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; 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（由适用提供）：吸入的药物气溶胶通常以非常低的沉积能力沉积在肺中。可能比沉积的药物数量更重要的是，这些药物气溶胶和相关剂量通常会观察到大型和受试者内的可变性。为了使许多下一代遗传药物成为可行的药物递送替代方案，肺部递送和扩大的受试者间变异性至关重要。这项研究的目的是开发一种方法，以改善纳米颗粒和亚微米气溶胶的肺输送和保留率，并使用增强的凝结生长。该概念包括将（1）可控的吸入水蒸气湿度与（2）亚微米的气溶胶生成和输送设备组合。湿度源用于在肺部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过饱和的水蒸气，并具有预先指定的温度和相对湿度（RH）条件。气溶胶以粒子或液滴形式同时或湿度源的受控事故后交付。气溶胶应具有有效地穿透口throat和上流气管支动管区域的尺寸，例如约1英寸及以下。进入肺部后，由于受控过饱和环境中的凝结生长（水积累）增加，气溶胶将增加大小，从而增加保留率。为了实现这一目标，提出了以下特定目标：具体目标1：开发体外系统，以评估上呼吸道中受控增强的凝结生长概念，并评估在稳定流动条件下RH的影响。特定目标2：开发和验证上流气管上区域中吸湿性液滴生长的计算流体动力学（CFD）模型，并应用该模型评估壁边界条件并运输到远端支气管中。特定目标3：采用开发的体外和CFD模型来测试（1）瞬时流动，（2）气溶胶浓度密度，以及（3）气溶胶吸湿性能和物理形式对100-1000 nm气溶胶的潮流生长的影响。通过将亚剪液计的量超过口throat，然后通过增强的凝结生长来增加气溶胶的大小，预计上呼吸道沉积显着减少并增加了肺部保留率。结果，可以实现剂量变异性的降低，这对于有效使用许多下一代药物气溶胶是必不可少的。 公共卫生相关性：许多可吸入的药物正在开发用于治疗呼吸道疾病（例如肺癌，呼吸道感染和囊性纤维化）和全身性疾病（例如糖尿病，慢性疼痛和生长缺乏症）。但是，这些下一代遗传药物向肺部的输送通常是无效的，这可以显着降低药物效率并增加不必要的副作用。该项目的总体目标是开发一种新型技术，用于有效地输送遗传药物，该药物最大程度地减少口腔和喉咙的沉积，并最大程度地提高肺部沉积。