Improved Lung Delivery of Medical Aerosols through Enhanced Condensation Growth

通过增强冷凝增长改善医用气雾剂的肺部输送

• 批准号: 7573264
• 负责人: P. Worth Longest
• 金额: $ 21.42万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-10 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573264
• 关键词: Adverse effects; Aerosols; Air; Air Conditioning; Albuterol; Albuterol Sulfate; Animals; Benign; Breathing; Bronchi; Computer Simulation; Coupling; Cromolyn Sodium; Cystic Fibrosis; Data; Deposition; Development; Devices; Diabetes Mellitus; Distal; Dose; Drug Delivery Systems; Effectiveness; Elements; Environment; Evaluation; Exhalation; Future; Gases; Generations; Goals; Growth; Guidelines; Heating; Housing; Human; Humidifier; Humidity; In Vitro; Insulin; Isotonic Exercise; Joints; Liquid substance; Lung; Lung diseases; Malignant neoplasm of lung; Measures; Medical; Medicine; Methods; Modeling; Oral cavity; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Pharyngeal structure; Phase; Physical condensation; Property; Proteins; Relative (related person); Reporting; Research; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Sample Size; Simulate; Solid; Solutions; Source; Specific qualifier value; System; Techniques; Temperature; Testing; Therapeutic; Tracheobronchial; Upper respiratory tract; Validation; Water; aqueous; base; chronic pain; conditioning; density; design; improved; in vitro Model; in vivo; insight; interest; nanoparticle; new technology; next generation; novel; particle; physical property; public health relevance; research study; respiratory; therapy development; water solution; water vapor

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.

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。也许比药物沉积的数量更重要的是，这些药物气雾剂和相关的肺部剂量经常出现巨大的受试者间和受试者内的差异。为了使许多下一代吸入性药物成为可行的给药选择，增加肺部给药和减少受试者间和受试者内的变异性至关重要。这项研究的目的是开发一种利用增强凝结生长来改善纳米颗粒和亚微米气雾剂的肺递送和滞留的方法。这一概念包括(1)受控可吸入水蒸气湿度源与(2)亚微米气溶胶产生和输送装置的结合。湿度源用于在肺部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先规定的温度和相对湿度(RH)条件的过饱和水蒸气来完成。气雾剂，以颗粒或液滴的形式，将同时或在受控吸入湿度源之后输送。气雾剂的大小应能有效地穿透口腔-喉咙和上气管-支气管区，例如大约1？m及以下。在进入肺部后，由于受控过饱和环境中的凝结生长(水分积累)增强，气溶胶的尺寸将增大，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：建立一个体外系统，以评估受控强化凝结生长概念在上呼吸道的概念，并评估在稳定流动条件下RH的效果。具体目标2：开发和验证吸湿性液滴在上气管、支气管区生长的计算流体动力学(CFD)模型，并应用该模型评估房水壁边界条件和向远端支气管的传输。具体目标3：使用开发的体外和CFD模型来测试(1)瞬变流动，(2)气溶胶浓度密度，(3)气溶胶吸湿特性和物理形态对100-1000 nm气溶胶吸湿生长的影响。通过将亚微米气雾剂输送到口腔-喉咙，然后通过增强凝结生长来增加气雾剂的尺寸，预计可以显著减少上呼吸道沉积和增加肺滞留。因此，可以减少剂量的可变性，这对于许多下一代药物气雾剂的有效使用是必要的。 公共卫生相关性：一些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)和全身疾病(如糖尿病、慢性疼痛和生长缺陷)。然而，这些下一代吸入型药物进入肺部的效率往往很低，这可能会显著降低药物有效性，并增加不想要的副作用。该项目的总体目标是开发一种新的技术，以有效地提供吸入药物，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中的沉积。