Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Contents......Page 5
Preface......Page 11
Acknowledgements......Page 14
Corresponding Authors......Page 15
1.1 INTRODUCTION......Page 18
1.2 THE CONCEPT OF BIOAVAILABILITY......Page 20
1.3.1 Epithelial interfaces......Page 22
1.3.2 Epithelial barriers to drug absorption......Page 23
1.3.3 Routes and mechanisms of drug absorption......Page 26
1.3.3.2 Transcellular route......Page 27
1.3.4 Physicochemical properties of the drug influencing drug absorption......Page 34
1.3.4.1 Lipid Solubility and Partition Coefficient......Page 35
1.3.4.2 Degree of ionization......Page 37
1.3.4.3 Molecular weight and molecular volume......Page 39
1.3.4.4 Solubility......Page 40
1.4 PHARMACOKINETIC PROCESSES......Page 43
1.4.1 Distribution......Page 44
1.4.2 Metabolism......Page 45
1.5.1 Zero-order controlled release......Page 46
1.5.2 Variable release......Page 47
1.6.1 Peptides and proteins......Page 49
1.6.2.1 Gene therapy......Page 54
1.6.2.2 Basic approach to gene therapy......Page 55
1.6.2.3 Vectors for gene therapy......Page 57
1.8 FURTHER READING......Page 58
1.9 SELF-ASSESSMENT QUESTIONS......Page 59
2.1 INTRODUCTION......Page 60
2.2.1 Convenience and compliance......Page 61
2.2.3 Protecting franchises......Page 62
2.2.5 Market expansion......Page 63
2.3 MARKET ANALYSIS......Page 64
2.3.2 Division of the market by region......Page 65
2.3.3 Analysis by therapeutic area......Page 66
2.3.4 Analysis by mode of administration......Page 68
2.4 INDUSTRY EVOLUTION AND STRUCTURE......Page 69
2.5 FURTHER READING......Page 70
2.6 SELF-ASSESSMENT QUESTIONS......Page 71
3 Advanced Drug Delivery and Targeting: An Introduction......Page 72
3.2 RATE-CONTROLLED RELEASE IN DRUG DELIVERY AND TARGETING......Page 73
3.2.1.1 Diffusion-controlled reservoir devices......Page 74
3.2.2 Dissolution-controlled release......Page 75
3.2.3 Osmosis-controlled drug release......Page 76
3.3 DRUG TARGETING SYSTEMS......Page 77
3.4.1 Types of dosage forms for drug delivery and targeting systems......Page 78
3.4.2 Properties of an “ideal” dosage form......Page 79
3.5.1 Properties of an “ideal” route of administration......Page 80
3.5.2 Overview of the routes of drug delivery......Page 83
3.6.1 Manipulation of the drug......Page 85
3.6.2.1 Penetration enhancers......Page 86
3.6.2.3 Enzyme inhibitors......Page 87
3.9 SELF-ASSESSMENT QUESTIONS......Page 88
4.1 INTRODUCTION......Page 90
4.2 ADVANTAGES AND DISADVANTAGES OF IMPLANTATION THERAPY......Page 91
4.2.1 Advantages......Page 92
4.3 BIOCOMPATIBILITY ISSUES......Page 93
4.4 NON-DEGRADABLE POLYMERIC IMPLANTS......Page 94
4.4.1.1 Solution diffusion......Page 95
4.4.1.2 Pore-diffusion......Page 98
4.4.1.3 Examples of non-degradable reservoir devices......Page 99
4.4.2 Matrix-type non-degradable polymeric implants......Page 100
4.4.2.1 Examples of matrix-type implants......Page 102
4.4.3 Reservoir/matrix hybrid-type polymeric implants......Page 103
4.5 BIODEGRADABLE POLYMERIC IMPLANTS......Page 104
4.5.1.1 Zoladex......Page 107
4.5.1.2 Lupron depot......Page 109
4.5.2 Polyanhydrides......Page 110
4.5.3.3 Poly(hydroxybutyrate)......Page 111
4.5.4 Natural biodegradable polymeric implants......Page 112
4.6.1 Osmotic implantable pumps......Page 113
4.6.1.1 Alzet miniosmotic pumps......Page 114
4.6.2 Mechanical implantable pumps......Page 116
4.6.2.3 Arrow implantable pump......Page 118
4.8 FURTHER READING......Page 119
4.9 SELF-ASSESSMENT QUESTIONS......Page 120
5.1 INTRODUCTION......Page 122
5.1.1 Rationale for the development of parenteral drug delivery and targeting systems......Page 123
5.1.2 Generalized description of parenteral drug delivery and targeting systems (DDTS)......Page 124
5.1.3 Anatomical, physiological and pathological considerations......Page 126
5.1.4.1 Passive targeting......Page 128
5.1.4.2 Active targeting......Page 129
5.2.1 Monoclonal antibodies......Page 131
5.2.1.1 Immunotoxins......Page 132
5.2.2 Soluble polymeric carriers......Page 133
5.2.2.1 HPMA derivatives......Page 134
5.3 PARTICIPATE CARRIERS FOR DRUG TARGETING......Page 135
5.3.1 Liposomes......Page 136
5.3.1.3 Immunoliposomes......Page 138
5.3.2 Polymeric micelles......Page 139
5.3.3 Poly(alkyl cyanoacrylate) nanoparticles......Page 140
5.3.5 Other participate carrier systems......Page 142
5.4 PHARMACEUTICAL ASPECTS OF CARRIER SYSTEMS......Page 143
5.5 CONCLUSIONS AND PROSPECTS......Page 145
5.7 SELF-ASSESSMENT QUESTIONS......Page 146
6.1 INTRODUCTION......Page 148
6.2.1 Structure of the GI tract......Page 149
6.2.2 Epithelium of the GI tract......Page 151
6.3 PHYSIOLOGICAL FACTORS AFFECTING ORAL BIOAVAILABILITY......Page 154
6.3.2 pH......Page 155
6.3.4 P-glycoprotein drug efflux pump......Page 156
6.3.6 Mucus......Page 157
6.3.7 Individual variations......Page 158
6.3.9 Transport routes and mechanisms......Page 159
6.3.9.2 The transcellular route......Page 160
6.4.1.1 Drug pKa......Page 161
6.4.1.3 Drug solubility......Page 162
6.4.2 Formulation factors affecting oral bioavailability......Page 163
6.4.2.1 Particle size......Page 164
6.4.2.2 Formulation additives......Page 165
6.5.1 Advantages......Page 167
6.5.2 Disadvantages......Page 168
6.6.1 Conventional dosage forms: tablets, capsules, suspensions, emulsions and solutions......Page 169
6.6.3 Matrix and reservoir systems......Page 170
6.6.4 Prodrugs......Page 172
6.7.1 Improvements in retention: mucoadhesives......Page 173
6.7.3 Exploiting natural transport mechanisms......Page 174
6.7.4 Penetration enhancers......Page 175
6.7.5.1 Osmotic pump......Page 176
6.7.6 Targeted drug delivery to the colon......Page 178
6.7.7 Drug targeting to the Peyer’s patches......Page 180
6.9 FURTHER READING......Page 182
6.10 SELF-ASSESSMENT QUESTIONS......Page 184
7.1 INTRODUCTION......Page 185
7.2.1 The oral epithelium......Page 186
7.2.3 The salivary glands......Page 188
7.3.4 Metabolic activity......Page 189
7.3.7 Species differences......Page 190
7.3.8.2 The transcellular route......Page 191
7.4.2 Factors associated with the dosage form......Page 192
7.5.1 Advantages......Page 193
7.5.2 Disadvantages......Page 194
7.6.1.1 Sublingual nitroglycerin......Page 195
7.6.2.2 Buccal nitroglycerin......Page 196
7.6.2.3 Other dosage forms for buccal delivery......Page 197
7.7.2.1 Patch type......Page 198
7.7.2.4 Patch hydmtion......Page 200
7.7.2.6 Patient acceptability and compliance......Page 201
7.7.3.1 Melatonin delivery......Page 202
7.9 FURTHER READING......Page 204
7.10 SELF-ASSESSMENT QUESTIONS......Page 205
8.1 INTRODUCTION......Page 206
8.2.1 Epidermis: structure and differentiation......Page 207
8.2.2 Stratum corneum: structure and barrier function......Page 208
8.3.1.1 Stratum corneum......Page 209
8.3.1.4 Age......Page 210
8.3.2.1 Physical chemistry of transport......Page 211
8.4.1 Advantages......Page 214
8.5.1 Conventional dosage forms......Page 215
8.5.2.1 Transdermal patch design, composition and manufacture......Page 216
8.5.2.2 Rate-control in transdermal delivery......Page 218
8.5.3 The need for penetration enhancement......Page 225
8.6.1 Chemical penetration enhancers......Page 226
8.6.2 Iontophoresis......Page 227
8.6.4.1 Colloidal systems......Page 229
8.7 CONCLUSIONS......Page 230
8.9 SELF-ASSESSMENT QUESTIONS......Page 231
9.1 INTRODUCTION......Page 232
9.2.1 Physiological structure......Page 233
9.2.3 Modification of inspired air......Page 234
9.2.4 Mucociliary clearance......Page 235
9.2.4.2 Mucus......Page 236
9.2.5 Cilia......Page 240
9.3.1 Area......Page 241
9.3.3 Contact time and mucociliary clearance......Page 243
9.3.4 Disease......Page 244
9.3.7 Mucus barrier......Page 245
9.3.8.1 The paracellular route......Page 246
9.4.1 Physicochemical factors associated with the drug......Page 247
9.4.3 Factors associated with the dosage form......Page 248
9.4.4 Other formulation factors......Page 249
9.5.1 Advantages......Page 250
9.5.2 Disadvantages......Page 251
9.6.2 Nasal drops......Page 252
9.7 NEW TECHNOLOGIES IN NASAL DELIVERY......Page 253
9.7.1 Increasing the permeability of the nasal epithelium......Page 255
9.7.2.2 Use of bioadhesives......Page 257
9.7.2.3 Reducing rate of mucociliary clearance......Page 258
9.7.4 Miscellaneous methods of absorption enhancement......Page 259
9.10 SELF-ASSESSMENT QUESTIONS......Page 260
10.1 INTRODUCTION......Page 261
10.2.1 Lung regions......Page 262
10.2.2 Architecture of the airways......Page 263
10.2.4 Ciliated cells......Page 264
10.2.5 Mucus......Page 266
10.3.1 Mechanisms of particle deposition in the airways......Page 267
10.3.2.1 Lung morphology......Page 269
10.3.2.6 Breath holding......Page 270
10.3.3.2 Size......Page 271
10.3.4.1 Mucus barrier......Page 272
10.3.4.2 Mucociliary clearance......Page 273
10.3.5.1 Area......Page 274
10.3.5.4 The importance of regional differences......Page 275
10.3.5.7 Transport routes......Page 276
10.4 ADVANTAGES AND DISADVANTAGES OF PULMONARY DRUG DELIVERY......Page 277
10.4.2 Systemically acting drugs......Page 278
10.5.1 Nebulizers......Page 279
10.5.1.1 Air-jet nebulizers......Page 280
10.5.1.3 Improvements in nebulizer design......Page 281
10.5.2 Pressurized metered-dose inhalers (pMDIs)......Page 282
10.5.3.1 Powder technology......Page 285
10.5.3.2 Device design......Page 286
10.6.2 Delivery of the “new biotherapeutics”......Page 287
10.6.3 Novel drug delivery systems......Page 288
10.8 FURTHER READING......Page 289
11 Vaginal Drug Delivery......Page 290
11.1 INTRODUCTION......Page 291
11.2.1 The vaginal epithelium......Page 292
11.3.1 Cyclical changes in the vaginal epithelium......Page 293
11.3.3 Vaginal pH......Page 295
11.3.5 Transport routes and mechanisms and the effect of cyclical changes on vaginal absorption mechanisms......Page 296
11.4.2 Factors associated with the dosage form......Page 299
11.5.1 Advantages......Page 300
11.5.2 Disadvantages......Page 302
11.6.1 Vaginal delivery of estrogens and progesterones......Page 303
11.6.2 Vaginal delivery of prostaglandins......Page 305
11.7.1 Therapeutic peptide delivery......Page 306
11.7.2 Penetration enhancers......Page 307
11.7.3 Antiviral vaginal delivery......Page 308
11.7.4 Vaginal mucosal vaccines......Page 309
11.7.5 Microparticulate systems......Page 311
11.7.6 Bioadhesives......Page 312
11.8 CONCLUSIONS......Page 313
12 Ophthalmic Drug Delivery......Page 314
12.1 INTRODUCTION......Page 315
12.2.1 The cornea......Page 317
12.3.1.1 Nasolacrimal drainage......Page 319
12.3.1.3 Surface tension......Page 320
12.3.2.1 Corneal route......Page 321
12.3.2.2 Noncorneal route......Page 322
12.3.3.3 Formulation factors affecting ocular bioavailability on topical application......Page 323
12.3.3.4 Formulation approaches to improve precorneal retention......Page 325
12.4.1 Intravitreal delivery......Page 330
12.4.1.1 Liposomes......Page 331
12.4.1.2 Microparticulates and nanoparticles......Page 332
12.4.2 Intraocular devices......Page 333
12.4.3 Iontophoresis......Page 334
12.6 FURTHER READING......Page 335
13 Drug Delivery to the Central Nervous System......Page 336
13.2 STRUCTURE AND FUNCTION OF THE BLOOD-BRAIN BARRIER......Page 337
13.3.1 Passive diffusion......Page 339
13.3.2.1 Carrier-mediated transport......Page 340
13.4.1.1 Lipid solubility and molecular weight......Page 341
13.4.1.1 p-Glycoprotein......Page 342
13.4.2 Physicochemical factors affecting other transport mechanisms......Page 343
13.5.1.1 Intracerebroventricular drug infusion......Page 344
13.5.2.1 Drug delivery systems......Page 345
13.5.3.1 Exploitation of carrier-mediated transport systems......Page 346
13.5.3.2 Exploitation of receptor-mediated transcytosis systems......Page 347
13.6.2 Antisense drug delivery to the brain......Page 348
13.7 CONCLUSIONS......Page 349
14 Plasmid-based Gene Therapy......Page 350
14.1 INTRODUCTION......Page 351
14.2.1 Promoter......Page 354
14.2.3 3'-UTR......Page 355
14.3.1 Lipid-based gene delivery......Page 356
14.3.1.4 Cationic liposomes......Page 357
14.3.2 Peptide-based gene delivery......Page 358
14.3.3.1 Polyvinyl pyrrolidone (PVP)-based formulations......Page 360
14.3.3.2 Cationic polymers......Page 361
14.4 BIODISTRIBUTION AND PHARMACOKINETICS......Page 362
14.4.1 Cellular uptake and intracellular trafficking......Page 365
14.5.1 Systemic gene therapy......Page 368
14.5.2 Cancer gene therapy......Page 369
14.5.4 Genetic vaccines......Page 371
14.6 CONCLUSION......Page 372
15 Integrating Drug Discovery and Delivery......Page 373
15.1 INTRODUCTION......Page 374
15.2.1 Peptide synthesis......Page 375
15.2.2 Split and mix combinatorial synthesis......Page 376
15.2.3 Indexed libraries......Page 377
15.3 HIGH-THROUGHPUT SCREENING......Page 379
15.4.1.1 Obtaining the gene sequences......Page 380
15.4.1.2 Determining exact gene expression levels......Page 382
15.4.1.3 Assembling protein signaling networks......Page 383
15.5 PROTEOMICS......Page 386
15.6 PHARMACOGENOMICS AND PHARMACOPROTEOMICS......Page 387
15.7 EXPLOITING PROTEOMICS AND GENOMICS IN DRUG TARGETING......Page 389
15.8 BIOINFORMATICS......Page 390
15.10 FURTHER READING......Page 391
16 New Generation Technologies......Page 392
16.2.1 Prodrugs......Page 393
16.2.2 Site-specific enzyme-based delivery systems......Page 394
16.2.4 Antibody-directed enzyme prodrug therapy (ADEPT)......Page 396
16.2.5 Gene-directed enzyme prodrug therapy (GDEPT)......Page 397
16.3 THE CHALLENGE OF CHRONOPHARMACOLOGY......Page 398
16.3.1 Biosensors......Page 399
16.3.2 Stimuli-sensitive intelligent hydrogels......Page 400
16.3.2.1 Temperature-sensitive gels......Page 401
16.3.2.2 pH-sensitive gels......Page 402
16.3.3 Bioresponsive drug delivery systems......Page 403
16.3.3.2 Erodible matrix system......Page 404
16.3.3.3 pH-sensitive membrane system......Page 406
16.3.3.4 Immobilized insulin system......Page 407
16.3.5 Genetically-engineered cell implants......Page 409
16.5 FURTHER READING......Page 411
16.6 SELF-ASSESSMENT QUESTIONS......Page 412
Appendix......Page 413
Index......Page 414