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

为了开发通过将含有抗结核剂的微球经肺递送至肺泡巨噬细胞来克服结核病的有效疗法，重要的是检查1）微球有效吞噬所必需的微球的表征，2）吞噬的微球对巨噬细胞生理条件的影响，（3）微球的肺泡吞噬作用和对结核分枝杆菌的杀菌作用。因此，以聚乳酸-羟基乙酸共聚物（PLGA）为基质，利福平为抗结核药物，采用喷雾干燥法制备了微球。然后，获得了如下所示的结果。1)3 μm的微球对于每个肺泡巨噬细胞的吞噬作用最有效，并且它们被肺泡中大量的巨噬细胞很好地摄取，2）3 μm的微球不影响巨噬细胞的可变性并且不诱导NO和TNF-α，表明PLGA微球对肺泡巨噬细胞没有毒性，和3）PLGA微球被很好地递送到大鼠肺泡，超过60%的微球被肺泡巨噬细胞吞噬。这些结果表明，载药的PLGA微球肺部给药将是有效的，以克服结核病。

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.