Antitubercular inhaled therapy: opportunities, progress and challenges

JAC Journal of Antimicrobial Chemotherapy (2005) 55, 430–435 doi:10.1093/jac/dki027 Advance Access publication 10 March 2005 Antitubercular inhaled therapy: opportunities, progress and challenges Rajesh Pandey and G. K. Khuller* Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh—160 012, India Pulmonary tuberculosis remains the commonest form of this disease and the development of methods for delivering antitubercular drugs directly to the lungs via the respiratory route is a rational therapeutic goal. The obvious advantages of inhaled therapy include direct drug delivery to the diseased organ, targeting to alveolar macrophages harbouring the mycobacteria, reduced risk of systemic toxicity and improved patient compliance. Research efforts have demonstrated the feasibility of various drug delivery systems employing liposomes, polymeric microparticles and nanoparticles to serve as inhalable antitubercular drug carriers. In particular, nanoparticles have emerged as a remarkably useful tool for this purpose. While some researchers have preferred dry powder inhalers, others have emphasized nebulization. Beginning with the respiratory delivery of a single antitubercular drug, it is now possible to deliver multiple drugs simultaneously with a greater therapeutic efficacy. More experience and expertise have been observed with synthetic polymers, nevertheless, the possibility of using natural polymers for inhaled therapy has yet to be explored. Several key issues such as patient education, cost of treatment, stability and large scale production of drug formulations, etc. need to be addressed before antitubercular inhaled therapy finds its way from theory to clinical reality. Keywords: tuberculosis, liposomes, polymers, nebulization, drug delivery Introduction A Greek pharmacist, Pedanus Discorides, introduced the concept of inhaled fumigation during the first century. Antiseptic aerosol therapy, e.g. boiling tar vapours, became a popular antitubercular medication in the middle of the 20th century, although it hardly had any therapeutic value.1 Since then, antitubercular inhaled therapy has come a long way to a stage of experimental reality with potential clinical applications. The importance of the subject stems from the fact that tuberculosis (TB) continues to be a leading killer disease causing 3 million deaths annually2 and has emerged as an occupational disease in the health care system.3 Oral therapy using the currently employed antitubercular drugs (ATDs) is very effective, but is still associated with a number of significant drawbacks. More than 80% of TB cases are of pulmonary TB alone and high drug doses are required to be administered because only a small fraction of the total dose reaches the lungs after oral administration. Even this small fraction is cleared in a matter of a few hours thus explaining the necessity to administer multiple ATDs on a regular basis, a regimen which the majority of TB patients find difficult to adhere to. Clearly, ATD delivery systems which can be administered via the pulmonary route and can avoid the daily dosing, would be a vast improvement because they would help in: (i) direct drug delivery to the diseased organ; (ii) targeting to alveolar macro- phages which are used by the mycobacteria as a safe site for their prolonged survival; (iii) reduced systemic toxicity of the drugs; and (iv) improved patient compliance. The present review highlights the progress made in antitubercular inhaled therapy especially with the ATDs formulated into suitable delivery systems. Modes of respiratory drug delivery A convenient way of delivering drugs to the lungs is the aerosolization of the drugs as fine powders with the aid of dry powder inhalers (DPIs). Alternatively, the drug may be first solubilized/ suspended in an aqueous medium and subsequently aerosolized (liquid aerosolization or nebulization) through a nebulizer. A nebulizer requires a dispersing force (either a jet of gas or ultrasonic waves) for aerosolization.4 A drug may also be delivered to the lungs directly, i.e. without prior aerosolization, using a device called an insufflator. Compared with a nebulizer, a DPI is more efficient in terms of drug delivery and less time consuming.5 However, nebulizers can be designed to make the best use of a patient’s breathing pattern, the so-called ‘breath-assisted nebulizers’.6 Further, with jet nebulizers, adjustments in drug dosing are easier to achieve.7 Although nebulization is the most common method of aerosol delivery of antibiotics, other factors .......................................................................................................................................................................................................................................................................................................................................................................................................................... *Corresponding author. Tel: +91-172-2747585, ext. 5174-75; Fax: +91-172-2744401/2745078; E-mail: .......................................................................................................................................................................................................................................................................................................................................................................................................................... 430 q The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Permissions, please e-mail: DownloadedFor from https://academic.oup.com/jac/article-abstract/55/4/430/801042 by guest on 14 May 2018 Review such as nebulizer technology, breath holding patterns, degree of airway disease, pulmonary function as well as the aerodynamics of the pharmaceutical aerosol, are all known to affect the efficiency of drug delivery.8,9 An important aerodynamic parameter is the mass median aerodynamic diameter (MMAD), the diameter above and below which 50% of the mass of aerosolized particles are contained. The smaller the diameter, the better are the chances that particle deposition would occur in the deeper parts of the lungs, i.e. the alveoli. The optimum range is defined as 0.5–5.0 mm (the respirable range) because particles < 0.5 mm are usually exhaled whereas particles > 5.0 mm are impacted in the oropharynx.10 Inhaled therapy with conventional or unformulated ATDs Many patients continue to remain sputum smear-positive for Mycobacterium tuberculosis despite ongoing chemotherapy, which is mainly attributable to (other than drug resistance) extensive cavitary lesions where the antimycobacterial drugs fail to reach when administered orally.11 Sacks et al.12 selected such patients of pulmonary TB who were sputum smear-positive after at least 2 months of conventional treatment. (...truncated)