Niosomal encapsulation of the antitubercular drug, pyrazinamide

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Abstract

It is estimated that more than one-third of the world population is infected with Mycobacterium tuberculosis. Pyrazinamide (PZA) plays a unique role in shortening therapy because it kills a population of semilatent tubercle bacilli residing in an acidic environment. Niosomes are vesicles made up of non-ionic surfactant and exhibit behavior similar to liposomes in vivo. Preparation of PZA niosomes took place using different molar ratios of Span 60 and Span 85, with cholesterol (CH) i.e. Span: CH (1:1) and (4:2). Dicetyl phosphate and stearyl amine were used in preparation of negative and positively charged niosomes, respectively. Free PZA was separated by cooling centrifugation and estimated spectrophotometrically at 268.4 nm. Niosomes were characterized by electron microscopy and differential scanning calorimetry. The highest percentage PZA entrapped was obtained using Span 60 and the molar ratio (4:2:1) negatively charged niosomes. This was followed by the neutral PZA neutral (4:2) Span 60 niosomes. Biological evaluation of selected PZA niosomal formulations took place on guinea pigs infected with M. tuberculosis. The present work is an attempt to target maximum concentration of PZA to the affected site (lungs) and to exclude undesirable side effects and decrease toxicity. Macrophage targeting and overcoming drug resistance is our final goal.

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Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis.

Sadhna Sharma, Bilal Zahoor, G. K. Khuller … (2003)

To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization. Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs. The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit. Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.