Delivery Systems for Tuberculosis Prevention and Treatment

Anthony J. Hickey, Distinguished Fellow (appointed June 2012), is a Program Director in Inhaled Therapeutics in the Center for Aerosol and Nanomaterials Engineering at the Research Triangle Institute, North Carolina, USA. Dr Hickey has more than 30 years of academic and research experience in pulmonary biology, aerosol physics, powder dynamics, pharmacokinetics and drug disposition, formulation design, and device development. Since joining RTI in 2011, he has conducted research related to pulmonary drug and vaccine delivery for tuberculosis treatment and therapy. Additionally, Dr. Hickey is an adjunct professor of biomedical engineering at the University of North Carolina at Chapel Hill School of Medicine, emeritus professor of molecular pharmaceutics at the University of North Carolina at Chapel Hill Eshelman School of Pharmacy, and founder and president of Cirrus Pharmaceuticals, Inc.

List of Contributors xvi Foreword xviii Series Preface xxi Preface xxiii 1 Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery 1 A.J. Hickey 1.1 Background 1 1.2 Dosage Form Classification 3 1.3 Controlled and Targeted Delivery 5 1.4 Physiological and Disease Considerations 6 1.5 Therapeutic Considerations 7 1.6 Conclusion 8 References 8 Section 1 Pathogen and Host 11 2 Host Pathogen Biology for Airborne Mycobacterium tuberculosis: Cellular and Molecular Events in the Lung 13 Eusondia Arnett, Nitya Krishnan, Brian D. Robertson and Larry S. Schlesinger 2.1 Introduction 13 2.2 Lung 14 2.3 General Aspects of Mucus and Surfactant 17 2.4 General M. tuberculosis 18 2.5 M. tuberculosis Interaction with the Lung Macrophage 19 2.6 M. tuberculosis Interaction with other Respiratory Immune Cells 23 2.7 TB Granuloma 29 2.8 Conclusion 30 References 30 3 Animal Models of Tuberculosis 48 David N. McMurray 3.1 Introduction 48 3.2 What is an Animal Model of TB? 49 3.3 How are Animal Models of TB Used? 50 3.4 TB Animal Models Currently Used for TB Drug and Vaccine Evaluation 51 3.5 Summary 58 References 59 Section 2 Immunological Intervention 67 4 Vaccine Preparation: Past, Present, and Future 69 Dominique N. Price, Nitesh K. Kunda, Amber A. McBride and Pavan Muttil 4.1 Introduction 69 4.2 Early Efforts in TB Vaccine Development 71 4.3 Current BCG Vaccine Formulation 73 4.4 Novel TB Vaccination Strategies 76 4.5 Future Perspective 84 4.6 Conclusions 85 References 85 5 TB Vaccine Assessment 91 Andre G. Loxton, Mary K. Hondalus and Samantha L. Sampson 5.1 Introduction 91 5.2 Preclinical Vaccine Assessment 92 5.3 Clinical Assessment of Vaccines 97 5.4 Laboratory Immunological Analysis and Assessment of Vaccine Trials 102 5.5 How well do the Available Preclinical Models Predict Vaccine Success in Humans? 103 References 105 Section 3 Drug Treatment 111 6 Testing Inhaled Drug Therapies for Treating Tuberculosis 113 Ellen F. Young, Anthony J. Hickey and Miriam Braunstein 6.1 Introduction 113 6.2 The Need for New Drug Treatments for Tuberculosis 114 6.3 Inhaled Drug Therapy for Tuberculosis 114 6.4 Published Studies of Inhalation Therapy for TB 115 6.5 The Guinea Pig Model for Testing Inhaled Therapies for TB 116 6.6 Guinea Pig Study Design 117 6.7 Purchase and Grouping Animals 118 6.8 Infecting Guinea Pigs with Virulent Mycobacterium tuberculosis 118 6.9 Dosing Groups of Guinea Pigs with TB Drugs 119 6.10 Collecting Data 121 6.11 Aerosol Dosing Chambers and Practice 122 6.12 Nebulizer Aerosol Delivery Systems for Liquids 123 6.13 Dry-Powder Aerosol Delivery Systems for Solids 125 6.14 Summary 127 Acknowledgements 127 References 127 7 Preclinical Pharmacokinetics of Antitubercular Drugs 131 Mariam Ibrahim and Lucila Garcia-Contreras 7.1 Introduction 131 7.2 Factors Influencing the Pharmacokinetic Behavior of Drugs 132 7.3 Pulmonary Delivery of Anti-TB Drugs 138 7.4 Pharmacokinetic Study Design 140 7.5 Implications of PK Parameters on Efficacy 144 7.6 Case Studies (Drugs Administered by Conventional and Pulmonary Routes) 146 References 152 8 Drug Particle Manufacture Supercritical Fluid, High-Pressure Homogenization 156 Kimiko Makino and Hiroshi Terada 8.1 Introduction 156 8.2 Preparation of Nano- and Micro-particles 157 References 159 9 Spray Drying Strategies to Stop Tuberculosis 161 Jennifer Wong, Maurizio Ricci and Hak-Kim Chan 9.1 Introduction 161 9.2 Overview of Spray Drying 162 9.3 Advances in Spray Drying Technology 174 9.4 Anti-Tuberculosis Therapeutics Produced by Spray Drying 179 9.5 Conclusion 187 9.6 Acknowledgements 187 References 187 10 Formulation Strategies for Antitubercular Drugs by Inhalation 197 Francesca Buttini and Gaia Colombo 10.1 Introduction