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

非专利口服吸入性药物产品(OIDP)有望降低成本，从而改善遵守 处方剂量方案，改善对哮喘和慢性肺部疾病等多种肺部疾病的控制 阻塞性肺病(COPD)。尽管有这些优势，但相对较少的普通OIDP收到了 美国食品和药物管理局(FDA)批准并进入市场，原因是相关挑战 建立吸入药物的生物等效性，很大程度上与确定区域肺的困难有关 剂量。这项研究的目标是开发和验证新的开源计算流体力学 用于基于溶液的计量吸入器(MDI)产品的(CFD)方法可以准确地预测区域 药物在呼吸道中的沉积，然后实施模型来建立体外-体内-相关性 (IVCS)在美国FDA推荐的体外试验指标和体内区域肺沉积之间。创新 在这个项目中包括首先将我们现有方法和技术翻译成开源的CFD软件 OpenFOAM。我们将改进现有的MDI模拟例程，以更好地捕捉MDI喷雾的物理过程 小颗粒溶液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。同时进行的内部试验将被用来广泛描述 MDI气雾剂，将提供真实呼吸道几何形状的体外沉积数据，作为CFD预测的基准。 我们的全气道模拟方法将得到显著扩展，以提高模型真实感并支持 呼气过程中沉积的模拟。最后，扩展的开源完整呼吸道模型将是 与在人类中评估的相同MDI产品的良好记录的2D和3D验证数据进行比较 患有轻度哮喘的受试者。然后，将实施开发和验证的完整呼吸道模型 在气溶胶大小分布的体外测试指标和区域肺沉积之间建立IVCs 多种拍摄对象大小。为实现项目目标，提出了以下目标： 目标1.开发用于预测基于溶液的MDI气溶胶形成的增强型CFD开源方法， 传输和上呼吸道沉积，并用现有的和新的体外数据验证模型预测。 目标2.开发增强的CFD开源方法，用于预测基于解决方案的MDI传输和 并使用2D和3D活体数据验证模型预测。 目的3.实现经过验证的开源完全呼吸道MDI模型，以发展IVIVC关系 FDA推荐的体外试验指标和预测的区域肺沉积之间的差异。 结果。项目成果旨在实现增加非专利药品吸入数量的最终目标 美国市场和世界各地的药物，预计将降低消费者成本，改善 遵守规定的吸入性药物方案，从而改善生活质量和控制多发性 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.