Pandey Rajesh, Sharma Anjali, Zahoor A, Sharma Sadhna, Khuller G K, Prasad B
Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh-160 012, India.
J Antimicrob Chemother. 2003 Dec;52(6):981-6. doi: 10.1093/jac/dkg477. Epub 2003 Nov 12.
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.
为提高抗结核药物（ATD）的生物利用度并评估经呼吸道给药的可行性，本研究报告了三种一线抗结核药物，即利福平、异烟肼和吡嗪酰胺包裹于适合雾化的聚（DL-丙交酯-乙交酯）纳米颗粒中的制剂。
采用复乳法制备载药纳米颗粒，真空干燥后对豚鼠进行雾化给药。针对每种药物的药代动力学及其在感染结核分枝杆菌的豚鼠体内的化疗潜力对该制剂进行评估。
雾化颗粒的质量中值空气动力学直径为1.88±0.11微米，有利于支气管肺泡肺部给药。对豚鼠单次雾化给药后，血浆中的治疗药物水平可持续6至8天，肺部可达11天。与口服给药相比，药物的消除半衰期和平均驻留时间显著延长，导致包裹药物的相对生物利用度提高（与口服给药相比）（利福平、异烟肼和吡嗪酰胺分别提高12.7倍、32.8倍和14.7倍）。与静脉注射相比，利福平、异烟肼和吡嗪酰胺的绝对生物利用度也分别提高了6.5倍、19.1倍和13.4倍。每隔10天对感染结核分枝杆菌的豚鼠雾化含药纳米颗粒，五次给药后肺部未检测到结核杆菌，而口服给药则需要46个日剂量才能获得同等的治疗效果。
基于纳米颗粒的抗结核药物雾化给药为提高药物生物利用度和降低给药频率以更好地管理肺结核奠定了良好基础。
