Pharmaceutical Inhalation Aerosol Technology

PHARMACEUTICAL INHALATION AEROSOL TECHNOLOGY......Page 1
FOREWORD......Page 9
FOREWORD TO THE FIRST EDITION......Page 11
PREFACE......Page 12
CONTENTS......Page 14
CONTRIBUTORS......Page 17
ANATOMY OF THE AIRWAYS......Page 20
CONTENTS......Page 0
STRUCTURE......Page 21
EPITHELIUM......Page 23
SMOOTH MUSCLE CELLS......Page 25
NERVES......Page 26
BLOOD SUPPLY......Page 29
CONDUCTING ZONE......Page 32
GAS EXCHANGE......Page 33
ACID–BASE BALANCE......Page 35
METABOLISM......Page 36
MEASURES OF PULMONARY VOLUMES......Page 37
MEASURES OF AIRWAY CALIBER......Page 39
AEROSOL DEPOSITION AND AIRWAY PHYSIOLOGY......Page 41
REFERENCES......Page 45
PHARMACODYNAMICS......Page 49
PHYSICAL FACTORS......Page 50
AIRWAY GEOMETRY......Page 51
CENTRAL AIRWAYS......Page 53
ALVEOLUS......Page 54
THERAPEUTIC USES OF AEROSOLS......Page 56
B-ADRENOCEPTOR AGONISTS......Page 57
MUSCARINIC CHOLINOCEPTOR ANTAGONISTS......Page 60
XANTHINE DERIVATIVES AND PHOSPHODIESTERASE INHIBITORS......Page 62
ANTIASTHMA DRUGS......Page 63
B-ADRENOCEPTOR AGONISTS.......Page 65
LIPOXYGENASE INHIBITORS.......Page 66
LEUKOTRIENE ANTAGONISTS.......Page 67
MUCUS SECRETION AND CLEARANCE......Page 68
ANTIBIOTIC AND ANTIVIRAL AGENTS......Page 69
OTHER POSSIBLE USES......Page 70
INSULIN......Page 71
PROTEASE INHIBITORS......Page 72
PATIENT COMPLIANCE......Page 73
IRRITANT ACTIVITY......Page 74
EPITHELIAL PERMEABILITY......Page 75
METABOLISM......Page 76
FUTURE DIRECTIONS FOR AEROSOL USE......Page 77
REFERENCES......Page 78
INTRODUCTION......Page 83
INERTIAL IMPACTION......Page 85
SEDIMENTATION......Page 86
INTERCEPTION......Page 87
METHODOLOGY......Page 88
STUDIES WITH STABLE MONODISPERSE AEROSOLS......Page 89
DEPOSITION OF THERAPEUTIC AEROSOLS......Page 91
PARTICLE VELOCITY AND FLOW RATE......Page 93
OTHER INHALATION MODE FACTORS......Page 94
SIZE DISTRIBUTION......Page 95
DENSITY......Page 96
KINETIC ASPECTS FOR LOCAL AND SYSTEMIC DELIVERY......Page 97
ABSORPTION AND METABOLISM......Page 98
AIRWAY CALIBER......Page 99
CONCLUSIONS......Page 100
REFERENCES......Page 101
INTRODUCTION......Page 107
GENERAL CONSIDERATIONS......Page 108
B2-ADRENOCEPTOR AGONISTS......Page 113
ANTIHISTAMINES......Page 118
ANTICHOLINERGICS......Page 122
GLUCOCORTICOIDS(GC)......Page 125
LEUKOTRIENES......Page 128
5-LIPOXYGENASE INHIBITORS......Page 130
THROMBOXANE-RECEPTOR ANTAGONISTS......Page 132
PLATELET ACTIVATING FACTOR (PAF) ANTAGONISTS......Page 133
ELASTASE INHIBITORS......Page 135
SOME STRUCTURAL FACTORS GOVERNING THE UPTAKE OF DRUGS......Page 136
PRODRUG APPROACHES TO EXTENDING DRUG ACTIVITY IN THE LUNG......Page 140
POTENTIAL USEFULNESS OF CELL MEMBRANE–BOUND ENZYME SUBSTRATES AND INHIBITORS, AND CELL MEMBRANE–BOUND RECEPTOR AGONISTS AND ANTAGONISTS AS DRUG CARRIERS WITH LUNG SPECIFICITY......Page 144
CONJUGATION OF DRUGS WITH MACROMOLECULES FOR SELECTIVE TARGETING TO THE LUNG......Page 148
IN VIVO FATE OF MACROMOLECULAR PRODRUGS AND LUNG TARGETING......Page 149
TARGETING OF MACROMOLECULE–DRUG CONJUGATES TO THE LUNG......Page 150
BIOADHESIVES AND DRUG TARGETING TO THE LUNG......Page 153
DRUG–MONOCLONAL ANTIBODY CONJUGATES FOR TARGETING TO THE LUNG......Page 158
CONCLUSIONS AND FUTURE DIRECTIONS......Page 162
REFERENCES......Page 164
INTRODUCTION......Page 173
THE NEED FOR SIMPLIFICATION......Page 175
EMPIRICAL MODELS......Page 176
LAGRANGIAN DYNAMICAL MODELS (LDMS)......Page 179
EULERIAN DYNAMICAL MODELS (EDMS)......Page 181
THREE-DIMENSIONAL PARTIAL LUNG SIMULATION......Page 183
SUMMARY......Page 184
REFERENCES......Page 186
INTRODUCTION......Page 189
CHARACTERIZATION OF THE AEROSOL FROM THE DELIVERY SYSTEM......Page 192
RADIOLABELING METHODS FOR AEROSOLS......Page 193
PRODUCTION OF RADIOLABEL......Page 194
VALIDATION OF A RADIOLABELED AEROSOL FORMULATION: PARTICLE SIZE AND UNIT DOSE......Page 198
CONTROL DURING INHALATION OF A RADIOLABELED AEROSOL AND SUBJECT VARIABLES......Page 205
DATA ANALYSIS......Page 207
DEFINING LUNG BORDERS AND REGIONS OF INTEREST......Page 208
TISSUE ATTENUATION OF RADIOACTIVITY......Page 209
DEFINING REGIONS OF INTEREST IN THE LUNG......Page 211
PLANAR (2D) SCINTIGRAPHY......Page 215
SINGLE-PHOTON-EMISSION COMPUTED TOMOGRAPHY (SPECT)......Page 217
POSITRON-EMISSION TOMOGRAPHY (PET)......Page 218
AEROSOLS USED IN CLINICAL INVESTIGATIONS OF DISEASE......Page 221
REFERENCES......Page 223
PULMONARY TARGETING—AS SEEN BY A PHARMACOKINETICIST’S EYE......Page 232
PHARMACODYNAMIC FACTORS IMPORTANT FOR PULMONARY TARGETING......Page 235
ORAL BIOAVAILABILITY......Page 237
SYSTEMIC CLEARANCE......Page 239
VOLUME OF DISTRIBUTION/PLASMA BINDING......Page 240
FREQUENCY OF DOSING......Page 242
PULMONARY RESIDENCE TIME......Page 244
AIRWAY EPITHELIAL CELL CULTURES......Page 247
ASSESSMENT OF THE MUCOCILIARY CLEARANCE OF A DRUG......Page 248
DRUG CONTENT IN LUNG TISSUE......Page 249
INFLUENCE OF DISEASE-STATE ON PHARMACOKINETIC STUDIES.......Page 250
OTHER IMPORTANT CONSIDERATIONS FOR PHARMACOKINETIC STUDIES.......Page 251
DEGREE OF SYSTEMIC AVAILABILITY.......Page 253
PHARMACOKINETIC TOOLS TO CHARACTERIZE ABSORPTION KINETICS.......Page 255
POTENTIAL ROLE OF PHARMACOKINETICS IN BIOEQUIVALENCE STUDIES.......Page 257
ASSESSMENT OF PULMONARY TARGETING IN ANIMAL MODELS.......Page 259
ASSESSMENT OF PULMONARY TARGETING IN HUMANS.......Page 260
REFERENCES......Page 265
INTRODUCTION......Page 270
EVAPORATION–CONDENSATION METHODS......Page 271
NEBULIZERS AND ATOMIZERS......Page 274
ELECTRICAL MOBILITY CLASSI.CATION......Page 278
ELECTROSPRAY AEROSOL GENERATOR......Page 279
VIBRATING-ORI.CE MONODISPERSE AEROSOL GENERATOR......Page 280
SPINNING-DISK AEROSOL GENERATOR......Page 284
DUST GENERATORS......Page 285
CONDITIONING AND TRANSFORMATION OF AEROSOL PARTICLES......Page 289
SUMMARY......Page 290
REFERENCES......Page 293
INTRODUCTION......Page 296
FORMULATIONS FOR NEBULIZATION......Page 298
DRY POWDER INHALATION FORMULATIONS......Page 299
METERED-DOSE INHALER FORMULATIONS......Page 302
INHALATION DRUG DELIVERY SYSTEM DESIGN—NEBULIZED DRUG DELIVERY......Page 304
NEBULIZER PERFORMANCE......Page 305
NEBULIZER SOLUTION FORMULATIONS......Page 307
INTRODUCTION......Page 308
FORMULATION COMPONENTS......Page 309
METERING VALVES......Page 314
ACTUATORS AND INHALATION AIDS......Page 315
MANUFACTURE AND EVALUATION OF METERED-DOSE INHALERS......Page 317
UNIT-DOSE DEVICES......Page 319
MULTIDOSE DEVICES......Page 320
FORMULATION ASPECTS......Page 322
REFERENCES......Page 324
INTRODUCTION......Page 327
DEFINITION OF TERMS......Page 328
GENERAL DESCRIPTION OF PRODUCT FILLER......Page 329
CRIMPING EQUIPMENT......Page 343
CRIMPING DIAMETER.......Page 345
CRIMPING HEIGHT.......Page 346
COMPRESSION.......Page 347
CONTROL OF QUALITY OF CRIMPING......Page 349
COLD FILLING.......Page 350
PROPELLANT COMPRESSOR PUMP.......Page 351
PROPELLANT FILLER UNIT.......Page 352
FILLING HEAD.......Page 353
MANUFACTURING FACILITIES......Page 354
CONTINUOUS ROTARY MACHINES......Page 357
REFERENCES......Page 358
INTRODUCTION......Page 360
INERTIAL IMPACTION......Page 361
FILTER HOLDERS......Page 362
FIBER FILTERS.......Page 363
MEMBRANE FILTERS.......Page 365
DYNAMIC PARTICLE BEHAVIOR......Page 367
TYPES OF CASCADE IMPACTORS......Page 370
IMPINGERS......Page 374
ELECTROSTATIC PRECIPITATION......Page 376
LIGHT MICROSCOPY......Page 379
ELECTRON MICROSCOPY......Page 381
SHAPE FACTORS AND PARTICLE MORPHOLOGY......Page 382
LIGHT-SCATTERING METHODS......Page 384
CALIBRATION......Page 385
LASER DIFFRACTION......Page 386
JET ACCELERATION......Page 389
ACOUSTIC VIBRATION......Page 390
PHARMACEUTICAL PRODUCT ASSESSMENT......Page 392
PERSPECTIVE ON RESEARCH SINCE THE EARLY 1990S......Page 393
REFERENCES......Page 394
INTRODUCTION......Page 400
PARTICLE SIZE AND OTHER PARTICLE CHARACTERISTICS......Page 401
COMPOUNDS COMMONLY ADMINISTERED TO THE LUNG......Page 406
NEBULIZERS......Page 409
METERED-DOSE INHALERS......Page 414
DRY POWDER GENERATORS......Page 418
BAFFLES......Page 423
SPACER DEVICES......Page 424
AEROSOL ADMINISTRATION BIOLOGICAL FACTORS......Page 427
METHODS OF AEROSOL ADMINISTRATION......Page 428
SUMMARY......Page 429
REFERENCES......Page 430
INTRODUCTION......Page 437
PARTICLE DEPOSITION......Page 438
LOCAL ABERRATIONS IN DEPOSITION......Page 439
POSTDEPOSITION DRUG DISTRIBUTION.......Page 440
TARGETING BY SIZE CONTROL......Page 441
TARGETING BY CONTROL OF HYGROSCOPIC GROWTH......Page 442
CONTROLLING INHALATION AND MODIFYING DELIVERY TECHNOLOGY......Page 443
ENANTIOMER PREPARATIONS OF INHALED DRUGS.......Page 444
INHALATION TECHNIQUE.......Page 445
SPACERS.......Page 446
THE “COMPETITION” BETWEEN MDIS AND DPIS......Page 447
NEW DEVICES AND MATERIALS.......Page 448
VENTILATOR AEROSOL DELIVERY......Page 449
AEROSOLS IN CYSTIC FIBROSIS......Page 450
RHDNASE.......Page 451
NEW AEROSOL APPLICATIONS......Page 452
INHALED STEROIDS.......Page 453
NICOTINE AEROSOL FOR SMOKING CESSATION.......Page 454
ALPHA 1 ANTITRYPSIN......Page 455
AEROSOLS IN TRANSPLANTATION......Page 456
SURFACTANT AEROSOL......Page 457
GENE THERAPY VIA AEROSOL......Page 458
PENTAMIDINE AEROSOL......Page 459
SCIENCE......Page 460
ECONOMICS......Page 461
REFERENCES......Page 462
INTRODUCTION......Page 472
AEROSOLIZED PENTAMIDINE RATIONALE AND EXPERIMENTAL ANIMAL STUDIES......Page 473
AEROSOL DEVICES USED TO DELIVER PENTAMIDINE......Page 474
HUMAN PHARMACOKINETIC DATA FOR PENTAMIDINE......Page 475
AEROSOLIZED PENTAMIDINE THERAPY FOR ACTIVE PNEUMOCYSTIS CARINII PNEUMONIA......Page 476
PATIENTS AT RISK FOR PNEUMOCYSTIS CARINII PNEUMONIA......Page 478
AEROSOLIZED PENTAMIDINE......Page 480
ADVERSE REACTIONS AND EFFECTS OF AEROSOLIZED PENTAMIDINE......Page 482
CONCLUSIONS......Page 483
REFERENCES......Page 484
INTRODUCTION......Page 486
RATIONALE FOR AEROSOLIZED ANTIBIOTIC THERAPY......Page 487
AEROSOL DEPOSITION OF ANTIMICROBIAL AGENTS......Page 488
OVERVIEW OF CYSTIC FIBROSIS......Page 489
POTENTIAL ROLE OF AEROSOLIZED ANTIBIOTICS......Page 490
CLINICAL TRIALS AND EXPERIENCE......Page 491
USE IN DELAYING OR PREVENTING ACQUISITION OF PSEUDOMONAS......Page 492
ROLE AS SUPPRESSIVE THERAPY IN REDUCING EXACERBATION FREQUENCY AND IMPROVING PULMONARY FUNCTION......Page 493
COMMERCIAL PRODUCT......Page 495
RESISTANCE CONCERNS......Page 496
DELIVERY DEVICE CONSIDERATIONS......Page 497
REFERENCES......Page 499
INTRODUCTION......Page 502
VIRAL VECTORS......Page 504
CATIONIC LIPOSOMES......Page 506
CATIONIC POLYMERS......Page 507
SIZE.......Page 508
DENSITY.......Page 509
PHYSIOLOGICAL BARRIERS TO GENE DELIVERY IN THE LUNG......Page 510
MUCUS......Page 511
COMPOSITION AND STRUCTURE OF MUCUS......Page 512
VISCOELASTIC AND RHEOLOGICAL PROPERTIES OF MUCUS......Page 513
PARTICLE TRANSPORT THROUGH MUCUS......Page 514
EFFECTS OF MUCUS DEGRADING AGENTS ON PARTICLE TRANSPORT......Page 516
ALVEOLAR MACROPHAGES......Page 517
INTRACELLULAR BARRIERS TO GENE DELIVERY......Page 518
CELLULAR UPTAKE......Page 519
ENDOSOME ESCAPE......Page 520
NUCLEAR UPTAKE......Page 521
TRANSCRIPTION AND NUCLEAR PERSISTENCE......Page 522
MULTIPLE PARTICLE TRACKING (MPT)......Page 523
TARGETING LUNG REGIONS BY CONTROLLED AEROSOLIZATION OF PARTICLES......Page 524
AEROSOL DEPOSITION......Page 525
INERTIAL IMPACTION......Page 527
DIFFUSION......Page 528
AEROSOL AGGREGATION PHENOMENA......Page 529
ADHESION FORCES......Page 530
PHYSICAL PROPERTIES OF AEROSOLS.......Page 532
NEW POLYMERS FOR CONTROLLED DELIVERY VIA THE LUNG.......Page 533
REFERENCES......Page 534
INTRODUCTION......Page 553
BACKGROUND......Page 554
INCREASING BIOAVAILABILITY: THE CASE FOR ETHANOL......Page 555
INCREASING DURATION OF THERAPEUTIC ACTION: THE CASE FOR NANOPARTICLES......Page 558
SUMMARY......Page 560
REFERENCES......Page 561
INTRODUCTION......Page 563
SALTS......Page 564
PRECIPITATES......Page 565
LIPOSOMES AND LIPIDS......Page 567
POLYMER CONJUGATION......Page 572
LIMITATIONS AND ISSUES......Page 573
REFERENCES......Page 575
INTRODUCTION......Page 583
THE INVENTIVE DECADE......Page 584
METERED-DOSE INHALERS......Page 585
DEVICES......Page 588
FORMULATIONS......Page 590
NEBULIZERS AND SOFT MIST INHALERS......Page 592
IMPROVED DELIVERY EFFICIENCIES......Page 594
MACROMOLECULE DELIVERY......Page 596
THE FUTURE......Page 597
REFERENCES......Page 599