Improved Lung Delivery of Medical Aerosols through Enhanced Condensation Growth

描述（由申请人提供）：吸入的药物气雾剂通常以非常低的沉积效率沉积在肺中。可能比沉积的药物量更重要的是，这些药用气雾剂和递送至肺部的相关剂量经常观察到的受试者间和受试者内的较大变异性。为了使许多下一代吸入药物成为可行的药物递送替代方案，增加肺部递送和降低受试者间和受试者内变异性至关重要。本研究的目的是开发一种使用增强的冷凝生长来改善纳米颗粒和亚微米气溶胶的肺部递送和保留的方法。该概念包括将（1）受控的可吸入水蒸气湿度源与（2）亚微米气溶胶产生和输送装置相结合。湿度源用于在肺的一般区域内创建受控的过饱和相对湿度环境。呼吸道的这种调节可以通过吸入具有预定温度和相对湿度（RH）条件的过饱和水蒸气来完成。颗粒或液滴形式的气雾剂将在受控吸入湿度源的同时或之后递送。气雾剂应具有可有效穿透口-喉和上气管支气管区域的尺寸，约1米及以下。在输送到肺中时，由于在受控的过饱和环境中增强的冷凝生长（水积聚），气溶胶的尺寸将增加，从而增加滞留。为了实现这一目标，提出了以下具体目标：具体目标1：开发一种体外系统，以评估上呼吸道中的受控增强冷凝生长概念，并评估稳态流动条件下RH的影响。具体目标二：开发并验证上气管支气管区域吸湿液滴生长的计算流体动力学（CFD）模型，并应用该模型评价水壁边界条件和向远端支气管的输送。具体目标3：采用开发的体外和CFD模型测试（1）瞬态流、（2）气溶胶浓度密度和（3）气溶胶吸湿特性和物理形态对100 - 1000 nm气溶胶吸湿增长的影响。通过将亚微米气溶胶递送通过口-喉，然后通过增强的冷凝生长来增加气溶胶尺寸，预期显著减少上呼吸道沉积和增加肺滞留。因此，可以减少剂量的变化，这是有效使用许多下一代药物气雾剂所必需的。 公共卫生相关性：许多可吸入药物正在开发中，用于治疗呼吸系统疾病（如肺癌，呼吸道感染和囊性纤维化）和全身性疾病（如糖尿病，慢性疼痛和生长缺陷）。然而，这些下一代吸入药物向肺部的输送通常效率低下，这会显著降低药物有效性并增加不希望的副作用。该项目的总体目标是开发一种新技术，用于有效输送吸入药物，最大限度地减少口腔和喉咙中的沉积，并最大限度地增加肺部的沉积。

DESCRIPTION (provided by applicant): Inhaled pharmaceutical aerosols are often deposited in the lung at very low deposition efficiencies. Perhaps more significant than the quantity of drug deposited is the large inter- and intra-subject variability that is often observed with these medicinal aerosols and the associated dose delivered to the lung. In order to make many next-generation inhaled medications a viable drug delivery alternative, increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The objective of this study is to develop an approach for improved lung delivery and retention of nanoparticle and submicrometer aerosols using enhanced condensation growth. This concept consists of combining (1) a controlled inhalable water vapor humidity source with (2) a submicrometer aerosol generation and delivery device. The humidity source is used to create a controlled supersaturated relative humidity environment within general regions of the lung. This conditioning of the respiratory tract may be accomplished through an inhalation of supersaturated water vapor with pre-specified temperature and relative humidity (RH) conditions. The aerosol, in particle or droplet form, will be delivered either concurrently or following the controlled inhalation of the humidity source. The aerosol should have a size that can effectively penetrate the mouth-throat and upper tracheobronchial regions, e.g., approximately 1 ¿m and below. Upon transport into the lung, the aerosol will increase in size due to enhanced condensation growth (water accumulation) in the controlled supersaturated environment, thereby increasing retention. To achieve this objective, the following specific aims are proposed: Specific Aim 1: Develop an in vitro system to evaluate the controlled enhanced condensation growth concept in the upper respiratory tract and assess the effects of RH under steady flow conditions. Specific Aim 2: Develop and validate a computational fluid dynamics (CFD) model of hygroscopic droplet growth in the upper tracheobronchial region and apply the model to evaluate aqueous wall boundary conditions and transport into distal bronchi. Specific Aim 3: Employ the developed in vitro and CFD models to test the effects of (1) transient flow, (2) aerosol concentration density, and (3) aerosol hygroscopic properties and physical form on the hygroscopic growth of 100 - 1000 nm aerosols. By delivering submicrometer aerosols past the mouth-throat and then increasing aerosol size through enhanced condensation growth, significant reductions in upper airway deposition and increased lung retention are expected. As a result, reduced variability in dose can be achieved, which is necessary for the effective use of many next-generation pharmaceutical aerosols. Public Health Relevance: A number of inhalable medications are in development for the treatment of respiratory diseases (such as lung cancer, respiratory infections, and cystic fibrosis) and systemic conditions (such as diabetes, chronic pain, and growth deficiency). However, the delivery of these next- generation inhaled pharmaceuticals to the lungs is often inefficient, which can significantly reduce drug effectiveness and increases unwanted side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled medicines that minimizes deposition in the mouth and throat and maximizes deposition in the lungs.