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.

普通口服吸入药品（OIDP）有望降低成本，从而提高遵守 处方剂量方案，导致对多种肺部疾病（如哮喘和慢性）的控制改善 阻塞性肺疾病（COPD）。尽管有这些优势，但相对较少的通用OIDP收到了 美国食品药品监督管理局（FDA）批准，并因挑战而进入市场 通过建立吸入药物的生物等效性，与确定区域肺的困难主要有关 剂量。这项研究的目的是开发和验证新的开源计算流体动力学 （CFD）基于溶液的计量剂量吸入器（MDI）产品的方法，该产品可以准确预测区域性 在整个气道中的药物沉积，然后实施模型以建立体内体内相关性 （IVIVC）在美国FDA之间建议体外测试指标和体内肺部沉积。创新 在此项目中，首先将我们现有的方法和技术转换为开源CFD软件 OpenFoam。我们将改善现有的MDI模拟程序，以更好地捕获MDI喷雾物理 基于天粒子溶液的产品的羽状形成和多组分液滴的蒸发 含有乙醇作为共溶剂。并发内部实验将用于广泛表征 MDI气溶胶并将在现实气道几何形状中提供体外沉积数据，以基准CFD预测。 我们的完整气动模拟方法将大大扩展，以改善模型现实主义并启用 呼气过程中沉积的模拟。最后，扩展的露天完整式摩托模型将是 与有据可查的2D和3D验证数据相比，人类评估的同一MDI产品 患有轻度哮喘的受试者。然后将实施开发和验证的完整模型 在气溶胶尺寸分布的体外测试度量与跨区域肺部沉积之间发展IVIVC 多个主题大小。为了实现项目目标，提出了以下目标： AIM 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， 使用现有和新的体外数据的运输和上呼吸道沉积和验证模型预测。 目标2。开发增强的CFD开源方法，以预测基于解决方案的MDI运输和 在整个肺部沉积，并用2D和3D体内数据验证模型预测。 目标3。实施经过验证的放水完整气流MDI模型以建立IVIVC关系 在FDA建议的体外测试指标和预测区域肺沉积之间。 结果。项目成果是针对增加通用吸入数量的最终目标 美国市场和全球的药物预计将降低消费者成本，改善 遵守处方药的药物方案，从而提高生活质量和多重控制 肺部疾病。