Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

Abstract

Background: The objective of this study was to compare aerosol deposition predictions of a new whole-airway CFD model with available in vivo data for a dry powder inhaler (DPI) considered across multiple inhalation waveforms, which affect both the particle size distribution (PSD) and particle deposition. Methods: The Novolizer DPI with a budesonide formulation was selected based on the availability of 2D gamma scintigraphy data in humans for three different well-defined inhalation waveforms. Initial in vitro cascade impaction experiments were conducted at multiple constant (square-wave) particle sizing flow rates to characterize PSDs. The whole-airway CFD modeling approach implemented the experimentally determined PSDs at the point of aerosol formation in the inhaler. Complete characteristic airway geometries for an adult were evaluated through the lobar bronchi, followed by stochastic individual pathway (SIP) approximations through the tracheobronchial region and new acinar moving wall models of the alveolar region. Results: It was determined that the PSD used for each inhalation waveform should be based on a constant particle sizing flow rate equal to the average of the inhalation waveform's peak inspiratory flow rate (PIFR) and mean flow rate [i.e., AVG(PIFR, Mean)]. Using this technique, agreement with the in vivo data was acceptable with <15% relative differences averaged across the three regions considered for all inhalation waveforms. Defining a peripheral to central deposition ratio (P/C) based on alveolar and tracheobronchial compartments, respectively, large flow-rate-dependent differences were observed, which were not evident in the original 2D in vivo data. Conclusions: The agreement between the CFD predictions and in vivo data was dependent on accurate initial estimates of the PSD, emphasizing the need for a combination in vitro-in silico approach. Furthermore, use of the AVG(PIFR, Mean) value was identified as a potentially useful method for characterizing a DPI aerosol at a constant flow rate.

Current Scientific Considerations to Verify Physiologically‐Based Pharmacokinetic Models and Their Implications for Locally Acting Products

“…Great progress has been made in recent years. For orally inhaled products, in vivo data using gamma scintigraphy with radiolabeled aerosols have been used to estimate central and peripheral deposition amounts . For topical dermatological products, dermal microdialysis and open‐flow microperfusion techniques have been directly applied to measure local cutaneous concentrations, which involve using tiny hollow filaments (“probes”) inserted into the dermis layer of the skin .…”

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

“…In addition to current work using a CFD‐DEM approach, several recent studies have used CFD with the more traditional Lagrangian approach for particle tracking to investigate DPI performance . The use of CFD with Lagrangian particle tracking for the investigation of DPI performance was also recently reviewed by Sommerfeld et al .…”

“…For CFD, several studies have validated the model via comparison of predicted regional deposition values with in vitro or in vivo data . For comparison with in vitro data, a replica of the computational geometry may be generated using rapid prototyping, and regional deposition after actuation of the device into the geometry may be quantified using high‐performance liquid chromatography .…”

“…For comparison with in vitro data, a replica of the computational geometry may be generated using rapid prototyping, and regional deposition after actuation of the device into the geometry may be quantified using high‐performance liquid chromatography . Validation with in vivo data uses data collected via gamma scintigraphy with radiolabeled aerosols, where two‐dimensional images of deposition locations are used to estimate central and peripheral deposition amounts . As shown in Figure , the regional deposition predictions of the Respimat Soft Mist inhaler drug delivery from Tian et al .…”

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

“…However, dose or dose/area values in the small airways have typically not been available due to limitations with in vivo deposition and imaging studies. Recent advances in complete-airway simulations of pharmaceutical aerosol deposition in the lungs have enabled predictions of inhaled medication dose in the small airways (23–28). In these simulations, computational fluid dynamics (CFD) is used to resolve the three-dimensional (3D) time-dependent flow physics of the complex pharmaceutical aerosol delivery process from the site of aerosol formation to the point of deposition (29).…”