Controlled Drug Delivery: Fundamentals and Applications, Second Edition

Contents......Page 14
Preface to the Second Edition......Page 8
Preface to the First Edition......Page 11
Contributors......Page 20
PART I: FUNDAMENTALS OF CONTROLLED RELEASE DRUG DELIVERY......Page 24
1. Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems......Page 25
I . Introduction......Page 26
II. Terminology......Page 27
III. Rationale of Sustained/Controlled Drug Delivery......Page 29
IV. Factors Influencing the Design and Performance of Sustained/Controlled Release Products......Page 31
V. Physicochemical Properties of a Drug Influencing Design and Performance......Page 34
A. Aqueous Solubility......Page 35
C. Drug Stability......Page 36
VI. Biological Factors Influencing Design and Performance of Sustained/Controlled Release Products......Page 37
A. Absorption......Page 38
B . Distribution......Page 40
C. Metabolism......Page 45
D . Duration of Action......Page 48
E. Side Effects......Page 52
F. Margin of Safety......Page 53
G. Role of Disease State......Page 55
H. Role of Circadian Rhythm......Page 57
VII. Selected Routes of Drug Administration......Page 58
A. Parenteral......Page 59
B. Oral......Page 62
C. Buccal/Sublingual......Page 64
D. Rectal......Page 65
E. Nasal......Page 66
F. Pulmonary......Page 67
G. Vaginal......Page 71
H. Intrauterine......Page 73
I. Transdermal......Page 75
J. Ocular......Page 77
VIII. Drug Targeting......Page 78
IX. Conclusions......Page 81
References......Page 83
2. Theory of Mass Transfer......Page 117
II. Random Walk Interpretation of Diffusion......Page 118
A. Free Energy Interpretation of Diffusion......Page 119
B. Diffusion as an Effective Transport Mechanism over Small Distances......Page 123
C. The Size of a Molecule and Its Ability to Diffuse......Page 126
D. Solute Binding and Its Effect on Diffusion......Page 130
E. The Variable Diffusion Coefficient and the Concept of a Mean Diffusion Coefficient......Page 131
F. Fick's Second Law in Three Dimensions and Its Coordinate Transformation......Page 133
IV. Passive Diffusion Through a Membrane—The Partition Coefficient......Page 135
V. Passive Diffusion Through a Membrane—The Stagnant Diffusion Layer......Page 141
VI. Application of Fick 's Second Law to the Determination of the Non-Steady-State Output Flux Through the Skin......Page 149
VII. Application of Fick 's First Law to theDetermination of Drug Release from a Polymeric Matrix or Ointment......Page 152
IX. Additional Concerns in Diffusional Mass Transport......Page 157
References......Page 158
3. Fundamentals of Polymer Science......Page 161
I . Introduction......Page 162
II. Polymer Classification and Polymerization Mechanisms......Page 163
A. Chain Polymerizations......Page 165
B. Step-Growth Polymerizations......Page 173
A. Polymerization Methods for Chain Polymerizations......Page 174
A. Molding......Page 178
C. Preparation of Films......Page 181
D. Use of Additives......Page 185
A. Molecular Weight and Molecular Weight Distribution......Page 186
B . Polymer Hydrophobicity......Page 188
C. Glass Transition Temperature......Page 189
D. Crystallinity......Page 190
A. Molecular Weight......Page 191
B. Thermal Analysis......Page 194
C. Mechanical Properties......Page 196
4. Use of Polymers in Controlled Release of Active Agents......Page 200
A. Monolithic Devices......Page 201
B. Reservoir Devices......Page 202
C. Examples of Diffusional Devices......Page 205
A. Osmotically Controlled Devices......Page 208
B. Examples of Osmotic Devices......Page 209
C. Swelling-Controlled Devices......Page 211
III. Chemically Controlled Devices......Page 212
A. Polymer Erosion Mechanisms......Page 213
B . Drug Release Mechanisms......Page 214
References......Page 231
I . Introduction......Page 234
A. Pharmacokinetics......Page 240
B. Pharmacodynamics......Page 253
III. Summary......Page 261
References......Page 262
6. Dosing Considerations and Bioavailability Assessment of Controlled Drug Delivery Systems......Page 273
I. Introduction......Page 274
II. Advantages of Controlled Release Dosage Forms......Page 275
III. Disadvantages of Controlled Release Dosage Forms......Page 277
IV. Compounds That Are Unsuitable for Controlled Release......Page 279
V. In Vitro Considerations......Page 282
VI. In Vivo Considerations......Page 283
A. First-Order Release......Page 285
B. Zero-Order Release......Page 288
C. Zero-Order Release with a Fast Release Component......Page 293
D. First-Order Release with a Fast Release Component......Page 297
VII. Bioavailability Testing......Page 304
VIII. Conclusions......Page 308
References......Page 309
7. Regulatory Assessment......Page 312
II. Terminology......Page 313
III. Rationale for Controlled Release Dosage Forms......Page 315
IV. Potential Pharmacodynamic Problems with Continuous Release Products......Page 317
V. Ideal Input Function......Page 318
B. Decreased Systemic Availability due to Incomplete Absorption......Page 323
D. Dose Dumping......Page 324
F. Effect of Diurnal Variation......Page 325
G. Increased Variability......Page 326
VII. Dissolution Rate--Assessment......Page 328
VIII. Biopharmaceutic Considerations in the Regulatory Assessment of Controlled Release Products......Page 340
A. Demonstration of Safety and Efficacy of Controlled Release Drugs......Page 341
B. Submitted Data......Page 342
C. Recommended Reference Standard for Comparative Studies......Page 343
D. Demonstration of a Product's Controlled Release Nature......Page 344
E. Consideration for Specialized Controlled Release Drug Delivery Systems......Page 347
References......Page 351
PART II: DESIGN AND FABRICATION OF TECHNOLOGY BASED CONTROLLED RELEASE DRUG DELIVERY SYSTEMS......Page 354
I . Introduction......Page 355
II. Prodrugs......Page 357
III. Classical Prodrugs as Chemical Delivery Systems......Page 358
IV. Sustained Chemical Delivery Systems......Page 360
V. Sustained Delivery of Natural Soft Drugs......Page 361
VI. Brain-Specific Sustained Chemical Delivery Systems......Page 375
VII. Conclusions......Page 386
References......Page 387
I. Introduction......Page 390
II. Design and Fabrication of Oral Systems......Page 392
A. Dissolution Controlled Release......Page 393
B . Diffusion Controlled Release......Page 408
C . Diffusion and Dissolution Controlled Release......Page 422
D. Ion-Exchange Resins......Page 429
E. pH-Independent Formulations......Page 430
F. Osmotically Controlled Release......Page 431
G. Altered Density Formulations......Page 435
III. Summary......Page 437
References......Page 438
10. Parenteral Products......Page 450
I. Introduction......Page 451
A. Subcutaneous......Page 452
D. Intraperitoneal......Page 453
III. Biopharmaceutics of Sustained/Controlled Release Parenteral Drug Products......Page 454
IV. Biocompatibility of Polymeric Materials......Page 457
V. Sustained/Controlled Release Parenteral Dosage Forms......Page 459
A. Aqueous Solutions......Page 460
B. Aqueous Suspensions......Page 462
C. Oil Solutions......Page 469
E. Emulsions......Page 472
F. Biocompatible Carriers......Page 476
G. Liposomes......Page 477
I. Implants......Page 479
K. Prodrugs......Page 480
VI. Summary......Page 481
References......Page 482
11. Implantable Therapeutic Systems......Page 498
II. Historical Development......Page 499
III. Approaches to Development of Implantable Therapeutic Systems......Page 501
A. Controlled Drug Release by Diffusion......Page 502
B . Controlled Drug Release by Activation......Page 515
IV. Benefits of Controlled Drug Administration Via Implantation......Page 526
A. The Environment of Living Tissues......Page 529
B . Reactions of Host to Implant......Page 530
C. Reactions of Implant to Host......Page 532
References......Page 533
12. Transdermal Therapeutic Systems......Page 540
II. Skin as a Site for Drug Infusion......Page 541
III. Fundamentals of Skin Permeation......Page 545
A. Membrane-Moderated Systems......Page 549
B. Adhesive Diffusion-Controlled Systems......Page 551
C. Matrix Dispersion-Type Systems......Page 552
D. Microreservoir Systems......Page 553
A. In Vitro Drug Release Kinetics......Page 555
B. In Vitro Skin Permeation Kinetics—Animal Model......Page 557
C. In Vitro Skin Permeation Kinetics—Human Cadaver......Page 559
D. In Vivo Transdermal Bioavailability in Humans......Page 560
E. In Vitro-In Vivo Correlations......Page 562
VI. Formulation Design and Optimization......Page 564
References......Page 566
PART III: BIOCHEMICAL AND MOLECULAR BIOLOGY APPROACHES TO CONTROLLED DRUG DELIVERY......Page 570
13. Microparticulate Drug Carriers: Liposomes, Microspheres, and Cells......Page 571
I. Introduction......Page 572
A. Liposomes......Page 573
B. Microspheres......Page 574
C. Cells......Page 575
III. In Vivo Barriers to Microparticulate Distribution......Page 577
A. The Endothelial Barrier......Page 578
B. The Reticuloendothelial RE System Barrier......Page 579
C. Cellular Barriers......Page 580
D. Factors Affecting the Clearance and Distribution of Microparticulate Carriers......Page 581
A. Liposomal Immunomodulators......Page 582
C. Liposomes in the Therapy of Obligate and Facultative Intracellular Pathogens......Page 584
D. Antitumor Drugs in Microspheres......Page 586
V. Summary......Page 587
References......Page 588
14. Selective Endocytosis of Macromolecular Drug Carriers......Page 597
A. Definition of Endocytosis......Page 598
B. Quantitation of Endocytosis......Page 604
C. Design of Drug-Carriers for Drug Delivery via Selective Endocytosis......Page 607
A. Selection According to Substrate Size......Page 612
B. Nonspecific Determinants Regulating Membrane Interactions......Page 613
C. Cell-Specific Recognition Systems......Page 615
III. Use of Selective Endocytosis for Drug Targeting......Page 620
IV. Conclusions......Page 622
References......Page 623
15. Antibodies for Drug Delivery......Page 638
A. General Aspects......Page 639
B. Antigens Defined by Monoclonal Antibodies in Some Human Cancers......Page 644
A. When Is Targeting Needed?......Page 648
B. Choice of Target Antigen......Page 649
C. Choice of Drugs......Page 650
D. Impact of Tumor Cell Heterogeneity......Page 652
F. Future Perspectives......Page 653
G. Current Planned Phase I–Phase II Trials with Monoclonal Antibody Conjugates......Page 655
IV. Conclusions......Page 656
References......Page 657
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