Computational Fluid Dynamics (CFD) Models to Aid the Development of Generic Metered Dose Inhalers

计算流体动力学 (CFD) 模型有助于通用计量吸入器的开发

• 批准号: 10459405
• 负责人: P. Worth Longest
• 金额: $ 19.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459405
• 关键词: Computational; Fluid; Dynamics; CFD; Models

Generic orally inhaled drug products (OIDPs) are expected to reduce cost and thereby improve compliance with prescribed dosage regimens, leading to improved control of multiple lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Despite these advantages, relatively few generic OIDPs have received US Food and Drug Administration (FDA) approval and entered the marketplace due to challenges associated with establishing bioequivalence of inhaled medications, largely related to difficulties in determining regional lung dose. The objective of this study is to develop and validate new open-source computational fluid dynamics (CFD) methods for a solution-based metered dose inhaler (MDI) product that can accurately predict regional drug deposition throughout the airways, and then implement the model to establish in-vitro-in-vivo-correlations (IVIVCs) between US FDA recommended in vitro test metrics and in vivo regional lung deposition. Innovations in this project include first translating our existing methods and techniques to open-source CFD software OpenFOAM. We will improve our existing MDI simulation routines to better capture the physics of MDI spray plume formation and the evaporation of multicomponent droplets for a small-particle solution-based product containing ethanol as a co-solvent. Concurrent in-house experiments will be used to broadly characterize the MDI aerosol and will provide in vitro deposition data in realistic airway geometries to benchmark CFD predictions. Our complete-airway simulation approach will be significantly expanded to improve model realism and enable simulation of deposition during exhalation. Finally, the expanded open-source complete-airway model will be compared with well-documented 2D and 3D validation data of the same MDI product evaluated in human subjects with mild asthma. The developed and validated complete-airway model will then be implemented to develop IVIVCs between the in vitro test metric of aerosol size distribution and regional lung deposition across multiple subject sizes. To accomplish the project objective, the following aims are proposed: Aim 1. Develop enhanced CFD open-source methods for predicting solution-based MDI aerosol formation, transport and upper airway deposition and validate model predictions with existing and new in vitro data. Aim 2. Develop enhanced CFD open-source methods for predicting solution-based MDI transport and deposition throughout the lungs and validate model predictions with 2D and 3D in vivo data. Aim 3. Implement the validated open-source complete-airway MDI model to develop IVIVC relationships between FDA recommended in vitro test metrics and predicted regional lung deposition. Outcomes. Project outcomes are directed toward an ultimate goal of increasing the number of generic inhaled medications in the US marketplace and worldwide, which is expected to reduce consumer cost, improve compliance with prescribed inhaled drug regimens and thereby improve quality of life and the control of multiple lung diseases.

仿制药口服吸入药品 (OIDP) 有望降低成本，从而提高对药物的依从性 规定的剂量方案，从而改善对多种肺部疾病的控制，例如哮喘和慢性病 阻塞性肺疾病（COPD）。尽管有这些优点，但获得认可的通用 OIDP 相对较少 由于相关挑战，美国食品和药物管理局 (FDA) 批准并进入市场 建立吸入药物的生物等效性，很大程度上与确定局部肺部的困难有关 剂量。本研究的目的是开发和验证新的开源计算流体动力学 基于溶液的定量吸入器 (MDI) 产品的 (CFD) 方法，可准确预测区域 药物沉积在整个气道中，然后实施模型来建立体外体内相关性 （IVIVC）美国 FDA 推荐的体外测试指标和体内区域肺沉积之间的关系。创新 该项目包括首先将我们现有的方法和技术转化为开源 CFD 软件 打开泡沫。我们将改进现有的 MDI 模拟例程，以更好地捕捉 MDI 喷雾的物理特性 基于小颗粒溶液的产品的羽流形成和多组分液滴的蒸发 含有乙醇作为共溶剂。并行的内部实验将用于广泛表征 MDI 气溶胶将提供真实气道几何形状的体外沉积数据，以作为 CFD 预测的基准。 我们的完整气道模拟方法将得到显着扩展，以提高模型的真实性并实现 模拟呼气过程中的沉积。最后，扩展的开源完整气道模型将 与在人体中评估的相同 MDI 产品的有据可查的 2D 和 3D 验证数据进行比较 患有轻度哮喘的受试者。然后将开发和验证的完整气道模型应用到 在气溶胶大小分布的体外测试指标和区域肺沉积之间开发 IVIVC 多种主题尺寸。为实现项目目标，提出以下目标： 目标 1. 开发增强型 CFD 开源方法来预测基于溶液的 MDI 气溶胶形成， 运输和上呼吸道沉积，并使用现有和新的体外数据验证模型预测。 目标 2. 开发增强型 CFD 开源方法来预测基于解决方案的 MDI 传输和 沉积在整个肺部，并使用 2D 和 3D 体内数据验证模型预测。 目标 3. 实施经过验证的开源完整气道 MDI 模型以开发 IVIVC 关系 FDA 推荐的体外测试指标和预测的区域肺沉积之间的关系。 结果。项目成果旨在实现增加仿制药吸入剂数量的最终目标 美国市场和世界各地的药物，预计将降低消费者成本，改善 遵守规定的吸入药物治疗方案，从而提高生活质量和控制多种疾病 肺部疾病。