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.

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• List of Contributors xviForeword xviiiSeries Preface xxiPreface xxiii1 Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery 1A.J. Hickey1.1 Background 11.2 Dosage Form Classification 31.3 Controlled and Targeted Delivery 51.4 Physiological and Disease Considerations 61.5 Therapeutic Considerations 71.6 Conclusion 8References 8Section 1 Pathogen and Host 112 Host Pathogen Biology for Airborne Mycobacterium tuberculosis: Cellular and Molecular Events in the Lung 13Eusondia Arnett, Nitya Krishnan, Brian D. Robertson and Larry S. Schlesinger2.1 Introduction 132.2 Lung 142.3 General Aspects of Mucus and Surfactant 172.4 General M. tuberculosis 182.5 M. tuberculosis Interaction with the Lung Macrophage 192.6 M. tuberculosis Interaction with other Respiratory Immune Cells 232.7 TB Granuloma 292.8 Conclusion 30References 303 Animal Models of Tuberculosis 48David N. McMurray3.1 Introduction 483.2 What is an Animal Model of TB? 493.3 How are Animal Models of TB Used? 503.4 TB Animal Models Currently Used for TB Drug and Vaccine Evaluation 513.5 Summary 58References 59Section 2 Immunological Intervention 674 Vaccine Preparation: Past, Present, and Future 69Dominique N. Price, Nitesh K. Kunda, Amber A. McBride and Pavan Muttil4.1 Introduction 694.2 Early Efforts in TB Vaccine Development 714.3 Current BCG Vaccine Formulation 734.4 Novel TB Vaccination Strategies 764.5 Future Perspective 844.6 Conclusions 85References 855 TB Vaccine Assessment 91Andre G. Loxton, Mary K. Hondalus and Samantha L. Sampson5.1 Introduction 915.2 Preclinical Vaccine Assessment 925.3 Clinical Assessment of Vaccines 975.4 Laboratory Immunological Analysis and Assessment of Vaccine Trials 1025.5 How well do the Available Preclinical Models Predict Vaccine Success in Humans? 103References 105Section 3 Drug Treatment 1116 Testing Inhaled Drug Therapies for Treating Tuberculosis 113Ellen F. Young, Anthony J. Hickey and Miriam Braunstein6.1 Introduction 1136.2 The Need for New Drug Treatments for Tuberculosis 1146.3 Inhaled Drug Therapy for Tuberculosis 1146.4 Published Studies of Inhalation Therapy for TB 1156.5 The Guinea Pig Model for Testing Inhaled Therapies for TB 1166.6 Guinea Pig Study Design 1176.7 Purchase and Grouping Animals 1186.8 Infecting Guinea Pigs with Virulent Mycobacterium tuberculosis 1186.9 Dosing Groups of Guinea Pigs with TB Drugs 1196.10 Collecting Data 1216.11 Aerosol Dosing Chambers and Practice 1226.12 Nebulizer Aerosol Delivery Systems for Liquids 1236.13 Dry-Powder Aerosol Delivery Systems for Solids 1256.14 Summary 127Acknowledgements 127References 1277 Preclinical Pharmacokinetics of Antitubercular Drugs 131Mariam Ibrahim and Lucila Garcia-Contreras7.1 Introduction 1317.2 Factors Influencing the Pharmacokinetic Behavior of Drugs 1327.3 Pulmonary Delivery of Anti-TB Drugs 1387.4 Pharmacokinetic Study Design 1407.5 Implications of PK Parameters on Efficacy 1447.6 Case Studies (Drugs Administered by Conventional and Pulmonary Routes) 146References 1528 Drug Particle Manufacture – Supercritical Fluid, High-Pressure Homogenization 156Kimiko Makino and Hiroshi Terada8.1 Introduction 1568.2 Preparation of Nano- and Micro-particles 157References 1599 Spray Drying Strategies to Stop Tuberculosis 161Jennifer Wong, Maurizio Ricci and Hak-Kim Chan9.1 Introduction 1619.2 Overview of Spray Drying 1629.3 Advances in Spray Drying Technology 1749.4 Anti-Tuberculosis Therapeutics Produced by Spray Drying 1799.5 Conclusion 1879.6 Acknowledgements 187References 18710 Formulation Strategies for Antitubercular Drugs by Inhalation 197Francesca Buttini and Gaia Colombo10.1 Introduction 19710.2 Lung Delivery of TB Drugs 19810.3 Powders for Inhalation and Liquids for Nebulization 20010.4 Antibacterial Powders for Inhalation: Manufacturing of Respirable Microparticles 20210.5 Antibacterial Powders for Inhalation: Devices and Delivery Strategies 20810.6 Conclusions and Perspectives 211References 21111 Inhaled Drug Combinations 213Sanketkumar Pandya, Anuradha Gupta, Rajeev Ranjan, Madhur Sachan, Atul Kumar Agrawal and Amit Misra11.1 Introduction 21311.2 Standard Combinations in Oral and Parenteral Regimens 21411.3 The Rationale for Inhaled Therapies of TB 21611.4 Combinations of Anti-TB Drugs with Other Agents 22211.5 Formulation of Inhaled Drug Combinations 22411.6 Conclusions 230References 23012 Ion Pairing for Controlling Drug Delivery 239Stefano Giovagnoli, Aurélie Schoubben and Carlo Rossi12.1 Introduction 23912.2 Ion Pairing Definitions and Concepts 24012.3 Ion Pairs, Complexes and Drug Delivery 24512.4 Remarks 252References 25413 Understanding the Respiratory Delivery of High Dose Anti-Tubercular Drugs 258Shyamal C. Das and Peter J. Stewart13.1 Introduction 25813.2 Tuberculosis 25913.3 Drugs Used to Treat Tuberculosis, Doses, Challenges and Requirements for Therapy in Lungs 26013.4 Approaches for Respiratory Delivery of Drugs 26213.5 Current DPI Formulations and Their Mechanisms of Aerosolization 26213.6 DPI Formulations for Tuberculosis and Requirements 26413.7 Issues to Consider in Respiratory Delivery of Powders for Tuberculosis 26413.8 Relationship between De-agglomeration and Tensile Strength 26613.9 Strategies to Improve De-agglomeration 26813.10 DPI Formulations having High Aerosolization 26913.11 Devices for High Dose Delivery 27013.12 Future Considerations 271References 272Section 4 Alternative Approaches 27514 Respirable Bacteriophage Aerosols for the Prevention and Treatment of Tuberculosis 277Graham F. Hatfull and Reinhard Vehring14.1 Introduction 27714.2 Treatment or Prevention of Tuberculosis Using Phage-based Agents 28214.3 Selection of Mycobacteriophages 28414.4 Respiratory Drug Delivery of Phages 28514.5 Summary and Outlook 288Acknowledgements 288References 28815 RNA Nanoparticles as Potential Vaccines 293Robert DeLong15.1 Introduction 29315.2 Nanoparticles 29315.3 RNA Nanoparticle Vaccines 29415.4 Progression of Nanomedicines into the Clinic 29515.5 The Stability Problem 29515.6 The Delivery Problem 29815.7 RNA as Targeting Agent or Adjuvant? 29815.8 Challenges for RNA Nanoparticle Vaccine Characterization 30015.9 On the Horizon 301References 30116 Local Pulmonary Host-Directed Therapies for Tuberculosis via Aerosol Delivery 307Mercedes Gonzalez-Juarrero16.1 Introduction 30716.2 Lung Immunity to Pulmonary M. tuberculosis Infection 30916.3 Host-Directed Therapies 31316.4 Limitations of Preclinical Studies to Develop Inhalational Host-Directed Therapies for Tuberculosis 31716.5 Preclinical Testing of Inhaled Small Interference RNA as Host-Directed Therapies for Tuberculosis 318Acknowledgements 319References 319Section 5 Future Opportunities 32517 Treatments for Mycobacterial Persistence and Biofilm Growth 327David L. Hava and Jean C. Sung17.1 Introduction 32717.2 Mycobacterial Persistence and Drug Tolerance 32817.3 Mycobacterial Multicellular Growth 32917.4 Mycobacterial Lipids Involved in Biofilm Formation 33017.5 Therapies to Treat Mycobacterial Biofilms and Persistence 33217.6 Conclusion 339References 33918 Directed Intervention and Immunomodulation against Pulmonary Tuberculosis 346Dominique N. Price and Pavan Muttil18.1 Introduction 34618.2 TB Immunology 34718.3 Animal Models of Immunotherapies and Vaccines for TB 35118.4 The Current TB Vaccine – Bacille Calmette Guérin 35318.5 Other Vaccines Platforms 35718.6 Pulmonary Immunization 36118.7 Immunotherapeutic Agents against TB 36418.8 Conclusion 367References 367Section 6 Clinical Perspective 37919 Clinical and Public Health Perspectives 381Ruvandhi R. Nathavitharana and Edward A. Nardell19.1 Introduction 38119.2 Background 38219.3 Clinical Considerations 38219.4 Public Health Considerations 38519.5 Inhaled Drugs and Other Alternative Delivery Systems 38719.6 Clinical Trials of Inhaled Injectable Drugs 38819.7 Other Novel Delivery Strategies 39319.8 Pediatric Delivery Systems 39319.9 Conclusion 394References 39420 Concluding Remarks: Prospects and Challenges for Advancing New Drug and Vaccine Delivery Systems into Clinical Application 400P. Bernard Fourie and Richard Hafner20.1 Introduction 40020.2 Progress in the Formulation and Manufacturing of Drugs and Vaccines for Tuberculosis 40120.3 Considerations in the Development of TB Drug and Vaccine Delivery Options 40420.4 Concluding Remarks 410References 411Index 415

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.

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• List of Contributors xviForeword xviiiSeries Preface xxiPreface xxiii1 Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery 1A.J. Hickey1.1 Background 11.2 Dosage Form Classification 31.3 Controlled and Targeted Delivery 51.4 Physiological and Disease Considerations 61.5 Therapeutic Considerations 71.6 Conclusion 8References 8Section 1 Pathogen and Host 112 Host Pathogen Biology for Airborne Mycobacterium tuberculosis: Cellular and Molecular Events in the Lung 13Eusondia Arnett, Nitya Krishnan, Brian D. Robertson and Larry S. Schlesinger2.1 Introduction 132.2 Lung 142.3 General Aspects of Mucus and Surfactant 172.4 General M. tuberculosis 182.5 M. tuberculosis Interaction with the Lung Macrophage 192.6 M. tuberculosis Interaction with other Respiratory Immune Cells 232.7 TB Granuloma 292.8 Conclusion 30References 303 Animal Models of Tuberculosis 48David N. McMurray3.1 Introduction 483.2 What is an Animal Model of TB? 493.3 How are Animal Models of TB Used? 503.4 TB Animal Models Currently Used for TB Drug and Vaccine Evaluation 513.5 Summary 58References 59Section 2 Immunological Intervention 674 Vaccine Preparation: Past, Present, and Future 69Dominique N. Price, Nitesh K. Kunda, Amber A. McBride and Pavan Muttil4.1 Introduction 694.2 Early Efforts in TB Vaccine Development 714.3 Current BCG Vaccine Formulation 734.4 Novel TB Vaccination Strategies 764.5 Future Perspective 844.6 Conclusions 85References 855 TB Vaccine Assessment 91Andre G. Loxton, Mary K. Hondalus and Samantha L. Sampson5.1 Introduction 915.2 Preclinical Vaccine Assessment 925.3 Clinical Assessment of Vaccines 975.4 Laboratory Immunological Analysis and Assessment of Vaccine Trials 1025.5 How well do the Available Preclinical Models Predict Vaccine Success in Humans? 103References 105Section 3 Drug Treatment 1116 Testing Inhaled Drug Therapies for Treating Tuberculosis 113Ellen F. Young, Anthony J. Hickey and Miriam Braunstein6.1 Introduction 1136.2 The Need for New Drug Treatments for Tuberculosis 1146.3 Inhaled Drug Therapy for Tuberculosis 1146.4 Published Studies of Inhalation Therapy for TB 1156.5 The Guinea Pig Model for Testing Inhaled Therapies for TB 1166.6 Guinea Pig Study Design 1176.7 Purchase and Grouping Animals 1186.8 Infecting Guinea Pigs with Virulent Mycobacterium tuberculosis 1186.9 Dosing Groups of Guinea Pigs with TB Drugs 1196.10 Collecting Data 1216.11 Aerosol Dosing Chambers and Practice 1226.12 Nebulizer Aerosol Delivery Systems for Liquids 1236.13 Dry-Powder Aerosol Delivery Systems for Solids 1256.14 Summary 127Acknowledgements 127References 1277 Preclinical Pharmacokinetics of Antitubercular Drugs 131Mariam Ibrahim and Lucila Garcia-Contreras7.1 Introduction 1317.2 Factors Influencing the Pharmacokinetic Behavior of Drugs 1327.3 Pulmonary Delivery of Anti-TB Drugs 1387.4 Pharmacokinetic Study Design 1407.5 Implications of PK Parameters on Efficacy 1447.6 Case Studies (Drugs Administered by Conventional and Pulmonary Routes) 146References 1528 Drug Particle Manufacture – Supercritical Fluid, High-Pressure Homogenization 156Kimiko Makino and Hiroshi Terada8.1 Introduction 1568.2 Preparation of Nano- and Micro-particles 157References 1599 Spray Drying Strategies to Stop Tuberculosis 161Jennifer Wong, Maurizio Ricci and Hak-Kim Chan9.1 Introduction 1619.2 Overview of Spray Drying 1629.3 Advances in Spray Drying Technology 1749.4 Anti-Tuberculosis Therapeutics Produced by Spray Drying 1799.5 Conclusion 1879.6 Acknowledgements 187References 18710 Formulation Strategies for Antitubercular Drugs by Inhalation 197Francesca Buttini and Gaia Colombo10.1 Introduction 19710.2 Lung Delivery of TB Drugs 19810.3 Powders for Inhalation and Liquids for Nebulization 20010.4 Antibacterial Powders for Inhalation: Manufacturing of Respirable Microparticles 20210.5 Antibacterial Powders for Inhalation: Devices and Delivery Strategies 20810.6 Conclusions and Perspectives 211References 21111 Inhaled Drug Combinations 213Sanketkumar Pandya, Anuradha Gupta, Rajeev Ranjan, Madhur Sachan, Atul Kumar Agrawal and Amit Misra11.1 Introduction 21311.2 Standard Combinations in Oral and Parenteral Regimens 21411.3 The Rationale for Inhaled Therapies of TB 21611.4 Combinations of Anti-TB Drugs with Other Agents 22211.5 Formulation of Inhaled Drug Combinations 22411.6 Conclusions 230References 23012 Ion Pairing for Controlling Drug Delivery 239Stefano Giovagnoli, Aurélie Schoubben and Carlo Rossi12.1 Introduction 23912.2 Ion Pairing Definitions and Concepts 24012.3 Ion Pairs, Complexes and Drug Delivery 24512.4 Remarks 252References 25413 Understanding the Respiratory Delivery of High Dose Anti-Tubercular Drugs 258Shyamal C. Das and Peter J. Stewart13.1 Introduction 25813.2 Tuberculosis 25913.3 Drugs Used to Treat Tuberculosis, Doses, Challenges and Requirements for Therapy in Lungs 26013.4 Approaches for Respiratory Delivery of Drugs 26213.5 Current DPI Formulations and Their Mechanisms of Aerosolization 26213.6 DPI Formulations for Tuberculosis and Requirements 26413.7 Issues to Consider in Respiratory Delivery of Powders for Tuberculosis 26413.8 Relationship between De-agglomeration and Tensile Strength 26613.9 Strategies to Improve De-agglomeration 26813.10 DPI Formulations having High Aerosolization 26913.11 Devices for High Dose Delivery 27013.12 Future Considerations 271References 272Section 4 Alternative Approaches 27514 Respirable Bacteriophage Aerosols for the Prevention and Treatment of Tuberculosis 277Graham F. Hatfull and Reinhard Vehring14.1 Introduction 27714.2 Treatment or Prevention of Tuberculosis Using Phage-based Agents 28214.3 Selection of Mycobacteriophages 28414.4 Respiratory Drug Delivery of Phages 28514.5 Summary and Outlook 288Acknowledgements 288References 28815 RNA Nanoparticles as Potential Vaccines 293Robert DeLong15.1 Introduction 29315.2 Nanoparticles 29315.3 RNA Nanoparticle Vaccines 29415.4 Progression of Nanomedicines into the Clinic 29515.5 The Stability Problem 29515.6 The Delivery Problem 29815.7 RNA as Targeting Agent or Adjuvant? 29815.8 Challenges for RNA Nanoparticle Vaccine Characterization 30015.9 On the Horizon 301References 30116 Local Pulmonary Host-Directed Therapies for Tuberculosis via Aerosol Delivery 307Mercedes Gonzalez-Juarrero16.1 Introduction 30716.2 Lung Immunity to Pulmonary M. tuberculosis Infection 30916.3 Host-Directed Therapies 31316.4 Limitations of Preclinical Studies to Develop Inhalational Host-Directed Therapies for Tuberculosis 31716.5 Preclinical Testing of Inhaled Small Interference RNA as Host-Directed Therapies for Tuberculosis 318Acknowledgements 319References 319Section 5 Future Opportunities 32517 Treatments for Mycobacterial Persistence and Biofilm Growth 327David L. Hava and Jean C. Sung17.1 Introduction 32717.2 Mycobacterial Persistence and Drug Tolerance 32817.3 Mycobacterial Multicellular Growth 32917.4 Mycobacterial Lipids Involved in Biofilm Formation 33017.5 Therapies to Treat Mycobacterial Biofilms and Persistence 33217.6 Conclusion 339References 33918 Directed Intervention and Immunomodulation against Pulmonary Tuberculosis 346Dominique N. Price and Pavan Muttil18.1 Introduction 34618.2 TB Immunology 34718.3 Animal Models of Immunotherapies and Vaccines for TB 35118.4 The Current TB Vaccine – Bacille Calmette Guérin 35318.5 Other Vaccines Platforms 35718.6 Pulmonary Immunization 36118.7 Immunotherapeutic Agents against TB 36418.8 Conclusion 367References 367Section 6 Clinical Perspective 37919 Clinical and Public Health Perspectives 381Ruvandhi R. Nathavitharana and Edward A. Nardell19.1 Introduction 38119.2 Background 38219.3 Clinical Considerations 38219.4 Public Health Considerations 38519.5 Inhaled Drugs and Other Alternative Delivery Systems 38719.6 Clinical Trials of Inhaled Injectable Drugs 38819.7 Other Novel Delivery Strategies 39319.8 Pediatric Delivery Systems 39319.9 Conclusion 394References 39420 Concluding Remarks: Prospects and Challenges for Advancing New Drug and Vaccine Delivery Systems into Clinical Application 400P. Bernard Fourie and Richard Hafner20.1 Introduction 40020.2 Progress in the Formulation and Manufacturing of Drugs and Vaccines for Tuberculosis 40120.3 Considerations in the Development of TB Drug and Vaccine Delivery Options 40420.4 Concluding Remarks 410References 411Index 415

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.

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• List of Contributors xviForeword xviiiSeries Preface xxiPreface xxiii1 Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery 1A.J. Hickey1.1 Background 11.2 Dosage Form Classification 31.3 Controlled and Targeted Delivery 51.4 Physiological and Disease Considerations 61.5 Therapeutic Considerations 71.6 Conclusion 8References 8Section 1 Pathogen and Host 112 Host Pathogen Biology for Airborne Mycobacterium tuberculosis: Cellular and Molecular Events in the Lung 13Eusondia Arnett, Nitya Krishnan, Brian D. Robertson and Larry S. Schlesinger2.1 Introduction 132.2 Lung 142.3 General Aspects of Mucus and Surfactant 172.4 General M. tuberculosis 182.5 M. tuberculosis Interaction with the Lung Macrophage 192.6 M. tuberculosis Interaction with other Respiratory Immune Cells 232.7 TB Granuloma 292.8 Conclusion 30References 303 Animal Models of Tuberculosis 48David N. McMurray3.1 Introduction 483.2 What is an Animal Model of TB? 493.3 How are Animal Models of TB Used? 503.4 TB Animal Models Currently Used for TB Drug and Vaccine Evaluation 513.5 Summary 58References 59Section 2 Immunological Intervention 674 Vaccine Preparation: Past, Present, and Future 69Dominique N. Price, Nitesh K. Kunda, Amber A. McBride and Pavan Muttil4.1 Introduction 694.2 Early Efforts in TB Vaccine Development 714.3 Current BCG Vaccine Formulation 734.4 Novel TB Vaccination Strategies 764.5 Future Perspective 844.6 Conclusions 85References 855 TB Vaccine Assessment 91Andre G. Loxton, Mary K. Hondalus and Samantha L. Sampson5.1 Introduction 915.2 Preclinical Vaccine Assessment 925.3 Clinical Assessment of Vaccines 975.4 Laboratory Immunological Analysis and Assessment of Vaccine Trials 1025.5 How well do the Available Preclinical Models Predict Vaccine Success in Humans? 103References 105Section 3 Drug Treatment 1116 Testing Inhaled Drug Therapies for Treating Tuberculosis 113Ellen F. Young, Anthony J. Hickey and Miriam Braunstein6.1 Introduction 1136.2 The Need for New Drug Treatments for Tuberculosis 1146.3 Inhaled Drug Therapy for Tuberculosis 1146.4 Published Studies of Inhalation Therapy for TB 1156.5 The Guinea Pig Model for Testing Inhaled Therapies for TB 1166.6 Guinea Pig Study Design 1176.7 Purchase and Grouping Animals 1186.8 Infecting Guinea Pigs with Virulent Mycobacterium tuberculosis 1186.9 Dosing Groups of Guinea Pigs with TB Drugs 1196.10 Collecting Data 1216.11 Aerosol Dosing Chambers and Practice 1226.12 Nebulizer Aerosol Delivery Systems for Liquids 1236.13 Dry-Powder Aerosol Delivery Systems for Solids 1256.14 Summary 127Acknowledgements 127References 1277 Preclinical Pharmacokinetics of Antitubercular Drugs 131Mariam Ibrahim and Lucila Garcia-Contreras7.1 Introduction 1317.2 Factors Influencing the Pharmacokinetic Behavior of Drugs 1327.3 Pulmonary Delivery of Anti-TB Drugs 1387.4 Pharmacokinetic Study Design 1407.5 Implications of PK Parameters on Efficacy 1447.6 Case Studies (Drugs Administered by Conventional and Pulmonary Routes) 146References 1528 Drug Particle Manufacture – Supercritical Fluid, High-Pressure Homogenization 156Kimiko Makino and Hiroshi Terada8.1 Introduction 1568.2 Preparation of Nano- and Micro-particles 157References 1599 Spray Drying Strategies to Stop Tuberculosis 161Jennifer Wong, Maurizio Ricci and Hak-Kim Chan9.1 Introduction 1619.2 Overview of Spray Drying 1629.3 Advances in Spray Drying Technology 1749.4 Anti-Tuberculosis Therapeutics Produced by Spray Drying 1799.5 Conclusion 1879.6 Acknowledgements 187References 18710 Formulation Strategies for Antitubercular Drugs by Inhalation 197Francesca Buttini and Gaia Colombo10.1 Introduction 19710.2 Lung Delivery of TB Drugs 19810.3 Powders for Inhalation and Liquids for Nebulization 20010.4 Antibacterial Powders for Inhalation: Manufacturing of Respirable Microparticles 20210.5 Antibacterial Powders for Inhalation: Devices and Delivery Strategies 20810.6 Conclusions and Perspectives 211References 21111 Inhaled Drug Combinations 213Sanketkumar Pandya, Anuradha Gupta, Rajeev Ranjan, Madhur Sachan, Atul Kumar Agrawal and Amit Misra11.1 Introduction 21311.2 Standard Combinations in Oral and Parenteral Regimens 21411.3 The Rationale for Inhaled Therapies of TB 21611.4 Combinations of Anti-TB Drugs with Other Agents 22211.5 Formulation of Inhaled Drug Combinations 22411.6 Conclusions 230References 23012 Ion Pairing for Controlling Drug Delivery 239Stefano Giovagnoli, Aurélie Schoubben and Carlo Rossi12.1 Introduction 23912.2 Ion Pairing Definitions and Concepts 24012.3 Ion Pairs, Complexes and Drug Delivery 24512.4 Remarks 252References 25413 Understanding the Respiratory Delivery of High Dose Anti-Tubercular Drugs 258Shyamal C. Das and Peter J. Stewart13.1 Introduction 25813.2 Tuberculosis 25913.3 Drugs Used to Treat Tuberculosis, Doses, Challenges and Requirements for Therapy in Lungs 26013.4 Approaches for Respiratory Delivery of Drugs 26213.5 Current DPI Formulations and Their Mechanisms of Aerosolization 26213.6 DPI Formulations for Tuberculosis and Requirements 26413.7 Issues to Consider in Respiratory Delivery of Powders for Tuberculosis 26413.8 Relationship between De-agglomeration and Tensile Strength 26613.9 Strategies to Improve De-agglomeration 26813.10 DPI Formulations having High Aerosolization 26913.11 Devices for High Dose Delivery 27013.12 Future Considerations 271References 272Section 4 Alternative Approaches 27514 Respirable Bacteriophage Aerosols for the Prevention and Treatment of Tuberculosis 277Graham F. Hatfull and Reinhard Vehring14.1 Introduction 27714.2 Treatment or Prevention of Tuberculosis Using Phage-based Agents 28214.3 Selection of Mycobacteriophages 28414.4 Respiratory Drug Delivery of Phages 28514.5 Summary and Outlook 288Acknowledgements 288References 28815 RNA Nanoparticles as Potential Vaccines 293Robert DeLong15.1 Introduction 29315.2 Nanoparticles 29315.3 RNA Nanoparticle Vaccines 29415.4 Progression of Nanomedicines into the Clinic 29515.5 The Stability Problem 29515.6 The Delivery Problem 29815.7 RNA as Targeting Agent or Adjuvant? 29815.8 Challenges for RNA Nanoparticle Vaccine Characterization 30015.9 On the Horizon 301References 30116 Local Pulmonary Host-Directed Therapies for Tuberculosis via Aerosol Delivery 307Mercedes Gonzalez-Juarrero16.1 Introduction 30716.2 Lung Immunity to Pulmonary M. tuberculosis Infection 30916.3 Host-Directed Therapies 31316.4 Limitations of Preclinical Studies to Develop Inhalational Host-Directed Therapies for Tuberculosis 31716.5 Preclinical Testing of Inhaled Small Interference RNA as Host-Directed Therapies for Tuberculosis 318Acknowledgements 319References 319Section 5 Future Opportunities 32517 Treatments for Mycobacterial Persistence and Biofilm Growth 327David L. Hava and Jean C. Sung17.1 Introduction 32717.2 Mycobacterial Persistence and Drug Tolerance 32817.3 Mycobacterial Multicellular Growth 32917.4 Mycobacterial Lipids Involved in Biofilm Formation 33017.5 Therapies to Treat Mycobacterial Biofilms and Persistence 33217.6 Conclusion 339References 33918 Directed Intervention and Immunomodulation against Pulmonary Tuberculosis 346Dominique N. Price and Pavan Muttil18.1 Introduction 34618.2 TB Immunology 34718.3 Animal Models of Immunotherapies and Vaccines for TB 35118.4 The Current TB Vaccine – Bacille Calmette Guérin 35318.5 Other Vaccines Platforms 35718.6 Pulmonary Immunization 36118.7 Immunotherapeutic Agents against TB 36418.8 Conclusion 367References 367Section 6 Clinical Perspective 37919 Clinical and Public Health Perspectives 381Ruvandhi R. Nathavitharana and Edward A. Nardell19.1 Introduction 38119.2 Background 38219.3 Clinical Considerations 38219.4 Public Health Considerations 38519.5 Inhaled Drugs and Other Alternative Delivery Systems 38719.6 Clinical Trials of Inhaled Injectable Drugs 38819.7 Other Novel Delivery Strategies 39319.8 Pediatric Delivery Systems 39319.9 Conclusion 394References 39420 Concluding Remarks: Prospects and Challenges for Advancing New Drug and Vaccine Delivery Systems into Clinical Application 400P. Bernard Fourie and Richard Hafner20.1 Introduction 40020.2 Progress in the Formulation and Manufacturing of Drugs and Vaccines for Tuberculosis 40120.3 Considerations in the Development of TB Drug and Vaccine Delivery Options 40420.4 Concluding Remarks 410References 411Index 415