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 197

10.2 Lung Delivery of TB Drugs 198

10.3 Powders for Inhalation and Liquids for Nebulization 200

10.4 Antibacterial Powders for Inhalation: Manufacturing of Respirable Microparticles 202

10.5 Antibacterial Powders for Inhalation: Devices and Delivery Strategies 208

10.6 Conclusions and Perspectives 211

References 211

11 Inhaled Drug Combinations 213
Sanketkumar Pandya, Anuradha Gupta, Rajeev Ranjan, Madhur Sachan, Atul Kumar Agrawal and Amit Misra

11.1 Introduction 213

11.2 Standard Combinations in Oral and Parenteral Regimens 214

11.3 The Rationale for Inhaled Therapies of TB 216

11.4 Combinations of Anti-TB Drugs with Other Agents 222

11.5 Formulation of Inhaled Drug Combinations 224

11.6 Conclusions 230

References 230

12 Ion Pairing for Controlling Drug Delivery 239
Stefano Giovagnoli, Aurélie Schoubben and Carlo Rossi

12.1 Introduction 239

12.2 Ion Pairing Definitions and Concepts 240

12.3 Ion Pairs, Complexes and Drug Delivery 245

12.4 Remarks 252

References 254

13 Understanding the Respiratory Delivery of High Dose Anti-Tubercular Drugs 258
Shyamal C. Das and Peter J. Stewart

13.1 Introduction 258

13.2 Tuberculosis 259

13.3 Drugs Used to Treat Tuberculosis, Doses, Challenges and Requirements for Therapy in Lungs 260

13.4 Approaches for Respiratory Delivery of Drugs 262

13.5 Current DPI Formulations and Their Mechanisms of Aerosolization 262

13.6 DPI Formulations for Tuberculosis and Requirements 264

13.7 Issues to Consider in Respiratory Delivery of Powders for Tuberculosis 264

13.8 Relationship between De-agglomeration and Tensile Strength 266

13.9 Strategies to Improve De-agglomeration 268

13.10 DPI Formulations having High Aerosolization 269

13.11 Devices for High Dose Delivery 270

13.12 Future Considerations 271

References 272

Section 4 Alternative Approaches 275

14 Respirable Bacteriophage Aerosols for the Prevention and Treatment of Tuberculosis 277
Graham F. Hatfull and Reinhard Vehring

14.1 Introduction 277

14.2 Treatment or Prevention of Tuberculosis Using Phage-based Agents 282

14.3 Selection of Mycobacteriophages 284

14.4 Respiratory Drug Delivery of Phages 285

14.5 Summary and Outlook 288

Acknowledgements 288

References 288

15 RNA Nanoparticles as Potential Vaccines 293
Robert DeLong

15.1 Introduction 293

15.2 Nanoparticles 293

15.3 RNA Nanoparticle Vaccines 294

15.4 Progression of Nanomedicines into the Clinic 295

15.5 The Stability Problem 295

15.6 The Delivery Problem 298

15.7 RNA as Targeting Agent or Adjuvant? 298

15.8 Challenges for RNA Nanoparticle Vaccine Characterization 300

15.9 On the Horizon 301

References 301

16 Local Pulmonary Host-Directed Therapies for Tuberculosis via Aerosol Delivery 307
Mercedes Gonzalez-Juarrero

16.1 Introduction 307

16.2 Lung Immunity to Pulmonary M. tuberculosis Infection 309

16.3 Host-Directed Therapies 313

16.4 Limitations of Preclinical Studies to Develop Inhalational Host-Directed Therapies for Tuberculosis 317

16.5 Preclinical Testing of Inhaled Small Interference RNA as Host-Directed Therapies for Tuberculosis 318

Acknowledgements 319

References 319

Section 5 Future Opportunities 325

17 Treatments for Mycobacterial Persistence and Biofilm Growth 327
David L. Hava and Jean C. Sung

17.1 Introduction 327

17.2 Mycobacterial Persistence and Drug Tolerance 328

17.3 Mycobacterial Multicellular Growth 329

17.4 Mycobacterial Lipids Involved in Biofilm Formation 330

17.5 Therapies to Treat Mycobacterial Biofilms and Persistence 332

17.6 Conclusion 339

References 339

18 Directed Intervention and Immunomodulation against Pulmonary Tuberculosis 346
Dominique N. Price and Pavan Muttil

18.1 Introduction 346

18.2 TB Immunology 347

18.3 Animal Models of Immunotherapies and Vaccines for TB 351

18.4 The Current TB Vaccine – Bacille Calmette Guérin 353

18.5 Other Vaccines Platforms 357

18.6 Pulmonary Immunization 361

18.7 Immunotherapeutic Agents against TB 364

18.8 Conclusion 367

References 367

Section 6 Clinical Perspective 379

19 Clinical and Public Health Perspectives 381
Ruvandhi R. Nathavitharana and Edward A. Nardell

19.1 Introduction 381

19.2 Background 382

19.3 Clinical Considerations 382

19.4 Public Health Considerations 385

19.5 Inhaled Drugs and Other Alternative Delivery Systems 387

19.6 Clinical Trials of Inhaled Injectable Drugs 388

19.7 Other Novel Delivery Strategies 393

19.8 Pediatric Delivery Systems 393

19.9 Conclusion 394

References 394

20 Concluding Remarks: Prospects and Challenges for Advancing New Drug and Vaccine Delivery Systems into Clinical Application 400
P. Bernard Fourie and Richard Hafner

20.1 Introduction 400

20.2 Progress in the Formulation and Manufacturing of Drugs and Vaccines for Tuberculosis 401

20.3 Considerations in the Development of TB Drug and Vaccine Delivery Options 404

20.4 Concluding Remarks 410

References 411

Index 415