AEROSOL FOR ANTITUBERCULAR DRUG DELIVERY

用于抗结核药物输送的气雾剂

• 批准号: 2771490
• 负责人: Anthony James Hickey
• 金额: $ 22.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2771490
• 关键词: Mycobacterium tuberculosis; alveolar macrophages; antibacterial agents; drug delivery systems; fluorescence microscopy; guinea pigs; human therapy evaluation; inhalation drug administration; lung lavage; phagocytosis; respiratory disorder chemotherapy; rifamycins; tissue /cell culture

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.

描述（改编自申请人的摘要）长期 这些研究的目的是使用气雾剂给药抗结核药物， 微粒中的药物转移到肺中的肺泡巨噬细胞（AM）。的 肺，特别是AM的群体，是一个主要的网站， 结核分枝杆菌感染。靶向给药 肺部将保持局部治疗浓度， 全身暴露缓慢溶解的聚合物微粒， 作为气雾剂给药，将表现出延长的停留时间， 肺，并可能改善药物输送到AM。 可生物降解的微粒气溶胶将被用于提供 利福平对M.感染结核病的豚鼠。这些 颗粒物将由于其大小而保留在肺部内， 溶解速度相对较慢。它们会被吞噬 巨噬细胞是M.结核病的早期阶段 感染缓慢降解的微粒将被运送到淋巴 nodes，M.结核病晚期 感染治疗靶向可以通过递送 含有作为气雾剂的抗结核剂的微粒， 巨噬细胞在患病动物的肺，并评估其 行动上第一个目标是准备和表征 含有抗结核药物的微粒，可吸入大小 (less 5毫米）。微粒将通过乳液 蒸发/溶剂萃取技术。FITC-葡聚糖（50 KD）将 作为聚（丙交酯-乙交酯）（PLGA）中的标记物 微粒。第二个目标是评估定量 这些微粒与AM的相互作用。荧光素的摄取 将监测粘附的AM细胞培养物的微粒， 通过荧光显微镜观察暴露6小时。第三个目标是 定量肺泡巨噬细胞的吞噬作用和 荧光微粒在正常豚鼠中的水溶液 悬浮液气雾剂递送。进行支气管肺泡灌洗， 肺和淋巴结组织的组织学检查将证实 微粒的位置/分布。最终目标 是为了确定利福平微粒的功效， 停留时间和不同的药物释放速率（作为干粉递送 气溶胶）在豚鼠结核病模型中的作用。完成这些 研究将显著推进实现治疗性的前景， 入侵微生物附近的药物浓度。