Pandey Rajesh, Sharma Sadhna, Khuller G K
Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
Drug Deliv. 2006 Jul-Aug;13(4):287-94. doi: 10.1080/10717540500398076.
Our objective was to evaluate the chemotherapeutic potential of oral poly lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated ethambutol in combination with PLG-nanoparticle encapsulated-(rifampicin + isoniazid + pyrazinamide) in a murine tuberculosis (TB) model. Our formulation was prepared by the multiple emulsion technique and administered orally to mice for the biodistribution, pharmacokinetic, and chemotherapeutic studies. A single oral administration of the formulation to mice could maintain sustained drug levels in the plasma for 5 days and in the organs (lungs, liver, spleen) for 7-9 days. There was a striking improvement in the pharmacokinetic parameters such as half-life and mean residence time as compared with free drugs. The relative/absolute bioavailability of the 4 antituberculosis drugs was enhanced several fold. Repeated administration of the formulation did not produce any hepatotoxicity as assessed on a biochemical basis. In M. tuberculosis H37Rv infected mice, just 3 oral doses of the 4-drug formulation administered at every 10th day resulted in undetectable bacilli in the organs replacing 28 conventional doses of free drugs. We concluded that polymeric nanoparticle based oral 4-drug combination bears significant potential to shorten the duration of TB chemotherapy, besides reducing the dosing frequency.
我们的目标是在小鼠结核病（TB）模型中评估口服聚丙交酯-乙交酯（PLG，一种合成聚合物）纳米颗粒包裹的乙胺丁醇与PLG纳米颗粒包裹的（利福平+异烟肼+吡嗪酰胺）联合使用的化疗潜力。我们的制剂通过复乳技术制备，并口服给药至小鼠以进行生物分布、药代动力学和化疗研究。对小鼠单次口服该制剂可使血浆中的药物水平持续维持5天，在器官（肺、肝、脾）中维持7 - 9天。与游离药物相比，药代动力学参数如半衰期和平均驻留时间有显著改善。4种抗结核药物的相对/绝对生物利用度提高了数倍。根据生化评估，重复给药该制剂未产生任何肝毒性。在感染结核分枝杆菌H37Rv的小鼠中，每10天口服3剂这种四联药物制剂，可使器官中的杆菌检测不到，替代了28剂传统的游离药物。我们得出结论，基于聚合物纳米颗粒的口服四联药物组合除了能降低给药频率外，还有显著潜力缩短结核病化疗疗程。
