Pulmonary delivery of microspheres loaded with antituberculosis agents to alveolar macrophages for development of antituberculosis therapy

为了开发含抗结核药物的微球肺递送至肺泡巨噬细胞治疗结核病的有效方法，必须研究1)微球有效吞噬所需微球的特性，2)被吞噬的微球对巨噬细胞生理状况的影响，3)微球肺递送至肺泡的吞噬作用和对结核分枝杆菌的杀菌作用。为此，采用喷雾干燥法制备了以乳酸和乙醇酸共聚物PLGA为基体，利福平为抗结核药物的微球。然后得到如下所示的结果。1) 3 μm微球对各肺泡巨噬细胞的吞噬效率最高，被肺泡内大量巨噬细胞吞噬；2)3 μm微球不影响巨噬细胞的变变性，不诱导NO和TNF-a，表明PLGA微球对肺泡巨噬细胞无毒性；3)PLGA微球能很好地进入大鼠肺泡。超过60%的微球被肺泡巨噬细胞吞噬。结果表明，负载抗结核药物的PLGA微球经肺给药可有效治疗结核病。

For development of the efficient therapy for overcoming tuberculosis by pulmonary delivery to alveolar macrophages of microspheres containing anti-tuberculosis agent, it is important to examine 1) characterization of microspheres necessary for efficient phagocytosis by microspheres, 2) effect of phagocytosed microspheres on the physiological conditions of macrophages, and 3) phagocytosis of microspheres delivered to alveoli and the bactericidal effect on Mycobacterium tuberculosis. Hence, the microspheres using PLGA (co-polymer consisting of lactic acid and glycolic acid) as a base, and rifampicin as an anti-tuberculosis agents were prepared by spray dry method. Then, the results shown below were obtained. 1) the 3 μm microspheres were most efficient for phagocytosis by each alveolar macrophage cell and they were well taken up by high population of macrophages in the alveoli, 2) the 3 μm microspheres did not affect the variability of macrophages and did not induce NO and TNF-a, showing that PLGA microspheres were not toxic to alveolar macrophages, and 3) PLGA microspheres were well delivered to the rat alveoli, and more than 60% of the microspheres delivered were phagocytosed by alveolar macrophages. These results showed that the pulmonary delivery of PLGA microspheres loaded with anti-tuberculosis agent will be efficient for overcoming tuberculosis.