Modified-Release Drug Delivery Technology (Drugs and the Pharmaceutical Sciences)

Modified-Release Drug Delivery Technology......Page 1
Table of Contents......Page 7
Preface......Page 4
Contributors......Page 15
I. INTRODUCTION......Page 22
Table of Contents......Page 0
II. PHYSIOLOGICAL AND PHYSICOCHEMICAL CONSIDERATIONS IN THE DESIGN OF ORAL MODIFIED-RELEASE FORMULATIONS......Page 23
III. RECENT ADVANCES AND FUTURE DIRECTIONS IN MODIFIED-RELEASE DELIVERY SYSTEMS FOR ORAL ADMINISTRATION......Page 25
REFERENCES......Page 29
I. INTRODUCTION......Page 32
A. Physical Characteristics of the Ungelled (Unwetted) System......Page 33
B. Physical Characteristcs of the Gelled (Wetted) System......Page 34
A. Formulation Considerations......Page 36
B. System Flexibility......Page 37
D. In Vitro–In Vivo Relationships......Page 38
REFERENCES......Page 39
I. INTRODUCTION......Page 41
II. EXPERIMENTAL......Page 42
A. Formulation Development......Page 43
B. Clinical Evaluations......Page 45
A. Formulation Development......Page 48
V. CONCLUSIONS......Page 52
REFERENCES......Page 53
I. INTRODUCTION......Page 54
A. Mechanism of Release......Page 55
B. Configurations......Page 57
IV. MANUFACTURING PROCESS......Page 59
V. DEVELOPMENT AND OPTIMIZATION OF TECHNOLOGY......Page 60
VII. IN VIVO STUDIES......Page 64
X. CONCLUSIONS......Page 66
REFERENCES......Page 67
II. HISTORICAL DEVELOPMENT......Page 68
A. Drug Release......Page 69
A. Technical Development......Page 72
B. Clinical Studies......Page 73
VI. TECHNOLOGY POSITION/COMPETITIVE ADVANTAGE......Page 74
REFERENCES......Page 75
I. INTRODUCTION......Page 77
II. MULTIPLE-LAYERED TABLETS......Page 78
III. MANUFACTURING TECHNOLOGY......Page 80
A. Theoretical Considerations......Page 81
B. Experimental Results......Page 85
REFERENCES......Page 93
II. DESCRIPTION OF THE TECHNOLOGY......Page 95
III. RESEARCH AND DEVELOPMENT......Page 98
V. TECHNOLOGY POSITION/COMPETITIVE ADVANTAGE......Page 103
VI. FUTURE DIRECTIONS......Page 104
REFERENCES......Page 105
II. HISTORICAL DEVELOPMENT......Page 106
III. DESCRIPTION OF TECHNOLOGY......Page 109
IV. RESEARCH AND DEVELOPMENT......Page 110
A. Demonstration of Pulsatile Release......Page 111
C. Effect of Extent of Coverage by the Impermeable Coating......Page 112
V. ANIMAL STUDY......Page 114
VII. TECHNOLOGY POSITION/COMPETITIVE ADVANTAGE......Page 115
REFERENCES......Page 116
II. THEORY OF OPERATION......Page 117
C. Patterned Drug Delivery......Page 121
A. Nifedipine......Page 123
B. Oxybutynin Chloride......Page 124
C. Methylphenidate HCl......Page 125
V. NONCLINICAL SAFETY PROGRAM......Page 126
VIII. MANUFACTURING......Page 127
B. Liquid Osmotic System (L-Oros)......Page 128
REFERENCES......Page 129
II. HISTORICAL DEVELOPMENT......Page 131
III. DESCRIPTION OF THE TECHNOLOGY......Page 132
IV. RESEARCH AND DEVELOPMENT......Page 133
A. Manufacturing Process......Page 134
B. In Vitro Studies......Page 135
C. In Vivo Studies......Page 136
V. CONCLUSION......Page 138
REFERENCES......Page 139
I. INTRODUCTION......Page 140
III. DESCRIPTION OF MELTREX TECHNOLOGY......Page 141
A. Controlled Release with Meltrex Technology......Page 143
B. Solid Dispersions with Meltrex Technology......Page 145
VI. TECHNOLOGY POSITION......Page 147
REFERENCES......Page 148
I. INTRODUCTION......Page 150
A. Production Technique for DissoCubes......Page 151
B. Special Features of DissoCubes......Page 152
C. Release Properties of DissoCubes......Page 154
B. Fabrication Technique for DissoCubes......Page 156
C. Scale-up Production of DissoCubes......Page 157
D. In Vitro Cell Culture Studies with DissoCubes......Page 158
E. In Vivo Studies with DissoCubes......Page 159
VI. TECHNOLOGY POSITION AND COMPETITIVE ADVANTAGES......Page 160
REFERENCES......Page 161
I. INTRODUCTION......Page 165
B. Drug-Vehicle Interaction......Page 170
A. Particle Size Reduction......Page 174
B. Particle Growth from Solution......Page 177
C. Solid Dosage Forms......Page 178
B. Release Pro.le and Bioavailability......Page 181
VI. COMPETITIVE ADVANTAGE AND FUTURE DIRECTIONS......Page 185
REFERENCES......Page 186
II. DRUG CHARACTERISTICS RELEVANT TO LIQUID FILLING TECHNOLOGY......Page 190
IV. SUITABILITY OF FILL MATERIALS......Page 191
A. Moisture Exchange Fill Shell......Page 192
C. Dissolution Stability Indicator......Page 193
E. Excipients Compatible with Hard Gelatin Capsules......Page 194
A. Capsule-Filling Machines......Page 195
B. Equipment for Sealing Hard Gelatin Capsules......Page 196
REFERENCES......Page 201
II. HISTORY......Page 204
IV. OTHER RELATED TECHNOLOGIES......Page 205
V. ZYDIS FORMULATION CONSIDERATIONS......Page 207
B. Forming-Filling......Page 208
VII. PACKAGING......Page 209
VIII. KEY ISSUES RESOLVED DURING DEVELOPMENT OF THE TECHNOLOGY......Page 210
IX. BUCCAL ABSORPTION......Page 211
XI. APPLICATIONS OF THE TECHNOLOGY......Page 212
REFERENCES......Page 213
II. HISTORICAL DEVELOPMENT......Page 215
A. Rationale for Formulating Quick-Dissolving Tablets......Page 216
B. Formulation and Manufacturing Technology......Page 217
C. Shipping Tests......Page 219
D. Organoleptic Tests......Page 220
E. Pharmacokinetic Tests on OraSolv......Page 224
V. TECHNOLOGY POSITION/COMPETITIVE ADVANTAGE......Page 226
REFERENCES......Page 227
I. INTRODUCTION......Page 229
II. FUNCTION OF THE COLON: THE IMPACT ON DRUG DELIVERY......Page 230
IV. ROLE OF CECAL FERMENTATION......Page 231
V. DISEASE AND THE COLONIC ENVIRONMENT......Page 232
VII. CONCLUDING REMARKS......Page 233
REFERENCES......Page 234
I. INTRODUCTION......Page 235
II. ENTERIC POLYMER MATERIALS......Page 236
A. Cellulose Acetate Phthalate (CAP)......Page 237
C. Polyvinylacetate Phthalate (PVAP)......Page 238
D. Methacrylic Acid Copolymers......Page 239
G. Polymethyl Vinyl Ether/Maleic Acid Copolymers......Page 240
III. EXAMPLES OF ENTERIC-COATED SYSTEMS FOR COLONIC DELIVERY......Page 241
REFERENCES......Page 243
I. INTRODUCTION......Page 245
A. Guar Gum......Page 246
C. Pectin......Page 247
D. Amylose......Page 248
F. Starch......Page 249
H. Cyclodextrin......Page 250
III. NONBIODEGRADABLE SWELLING POLYMERS......Page 251
REFERENCES......Page 253
I. INTRODUCTION......Page 255
B. Colon-Targeted Delivery System......Page 256
C. Time-Controlled Ethylcellulose System......Page 257
E. Controlled-Release Drug Dellvery Device......Page 258
F. Time Clock......Page 259
REFERENCES......Page 260
I. INTRODUCTION......Page 261
III. DESCRIPTION OF THE TECHNOLOGY......Page 262
A. Zero-Order Release Rate......Page 264
V. REGULATORY ISSUES......Page 267
REFERENCES......Page 268
II. PULSINCAP TECHNOLOGIES......Page 269
IV. CONCLUDING REMARKS......Page 273
REFERENCES......Page 274
I. INTRODUCTION......Page 275
A. Matrix Erosion......Page 276
B. Agitation......Page 277
C. Geometry......Page 278
D. Burst Release......Page 279
VI. COMPETITIVE ADVANTAGES/UNIQUE FEATURES......Page 280
REFERENCES......Page 282
I. INTRODUCTION......Page 284
A. High-Frequency (HF) Capsule (Battelle-Institute V, Frankfurt am Main, Germany)......Page 286
C. Telemetric Capsule (INSERM U61, Strasbourg Cedex, France)......Page 287
III. DESCRIPTION OF THE TECHNOLOGY......Page 288
A. Design and Fabrication......Page 290
B. “Proof of Concept” Clinical Study......Page 291
D. Application of the Technology......Page 292
V. REGULATORY ISSUES......Page 295
C. Biotechnology Compounds......Page 296
REFERENCES......Page 297
I. INTRODUCTION......Page 300
A. Anatomical and Physiological Features of the Eye......Page 301
B. Drug Delivery to the Internal Regions of the Eye......Page 302
C. Assessment of the Performance of Ophthalmic Formulations......Page 303
E. Other Formulation Considerations......Page 305
III. FORMULATION APPROACHES......Page 306
B. Dispersed Systems......Page 307
C. Inserts......Page 308
IV. RECENT RESEARCH......Page 310
V. CONCLUSIONS......Page 314
REFERENCES......Page 315
I. INTRODUCTION......Page 325
B. Product Challenges......Page 326
D. Ion Exchange Resins......Page 327
A. The Formulation......Page 328
B. Patient Comfort......Page 332
D. Dose Reduction......Page 334
F. Regulatory Considerations......Page 335
V. CONCLUSIONS......Page 336
REFERENCES......Page 337
II. OPHTHALMIC INSERTS......Page 339
A. Concept and Design......Page 340
C. Formulation and Manufacturing Process......Page 341
A. Gamma Scintigraphy in Human Volunteers......Page 342
B. Bioavailability and Ef.cacy in Human Subjects......Page 344
V. REGULATORY ISSUES......Page 347
VI. MARKETING......Page 348
REFERENCES......Page 349
I. INTRODUCTION......Page 350
A. Initial Development Results......Page 351
B. Further Developmental Studies......Page 353
C. Mechanism of Drug Release......Page 354
IV. CONCLUSION......Page 355
REFERENCES......Page 356
I. INTRODUCTION......Page 357
II. STRUCTURE AND FUNCTION OF ORAL MUCOSA......Page 358
V. SALIVA AND MUCUS......Page 360
VI. THE ABSORPTION BARRIER......Page 361
A. Design of Solid Oral Dosage Forms According to Their Mobility in the Oral Cavity......Page 362
C. Accelerated-Release Solid Oral Mucosal Dosage Forms......Page 364
D. Controlled-Release Solid Oral Dosage Forms......Page 365
REFERENCES......Page 369
I. INTRODUCTION......Page 373
B. In Vivo Studies......Page 374
B. BCTS......Page 383
IV. CONCLUSION......Page 387
REFERENCES......Page 388
I. INTRODUCTION......Page 389
A. Driver Gas Reservoir......Page 390
III. DOME DESIGN......Page 391
IV. IN VITRO DEVICE TESTS......Page 392
V. IN VIVO TESTS (HUMANS)......Page 394
B. Ef.cacy Tests......Page 395
VI. CONCLUSIONS......Page 396
REFERENCES......Page 397
II. HISTORICAL BACKGROUND......Page 398
A. Toxicology (Perio Products Ltd.—In-House Data)......Page 399
B. Pharmacokinetics......Page 401
C. Efficacy and Safety Studies......Page 402
V. FUTURE DEVELOPMENTS OF THE TECHNOLOGY......Page 405
REFERENCES......Page 406
A. Reasons for Selecting the Oral Mucosal Route......Page 408
B. Enzymatic Degradation......Page 411
D. Formulation Considerations......Page 412
A. Objectives......Page 414
B. In Vitro Studies......Page 415
IV. CONCLUSION......Page 419
REFERENCES......Page 422
I. INTRODUCTION......Page 426
III. REGULATORY ISSUES......Page 427
B. Taste and Mouthfeel......Page 428
A. Methods......Page 429
B. Scale-Up Problems......Page 430
A. Factors Affecting Release......Page 431
C. In Vitro/In Vivo Correlation......Page 433
IX. FUTURE DEVELOPMENTS......Page 434
REFERENCES......Page 435
I. INTRODUCTION......Page 437
II. CURRENT APPLICATIONS......Page 438
B. Clinical Results......Page 439
IV. DISCUSSION......Page 445
V. SUMMARY......Page 450
REFERENCES......Page 451
I. INTRODUCTION......Page 453
A. In Vitro Evaluation of Liquid Crystalline Phases of GMO......Page 454
B. Effect of Liquid Crystalline Phases of GMO on Buccal Permeation of Peptides......Page 456
III. CONCLUSIONS......Page 457
REFERENCES......Page 458
I. INTRODUCTION......Page 459
A. Delivery to the Periodontal Pocket......Page 460
C. Delivery of Antigens......Page 464
REFERENCES......Page 466
I. INTRODUCTION......Page 468
III. DESCRIPTION OF THE TECHNOLOGY......Page 469
IV. RESEARCH AND DEVELOPMENT......Page 470
REFERENCES......Page 474
II. THE CHALLENGE......Page 475
A. Advantages......Page 476
C. The Skin as a Barrier......Page 477
D. Factors Affecting Skin Permeation......Page 478
E. Permeation Enhancement......Page 479
V. REGULATORY ISSUES......Page 481
REFERENCES......Page 482
I. INTRODUCTION......Page 485
B. Rationale for Development of D-Trans Technology......Page 486
C. Development Status......Page 488
D. Marketed Products......Page 489
C. Rate-Controlling Membranes......Page 492
F. Backing Membranes and Peelable Liners......Page 493
C. Human In Vitro/In Vivo Correlation......Page 494
V. PRECLINICAL DEVELOPMENT......Page 495
VI. CLINICAL ASSESSMENT......Page 496
ACKNOWLEDGMENTS......Page 498
REFERENCES......Page 499
II. THEORY AND MECHANISM OF ELECTROTRANSPORT......Page 503
III. RATIONALE FOR DEVELOPMENT OF E-TRANS. TECHNOLOGY......Page 505
A. Electronic Components......Page 506
B. Electrodes......Page 507
C. Formulation......Page 509
V. PRECLINICAL DEVELOPMENT......Page 510
VIII. MANUFACTURING......Page 511
REFERENCES......Page 513
I. INTRODUCTION......Page 516
II. FABRICATION OF MICRONEEDLES......Page 517
C. Microfabrication of Hollow Microneedles......Page 518
III. TESTING OF MICRONEEDLES......Page 520
IV. REGULATORY ISSUES......Page 521
A. Comparison with Hypodermic Needles and Transdermal Patches......Page 523
ACKNOWLEDGMENTS......Page 524
REFERENCES......Page 525
I. INTRODUCTION......Page 526
A. Possible Enhancement Mechanisms......Page 527
IV. RESEARCH AND DEVELOPMENT......Page 529
VI. COMPETITIVE ADVANTAGES OF THE MDTS......Page 532
REFERENCES......Page 533
I. INTRODUCTION......Page 535
II. HISTORICAL DEVELOPMENT......Page 536
III. TECHNOLOGY......Page 537
A. Transfersome Preparation......Page 539
B. Transfersome Characterization......Page 540
V. CURRENT AND FUTURE RESEARCH AND DEVELOPMENT......Page 543
VII. FUTURE DIRECTIONS......Page 546
REFERENCES......Page 547
I. INTRODUCTION......Page 549
III. A TOPICAL PRODUCT FOR WOUNDS: IMPORTANT CONSIDERATIONS......Page 550
IV. THE ROLE OF THE VEHICLE......Page 554
V. THE ROLE OF A SECONDARY DRESSING MATERIAL IN DRUG DELIVERY......Page 555
VI. REGULATORY ISSUES......Page 556
VII. FUTURE OPPORTUNITIES FOR ADVANCES IN WOUND HEALING......Page 558
REFERENCES......Page 559
II. HISTORICAL DEVELOPMENT......Page 562
A. Continuous Sonophoresis......Page 563
IV. RESEARCH AND DEVELOPMENT......Page 564
REFERENCES......Page 568
I. INTRODUCTION......Page 571
A. Limitations of Existing Technologies......Page 572
A. Laboratory-Scale Production......Page 573
A. Drug Incorporation......Page 574
B. Drug Release......Page 575
A. Loading of Creams and Gels with SLN......Page 577
B. Properties of SLN Formulations......Page 579
VII. TECHNOLOGY POSITION AND ITS COMPETITIVE ADVANTAGES......Page 584
REFERENCES......Page 585
I. INTRODUCTION......Page 588
II. MANUFACTURING......Page 589
A. Dry-Coated Macroflux.......Page 590
B. D-TRANS. Macroflux.......Page 592
IV. DISCUSSION AND CONCLUSION......Page 595
REFERENCES......Page 596
I. INTRODUCTION......Page 598
II. HISTORICAL DEVELOPMENT......Page 599
III. DESCRIPTION OF TECHNOLOGY......Page 600
IV. RESEARCH AND DEVELOPMENT......Page 601
VII. TECHNOLOGY POSITION......Page 602
VIII. FUTURE DIRECTIONS......Page 603
REFERENCES......Page 604
II. HISTORICAL DEVELOPMENT......Page 606
B. Dermal PowderJect Device......Page 607
C. Targeted Delivery to Skin Layers......Page 608
A. Prototype Devices Tested......Page 609
B. Experimental and Analytical Methods......Page 610
C. Measured Gas and Particle Flows......Page 611
A. The PowderJect System and Drug Delivery......Page 612
B. The PowderJect System and Vaccine Delivery......Page 613
VI. FUTURE DIRECTIONS AND CONCLUSION......Page 615
REFERENCES......Page 616
B. Weston Medical Group plc......Page 617
II. HISTORICAL DEVELOPMENT......Page 618
B. How Intraject Works......Page 620
B. Clinical Studies......Page 622
VI. MANUFACTURING STRATEGY......Page 626
IX. FUTURE DIRECTIONS......Page 627
REFERENCES......Page 629
I. INTRODUCTION......Page 630
II. IMPLANTS......Page 631
III. INJECTABLE MODIFIED-RELEASE SYSTEMS......Page 632
IV. CONCLUSION......Page 633
REFERENCES......Page 634
I. INTRODUCTION......Page 636
A. Solvent Choice and Phase Inversion......Page 637
B. Protein Particle Development......Page 639
III. PRECLINICAL EVALUATION......Page 640
VI. SUMMARY AND OUTLOOK......Page 641
REFERENCES......Page 642
I. INTRODUCTION......Page 644
II. FORMULATION AND DEVELOPMENT......Page 645
III. MANUFACTURING, STERILIZATION, AND PACKAGING......Page 649
IV. APPLICATIONS......Page 650
REFERENCES......Page 651
I. INTRODUCTION......Page 653
II. DUROS PRODUCTS......Page 654
III. SYSTEM DESIGN AND OPERATING PRINCIPLES......Page 656
V. CLINICAL DEVELOPMENT OF VIADUR......Page 657
A. Materials......Page 660
VIII. REGULATORY ASPECTS......Page 662
ACKNOWLEDGMENTS......Page 663
REFERENCES......Page 664
I. INTRODUCTION......Page 666
III. THE PROLEASE ENCAPSULATION PROCESS......Page 667
IV. STERILIZATION......Page 669
V. ADMINISTRATION AND DRUG RELEASE......Page 670
REFERENCES......Page 672
I. INTRODUCTION......Page 673
II. EVOLUTION OF SAIB FOR PARENTERAL DELIVERY......Page 674
IV. SABER TECHNOLOGY......Page 675
VI. APPLICATIONS......Page 678
VIII. FUTURE DIRECTIONS......Page 679
REFERENCES......Page 680
I. INTRODUCTION......Page 682
A. Design Features......Page 684
C. Production Methodology......Page 687
D. Clinical Experience......Page 689
III. FUTURE DIRECTIONS......Page 690
IV. CONCLUSIONS AND PERSPECTIVES......Page 691
REFERENCES......Page 692
I. INTRODUCTION......Page 698
II. DEPOFOAM TECHNOLOGY......Page 699
III. DEPOFOAM APPLICATIONS......Page 700
B. Anesthetics and Analgesics......Page 701
C. Antibiotics and Antivirals......Page 702
IV. CONCLUSION......Page 703
REFERENCES......Page 704
I. INTRODUCTION......Page 706
III. DESCRIPTION OF THE TECHNOLOGY......Page 707
IV. RESEARCH AND DEVELOPMENT......Page 712
V. HUMAN STUDIES......Page 714
VI. EXAMPLES OF DRUG/CLINICAL APPLICATIONS OF TECHNOLOGY......Page 715
VII. REGULATORY ISSUES......Page 716
REFERENCES......Page 717
I. INTRODUCTION......Page 719
II. NASAL ANATOMY AND PHYSIOLOGY......Page 720
III. INTRANASAL DRUG ABSORPTION......Page 723
A. Drug Formulation......Page 724
B. Dosage Form......Page 726
C. Delivery Device......Page 727
V. TECHNOLOGIES FOR MODIFIED INTRANASAL DRUG DELIVERY......Page 728
REFERENCES......Page 732
II. HISTORICAL DEVELOPMENT......Page 741
III. TECHNOLOGY DESCRIPTION AND RESEARCH AND DEVELOPMENT......Page 742
A. In Vitro Release Mechanisms......Page 744
B. In Vivo Studies......Page 745
IV. FUTURE DIRECTIONS......Page 747
REFERENCES......Page 748
I. INTRODUCTION......Page 751
II. INFLUENCE OF VAGINAL ANATOMY AND PHYSIOLOGY ON DRUG DELIVERY......Page 752
III. INTRAVAGINAL DRUG ABSORPTION......Page 755
IV. DESIGNING AN INTRAVAGINAL DRUG DELIVERY SYSTEM: KEY CONSIDERATIONS......Page 757
V. INTRAVAGINAL DRUG DELIVERY TECHNOLOGIES......Page 758
A. Bio(muco)adhesive Semisolids......Page 760
D. Carriers for Intravaginal Delivery of Peptide and Protein Drugs......Page 761
REFERENCES......Page 763
I. INTRODUCTION......Page 767
II. HISTORICAL DEVELOPMENT OF THE IVR......Page 768
A. Manufacture......Page 770
B. IVR Types and Release Mechanisms......Page 771
IV. IVR RESEARCH AND DEVELOPMENT......Page 775
REFERENCES......Page 777
B. Occurrence and Uses......Page 783
IV. PROLIPOSOMES......Page 784
B. SupraVail Vaginal Gels......Page 785
C. Applications of SupraVail Vaginal Gels......Page 787
B. Formulation Issues and Product Stability......Page 788
IX. COMPETITIVE ADVANTAGE......Page 791
REFERENCES......Page 792
II. DESCRIPTION OF TECHNOLOGY......Page 793
III. PHARMACOLOGICAL CONSIDERATIONS......Page 794
IV. CLINICAL EVALUATION......Page 795
V. OTHER DRUG APPLICATIONS......Page 796
REFERENCES......Page 797
I. INTRODUCTION......Page 799
II. BASIC PRINCIPLES......Page 800
A. Pressurized Metered-Dose Inhalers (MDIs or pMDIs)......Page 801
B. Dry Powder Inhalers (DPIs)......Page 802
IV. BEYOND THE CONVENTIONAL DELIVERY OF RESPIRATORY DRUGS......Page 803
VI. CONCLUSIONS......Page 805
REFERENCES......Page 806
I. INTRODUCTION......Page 808
V. RESPIRATORY PROGRAM......Page 810
VII. COMPARISONS/CONTRASTS WITH OTHER PULMONARY DELIVERY TECHNOLOGIES......Page 811
IX. TECHNOLOGY RESEARCH AND DEVELOPMENT......Page 812
REFERENCES......Page 813
I. INTRODUCTION......Page 815
III. THE AERx DOSAGE FORM......Page 816
IV. THE AERx DEVICE......Page 817
V. CLINICAL DATA......Page 821
REFERENCES......Page 822
II. PATENT INFORMATION/STATUS......Page 825
III. HISTORICAL PERSPECTIVE......Page 826
IV. NEED FOR THE TECHNOLOGY......Page 827
V. DIFFERENCES FROM RELATED TECHNOLOGIES......Page 828
VI. DESCRIPTION OF TECHNOLOGY......Page 829
B. Dissolution and Disposition......Page 830
B. In Vivo Studies (Animals)......Page 831
X. FABRICATION TECHNIQUES......Page 832
XII. SPECIALIZED/UNIQUE REGULATORY ISSUES......Page 833
XIII. FUTURE DEVELOPMENTS......Page 834
REFERENCES......Page 835
I. INTRODUCTION......Page 839
A. Jet Nebulizers......Page 840
C. Passive Mesh-Type Piezoelectric Nebulizer......Page 842
D. Vibrating Membrane-Type Piezoelectric Systems......Page 843
III. REGULATORY ISSUES......Page 844
REFERENCES......Page 845
I. INTRODUCTION......Page 847
A. Micromeritics......Page 850
B. Liposomal Systems......Page 851
C. Polymer Matrices and Encapsulated Systems......Page 852
E. Prodrugs and Pegylation......Page 853
III. CONCLUSIONS......Page 854
REFERENCES......Page 855
I. INTRODUCTION......Page 857
II. HISTORICAL DEVELOPMENT......Page 858
III. CURRENTLY MARKETED PASSIVE DRY POWDER INHALERS......Page 859
A. The Diskus Inhaler......Page 860
B. The Turbuhaler inhaler......Page 861
VI. IN VITRO/IN VIVO CORRELATIONS......Page 864
VIII. CONCLUDING REMARKS......Page 865
REFERENCES......Page 866
II. BIOCHEMICAL STABILITY......Page 868
III. PHYSICAL STABILITY......Page 869
IV. DISPERSIBILITY......Page 870
B. Co-Spray Drying with a Suitable Excipient......Page 871
C. Blending with a Suitable Carrier......Page 872
E. Pulmospheres......Page 873
F. Use of Wrinkled Particles......Page 874
B. Spray Freeze Drying......Page 875
E. Solvent Precipitation......Page 876
REFERENCES......Page 877
I. INTRODUCTION......Page 880
II. FORMULATING POROUS PARTICLES FOR FLEXIBLE DRUG DELIVERY......Page 881
III. AEROSOL PARTICLE PHYSICS......Page 883
IV. MANUFACTURING OF LARGE POROUS PARTICLES......Page 886
V. TOXICOLOGICAL TESTING OF LARGE POROUS PARTICLES......Page 887
VI. INHALER DEVELOPMENT FOR LARGE POROUS PARTICLES......Page 889
VII. CONCLUSION......Page 890
REFERENCES......Page 891
II. UNIQUE REQUIREMENTS......Page 892
IV. INHALE’S PROPRIETARY TECHNOLOGY......Page 893
V. MECHANISM OF DRUG RELEASE......Page 894
VI. RESEARCH AND DEVELOPMENT......Page 895
VII. SAFETY CONCERNS......Page 896
X. REGULATORY ISSUES......Page 898
XI. FUTURE DEVELOPMENTS......Page 899
REFERENCES......Page 900
I. INTRODUCTION......Page 902
II. SPIROS TECHNOLOGY......Page 903
B. Particle Size Reduction......Page 905
B. Stability/Activity Assessment......Page 907
IV. HUMAN CLINICAL STUDIES......Page 910
REFERENCES......Page 913
I. INTRODUCTION......Page 914
III. DEVELOPMENT OF RESPIMAT......Page 915
IV. MODE OF ACTION OF RESPIMAT......Page 918
A. Technical Performance Data......Page 919
B. Clinical Performance Data......Page 920
VI. CONCLUSIONS......Page 921
REFERENCES......Page 922
I. INTRODUCTION......Page 923
II. CHEMISTRY, MANUFACTURING, AND CONTROLS......Page 924
III. PRECLINICAL TOXICOLOGY TESTING......Page 926
IV. CLINICAL REQUIREMENTS......Page 927
V. CONCLUSION......Page 928
REFERENCES......Page 929
I. INTRODUCTION......Page 930
III. CONTROLLED-RELEASE NEW DRUG APPLICATIONS......Page 931
IV. CODE OF FEDERAL REGULATIONS: BIOAVAILABILITY STUDY REQUIREMENTS FOR CONTROLLED-RELEASE PRODUCTS......Page 932
A. Demonstration of Safety and Ef.cacy Primarily Based on Clinical Trials......Page 933
B. Demonstration of Safety and Ef.cacy Based on PK, PK/PD Trials......Page 935
VII. GENERIC EQUIVALENCE OF AN APPROVED CONTROLLED-RELEASE PRODUCT......Page 937
B. Bioequivalence Requirements......Page 938
VIII. SCALE-UP AND POSTAPPROVAL CHANGES FOR MODIFIED-RELEASE FORMULATIONS......Page 939
A. IVIVC......Page 952
B. Setting Dissolution Speci.cations......Page 957
X. CONCLUSION......Page 960
REFERENCES......Page 961