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.

Keywords: actuation–inhalation coordination; dispersion; high-speed imaging; metered dose inhaler (MDI); orifice; polydisperse distribution; press-and-breathe.

Figure 1

High-speed imaging of MDI releasing.

Figure 2

Computational model: (a) metered-dose inhaler (MDI) with an aerosol-exiting nozzle, (b) the integrated MDI–mouth–lung model, and (c) multi-block computational mesh with refined cells downstream of the nozzle. The airway model was divided into mouth, pharynx, larynx, tracheobronchial region (TB), and five lung lobes.

Figure 3

MDI delivery parameters and sensitivity studies: (a) deep slow inhalation and MDI administration waveforms; (b) MDI droplet size distribution, with a mean diameter of 11.0 µm and a geometric standard deviation of 1.57; (c) grid independence study with the mesh size ranging 4–16 million; and (d) droplet count sensitivity study with the number of sample droplet ranging 20–150 k. To study the effect of the MDI actuation timing on drug delivery, the MDI was applied at three more points within the inhalation cycle (i.e., 0.0, 1.5, and 2.5 s after inhalation onset) were considered in addition to the baseline case (i.e., 0.63 s after inhalation onset, red solid line).

Figure 4

Estimating the droplet exiting velocity at the nozzle based on experimental measurements at downstream locations: (a) numerically predicted mean droplet velocities at 3 and 6 cm from the nozzle for three nozzle speeds (35, 40, and 45 m/s) in comparison to the phase Doppler anemometry (PDA) measurements [30]; (b) comparison between the numerically predicted and recorded MDI plumes.

Figure 5

Airflow and droplet dynamics during MDI actuation (0.5–3.0 ms): (a) mid-plane velocity contour showing the jet flow from the nozzle and the heterogeneous flow distribution in the oral cavity, (b) jet-induced vortex structures in the mouthpiece of the MDI, and (c) snapshots of the MDI plume at varying instants (0.5–3.0 ms) after actuation. Flow and droplets were colored by their perspective velocities.

Figure 6

Droplet dynamics within the oral cavity 20–60 ms after MDI actuation within a 2 mm–thick slice: (a) two sampling locations, namely a sagittal slice (red, mid-plane) and an axial slice (blue); and snapshots of droplets in the sagittal and axial slices at three instants: (b) 20 ms, (c) 40 ms, and (d) 60 ms. Symbols of droplets were colored and scaled by their sizes.

Figure 7

Airflow and droplet dynamics at peak inhalation (1.23 s, 61.2 L/min): (a) mid-plane 2D velocity contour, (b) snapshots of droplet positions, and instantaneous vortex structures defined by Q-criterion at two different levels (c,d).

Figure 8

Characterization of the albuterol MDI delivery: (a) surface deposition with droplets scaled and colored by the droplet size, (b) dose distribution in terms of the deposition enhancement factor (DEF), (c) mass-based deposition fraction in different regions of the respiratory tract, and (d) drug fraction penetrating beyond the G9 bronchioles (i.e., the penetration rate).

Figure 9

Airflow and droplet dynamics with MDI actuation before inhalation (t = 0.0): (a) mid-plane velocity contour showing the jet flow from the nozzle and the heterogeneous flow distribution in the oral cavity, (b) jet-induced vortex structures in the mouthpiece of the MDI, (c) snapshots of the MDI plume at varying instants (0.5–3.0 ms) after actuation with droplets colored by droplet velocity, and (d) comparison of the plume snapshots at 5.0 ms colored by droplet velocity and droplet size.

Figure 10

Droplet dynamics in the upper airway at varying instants (20–400 ms) when actuating the inhaler before inhalation: (a) dynamics during 20–200 ms, and (b) dynamics during 200–400 ms. Droplets were scaled and colored by droplet diameters. The Q-criterion iso-surfaces were colored by flow velocity.

Figure 11

Comparison of the mass-based dosimetry between four delivery scenarios when the MDI was actuated at four different time-points of the inhalation waveform: (a) regional wall deposition and (b) lobar penetration rate.

Figure 12

Comparison of surface deposition and DEF maps among three MDI actuation times: (a) firing at 0.0 s, (b) 1.5 s, and (c) 2.5 s.