Drug Delivery (eBook)

Preface 5
Contents 8
Part I Fundamentals 14
Passive and Active Drug Targeting: Drug Delivery to Tumors as an Example 15
Drug Targeting: General Considerations 16
Concepts of Passive and Active Targeting 18
Pharmaceutical Carriers: Liposomes and Micelles as Examples 22
Chemistry Used to Provide Pharmaceutical Nanocarriers with Various Functions 27
Longevity of Nanocarriers in the Blood and its Importance for Drug Delivery 29
Passive Accumulation of Liposomes and Micelles in Tumors 33
Active Tumor Targeting with Drug-Loaded Liposomes 38
Active Tumor Targeting with Drug-Loaded Micelles 45
Conclusion 47
References 48
Nanoparticle Technologies for Cancer Therapy 66
Introduction 67
Nanoparticle Technologies 70
Liposome Nanoparticles 72
Polymer-Drug Conjugates Nanoparticles 73
Polymeric Nanoparticles 74
Micelle Nanoparticles 75
Dendrimer Nanoparticles 76
Polymersome Nanoparticles 77
Protein Nanoparticles 77
Biological Nanoparticles 78
Inorganic Nanoparticles 78
Hybrid Nanoparticles 80
Strategies for Cancer Therapy Using Nanoparticles 81
Metastatic Cancer 81
Non-Targeted Nanoparticles 82
Targeted Nanoparticles 85
Summary 87
References 88
Biosensing and Drug Delivery at the Microscale 98
Progress and Challenges in Controlled Drug Delivery 99
Polymer Actuator for Controlled Drug Delivery 101
Complex Drug Releasing Systems for Synchronous Drug Delivery 103
A Novel Nanoscale Valve Responding to pH Changes May Allow a Targeted Drug Release 104
pH-Responsive Supramolecular Nano-valves 105
Electronically Controlled ``Smart´´ Pill 106
Novel Micro- and Nano-Mechanical Drug Delivery Implants 108
Highlights in Micro-Machined Biosensing Drug Delivery Devices 111
Novel Technological Challenges in Drug Delivery - Nano-Micro-Implants 114
Novel Aspects of Electronically Controlled Drug Delivery Systems 116
Biosensing of Drug Delivery in In Vitro Tissue Models 118
Biosensing of Drug Delivery In Vivo - Microelectrodes in Endoluminal Sensors 119
References 121
Part II Devices 124
Lipid Nanoparticles: Effect on Bioavailability and Pharmacokinetic Changes 125
Introduction 127
Definition of Lipid Nanoparticles (SLN vs. NLC) 128
Solid Lipid Nanoparticles (SLN) 131
Nanostructured Lipid Carriers (NLC) 132
Effects of Lipid Polymorphism on API Bioavailability 133
Lipid Nanoparticles Applications 135
Oral Delivery 135
Pulmonary Delivery 138
Parenteral Delivery and Drug Distribution 140
Brain Targeting 141
Conclusions and Perspectives 144
References 144
Viral Vectors for Gene Transfer: Current Status of Gene Therapeutics 152
Gene Therapy: Definition and State of the Art 154
AAV Vectors for Gene Therapy 156
Overview of Properties 156
AAV Structure 157
AAV Life Cycle 157
Cell Receptors Used by AAV 158
AAV Vector Production 158
AAV Vector Production by Cotransfection of Packaging Plasmids 158
Upscaling of AAV Vector Production 159
AAV Vector Purification 161
Quantification of AAV Vector Yields 162
AAV Vector Persistence and Safety 163
AAV Split Vectors 164
Dimeric, Self-Complementary (sc) AAV Vectors 164
Cell Targeting Strategies for AAV 165
Future Directions 166
Retrovirus Vectors for Gene Therapy 166
Retrovirus Structure and Life Cycle 167
Design and Development of Oncoretroviral Vectors 167
Self-Inactivating (SIN) Oncoretroviral Vectors 168
Design and Development of Lentiviral Vectors 170
Safety of Retrovirus Integration 171
Production and Stability of Retroviral Vectors 172
Purification and Upscaling of Retroviral Vectors 173
Vector Quantitation and Quality Assessment 174
Future Directions of Retroviral Vector Development 175
Outlook 176
References 177
Pulmonary Drug Delivery: Medicines for Inhalation 180
Introduction 182
Principles of Aerosol Delivery 183
Inhalation Therapy 183
Lung Structure 184
Aerosol Deposition 185
Lung Clearance 186
Pulmonary Drug Delivery Approaches 188
Asthma/COPD 188
Immunosuppressives 189
Vaccines 190
Anti-Infectives 191
Pulmonary Gene Therapy 192
Lung Cancer Therapy 194
Future Prospects 195
References 196
Needle-Free Vaccine Injection 202
Introduction 203
Targeting Skin and Mucosal Cells: The Immunological Rationale 204
Engineering of Physical Approaches for the Targeting of Skin and Mucosal Cells 206
Mechanical Properties of the SC Barrier 207
Biological Approaches 207
Physical Cell Targeting Approaches 208
Biolistic Microparticle Delivery 210
Biolistics Operating Principle 210
Engineering of Hand-Held Biolistic Devices for Clinical Use 211
Ballistics Microparticle Delivery to Skin 216
Theoretical Model for Ballistic Impact into Skin 216
Locations of Microparticles into Skin 217
Skin Cell Death from Ballistic Impact 220
Clinical Results and Commercial Application 221
Conclusion 224
References 224
Pharmaceutically Used Polymers: Principles, Structures, and Applications of Pharmaceutical Delivery Systems 229
Introduction 230
Pharmaceutically Used Polymers and Biomaterials 232
Classification of Pharmaceutically Used Polymersand Biomaterials - An Overview 233
Orally Applied Polymers: Properties and Applications 234
Starch 234
Hydroxylpropyl Methylcellulose 239
Eudragit 240
Carbopol Polymers 241
Pluronic Block Copolymers 241
Alginates 242
Systemically Applied Polymers 243
Poly(lactide-co-glycolide) and Related Polymers 244
PEG Polymers 244
Dextran 245
HPMA Copolymers 245
Poly(anhydrides) 246
Current Developments: Dendritic Polymers 247
Specific Aspects of Polymers in Oral Drug Delivery 249
Modified Release Dosage Forms 250
Gastro-enteric Coatings 251
Matrix Systems 251
Reservoir Systems 252
Osmotic Pump Systems 253
References 255
Mucoadhesive Drug Delivery Systems 259
Introduction 260
Mucoadhesion 260
Mucus 260
Mucoadhesion Theories and Binding Types 261
Chemical Bonds 261
Theories of Adhesion 261
Mucoadhesion Tests 262
Visual Tests 262
Tensile Tests 264
Rheological Tests 264
In Vivo Methods 264
Factors Influencing Mucoadhesion 265
Polymeric Factors 265
Environmental Factors 265
Mucus Physiology 266
Mucoadhesive Polymers and Derivatives 266
Anionic Polymers 266
Cationic Polymers 266
Non-Ionic Polymers 268
Amphiphilic Polymers 268
Polymer Derivatives 268
Drug Delivery Systems 269
Nasal 269
Buccal 269
Vaginal 270
Ocular 270
Oral 271
Conclusion 272
References 273
Intrauterine Drug Delivery for Contraception and Gynaecological Treatment: Novel Approaches 275
Introduction 276
Frameless Intrauterine Devices and Systems 278
Development of Frameless Intrauterine Devices and Systems 278
Frameless Copper-Releasing Intrauterine Devices 280
Description 280
Efficacy 281
Safety and Side Effects 281
Insertion, Expulsion and Removal 283
Perforation 283
Special Uses of the Frameless Copper IUD 284
Lifespan 285
The Frameless Levonorgestrel Intrauterine System (LNG-IUS) 285
Description 285
Clinical Performance of the Frameless LNG-IUS 286
Acceptability and Endometrial Safety of the Frameless LNG-IUS in Women Using Estrogen Replacement Therapy (ERT) 287
Effect on Menstrual Blood Loss 287
Contraceptive Efficacy 288
The Effect of the Frameless LNG-IUS in Women Suffering from Primary or Secondary Dysmenorrhea 288
Framed Levonorgestrel-Releasing Intrauterine Systems 289
Development 289
The Framed Standard Levonorgestrel-Releasing Intrauterine System 290
Description 290
Clinical Performance of the Framed Standard LNG-IUS 291
Ease and Safety of Insertion and Contraceptive Performance 291
Retention 291
Effect on Menstrual Blood Loss 292
Long-Term Treatment of Non-Atypical and Atypical Endometrial Hyperplasia 293
The Framed Slim Levonorgestrel-Releasing Intrauterine System 294
Clinical Performance of the Framed Slim LNG-IUS 294
Acceptability and Long-Term Endometrial Safety of the Femilis Slim LNG-IUS in Postmenopausal Women Using Estrogen Replace 294
Concluding Remarks 295
Long-Acting Contraceptive Methods Should Be Used to Prevent Unintended Pregnancies 295
Long-Term Intrauterine Contraceptive Methods to Replace Irreversible Female Sterilization 296
Safer Contraception 296
Pain Control with Intracervical Anesthesia for IUD/IUS Insertion 297
Intrauterine Hormonal, Period-Free, Contraception for All Women 297
Intrauterine Hormonal Contraception Can Prevent the Need for Hysterectomy 298
Reducing The Risk of Postmenopausal Heart Disease, Stroke, Dementia and Alzheimer disease 299
The Future 300
References 301
Drug-Eluting Medical Implants 307
Drug-Eluting Vascular Stents 308
Introduction: Restenosis and Drug-Eluting Stents 308
The First Generation of Drug-Eluting Stents (DES-I) 309
Agents 310
Drug Release Mechanisms 311
Real World 313
The Second Generation of Drug-Eluting Stents (DES-II) 316
Platforms 316
New Agents 316
New Drug-Release Mechanisms 317
Biodegradable Stents 319
Novel Drug-Eluting Highly Porous Stent Coatings 324
Drug-Eluting Wound Dressings 326
Introduction: Infection, Wound Dressings and Local Antibiotic Release 326
Wound Dressings Based on Synthetic Polymers 328
Wound Dressings Based on Natural Polymers 329
Composite Fiber Structures Loaded with Antibacterial Drugs for Wound Healing Applications 331
Protein-Eluting Scaffolds for Tissue Regeneration 338
References 340
Part III Clinical and Preclinical Applicationof Therapeutics for Systemic Use 350
Improving Oral Delivery 351
Introduction 352
Physicochemical Considerations 354
Physiological Conditions in the GI Tract 355
Oral Cavity and Oesophagus 357
Stomach 357
Small Intestine 359
Large Intestine 361
Formulation Parameters to Improve Oral Delivery 363
Size 363
Effects of Nanosizing 363
Techniques for the Nanosizing of Drug Particles 365
Bottom-Up Processes 366
Top-Down Processes 367
Wet-Milling 367
High Pressure Homogenisation 368
Piston-Gap Homogenisers 368
Microfluidisation 369
Absorption of Nanoparticles 369
pH-Dependent Drug Delivery 371
pH-Sensitive Coatings 372
pH and Colon Targeting 373
pH-Responsive Hydrogels 374
Swelling 375
Osmotic Pressure 378
Density 380
Enzyme-Mediated Release in the Colon 383
Prodrugs 384
Polymeric Coatings and Matrices 384
Biorecognition 386
Targeting to Enterocytes 387
Targeting to M Cells 387
Miscellaneous 390
Absorption Enhancers 390
General Considerations 390
Strategies of Absorption Enhancement 391
Solubilising Excipients 392
The Transcellular Route 393
The Paracellular Route 393
Secretory Transport Inhibitors 394
Outlook 394
Future Perspectives 395
References 395
Transdermal Drug Delivery 405
Introduction 406
The Present State of Transdermal Drug Delivery 407
Barrier Function of Skin 407
Transdermally Delivered Drugs 407
Enhancement of Transdermal Drug Delivery 409
Local and ``Subcutaneous´´ Drug Delivery 414
Conclusions 414
References 415
Targeting the Brain - Surmounting or Bypassing the Blood-Brain Barrier 417
Introduction 418
Structure and Function of the Blood-Brain Barrier 418
The Blood-Brain Barrier as a Limiting Factor in the Treatment of CNS Diseases 420
Modulation of Blood-Brain Barrier Function 422
Opening of the BBB 423
Inhibition of Efflux Transport 424
Prevention of Disease-Associated or Therapy-Induced Changes of the Blood-Brain Barrier 426
Bypassing the Blood-Brain Barrier 429
Nano-Sized Carrier Systems and Drug Conjugates 429
Intranasal Administration 430
Intracerebral Administration 430
Conclusions 432
References 432
Carriers in the Topical Treatment of Skin Disease 439
Introduction 441
(Per-)Cutaneous Absorption 441
Skin Morphology and Barrier Function 441
Skin Penetration Pathways 443
Assessment of (Per-)Cutaneous Absorption 444
Enhancement of (Per-)Cutaneous Absorption 445
Drug Carriers - Technological Aspects 446
Liposomes 447
Niosomes 449
Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 449
Micro- and Nanoemulsions 450
Polymer Particles Including Dendrimers 450
Miscellaneous Nanoparticles 451
Current Therapy in the Main Target Indications for API-Loaded Nanoparticulate Delivery Systems 452
Clinical and Preclinical Data of Carrier-Loaded API 453
Liposomes and Niosomes 453
Lipid Nanoparticles 457
Microparticles 461
Microemulsions 462
Polymer Particles Including Microparticles and Dendrimers 464
Miscellaneous Approaches 465
Conclusion 465
References 465
Medical Devices for the Treatment of Eye Diseases 473
Introduction 474
Targeted Vitreoretinal Diseases 477
Cytomegalovirus (CMV) Retinitis 478
Noninfectious Uveitis 479
Macular Edema 479
Retinitis Pigmentosa 480
Age-Related Macular Degeneration (AMD) 481
Proliferative Vitreoretinopathy (PVR) 482
Nonbiodegradable Devices 483
Vitrasert: Nonbiodegradable Implant with Ganciclovir 483
Retisert: Nonbiodegradable Implant with Fluocinolone Acetonide 485
I-vationTM: Nonbiodegradable Implant with Triamcinolone Acetonide 486
Medidur: Nonbiodegradable Insert with Fluocinolone Acetonide 486
Biodegradable Devices 487
Posurdex: Biodegradable Insert with Dexamethasone 487
Injectable Microspheres 488
Triamcinolone Acetonide Crystal Suspensions 488
NT-501: Encapsulated Cell Technology (ECT) 489
Conclusion 489
References 490
Index 494