Use of computational fluid dynamics deposition modeling in respiratory drug delivery

Abstract

Introduction: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption. Areas Covered: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols. Areas covered include the development of new complete-airway CFD deposition models and the application of these models to develop a next generation of respiratory drug delivery strategies. Expert Opinion: Complete-airway deposition modeling is a valuable research tool that can improve our understanding of pharmaceutical aerosol delivery and is already supporting medical hypotheses, such as the expected under-treatment of the small airways in asthma. These complete-airway models are also being used to advance next generation aerosol delivery strategies, like controlled condensational growth. We envision future applications of CFD deposition modeling to reduce the need for human subject testing in developing new devices and formulations, to help establish bioequivalence for the accelerated approval of generic inhalers, and to provide valuable new insights related to drug dissolution and clearance leading to microdosimetry maps of drug absorption.

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…74 In addition to its ability to model effects of device and formulation changes on OIDP drug delivery, CFD may also be useful for characterizing effects of intersubject variability according to healthy and diseased lung structure, which are pertinent to understanding the BE of two drug products. Disease modeling is covered by Longest et al 16 in some detail and is not repeated here. A recent review by Martin et al 75 included a discussion that highlighted the ability of in vitro and analytical methods to predict mouththroat and total lung deposition on a population basis.…”

“…As reviewed by others, several methods have been developed to allow for the prediction of regional drug deposition from the extrathoracic region all the way to the alveolar region. 16,21 However, although there are several studies that have investigated small-airway deposition using a variety of CFD methods, 21,34,46,76,77 very few have addressed the effects of small-airway variability. A technique developed by de Backer and colleagues uses four computed tomography scans for each of several subjects to define upper-airway geometries, where scans are taken after normal expiration at functional residual capacity and after deep inhalation at total lung capacity before and after treatment.…”

“…In addition to its ability to model effects of device and formulation changes on OIDP drug delivery, CFD may also be useful for characterizing effects of intersubject variability according to healthy and diseased lung structure, which are pertinent to understanding the BE of two drug products. Disease modeling is covered by Longest et al . in some detail and is not repeated here.…”

“…As reviewed by others, several methods have been developed to allow for the prediction of regional drug deposition from the extrathoracic region all the way to the alveolar region . However, although there are several studies that have investigated small‐airway deposition using a variety of CFD methods, very few have addressed the effects of small‐airway variability.…”

“…13,14 Several recent reviews have summarized much of the work that has occurred since the early efforts of Gradon and Orlicki 13 and Hofmann and Balásházy, 14 which include a comprehensive review by Longest and Holbrook 15 of all in silico models used to predict lung deposition. Recently, Longest et al 16 followed up the previous review 15 with updates in wholelung modeling capabilities using CFD, a discussion on the role of CFD with inhaler design, the use of CFD for development of new respiratory drug-delivery studies, CFD studies in special populations, and a discussion on the merging of CFD and PK models. Reviews by Wong et al 17 and Ruzycki et al 18 focus on the role of CFD within inhaler design, where as Wong et al 17 also describe discrete element modeling (DEM), a computational technique that considers particles as three-dimensional (3D) domains as opposed to the standard Lagrangian method, which considers particles as point masses.…”