AEROSOL FOR ANTITUBERCULAR DRUG DELIVERY

描述(改编自申请人的摘要)长期条款 这些研究的目的是使用气雾剂提供抗结核药物 微粒中的药物到肺中的肺泡巨噬细胞(AM)。这个 肺，特别是AM的人口，是AM的主要部位 结核分支杆菌感染。靶向给药 肺部将保持局部治疗浓度，并尽量减少 全身性暴露。慢慢溶解聚合物微粒， 作为气雾剂给药，将显示延长的停留时间 并可能改善对AM的药物输送。 可生物降解的微粒气雾剂将用于提供 利福平对结核分枝杆菌感染豚鼠肺的作用。这些 颗粒由于其大小和大小将留在肺内 溶解速度相对较慢。它们会被吞噬 巨噬细胞，结核分枝杆菌早期的主要部位 感染。缓慢降解的微粒将被输送到淋巴中 结节，结核分枝杆菌的主要部位，在 感染。治疗靶向可以通过提供 含有抗结核药物的微粒作为气雾剂以 患病动物肺内巨噬细胞及其功能的研究 行动。第一个目标是准备和表征 含抗结核药物的微粒，呼吸尺寸 (小于5毫米)。微粒将由一种乳剂制成 挥发/溶剂萃取技术。FITC-葡聚糖(50KD)将 聚丙交酯-乙交酯(PLGA)的标记作用 微粒。第二个目标是评估量化的 这些微粒与AM的相互作用。对荧光的摄取 AM贴壁细胞培养的微粒将在以下情况下进行监测 荧光显微镜下观察暴露6h。第三个目标是 肺泡巨噬细胞吞噬功能的定量及其处置 正常豚鼠房水后荧光微粒的变化 悬浮气雾剂投放。进行支气管肺泡灌洗和 肺部和淋巴组织的组织学检查将证实 微粒的位置/分布。最终目标 就是用不同的利福平微球测定其疗效 滞留时间和不同的药物释放速率(以干粉形式提供 气雾剂)对豚鼠结核病模型的影响。完成这些工作 研究将大大推进实现治疗的前景 入侵微生物附近的药物浓度。

DESCRIPTION (Adapted from the applicant's abstract) The long term objective of these studies is to use aerosols to deliver antitubercular drugs in microparticles to alveolar macrophages (AMs) in the lung. The lungs, specifically the population of AMs, are a major site of Mycobacterium tuberculosis infection. Targeted drug delivery to the lungs will maintain local therapeutic concentrations and minimize systemic exposure. Slowly dissolving polymeric microparticles, administered as aerosols, will exhibit extended residence times in the lungs and may improve drug delivery to AMs. Biodegradable microparticulate aerosols will be used to deliver rifampicin to the lungs of M. tuberculosis infected guinea pigs. These particles will remain within the lungs by virtue of their size and relatively slow dissolution rate. They will be phagocytosed by macrophages, a primary site of M. tuberculosis in the early stages of infection. Slowly degrading microparticles will be transported to lymph nodes, a principal site of M. tuberculosis in the later stages of infection. Therapeutic targeting may be demonstrated by delivering microparticles containing antitubercular agents as aerosols to macrophages in the lungs of diseased animals and evaluating their action. The first objective is to prepare and characterize microparticles, containing antitubercular drug, in respirable sizes (less than 5 Mm). Microparticles will be manufactured by an emulsion evaporation/solvent extraction technique. FITC-dextran (50KD) will be incorporated as a marker in poly(lactide-coglycolide)(PLGA) microparticles. The second objective is to evaluate the quantitative interaction of these microparticles with AMs. The uptake of fluorescent microparticles by adhered cell cultures of AMs will be monitored after 6 hours of exposure by fluorescence microscopy. The third objective is to quantify the phagocytosis by alveolar macrophages and the disposition of fluorescent microparticles in normal guinea pigs following aqueous suspension aerosol delivery. Performing broncho-alveolar lavage and histological examination of the lungs and lymph node tissues will verify the location/distribution of the microparticles. The final objective is to determine the efficacy of rifampicin microparticles with different residence times and different drug release rates (delivered as dry powder aerosols) in a guinea pig model of tuberculosis. Completion of these studies will significantly advance the prospect of achieving therapeutic drug concentrations in the vicinity of invading micro-organisms.