Abstract
Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation–inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI–mouth–lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth–throat, and lung. Concerning the device–patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth–throat loss and increased lung doses in both the central and peripheral regions.
Highlights
Introduction iationsAssessment of the therapeutic efficacy of oral inhalation drug products (OIDPs), such as metered-dose inhaler (MDI) formulations, requires accurate knowledge of their deposition in the targeted areas [1,2]
Surrogate computational fluid dynamics (CFD) simulations have become increasingly important in providing comparable results and deposition details [10,11]
The objective of this study is to develop an integrated MDI–mouth–lung model extendThe objective of this study is to develop an integrated MDI–mouth–lung model exing to G9 and use it to investigate the effects of MDI actuation time on inhalation dosimetry
Summary
Assessment of the therapeutic efficacy of oral inhalation drug products (OIDPs), such as metered-dose inhaler (MDI) formulations, requires accurate knowledge of their deposition in the targeted areas [1,2]. SPECT/CT can visualize the in vivo drug depositions, its application in studying inhalation drug delivery is limited due to high cost, radiation risks, and ethical issues [3,4,5,6]. Surrogate computational fluid dynamics (CFD) simulations have become increasingly important in providing comparable results and deposition details [10,11]. An accurate CFD predicted dosimetry requires a precise representation of the drug properties, respiratory geometry, and breathing condition. Significant variability exists among individuals in respiratory structures, inhalation patterns, disease severity, and the MDI dose distributions, which are Licensee MDPI, Basel, Switzerland
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