Inhalation Aerosols. jnforma healthcare. Physical and Biological Basis for Therapy. Second Edition. Edited by. Anthony J. Hickey

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1 Inhalation Aerosols Physical and Biological Basis for Therapy Second Edition Edited by Anthony J. Hickey University of North Carolina Chapel Hill, North Carolina, U.S.A. jnforma healthcare New York London

2 Contents Introduction Claude Lenfant.... v Preface... vii Contributors... ix PART I: AERODYNAMIC BEHAVIOR 1. Deposition Mechanics of Pharmaceutical Particles in Human Airways / Gabriela Sbirlea-Apiou, Ira Katz, Georges Caillibotte, Ted Martonen, and Yadong Yang I. Introduction... 1 II. Deposition Model for Aerosolized Drugs... 2 III. Results and Discussion References Thermodynamics of Inhaled Hygroscopic Drugs 31 Ira Katz, Gabriela Sbirlea-Apiou, and Ted Martonen I. Introduction II. Methods to Study Aerosol Thermodynamics III. Discussion of Aerosol Drug Hygroscopicity Within Human Airways IV. Summary References Use of Mathematical Aerosol Deposition Models in Predicting the Distribution of Inhaled Therapeutic Aerosols 55 David Swift, Bahman Asgharian, and Julia S. Kimbell I. Introduction II. Historical Review of Respiratory Tract Deposition Models III. NCRP Lung-Deposition Model 65 xui

3 Y(V Contents IV. ICRP Lung-Deposition Model V. General Features of Deposition Models VI. A Multiple-Path Particle Dosimetry Model 70 VII. Aerosol Sampling Conventions Related to Respiratory Deposition VIII. Special Features of Therapeutic Aerosols IX. Future Developments in Deposition Modeling: A Model for Therapeutic Aerosols? X. Summary and Conclusions References PART II: BIOLOGICAL CONSIDERATIONS 4. Physiology and Pharmacology of the Airways 83 Ralph J. Altiere and David C. Thompson I. Introduction II. Physiology of the Lung III. Pharmacology of the Airways References Solute Transport Following Aerosol Deposition in the Lungs Richard M. Ejfros I. Introduction II. Radioaerosols III. Factors Affecting Clearance of Solutes from the Lungs IV. Lipid Solubility V. Electrolyte Transport VI. Strong Acids 133 VII. Water Transport 134 VIII. Redox Indicators 135 IX. Macromolecules X. Exhaled Breath Condensates XL Conclusions References Drug Metabolism and Enzyme Kinetics in the Lung 147 Meenakshi Bhat, Joseph K. H. Ma, Yongyut Rojanasakul, and Ronald K. Wolff I. Introduction II. Enzymatic Systems and Their Distribution in the Respiratory Tract

4 Contents n. III. Gross Anatomical Considerations in Aerosol Drug Delivery IV. Experimental Models in Lung Metabolism Studies V. Current Application of Aerosols in Drug Therapy VI. Conclusions 173 References Bioavailability and Pharmacokinetics of Inhaled Drugs 187 Akwete L. Adjei, Yihong Qiu, and Pramod K. Gupta I. Introduction II. Formulation Effects and Bioavailability III. Factors Affecting Bioavailability of Inhaled Drugs IV. Pharmacokinetics of Inhaled Drugs V. Clinical and Regulatory Issues VI. Epilogue VII. Conclusions References Therapeutic Uses of Lung Aerosol 219 Jonathan A. Bernstein, Hetal Amin, and Steven J. Smith I. Introduction II. Systemic Routes of Medication Delivery for Asthma and Other Lower Respiratory Disorders III. Aerosolized Use of Drugs in Asthma Therapy IV. Cystic Fibrosis 244 V. Gene Therapy References PART III: PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY 9. Atomization and Nebulizers 253 Ralph W. Niven and Anthony J. Hickey I. Introduction II. Atomization III. Nebulizers IV. Formulation

5 Contents V. Summary and Conclusions References Ultrasonic and Electrohydrodynamic Methods for Aerosol Generation 285 Bernard J. Greenspan I. Introduction II. Ultrasonic Nebulizers III. Electrohydrodynamic Atomization IV. Conclusions References Spray-Drying and Supercritical Fluid Particle Generation Techniques 307 Michiel M. Van Oort and Mark Sacchetti I. Background II. Spray Drying 308 III. Particle Generation Using Supercritical Fluids IV. Properties of Spray-Dried and SCF Powders and Methods of Characterization References Interfacial Phenomena and Phase Behavior in Metered Dose Inhaler Formulations 347 Keith A. Johnson I. Nomenclature II. Introduction 348 III. Estimating Suspension Stability IV. Propellant Physical Properties and Phase Behavior V. Experimental Design and Methods VI. Summary and Conclusions References Molecular Scale Behavior in Alternative Propellant-Based Inhaler Formulations 373 Libo Wu, Robson P. S. Peguin, Parthiban Selvam, Uday an Chokshi, and Sandro R. P. da Rocha I. Introduction II. Alternative pmdis 374 III. Microscopic Tools for the Development of Alternative pmdis 380

6 Contents vr// IV. Conclusions and Outlook References Aerosol Generation from Propellant-Driven Metered Dose Inhalers 399 Hugh D. C. Smyth, Richard M. Evans, and Anthony J. Hickex I. Introduction II. Observed Droplet Formation and Dispersion III. Fundamentals of Droplet Formation IV. Theoretical Framework Describing Droplet Formation V. Semiempirical Model of Droplet Formation VI. Conclusion References Medical Devices for the Delivery of Therapeutic Aerosols to the Lungs 417 Richard N. Dalby, Susan L. Tiano, and Anthony J. Hickex I. Introduction II. Pressurized Metered-Dose Inhalers III. Dry Powder Inhalers 425 IV. Nebulizers V. Selection of a Delivery System VI. Future Developments References Next Generation Dry Powder Inhalation Delivery Systems 445 Anthony J. Hickey and Timothy M. Crowder I. Introduction II. Formulation III. Metering Systems IV. Dispersion Mechanisms V. Inhaler Designs (Patent Review) 454 VI. Characterization of Dry-Powder Inhaler Products VII. Conclusions 456 VIII. General Conclusion 457 References Index 461