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

仿制的口服吸入药物产品（OIDP）有望降低成本，从而提高对 处方剂量方案，导致改善对多种肺部疾病的控制，如哮喘和慢性 阻塞性肺疾病（COPD）。尽管有这些优势，但相对较少的通用OIDP得到了 美国食品药品监督管理局（FDA）的批准，并进入市场，由于相关的挑战 建立吸入药物的生物等效性，主要与难以确定局部肺 次给药结束本研究的目的是开发和验证新的开源计算流体动力学 (CFD)用于基于溶液的定量吸入器（MDI）产品的方法， 药物沉积在整个气道，然后实施该模型，以建立体外-体内相关性 （IVIVCs）之间的美国FDA推荐的体外测试指标和体内局部肺沉积。创新 在这个项目中，包括首先将我们现有的方法和技术转化为开源的CFD软件 OpenFOAM。我们将改进现有的MDI模拟程序，以更好地捕捉MDI喷雾的物理特性 用于小颗粒溶液基产品的多组分液滴的羽流形成和蒸发 含有乙醇作为共溶剂。同时进行的内部实验将用于广泛表征 MDI气雾剂，并将提供真实气道几何形状的体外沉积数据，以基准计算流体动力学预测。 我们的全气道模拟方法将大大扩展，以提高模型的真实性， 模拟呼气过程中的沉积。最后，扩展的开源完全气道模型将 与在人体中评价的相同MDI产品的有据可查的2D和3D验证数据相比 轻度哮喘患者。然后将实施开发和验证的完整气道模型， 在气溶胶粒度分布的体外测试指标和区域肺沉积之间开发IVIVC， 多个受试者尺寸。为实现项目目标，建议实现以下目标： 目标1。开发增强的CFD开源方法，用于预测基于溶液的MDI气溶胶形成， 运输和上气道沉积，并验证模型预测与现有的和新的体外数据。 目标二。开发增强的CFD开源方法，用于预测基于溶液的MDI传输， 通过测量整个肺部的沉积，并使用2D和3D体内数据验证模型预测。 目标3。实施经验证的开源完全气道MDI模型，以建立IVIVC关系 FDA推荐的体外测试指标和预测的局部肺沉积之间的差异。 结果。项目成果的最终目标是增加吸入仿制药的数量， 在美国市场和世界范围内的药物，这有望降低消费者成本，改善 遵守规定的吸入药物方案，从而提高生活质量和控制多种 肺部疾病

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.