2.4 Other Parenteral Routes 5</p> <p>1.3 Oral Route and Delivery Systems 6</p> <p>1.4 Nasal Drug Delivery 6</p> <p>1.5 Pulmonary Drug Delivery 7</p> <p>1.6 Transdermal Drug Delivery 7</p> <p>1.7 Ocular Drug Delivery 9</p> <p>1.8 Drug Delivery System Development Process 11</p> <p>1.9 Conclusion 12</p> <p>References 12</p> <p><b>2 Challenges in Design of Drug Delivery Systems </b><b>15</b><i><br /> S. Narasimha Murthy, Shivakumar H.N, and Sarasija Suresh</i></p> <p>2.1 Drug Properties to be Considered in Design of Controlled Release Products 19</p> <p>2.2 Physicochemical Factors that Need to be Considered in Design of CRDDS 19</p> <p>2.2.1 Dose Size 19</p> <p>2.2.2 MolecularWeight/Size 19</p> <p>2.2.3 Aqueous Solubility 21</p> <p>2.2.4 Lipid Solubility and Partition Coefficient 25</p> <p>2.2.5 Physicochemical Stability 26</p> <p>2.3 Biopharmaceutical Properties that Deserve Consideration in Design of Controlled Release Products 26</p> <p>2.3.1 Biological Half-life 26</p> <p>2.3.2 Absorption 27</p> <p>2.3.3 Metabolism 30</p> <p>2.3.4 Presystemic Clearance 32</p> <p>2.3.5 Margin of Safety 32</p> <p>2.3.6 Adverse Effects 33</p> <p>2.3.7 Therapeutic Need 33</p> <p>2.3.8 Role of Circadian Rhythm 34</p> <p>2.4 Conclusion 35</p> <p>References 35</p> <p><b>3 Drug Delivery of the Future (?) </b><b>39</b><i><br /> Adrian Williams</i></p> <p>3.1 Introduction 39</p> <p>3.2 Therapeutic Indicators 40</p> <p>3.3 Drugs of the Future 43</p> <p>3.4 Delivering the Drugs of the Future 45</p> <p>3.5 A View to the Longer Term? 47</p> <p>3.6 Conclusion 50</p> <p>References 50</p> <p><b>4 The Pharmaceutical Drug Development Process: Selecting a Suitable Drug Candidate </b><b>37<br /> </b><i>Lionel Trottet</i></p> <p>4.1 The Oral Drug Candidate: How to Get There and Questions to Answer 53</p> <p>4.2 Challenges for Selecting a Topical Drug Candidate 55</p> <p>4.3 Percutaneous Flux as a Surrogate Measurement of Skin Tissue Concentration 57</p> <p>4.4 Learnings from Past Topical Drug Development of Factors Affecting Efficacy 58</p> <p>4.5 Dermal Pharmacokinetics/Pharmacodynamics 62</p> <p>4.6 Assessment of Systemic Exposure 63</p> <p>4.7 Screening Cascade Approach to Select a Dermal Drug Candidate 64</p> <p>4.7.1 Efficacy (Lack of Target Engagement) 64</p> <p>4.7.2 Developability 65</p> <p>4.7.3 Local Safety 65</p> <p>4.7.4 Systemic Safety 65</p> <p>4.8 Opportunities for Repurposing Molecules into Dermally Active Treatments for Cosmeceutical or Pharmaceutical Approaches 66</p> <p>4.9 Conclusion 66</p> <p>References 67</p> <p><b>5 Preformulation and Physicochemical Characterization Underpinning the Development of Controlled Drug Delivery Systems </b><b>73<br /> </b><i>Ronak Savla and Julien Meissonnier</i></p> <p>5.1 When Is a Controlled Drug Delivery System Needed? 73</p> <p>5.2 Optimizing Drug Characteristics 74</p> <p>5.3 Defining the Product Profile 75</p> <p>5.4 Preformulation and Physicochemical Characterization Underpinning Development of CDD 77</p> <p>5.4.1 Feasibility and Risk Assessment 78</p> <p>5.4.2 Solubility and Dissolution Rate 79</p> <p>5.4.3 Permeability 82</p> <p>5.4.4 Drug and Drug Product Particle Sizes 83</p> <p>5.4.5 Solid-State Chemistry 84</p> <p>5.4.6 Stability 85</p> <p>5.4.7 Excipient Compatibility 86</p> <p>5.4.8 Bulk Powder Properties 87</p> <p>5.4.9 Drug Metabolism and Pharmacokinetic Modeling 88</p> <p>5.5 Conclusion 89</p> <p>References 89</p> <p><b>6 Mathematical Models Describing Kinetics Associated with Controlled Drug Delivery Across Membranes </b><b>95<br /> </b><i>Annette L. Bunge</i></p> <p>6.1 Introduction 95</p> <p>6.1.1 General Description 95</p> <p>6.1.2 Governing Equations 98</p> <p>6.1.3 Other Derived Quantities 100</p> <p>6.1.4 Dimensionless Variables and Groups 102</p> <p>6.2 Model Solutions 104</p> <p>6.2.1 Type A Models –Well-Stirred Vehicle on One Membrane 104</p> <p>6.2.2 Type B Models – Unstirred Semi-infinite Vehicle on One Membrane 140</p> <p>6.2.3 Type C –Well Stirred Vehicle on Two Membranes in Series 145</p> <p>6.3 Solution Methods 149</p> <p>6.3.1 Separation of Variables Solutions 150</p> <p>6.3.2 Laplace Transform Solutions 159</p> <p>6.3.3 Useful Identities 169</p> <p>References 169</p> <p><b>7 Understanding Drug Delivery Outcomes: Progress in Microscopic Modeling of Skin Barrier Property, Permeation Pathway, Dermatopharmacokinetics, and Bioavailability </b><b>171<br /> </b><i>Guoping Lian, Tao Chen, Panayiotis Kattou, Senpei Yang, Lingyi Li, and Lujia Han</i></p> <p>7.1 Introduction 171</p> <p>7.2 Governing Equation 172</p> <p>7.2.1 Homogenized Model 172</p> <p>7.2.2 Microscopic Model 174</p> <p>7.2.3 Numerical Methods 175</p> <p>7.3 Input Parameters 176</p> <p>7.3.1 SC Microstructure 176</p> <p>7.3.2 SC Lipid–Water Partition 177</p> <p>7.3.3 Diffusivity in SC Lipids 177</p> <p>7.3.4 Binding to Keratin 179</p> <p>7.3.5 Diffusivity in Corneocytes 181</p> <p>7.3.6 Solute Diffusivity and Partition in Sebum 181</p> <p>7.4 Application 183</p> <p>7.4.1 Steady-State 183</p> <p>7.4.2 Dermatopharmacokinetics 184</p> <p>7.4.3 Systemic Pharmacokinetics 184</p> <p>7.4.4 Shunt Pathway 185</p> <p>7.5 Perspective 186</p> <p>References 188</p> <p><b>8 Role of Membrane Transporters in Drug Disposition </b><b>193</b><i><br /> Hong Yang and Yan Shu</i></p> <p>8.1 Introduction 193</p> <p>8.2 Distribution of Major Drug Transporters in Human Tissues 194</p> <p>8.2.1 Major Drug Transporters in the Intestine 194</p> <p>8.2.1.3 Expression of Drug Transporters in Different Intestinal Regions 197</p> <p>8.2.2 Major Drug Transporters in the Liver 197</p> <p>8.2.3 Major Drug Transporters in the Kidney 199</p> <p>8.2.4 Major Drug Transporters in the Central Nervous System (CNS) 201</p> <p>8.2.5 Major Drug Transporters in Other Tissues 202</p> <p>8.3 Role of Drug Transporters in Drug Disposition 205</p> <p>8.3.1 Role of P-gp in Drug Disposition 206</p> <p>8.3.2 Role of BCRP in Drug Disposition 207</p> <p>8.3.3 Role of BSEP in Drug-Induced Cholestatic Liver Injury 214</p> <p>8.3.4 Role of MRPs (MRP2, MRP3, and MRP4) in Drug Disposition 214</p> <p>8.3.5 Role of OATPs (OATP1B1, OATP1B3, and OATP2B1) in Drug Disposition 215</p> <p>8.3.6 Role of OATs (OAT1 and OAT3) in Drug Disposition 216</p> <p>8.3.7 Role of OCTs (OCT1 and OCT2)/MATEs (MATE1 and MATE2-K) in Drug Disposition 217</p> <p>8.4 Closing Remarks 218</p> <p>References 219</p> <p><b>Part II Challenges in Controlled Drug Delivery and Advanced Delivery Technologies </b><b>231</b></p> <p><b>9 Advanced Drug Delivery Systems for Biologics </b><b>233</b><i><br /> May Wenche Jøraholmen, Selenia Ternullo, Ann Mari Holsæter, Gøril Eide Flaten, and Nataša Škalko-Basnet</i></p> <p>9.1 Introduction 233</p> <p>9.2 Considerations in Biologics Product Development 234</p> <p>9.2.1 Challenges Specific to the Route of Administration 234</p> <p>9.2.2 Challenges Related to Parenteral Administration 234</p> <p>9.2.3 Optimization of Dosage Regimens 234</p> <p>9.3 Administration Routes for Biologics Delivery 235</p> <p>9.3.1 Parenteral Route 235</p> <p>9.3.2 Oral Route 236</p> <p>9.3.3 Buccal Route 237</p> <p>9.3.4 Sublingual Route 238</p> <p>9.3.5 Pulmonary Route 238</p> <p>9.3.6 Intranasal Route 239</p> <p>9.3.7 Trans(dermal) Delivery 240</p> <p>9.3.8 Dermal Delivery of Growth Hormones 243</p> <p>9.3.9 Vaginal Route 247</p> <p>9.4 Conclusion 251</p> <p>References 251</p> <p><b>10 Recent Advances in Cell-Mediated Drug Delivery Systems for Nanomedicine and Imaging </b><b>263<br /> </b><i>Li Li and Zhi Qi</i></p> <p>10.1 Introduction 263</p> <p>10.2 Cell Types and Modification for Therapeutic Agent Delivery 264</p> <p>10.2.1 Cell Types 264</p> <p>10.2.2 Cargo Loading Methods 269</p> <p>10.3 Imaging and Tracking of Cell-Based Delivery Systems 270</p> <p>10.3.1 MRI 271</p> <p>10.3.2 PET 272</p> <p>10.3.3 X-Ray Imaging 272</p> <p>10.3.4 Multimodal Imaging Techniques 272</p> <p>10.4 Cell-Mediated Drug Delivery Systems for Disease Treatment 272</p> <p>10.4.1 Cancer Therapy 272</p> <p>10.4.2 Immunotherapy 272</p> <p>10.4.3 Brain-Related Diseases 274</p> <p>10.4.4 Inflammatory Diseases 274</p> <p>10.4.5 Theranostic Application 275</p> <p>10.4.6 Others 275</p> <p>10.5 The Mechanism of Cell-Mediated Delivery Systems for the Cell Therapies 275</p> <p>10.5.1 Detoxification 276</p> <p>10.5.2 Adhesive Mechanism 277</p> <p>10.5.3 Homing Mechanism 278</p> <p>10.6 The Administration Approach of Cell-Assist Drug Delivery System 278</p> <p>10.7 Clinical Application of Cell-Based Delivery Systems 279</p> <p>10.8 Conclusion and Outlook 279</p> <p>References 280</p> <p><b>11 Overcoming the Translational Gap – Nanotechnology in Dermal Drug Delivery </b><b>285<br /> </b><i>Christian Zoschke and Monika Schäfer-Korting</i></p> <p>11.1 Nanotechnology – Failure or Future in Drug Delivery? 285</p> <p>11.2 Identification of the Clinical Need 286</p> <p>11.3 Nanoparticle Design and Physicochemical Characterization 289</p> <p>11.4 Biomedical Studies 294</p> <p>11.4.1 Atopic Dermatitis 294</p> <p>11.4.2 Psoriasis 295</p> <p>11.4.3 Ichthyosis 296</p> <p>11.4.4 Wound Healing 297</p> <p>11.4.5 Infections 297</p> <p>11.4.6 Skin Cancer 298</p> <p>11.4.7 Alopecia Areata 299</p> <p>11.5 Approaches to Fill the Translational Gaps in Nanotechnology 299</p> <p>References 303</p> <p><b>12 Theranostic Nanoparticles for Imaging and Targeted Drug Delivery to the Liver </b><b>311<br /> </b><i>Haolu Wang, Haotian Yang, Qi Ruan, Michael S. Roberts, and Xiaowen Liang</i></p> <p>12.1 Introduction 311</p> <p>12.2 The Types of Theranostic NPs 312</p> <p>12.2.1 Lipid- and Polymer-Based NPs 312</p> <p>12.2.2 Mesoporous Silica NPs 312</p> <p>12.2.3 Bio-nanocapsules 313</p> <p>12.2.4 Iron Oxide NPs 313</p> <p>12.3 Mechanisms of NPs Targeting the Liver 313</p> <p>12.3.1 Passive Targeting to the Liver 313</p> <p>12.3.2 Active Targeting to the Liver 314</p> <p>12.3.3 Strategies for Combining Passive and Active Targeting 315</p> <p>12.4 NPs in Liver Target Imaging 315</p> <p>12.4.1 NP-Based Contrast Agents in Liver MRI 315</p> <p>12.4.2 NP-Based Contrast Agents in Liver CT Imaging 316</p> <p>12.4.3 NPs for Near-Infrared Fluorescence Imaging in Liver 316</p> <p>12.5 NPs for Therapeutic and Drug Delivery in Liver Disease 316</p> <p>12.5.1 NP Delivery System in HCC 316</p> <p>12.5.2 NP Delivery System in Non-tumoral Liver Disease 318</p> <p>12.6 Theranostic NPs in Liver Diseases 318</p> <p>12.7 Conclusions 322</p> <p>References 323</p> <p><b>13 Toxicology and Safety of Nanoparticles in Drug Delivery System </b><b>329</b><i><br /> Klintean Wunnapuk</i></p> <p>13.1 Introduction 329</p> <p>13.2 Lipid-Based Nanocarrier: Liposomes 329</p> <p>13.3 Cellular Uptake Mechanism of Liposomes 330</p> <p>13.4 Biodistribution, Clearance and Toxicity of Liposomes 331</p> <p>13.4.1 Effect of Lipid Compositions on Liposome Distribution and Blood Circulation 331</p> <p>13.4.2 Effect of Surface Charge on Liposome Distribution and Blood Circulation 333</p> <p>13.4.3 Effect of Size on Liposome Distribution and Blood Circulation 333</p> <p>13.5 Application of Liposomes in Drug Delivery 334</p> <p>13.6 Inorganic Nanocarrier: Carbon Nanotubes 336</p> <p>13.7 Cellular Uptake Mechanism of Carbon Nanotubes 337</p> <p>13.8 Biodistribution, Clearance, and Toxicity of Carbon Nanotubes 337</p> <p>13.9 Application of Carbon Nanotubes in Drug Delivery 342</p> <p>13.10 Conclusion 342</p> <p>References 342</p> <p><b>Part III Administrative Routes for Controlled Drug Delivery </b><b>349</b></p> <p><b>14 Controlled Drug Delivery via the Ocular Route </b><b>351</b><i><br /> Peter W.J. Morrison and Vitaliy V. Khutoryanskiy</i></p> <p>14.1 Introduction 351</p> <p>14.2 Physiology of the Eye 352</p> <p>14.2.1 Ocular Membranes; Conjunctiva, Cornea, and Sclera 353</p> <p>14.2.2 Internal Ocular Structures 354</p> <p>14.2.3 Anterior Chamber, Lens, and Vitreous Body 355</p> <p>14.3 Ocular Disorders 355</p> <p>14.3.1 Periocular Disorders 355</p> <p>14.3.2 Intraocular Disorders 356</p> <p>14.4 Controlled Drug Delivery Systems 357</p> <p>14.4.1 Formulation Strategies 358</p> <p>14.4.2 Mucoadhesive Systems 358</p> <p>14.4.3 Solution to Gel <i>In Situ </i>Gelling Systems 359</p> <p>14.4.4 Penetration Enhancers 361</p> <p>14.4.5 Contact Lenses and Ocular Inserts 364</p> <p>14.4.6 Intraocular Systems (Implants, Injectables, and Degradable Microparticles) 366</p> <p>14.4.7 Phonophoresis and Ionophoresis 367</p> <p>14.4.8 Topical Prodrugs 368</p> <p>14.4.9 Microneedle Systems 368</p> <p>14.5 Conclusions 369</p> <p>References 370</p> <p><b>15 Controlled Drug Delivery via the Otic Route </b><b>377</b><br /> <i>Jinsong Hao and S. Kevin Li</i></p> <p>15.1 Introduction 377</p> <p>15.2 Anatomy and Physiology of the Otic Route 377</p> <p>15.2.1 Anatomy of the Otic Route 377</p> <p>15.2.2 Barriers Relevant to Inner Ear Drug Delivery 378</p> <p>15.3 Controlled Drug Delivery Systems 381</p> <p>15.3.1 Intratympanic Administration 381</p> <p>15.3.2 Trans-OvalWindow Administration 384</p> <p>15.3.3 Intracochlear Administration 385</p> <p>15.4 Conclusions 388</p> <p>References 388</p> <p><b>16 Controlled Drug Delivery via the Nasal Route </b><b>393</b><i><br /> Barbara R. Conway and Muhammad U. Ghori</i></p> <p>16.1 Introduction 393</p> <p>16.2 Anatomy and Physiology of the Nose 393</p> <p>16.3 Absorption from the Nasal Cavity 395</p> <p>16.3.1 The Epithelial Barrier 395</p> <p>16.3.2 Absorption 395</p> <p>16.4 Mucus and Mucociliary Clearance 398</p> <p>16.5 Drug Delivery Systems 399</p> <p>16.5.1 Solutions and Suspensions 400</p> <p>16.5.2 Mucoadhesive Polymers 401</p> <p>16.5.3 The Nasal Route and the Blood–Brain Barrier 415</p> <p>16.5.4 The Nasal Route for Vaccinations 419</p> <p>16.5.5 <i>In Vitro</i>/<i>in Vivo </i>Models for Nasal Absorption 421</p> <p>16.6 Conclusion 423</p> <p>References 423</p> <p><b>17 Controlled Drug Delivery via the Buccal and Sublingual Routes </b><b>433</b><i><br /> Javier O. Morales, Parameswara R. Vuddanda, and Sitaram Velaga</i></p> <p>17.1 Introduction 433</p> <p>17.2 Buccal and Sublingual Physiology and Barriers to Drug Delivery 434</p> <p>17.2.1 Saliva and Mucus 434</p> <p>17.2.2 Buccal and Sublingual Epithelium and Permeation Barrier 434</p> <p>17.3 Controlled Drug Delivery Systems 436</p> <p>17.3.1 Tablets 436</p> <p>17.3.2 Films 437</p> <p>17.3.3 Gels, Ointments, and Liquid Formulations 438</p> <p>17.3.4 Spray 438</p> <p>17.3.5 Wafers 439</p> <p>17.3.6 Lozenges 439</p> <p>17.3.7 Advanced and Novel Drug Delivery Systems 439</p> <p>17.4 Functional Excipients Used in Controlled Release Systems to Enhance Buccal and Sublingual Drug Bioavailability 440</p> <p>17.4.1 Permeation Enhancers 440</p> <p>17.4.2 Mucoadhesive Polymers 441</p> <p>17.5 Conclusions 442</p> <p>Acknowledgments 443</p> <p>References 443</p> <p><b>18 Controlled Drug Delivery via the Lung </b><b>449</b><i><br /> María V. Ramírez-Rigo, Nazareth E. Ceschan, and Hugh D. C. Smyth</i></p> <p>18.1 Introduction 449</p> <p>18.2 The Relevant Physiology of the Route Including the Barriers to Drug Delivery 449</p> <p>18.3 Controlled Drug Delivery Systems 451</p> <p>18.3.1 Formulations 451</p> <p>18.3.2 Devices 459</p> <p>18.4 Conclusions 464</p> <p>Acknowledgments 464</p> <p>References 464</p> <p><b>19 Controlled Drug Delivery via the Vaginal and Rectal Routes </b><b>471</b><i><br /> José das Neves and Bruno Sarmento</i></p> <p>19.1 Introduction 471</p> <p>19.2 Biological Features of the Vagina and Colorectum 472</p> <p>19.2.1 Vagina 472</p> <p>19.2.2 Colorectum 473</p> <p>19.3 Controlled Drug Delivery Systems 474</p> <p>19.3.1 Vaginal Route 476</p> <p>19.3.2 Rectal Route 489</p> <p>19.4 Conclusions 494</p> <p>Acknowledgments 494</p> <p>References 494</p> <p><b>20 Controlled Drug Delivery into and Through Skin </b><b>507</b><i><br /> Adrian Williams</i></p> <p>20.1 Introduction 507</p> <p>20.1.1 Human Skin Structure and Function 507</p> <p>20.1.2 Drug Transport Through Skin 512</p> <p>20.2 Controlled Drug Delivery into and Through Skin 513</p> <p>20.2.1 Skin Barrier Modulation 513</p> <p>20.2.2 Controlled Release Transdermal and Topical Systems 515</p> <p>20.2.2.5 Particles 520</p> <p>20.2.3 Device-Based Controlled Delivery 522</p> <p>20.3 Combination Approaches 528</p> <p>20.4 Conclusions 528</p> <p>References 529</p> <p>Index 535</p>

<p><b>Heather A.E. Benson, PhD</b> is an Associate Professor at the Curtin Medical School, Curtin University, Australia, where she leads the Skin Delivery Research Group.</p> <p><B>Michael S. Roberts, PhD</b> 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. <p><b>Adrian C. Williams, PhD</b> is Professor of Pharmaceutics and Research Dean at University of Reading, England, UK. <p><b>Xiaowen Liang, PhD</b> is the UQ Development Fellow at The University of Queensland, Australia.

<p><b>A comprehensive guide to the current research, major challenges, and future prospects of controlled drug delivery systems</B></p> <p>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. <i><b>Fundamentals of Drug Delivery</b></i> 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. <p>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: <ul><li>Covers each main stage of the drug development process, including selecting pharmaceutical candidates and evaluating their physicochemical characteristics</li> <li>Describes the role and application of mathematical modelling and the influence of drug transporters in pharmacokinetics and drug disposition</li> <li>Details the physiology and barriers to drug delivery for each administration route</li> <li>Presents a historical perspective and a look into the possible future of advanced drug delivery systems</li> <li>Explores nanotechnology and cell-mediated drug delivery, including applications for targeted delivery and toxicological and safety issues</li> <li>Includes comprehensive references and links to the primary literature</li></ul> <p>Edited by a team of of internationally-recognized experts, <i>Fundamentals of Drug Delivery</i> 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.

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