Delivery Systems for Tuberculosis Prevention and Treatment E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Advances in Pharmaceutical Technology
• Sprache: Englisch

Seitenzahl: 1017

Veröffentlichungsjahr: 2016

Beschreibung

Provides a review of novel pharmaceutical approaches for Tuberculosis drugs

• Presents a novel perspective on tuberculosis prevention and treatment
• Considers the nature of disease, immunological responses, vaccine and drug delivery, disposition and response
• Multidisciplinary appeal, with contributions from microbiology, immunology, molecular biology, pharmaceutics, pharmacokinetics, chemical and mechanical engineering

Leseprobe

ADVANCES IN PHARMACEUTICAL TECHNOLOGY

A Wiley Book Series

Series Editors:Dennis Douroumis, University of Greenwich, UKAlfred Fahr, Friedrich–Schiller University of Jena, GermanyJűrgen Siepmann, University of Lille, FranceMartin Snowden, University of Greenwich, UKVladimir Torchilin, Northeastern University, USA

Titles in the Series

Hot-Melt Extrusion: Pharmaceutical ApplicationsEdited by Dionysios Douroumis

Drug Delivery Strategies for Poorly Water-Soluble DrugsEdited by Dionysios Douroumis and Alfred Fahr

Computational Pharmaceutics: Application of Molecular Modeling in Drug DeliveryEdited by Defang Ouyang and Sean C. Smith

Pulmonary Drug Delivery: Advances and ChallengesEdited by Ali Nokhodchi and Gary P. Martin

Novel Delivery Systems for Transdermal and Intradermal Drug DeliveryEdited by Ryan Donnelly and Raj Singh

Forthcoming titles:

In Vitro Drug Release Testing of Special Dosage FormsEdited by Nikoletta Fotaki and Sandra Klein

Drug Delivery Systems for Tuberculosis Prevention and Treatment

Editor

ANTHONY J. HICKEY

RTI International, Research Triangle Park, NC, USA

Consulting Editors

AMIT MISRA

CSIR Central Drug Research Institute, Lucknow, India

P. BERNARD FOURIE

University of Pretoria, Pretoria, South Africa

This edition first published 2016© 2016 John Wiley & Sons, Ltd.

Registered OfficeJohn Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com.

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication data applied for

ISBN: 9781118943175

A catalogue record for this book is available from the British Library.

List of Contributors

Atul Kumar Agrawal, CSIR Central Drug Research Institute, Lucknow, India

Eusondia Arnett, Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, USA

Miriam Braunstein, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA

Francesca Buttini, Department of Pharmacy, University of Parma, Viale delle Scienze, Parma, Italy and Institute of Pharmaceutical Science, King's College London, London, UK

Hak-Kim Chan, Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia

Gaia Colombo, Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara, Ferrara, Italy

Shyamal C. Das, School of Pharmacy, University of Otago, Dunedin, New Zealand

Robert DeLong, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA

P. Bernard Fourie, Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

Lucila Garcia-Contreras, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Stefano Giovagnoli, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Mercedes Gonzalez-Juarrero, Mycobacteria Research Laboratories, Microbiology Immunology and Pathology, Colorado State University, Fort Collins, CO, USA

Anuradha Gupta, CSIR Central Drug Research Institute, Lucknow, India

Richard Hafner, National Institute of Allergy and Infectious Disease and National Institutes of Health, Bethesda, MD, USA

Graham F. Hatfull, Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

David L. Hava, Pulmatrix Inc., Lexington, MA, USA

Anthony J. Hickey, Discovery Sciences Technologies Group, RTI International, Research Triangle Park, NC, USA

Mary K. Hondalus, Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA

Mariam Ibrahim, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Nitya Krishnan, MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London, UK

Nitesh K. Kunda, Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA

Andre G. Loxton, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Kimiko Makino, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Japan

Amber A. McBride, Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA

David N. McMurray, Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, College Station, TX, USA

Amit Misra, CSIR Central Drug Research Institute, Lucknow, India

Pavan Muttil, Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA

Edward A. Nardell, Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA

Ruvandhi R. Nathavitharana, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA

Sanketkumar Pandya, CSIR Central Drug Research Institute, Lucknow, India

Dominique N. Price, Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA

Rajeev Ranjan, CSIR Central Drug Research Institute, Lucknow, India

Maurizio Ricci, Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia, Italy

Brian D. Robertson, MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London, London, UK

Carlo Rossi, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Madhur Sachan, CSIR Central Drug Research Institute, Lucknow, India

Samantha L. Sampson, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Larry S. Schlesinger, Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, USA

Aurélie Schoubben, Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

Peter J. Stewart, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

Jean C. Sung, Pulmatrix Inc., Lexington, MA, USA

Hiroshi Terada, Niigata University of Pharmacy and Applied Sciences, Niigata, Japan

Reinhard Vehring, Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada

Jennifer Wong, Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia

Ellen F. Young, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA

Foreword

“As a physician, I have seen how much pain TB patients experience after months of treatment by intramuscular injection (IM). It is almost impossible to inject by IM after one month. I think that aerosol delivery is the future for TB drug delivery because it is directly delivered to the target organ, and it is even more important for patients who have a hard time to take pills. I believe that aerosol delivery of TB drug(s) will be a milestone in TB treatment if successful.” Li Liang, Vice Director Beijing Chest Hospital

Having plagued societies for centuries, tuberculosis (TB) is one of the oldest diseases known to man. While the first drug effective against TB was not developed until 1943, over the next three decades many additional anti-TB drugs were discovered and developed that significantly reduced morbidity and mortality. Yet today it is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. The most recent World Health Organization’s report indicated that TB killed 1.5 million people in 2014, making it a larger cause of death than HIV/AIDS, which was responsible for 1.2 million deaths. Thus, despite the perception that tuberculosis is a disease of the past or a disease of only low-income countries, it remains a major global public health challenge that carries significant global and domestic disease burdens and risks. Because serious societal challenges remain, including extreme poverty, inequity, and disproportionate TB burdens in women and children, TB will remain a significant challenge for the foreseeable future. Furthermore, the face of TB is changing. While global numbers of new TB cases and TB deaths have decreased at an average rate of at least 2 percent per year, TB strains that are resistant to the most commonly used, inexpensive, and least-toxic TB drugs have been identified in almost every country. These multidrug-resistant TB (MDR-TB) strains as well as the growing numbers of the even more serious extensively drug-resistant TB (XDR-TB) strains have been reported from nearly all countries. MDR-TB and XDR-TB cases can be exceedingly difficult and expensive to diagnose and treat successfully.

One of the major barriers to treatment of MDR-TB today is the high cost of second-line drugs that may be 300 to 3000 times more expensive than first-line therapy. Second-line regimens which are administered for between 18 to 24 months are associated with significant adverse events that often lead to discontinuation of treatment. Despite prolonged treatment duration, these regimens are not associated with high cure rates and incomplete, sub-optimal therapy of MDR-TB likely contributes to emergence of XDR-TB. In the face of M. tuberculosis strains resistant to all known classes of anti-TB drugs, leaders in global public health are asking whether XDR-TB is signaling a return to a pre-antibiotic era in TB control. Thus the need for new TB drugs has never been more urgent. Importantly, the search for new regimens and alternative strategies requires a thorough understanding of the preparation and performance of dosage forms.

Recent important gains in TB discovery research, product development, and implementation science and regulatory approval of the first new TB drug in 30 years give reason for optimism. Systematic studies of the biological effects of TB infection are beginning to shed light on the complexity of the human immune response and the dynamic nature of the disease process. As the disease becomes better understood in terms of both pathogen and host molecular biology there is an opportunity for new pharmaceutical approaches based on the route and means of delivery of a range of novel therapeutic agents. New studies are identifying molecules that can be used to diagnose TB or provide the basis of new TB vaccine research strategies, as well as critical biological processes against which new drug targets can be identified. Indeed the current global TB pipeline has multiple candidates in clinical trials – but there are few novel molecular entities. Many more candidates with novel mechanisms of action and chemical diversity are needed to overcome historical drug development attrition rates and emergence of resistance.

In the past, natural products have played a pivotal role in antibiotic drug discovery with most antibacterial drugs being derived from a natural product or natural product lead. A key challenge in the development of natural products as drugs is to combine their inherent antibacterial properties with physicochemical properties that confer oral bioavailability, an attribute that is highly desirable for treatment of MDR-TB. Many drugs are lost to development due to lack of oral bioavailability. However, new approaches to TB drug delivery as described in the current volume have the potential to overcome this barrier. New developments in drug delivery systems and technologies open an exciting avenue that may potentially lead to the repurposing of old drugs and re-evaluation of potential new drugs hitherto thought undeliverable.

Finally, while BCG vaccine remains the world’s most widely used vaccine and protects children against disseminated TB and meningitis, its effectiveness in preventing disease in adults varies widely. New candidate vaccines are being developed that provide protection against disease and possibly infection in animal models. Since the battle between the pathogen and immune response in TB is fought out largely in the lung, it will be essential both to understand protective immune responses in the lung and how to deliver new vaccine candidates to generate protection in the lung. This is another of the key issues in TB treated in this book.

This is a timely volume addressing the application of pharmaceutical sciences and dosage-form design to the development of novel strategies for TB therapy. This volume is arranged to consider the nature of disease, immunological responses, vaccine and drug delivery, disposition and response. In addition to conventional treatments some novel approaches are presented that if successful would create rapid development pathways. The contributors are drawn from the relevant fields of microbiology, immunology, molecular biology, pharmaceutics, pharmacokinetics, and chemical and mechanical engineering. No doubt the knowledge shared by the authors will have a major impact upon development of urgently needed new tools to address the continuing global crisis of TB and the increasing threat of drug-resistant strains.

Gail H. Cassell, Ph.D., D.Sc. (hon)Executive Vice President TB Drug DevelopmentInfectious Disease Research InstituteSenior Lecturer, Department of Global Health and Social MedicineHarvard Medical SchoolVice President Scientific Affairs, Eli Lilly and Company (ret.)

Barbara E. Laughon, Ph.D.Senior Scientist for TB Drug Development Partnerships in the Office of the DirectorDivision of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious DiseasesU.S. National Institutes of Health

Barry Bloom, Ph.D.Harvard University Distinguished Service Professor and Joan L. and Julius H. Jacobson Professor of Public HealthHarvard T. H. Chan School of Public Health

Li Liang, M.D.Vice Director, Beijing Chest HospitalVice Director, Clinical Center on Tuberculosis, China CDCDesignated Director General, TB Society of China Medical Association

Advances in Pharmaceutical Technology: Series Preface

The series Advances in Pharmaceutical Technology covers the principles, methods and technologies that the pharmaceutical industry uses to turn a candidate molecule or new chemical entity into a final drug form and hence a new medicine. The series will explore means of optimizing the therapeutic performance of a drug molecule by designing and manufacturing the best and most innovative of new formulations. The processes associated with the testing of new drugs, the key steps involved in the clinical trials process and the most recent approaches utilized in the manufacture of new medicinal products will all be reported. The focus of the series will very much be on new and emerging technologies and the latest methods used in the drug-development process.

The topics covered by the series include the following:

Formulation:

The manufacture of tablets in all forms (caplets, dispersible, fast-melting) will be described, as will capsules, suppositories, solutions, suspensions and emulsions, aerosols and sprays, injections, powders, ointments and creams, sustained release and the latest transdermal products. The developments in engineering associated with fluid, powder and solids handling, solubility enhancement and colloidal systems, including the stability of emulsions and suspensions, will also be reported within the series. The influence of formulation design on the bioavailability of a drug will be discussed and the importance of formulation with respect to the development of an optimal final new medicinal product will be clearly illustrated.

Drug Delivery:

The use of various excipients and their role in drug delivery will be reviewed. Amongst the topics to be reported and discussed will be a critical appraisal of the current range of modified-release dosage forms currently in use and also those under development. The design and mechanism(s) of controlled-release systems including macromolecular drug delivery, microparticulate-controlled drug delivery, the delivery of biopharmaceuticals, delivery vehicles created for gastrointestinal tract-targeted delivery, transdermal delivery and systems designed specifically for drug delivery to the lung will all be reviewed and critically appraised. Further site-specific systems used for the delivery of drugs across the blood–brain barrier including dendrimers, hydrogels and new innovative biomaterials will be reported.

Manufacturing:

The key elements of the manufacturing steps involved in the production of new medicines will be explored in this series. The importance of crystallization; batch and continuous processing; seeding; and mixing including a description of the key engineering principles relevant to the manufacture of new medicines will all be reviewed and reported. The fundamental processes of quality control including good laboratory practice, good manufacturing practice, Quality by Design, the Deming Cycle, Regulatory requirements and the design of appropriate robust statistical sampling procedures for the control of raw materials will all be an integral part of this book series.

An evaluation of the current analytical methods used to determine drug stability, as well as the quantitative identification of impurities, contaminants and adulterants in pharmaceutical materials will be described, as will the production of therapeutic bio-macromolecules, bacteria, viruses, yeasts, moulds, prions and toxins through chemical synthesis and emerging synthetic/molecular biology techniques. The importance of packaging including the compatibility of materials in contact with drug products and their barrier properties will also be explored.

Advances in Pharmaceutical Technology is intended as a comprehensive one-stop shop for those interested in the development and manufacture of new medicines. The series will appeal to those working in the pharmaceutical and related industries, both large and small, and will also be valuable to those who are studying and learning about the drug-development process and the translation of those drugs into new life-saving and life-enriching medicines.

Dennis DouroumisAlfred FahrJűrgen SiepmannMartin SnowdenVladimir Torchilin

Preface

Tuberculosis remains the world’s most serious cause of disease due to a single infectious micro-organism. Despite the development of a vaccine almost a century ago and with the advent of drug treatment in the intervening period we appear to be no closer to eradicating this disease. New vaccine antigens and novel drugs have been the major focus in prevention and treatment of tuberculosis. While great effort has been expended and progress has been made in drug therapy it has occurred at a remarkably slow pace. Indeed, the challenges posed by multiple and extensively drug-resistant disease and co-infection with human immuno-deficiency virus have rendered the need for novel approaches urgent.

As the disease becomes better understood in terms of both pathogen and host molecular biology there is an opportunity for new pharmaceutical approaches based on the route and means of delivery of a range of novel therapeutic agents.

This volume is arranged to consider the nature of disease, immunological responses, vaccine and drug delivery, disposition and response. In addition to conventional treatments some novel approaches are presented that, if successful, would create rapid development pathways. The contributors are drawn from the relevant fields of microbiology, immunology, molecular biology, pharmaceutics, pharmacokinetics, and chemical and mechanical engineering.

The role of therapeutic targeting strategy, dosage-form design and route of administration in the effective treatment of tuberculosis has been a topic of personal interest that we have shared for approaching twenty years and it is our privilege to be able to bring current thinking on a range of topics into one volume. We owe a great deal to our friends and colleagues most of whom are authors of chapters in this volume who attended the meetings on ‘Inhaled Tuberculosis Therapy’ held in New Delhi and Tokyo in 2009 and 2013, respectively. Without their insight, enthusiasm and encouragement we would not have been able to complete this text.

It has been a great pleasure working with the staff at Wiley on the preparation of the book and we are particularly grateful for the contributions of Samanaa Srinivas, Emma Strickland and Rebecca Stubbs. Many thanks for their patience and accommodation throughout the process.

Anthony J. Hickey,Research Triangle Park, NC, USA

Amit Misra,Lucknow, India

P. Bernard Fourie,Pretoria, South Africa

July 2016

1Introduction: A Guide to Treatment and Prevention of Tuberculosis Based on Principles of Dosage Form Design and Delivery

A.J. Hickey

RTI International, RTP, NC, USA

1.1 Background

Tuberculosis has been a scourge of mankind for millennia. The discovery by Koch of the causative organism Mycobacterium tuberculosis at the end of the nineteenth century was hailed as the discovery that would rapidly lead to its eradication [1]. Despite the speed of development of a vaccine, attenuated Mycobacterium bovis (bacille Calmette Guerin), and the discovery of a therapeutic drug within only a few decades, circumstances that could not have been foreseen with respect to new strains, multiple-drug resistance and co-infection with human immunodeficiency virus, have rendered the disease a more complicated challenge than originally envisaged.

As the twentieth century progressed physicians were horrified to discover that the vaccine was not universally protective and that resistance to the drug of choice, streptomycin, was increasing rapidly [2]. These observations led to further activities in both the realm of vaccine and drug development, the latter being the more clinically successful but the former yielding much need information on the pathogen, the host immunity and pathogenesis of disease.

During this period pharmacy and pharmaceutical dosage form design were also entering a golden age. Manufacturing of drug products or compounding, which was traditionally an activity that took place in a pharmacy, was transferred to an industrial setting. Commercial products involving a variety of dosage form were being standardized to allow production on a scale previously unknown. The introduction of legislation regulating the quality of products, particularly to address adulteration and ensure safety, commenced most notably in the 1930s with the Food Drug and Cosmetics Act of the United States [3]. In the latter half of the twentieth century the underlying physical chemistry and chemical engineering required to manufacture under rigorously controlled conditions that ensured the quality, uniformity, efficacy and safety of the product were developed.

With this background it is noteworthy that the parallel developments in dosage form and tuberculosis (TB) treatment led to their convergence in the early part of the twentieth century when reproducible drug delivery could only be achieved by oral administration (tablets and capsules) or parenteral administration (injection). As a consequence, other routes and means of delivery were rarely, if ever, considered for the delivery of drugs or vaccines. This can be contrasted with the products of biotechnology developed in the late twentieth century for which both oral and parenteral administration were rarely feasible. Of course, the ease of delivery and the required dose were the leading reasons for the selection of these routes of administration.

There was a brief period in the middle of the twentieth century when the absence of new drugs and the increase in drug resistance led to studies of inhaled therapy for tuberculosis but the development of new drugs resulted in this approach being abandoned and only revisited during times when there were no apparent oral and parenteral dosage forms to meet the immediate challenge. Figure 1.1 presents the number of publications that can be found in the accessible literature for the period since the initial rise in drug-resistant tuberculosis in the 1940s. A subsequent peak appears following the rise in human immunodeficiency virus co-infected patients and multiple-drug-resistant tuberculosis requiring alternative therapeutic strategies.

Figure 1.1Reports of Aerosol Delivery Extracted from PubMed from the earliest citations in the modern literature

1.2 Dosage Form Classification

The route of administration by which drugs are delivered dictates the dosage form employed. The United States Pharmacopeia has classified therapeutic products in terms of three tiers: route of administration, dosage forms and performance test which captures all conventional and most novel strategies for disease treatment as shown in Figure 1.2 [4]. The performance measure of significance for the majority of dosage forms is the dissolution rate which, together with the biological parameter of permeability for those drugs presented at mucosal sites, dictates the appearance of the drug in the systemic circulation and ultimately its therapeutic effect.

Figure 1.2United States Pharmacopeia Taxonomy of Dosage Forms structured from: Tier 1 – Route of Administration; through Tier 2 – Dosage Form to; Tier 3 – Performance (not shown).

(Modified from ref. [4] Courtesy of Margareth Marques and the USP)

1.2.1 Dosage Forms

It would not be possible to do justice to the science and technology underpinning the wide range of dosage forms available for drug delivery. However, to put those used in the treatment and prevention of tuberculosis in context a brief review of the key components and processes involved may be helpful to the reader.

1.2.1.1 Solid Oral Dosage Forms

These consist of a mixture of powders each of which is intended to confer a desirable property on the dosage form that leads to effective manufacture, drug delivery and therapeutic effect [5, 6].

In addition to the drug substance which must be well characterized, glidants help the powder flow which aids in filling, surfactants enhance dissolution and diluents are considered inert bulking agents that assist in metering small quantities of drug during filling and may help in compaction. Binding agents, as the name suggests, help in binding all components into a granule or tablet to preserve the integrity of the dosage form on storage and prior to administration. The common dosage forms are capsules and tablets that differ in that the former consists of a powder or granulated loose fill while the latter requires compaction [5, 6]. The most common capsule is prepared with gelatin and filled with the optimized formulation of drug in excipients to allow for stability on storage and reproducible and efficacious dose delivery. Tablets also contain the drug and excipient compacted into a single solid dosage form that has desired performance properties in terms of stability, dissolution, dose delivery and efficacy. Biopharmaceutical considerations are of great significance to the disposition of drugs from solid oral dosage forms. Their behavior under the wide range of pH conditions (1–8) in the gastro-intestinal tract and an understanding of the influence of anatomy and physiology on local residence time and regions of absorption are significant considerations in optimization of the dosage form. Relatively recently the publication of Lipinski’s rules [7] and the biopharmaceutical classification system [8] have been an enormous help in the selection of drugs and requirements of formulations that correlate with successful drug delivery by the oral route of administration.

1.2.1.2 Parenteral Dosage Forms

These are intended for injection either directly into the blood circulation [intravenous (IV)] or at a site from which the drug can readily be transported to the vasculature as would occur following subcutaneous or intramuscular administration [9]. There are other infrequently employed (intraperitoneal) or specialized (intrathecal or intratumoral) sites of injection that are not relevant to tuberculosis therapy. The key elements of a parenteral dosage form are the requirement for a formulation suitable for delivery from a syringe through a needle to the intended site. The formulation can range from simple solutions to a variety of dispersed systems (emulsions, micelles, liposomes and solid suspensions). Important physico-chemical properties must be considered to avoid local tissue damage on injection. Primarily these relate to the requirement to approximate physiological pH and ionic strength (tonicity) [10]. However, there are other safety considerations for injectable dispersed systems that relate to physical obstruction of capillaries (embolism), as well as uptake by the reticulo-endothelial system (inflammation, irritation or immune responses) [11]. The composition of any excipients, carrier systems and the nature of the injected active ingredient will dictate expectations of any of these responses.

1.2.1.3 Inhaled Dosage Forms

These deliver droplets or particles to the pulmonary mucosa that are then distributed locally and transported to the systemic circulation by absorption. The most important criteria for the efficacy of inhaled therapeutics are the aerodynamic particle size distribution and the dose delivered. The particle size range that is targeted for efficient delivery of drug to the lungs is 1–5 μm [12]. The United States Pharmacopeia has described types of inhaled drug product. Of those shown in Figure 1.3 the most important aerosol products for the treatment of pulmonary disease fall into three categories: metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizer systems. MDIs employ high-vapor-pressure propellant to deliver rapidly evaporating droplets containing the active ingredient; dry powder inhalers deliver particles of drug alone or by the use of a carrier particle; and nebulizers deliver aqueous solutions or suspensions of the active ingredient [12]. It is important to note that the primary performance measures for aerosol systems are aerodynamic particle size distribution and delivered dose since these are determinants of the drug reaching the mucosal site for action or absorption. Owing to the solubility, very small particle size and surface area of inhaled particles and droplets, dissolution is rarely the dominant factor in drug bioavailability. However, where the drug substance exhibits poor solubility or is prepared as a controlled release, dissolution is limited, and formulation dissolution rate will play an important role in location and extent of bioavailability.

Figure 1.3Dosage forms intended for delivery of drugs to the respiratory tract divided according to the USP taxonomy of route of administration (tier 1), dosage form (tier 2) and performance measures (tier 3)

(Modified from Ref. [4] Courtesy of Vinod Shah and the USP)

Metered dose inhaler formulations are non-aqueous-based solutions or suspensions and in general are limited to delivering boluses of relatively low doses, rarely above a milligram. Dry powder inhalers in which carriers such as lactose particles are employed also deliver boluses of relatively low doses. However, the use of drug alone in engineered particles has increased the potential dose to 100 mg. Nebulizers do not deliver bolus doses, rather they deliver steady-state aerosols from a reservoir until the fixed volume has been depleted. The total dose delivered from these devices is only limited by the rate (liquid volume/time) and duration of delivery. Delivery for 15–20 minutes is commonly conducted, and precedent for the dose of antimicrobial agent has been set at several hundred milligrams.

1.3 Controlled and Targeted Delivery

In the mid-1980s the attention of some researchers turned to controlling the dissolution rate of orally administered drugs to treat tuberculosis by preparing polymeric microparticles [13, 14]. The intent was to more effectively deliver the drug and to potentially increase the duration of action by extending the period that circulating concentrations remained above the minimum inhibitory concentration. Interestingly, when the dissolution profiles of rifampicin are examined as shown in Figure 1.4, the effect of pH, in the range of relevance to oral delivery, is to lower the dissolution rate and extent at lower pH. This raised the potential not only for controlled but also targeted delivery when particles of similar composition but in a respirable size range were delivered by inhalation. Aerosol particles that do not dissolve immediately when delivered to the lungs are phagocytosed by alveolar macrophages and the low pH (~5.0–5.5) in the endosome presents the opportunity for extended duration of delivery [15]. Therefore, the therapeutic effect will be enhanced in this location within the host cell for Mycobacterium tuberculosis [16, 17]. This observation has since launched a wide range of control and targeting strategies (nanoparticles, liposomes, micelles, etc.) for drug delivery to the lungs to treat tuberculosis [18]. The link to observations from oral delivery should not be forgotten. As more potent agents are developed and gastro-intestinal targeting strategies are informed by greater biological and biophysical understanding it is conceivable that lessons from pulmonary delivery can be translated into future options for oral dosage forms.

Figure 1.4Dissolution of 7.5% rifampicin in poly(lactide-co-glycolide) in three media of different pH values (4.0, 7.4 and 9.0) (Ref. [15])

1.4 Physiological and Disease Considerations

Delivery of drugs by the oral route in tablets or capsules requires that the drug is absorbed and distributed from the gastro-intestinal tract to the systemic circulation where it can subsequently present to infected organs and tissues at concentrations sufficient (above the minimum inhibitory concentration) to treat the infection. The large volume of distribution for systemically circulating drugs currently in use for TB therapy usually requires large amounts of drug in order to achieve therapeutic concentrations. The need for multiple drug therapy for many months is a burden for patients and is seriously exacerbated in those with multiple or extensively drug-resistant disease where many more drugs are administered for even longer periods of time. Simply ingesting the large quantities of medicine required is