Optimization of next generation pulmonary dry powder delivery systems

项目摘要 结核病（TB）仍然是全世界成年人最大的单一传染性杀手，药物的开发， 耐药菌株是一个公共卫生危机。作为结核病治疗中口服和静脉给药的替代方案，直接肺给药 通过干粉吸入器（DPI）递送可用于实现更短的治疗方案，克服药物依赖性， 阻力，并迅速降低传播率。然而，传统的低效力DPI没有被优化以 满足结核病治疗的挑战（高剂量、窄治疗指数和不稳定分子的递送）。 下一代DPI必须表现出有效的粉末雾化，促进药物稳定性，并确保 不依赖于肺功能的可再现的肺沉积。这必须在结核病的成本限制范围内进行， 这就需要采取系统和精简的发展办法。据推测，高剂量， 无载体干粉必须表现出某些特性，以实现雾化， 适当的装置分散机制的这些特性将使吸气流量独立的肺 证词在三年的时间里，这一假设将通过对以下内容的全面分析来检验 与雾化有关的微粉化药物粉末的关键物理化学特性， 这些发现是一个具有挑战性的单克隆抗体模型，并通过研究的行为，可吸入的 药物颗粒在各种装置和吸入装置中的应用。通过这些研究得出的经验数据将 用于模拟颗粒凝聚力、器械分散和雾化之间的关系，以进一步 优化现有的高剂量DPI并预测新型DPI的性能。培训环境（大学） 德克萨斯州）将通过提供粒子工程所需的资源， 分子和生物分析以及气溶胶测试。除了有希望的科学见解， 研究将提供广泛的培训，在粉末表征技术，设备原型，小分子 生物处理和分析，以及数学建模，这些都是发展到一个 在制药科学的独立研究生涯。这项研究的总体意义在于，它是一个 转化研究方法，将对可吸入颗粒行为的机械理解与前 针对毁灭性肺部疾病（如 结核该系统方法将大大简化未来小分子和 生物制药吸入疗法，并降低临床前临床转化的风险。

PROJECT SUMMARY Tuberculosis (TB) remains the single largest infectious killer of adults worldwide, and development of drug- resistant strains is a public health crisis. As an alternative to oral and IV delivery in TB treatment, direct lung delivery via dry powder inhaler (DPI) can be used to achieve shorter treatment regimens, overcome drug resistance, and rapidly reduce transmission rates. However, traditional, low-potency DPIs are not optimized to meet the challenges of TB therapy (high doses, narrow therapeutic indices, and delivery of labile molecules). Next-generation DPIs must exhibit efficient powder aerosolization, promote drug stability, and ensure reproducible lung deposition independent of lung function. This must occur within the cost-constraints of TB, which necessitates a systematic and streamlined development approach. It is hypothesized that high-dose, carrier-free dry powders must exhibit certain properties for aerosolization to be achieved, and that the pairing of these properties to the appropriate device dispersion mechanism will enable inspiratory flow-independent lung deposition. Over the course of three years, this hypothesis will be tested through a comprehensive analysis of critical physicochemical characteristics of micronized drug powders in relation to aerosolization, application of these findings to a challenging monoclonal antibody model, and through a study of the behavior of respirable drug particles in a variety of device and inhalation settings. The empirical data derived through these studies will be used to model the relationship between particle cohesion, device dispersion, and aerosolization to further optimize existing high dose DPIs and predict performance of novel DPIs. The training environment (University of Texas) will fully support this study by providing the necessary resources for particle engineering, small molecule and biologic analysis, and aerosol testing. In addition to promising scientific insights, the proposed study will provide extensive training in powder characterization techniques, device prototyping, small molecule and biological processing and analysis, and mathematical modeling that are necessary for progression to an independent research career in the pharmaceutical sciences. The overall significance of this study is that it is a translational research approach that links a mechanistic understanding of respirable particle behavior to the pre- clinical development of targeted and cost-effective therapies for devastating pulmonary diseases like tuberculosis. The systematic approach will greatly streamline the development of future small molecule and biopharmaceutical inhaled therapies and reduce the risk of pre-clinical to clinical translation.