Metered Dose Inhaler Technology

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1 Metered Dose Inhaler Technology Edited by Tol S. Purewal and David J. W. Grant Interpharm Press, Inc. Buffalo Grove, Illinois

2 Contents 1. INTRODUCTION 1 T. S. Purewal Definition of the Metered Dose Inhaler 2 Definition of an "Aerosol" 2 A Historical Perspective 4 General Consumer Aerosol Dispensers 4 The Pharmaceutical Metered Dose Inhaler 5 References 7 1U

3 iv Metered Dose Inhaler Technology 2. FORMULATION OF METERED DOSE INHALERS 9 T. S. Purewal Abstract 9 Introduction 10 The Composition of a MDI 11 The Active Substance 12 The Propellant System 16 The Surfactant (Surface Active Agent) 24 The Metering Valve 39 The Container 45 The Actuator and Adaptor 46 CFCs and the Ozone Layer 53 Formulating with Ozone Benign Propellants 54 Hydrocarbons 54 Hydrochlorofluorocarbons (HCFCs) 55 Dimethyl Ether 56 Perfluorocarbons 56 Hydrofluorocarbons (i.e., Hydrofluoroalkanesj (HFCs/HFAsj 57 Compressed Gases and High Pressure Liquefied Gases 58 Use of Spacer Devices with MDIs 60 A Comparison of MDI and DPI (Dry Powder Inhaler) Technologies 62 References 65

4 Contents v 3. THE MANUFACTURE OF METERED DOSE INHALERS 69 Anthony Wilkinson Abstract 69 Manufacturing History 70 Manufacturing Overview 71 Micronisation 73 General Principles 73 Outline of Operation 74 Design Variations 77 Optimisation 78 The Cold Fill Process 79 Process Outline 79 Concentrate Manufacture 80 Vessel Charging 82 Filling 88 Valves and Canisters 95 The Pressure Fill Process 96 Process Overview 96 Two-Stage Pressure Filling 97 Single-Stage Pressure Filling 105 Valves and Canisters 107 CFC and HFA Propellants 109 Validation 110 Overview 110 Process Optimisation 111 Process Validation 113 Conclusion 114 References 115

5 vi Metered Dose Inhaler Technology 4. PARTICLE SIZE ANALYSIS IN INHALATION THERAPY 117 Clive Washington The Characterisation of Solid Feedstocks 119 The Study of Particles in the Aerosol Plume 121 Inertia! Impaction 121 BP Aerosol Samplers 124 Multistage Impactors 127 Optical Methods 129 Diffraction Sizers 131 Single Particle Sizers 132 Doppler and Phase Doppler Anemometry 134 Characterisation of Particles in Propellant Suspensions 134 Microscopic Studies 137 Rheometer-Based Studies 138 Conclusions 145 References ANALYTICAL DEVELOPMENT AND TESTING 147 R. Harris Cummings Alfred G. Childers Michael T. Riebe Life Cycle of Characterization and Testing 150 Preformulation 150 Formulation 150 Raw Materials 151

6 Contents vii Component Selection and Quality Control 151 Manufacturing Process Development, Optimization, and Validation 152 Final Development 153 Stability Testing of MDIs 153 Quality Control and Release Testing 155 Commercial Stability Programs 156 Description and Discussion of MDI Tests 156 Dose Delivery 157 Weight per Actuation 162 Actuator Deposition 163 Label Claim Number of Actuations 163 Pressure 164 Microbial Limits 165 Priming 165 Cascade Impaction 166 Microscopic Particle Size Analysis 170 Identification of the Drug Product 172 Appearance 172 Drug-Related Impurities, Drug Content in the Can, and Net Fill Weight 173 Weight Change of Reserve Cans 174 USP Leak Rate 174 Water Content 175 Spray Pattern 176 Plume Geometry 177 Foreign Particulate Matter 179 Extractables 180 Summary 182 References 183 Bibliography 184

7 viii Metered Dose Inhaler Technology 6. PHARMACOKINETICS AND METABOLISM OF PROPELLANTS 187 Lester I. Harrison Abstract 187 Introduction 188 Respiratory Physiology 189 Propellant Dose: A Perspective 191 Propellant Measurement in Biological Fluids: Gas Chromatography 192 Propellant Measurement in Biological Fluids and Tissues: Other Methods 194 Partition Coefficients 197 Absorption 198 Calculation of the Administered Dose 198 Absorption Studies 200 Rate and Extent of Absorption 202 Data Analysis 202 Distribution 205 Metabolism 207 In Vitro Metabolism 209 In Vivo Studies 210 Metabolic Adducts 210 Elimination 211 Pharmacokinetic Modeling 212 Pharmacokinetic Risk Assessment 216 Summary 217 References 220

8 Contents ix 7. TOXICOLOGY OF PROPELLANTS 229 Chet L. Leach Abstract 229 Introduction 230 Who Should Conduct the Toxicology Program? 231 What Determines the Scale of the Toxicology Program? 232 What Is an Example of a Full Toxicology Program? 233 Genetic Toxicology Testing 234 Primary Irritation Studies 236 Inhalation Studies 236 The Inhalation Exposure System 236 Propellant Concentration Monitoring 239 Dose Selection 241 Acute Inhalation Toxicology Tests 243 Safety Pharmacology Inhalation Tests 243 Subchronic Inhalation Toxicology Tests 247 Reproductive Inhalation Toxicology Tests 248 Carcinogenicity and Chronic Inhalation Studies 249 Metabolism and Pharmacokinetic Studies 251 Conclusions 251 References 252 INDEX 255

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