Development of computational models to predict delivery of inhalation drug powders: from deagglomeration in devices to deposition in airways
开发计算模型来预测吸入药物粉末的输送:从设备中的解聚到气道中的沉积
基本信息
- 批准号:9770848
- 负责人:
- 金额:$ 19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Project Summary/Abstract
Background: Dry powder inhalation (DPI) devices represent up to 40% of total sales of the global inhalation
market which was over US$ 23bn in 2016 and expected to increase to US$ 35bn by 2023. Because of the wide
application and high profit margin of DPIs, there have been great efforts in the pharmaceutical industry to develop
generic DPI devices. To be approved by the US FDA, a generic version needs to show bioequivalence (BE) to
the corresponding brand DPI device. The current approach to establish BE is based on the aggregated "weight
of evidence" which includes in vitro test, pharmacokinetic, and pharmacodynamic or clinical endpoint studies.
Importantly the performance of a DPI device in the in vitro study should be linked to in vivo regional deposition.
It is preferable that the aerodynamic particle size distribution (APSD) can be used to establish the in vitro-in vivo
correlation (IVIVC). However, so far there is no enough evidence to support this idea due to difficulty to
experimentally obtain in vivo data. Numerical modelling based on computational fluid dynamics (CFD) alone is
also unable to predict the dynamics of particles due to non-spherical shape of powder fragments.
Research Design: The goal of the project is to develop a coupled discrete element method (DEM) and CFD
model to predict agglomeration and deagglomeration of carrier-API systems in DPIs. Combined with the latest
imaging tools, advanced laser diagnostic techniques, and powder characterization technology feeding into the
model, the CFD-DEM model can be used to quantitatively evaluate the effects of powder formulations and device
design on the aerosol performance of DPIs. This model will also be linked to CFD-DPM to provide a three-way
coupling to model powder airway deposition. This project includes 3 main phases. In Phase 1, a coupled CFD-
DEM model will be developed by explicitly considering the key particle-particle and particle-flow interactions,
including van der Waals and electrostatic forces. The multi-sphere approach will be used to mimic the non-
spherical shape of particles. In Phase 2, the model will be vigorously validated by conducting detailed
experimental analysis using novel measurement techniques developed by the team. Both agglomeration and
deagglomeration of powders under different conditions will be investigated. In particular, fluid flow and APSD at
the device mouthpiece will be linked to the deposition in mouth-throat region represented by USP induction port
as well as optically accessible realistic collapsible mouth-throat model. In Phase 3, sensitivity tests will be carried
out by changing powder formulations, device design and operation. Their effects on deagglomeration in DPI
device and regional deposition in airways will be analysed, aiming to develop metrics for IVIVC.
Significance: This project will provide an enabling technology which is able to quantitatively evaluate the in vitro
efficiency and in vivo deposition of a DPI design for any given the powder formulation properties. A predictive,
3-way coupled DEM-CFD-DPM model based on in-depth understanding of the complex interactions
between devices and formulations can provide detailed information at the particle scale, which will be
useful for the BE study.
项目概要/摘要
背景:干粉吸入 (DPI) 装置占全球吸入总销量的 40%
2016 年,该市场规模超过 230 亿美元,预计到 2023 年将增至 350 亿美元。
DPI的应用和高利润率,制药行业一直在大力开发
通用 DPI 设备。要获得美国 FDA 的批准,仿制药需要显示生物等效性 (BE)
相应品牌的DPI设备。当前建立BE的方法是基于聚合的“权重”
证据”,包括体外试验、药代动力学、药效学或临床终点研究。
重要的是,DPI 装置在体外研究中的性能应与体内区域沉积相关。
优选的是,空气动力学粒度分布(APSD)可用于建立体外-体内
相关性(IVIVC)。然而,由于难以实现,目前还没有足够的证据支持这一想法。
实验获得体内数据。仅基于计算流体动力学 (CFD) 的数值建模
由于粉末碎片的非球形形状,也无法预测颗粒的动力学。
研究设计:该项目的目标是开发耦合离散元方法 (DEM) 和 CFD
预测 DPI 中载体 API 系统的聚集和解聚的模型。结合最新
成像工具、先进的激光诊断技术和粉末表征技术进入
模型,CFD-DEM模型可用于定量评价粉体配方和装置的效果
DPI 的气溶胶性能设计。该模型还将链接到 CFD-DPM 以提供三向
耦合到模型粉末气道沉积。该项目包括 3 个主要阶段。在第一阶段,耦合 CFD-
DEM 模型将通过明确考虑关键的粒子-粒子和粒子-流相互作用来开发,
包括范德华力和静电力。多球体方法将用于模仿非
颗粒形状为球形。在第二阶段,将通过进行详细的研究来大力验证该模型
使用团队开发的新颖测量技术进行实验分析。既集聚又
将研究不同条件下粉末的解团聚。特别是,流体流量和 APSD
装置吸嘴将连接到 USP 感应端口代表的口腔区域的沉积物
以及光学可访问的逼真可折叠口咽模型。第三阶段将进行敏感性测试
通过改变粉末配方、设备设计和操作来解决。它们对 DPI 解聚的影响
将分析气道中的设备和区域沉积,旨在制定 IVIVC 指标。
意义:该项目将提供一种能够定量评估体外研究的使能技术。
对于任何给定的粉末配方特性,DPI 设计的效率和体内沉积。一个预测性的、
基于对复杂相互作用的深入理解的三向耦合DEM-CFD-DPM模型
设备和配方之间的信息可以提供颗粒尺度的详细信息,这将是
对于 BE 研究很有用。
项目成果
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