Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model

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.

Lower Inspiratory Breathing Depth Enhances Pulmonary Delivery Efficiency of ProAir Sprays

“…These included: (1) different inhalation conditions (transient vs. constant), and (2) the accuracy of modeling spray properties. The mean diameter of 16.54 µm and an initial speed of 100-120 m/s were used for discharged Ventolin sprays [14], which are significantly higher than the mean diameter of 9.1 µm measured by Liu et al [20], and the initial velocity of 40 m/s predicted by Talaat et al [19]. The mouth-throat models in Biswas et al [8] and Yousefi et al [14] are also different, even though they may not be significant contributors to their observed differences.…”

“…The airway model extended from the mouth-opening to lung bronchioles of the ninth generation of bifurcations (i.e., G9). This model was developed in our previous studies, with detailed procedures reported in [17][18][19]. The shape of the mouth opening was adapted to connect snuggly with the inhaler mouthpiece.…”

Liposomes or Extracellular Vesicles: A Comprehensive Comparison of Both Lipid Bilayer Vesicles for Pulmonary Drug Delivery

“…Pressurized metered-dose inhalers (pMDIs) are sturdy containers that hold medication dissolved or dispersed in liquefied propellants. Device actuation–patient inspiration, i.e., device–patient coordination results in precise inhalation dosimetry [ 218 ]. The propellants rapidly evaporate due to their high vapor pressure, allowing the patient to breathe in the aerosolized medication particles.…”

The Impact of Actuator Nozzle and Surroundings Condition on Drug Delivery using Pressurized-Metered Dose Inhalers

“…Our geometries, including a cylinder representing the open-air environment, two nozzle geometries, and the real MT model, were discretized using tetrahedral elements in ANSYS® Workbench. The prism elements with eight layers of thickness and a transition ratio of 0.272 were generated in the region near the airway wall to capture the high gradients near the walls (Feng et al 2021;Talaat et al 2022). The geometries and mesh were imported into ANSYS Fluent 2020R2 (ANSYS, Inc).…”

“…Plume properties also change when inhalation flow is used, compared to no-flow conditions (Moraga-Espinoza et al 2018). Talaat et al (2022) recently suggested that a study on plume behaviour should be done under close to real conditions during drug delivery, but this is currently not experimentally feasible.…”