Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Abstract

Purpose: To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms.

Methods: A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated.

Results: Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells.

Conclusions: Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.

Keywords: Asthma; Computational fluid dynamics; Nanoaerosol; Nanoaggregate; Pharmaceutical aerosols.

Figure 1

Deposition fraction (DF) from Walenga et al. (13) for the Flovent HFA MDI in the device mouthpiece (MP) and different regions of the conducting airways including the mouth-throat (MT), upper tracheobronchial (TB) region containing the main bifurcation (B1) through B3, and bifurcation segments B4-B7 and B8-B15. Magnified views of deposited particles in the lower airways are shown in the panels, including the deposition of particles in the size range of 1–3 μm in airway generation G13. For an aerosolized dose of 250 μg of fluticasone propionate, Walenga et al. (13) predicted a deposited surface dose in B8-B15 of 1.3 ng/cm², which includes airway generation G13.

Figure 2

Illustration of the small airway epithelial surface including the airway surface liquid (ASL) and characteristic deposited particles in the form of (a) microparticles and (b) nanoparticles.

Figure 2

Illustration of the small airway epithelial surface including the airway surface liquid (ASL) and characteristic deposited particles in the form of (a) microparticles and (b) nanoparticles.

Figure 3

Transient inhalation characteristics for a tidal volume of 500 ml and breathing frequency of 12 breaths per minute expressed as (a) flow rate and lung volume over time, (b) minimum (t = 0) and maximum (t = 2.5 s) expansion of the G13 cross section, and (c) minimum and maximum expansion of the G13 surface model.

Figure 4

Moving mesh model of the ASL in respiratory generation G13 with a diameter of 0.7 mm. An inlet boundary condition simulated bulk ASL clearance and expanding/contracting wall motion enhanced convective and diffusive transport within the ASL layer.

Figure 5

Cumulative absorption efficiency of budesonide (BD) into the respiratory epithelial cells as a percent of initially deposited drug mass for fast clearance conditions. The position where the cumulative absorption curve becomes horizontal denotes a dividing line in each case between the percentage of cells absorbing drug (left of the horizontal position) and percentage of cells not absorbing drug (right of the horizontal position). Both microparticles and nanoaggregates of BD are absorbed by very few cells in the geometry. For example, >95% of the cells receive no drug with the microparticle and nanoaggregate forms. In contrast, the nanoaerosol provides drug to a majority of the epithelial cells (~63%). The maximum cumulative absorption efficiency is equal to the total absorption efficiency (AE) reported in Table 2.

Figure 6

Cumulative absorption efficiency of fluticasone propionate (FP) into the respiratory epithelial cells as a percent of initially deposited drug mass under fast clearance conditions. With microparticles, >95% of cells receive no drug and total absorption efficiency (AE) is very low (<1%). Nanoaggregates improve AE by a factor of 57-fold and increase the number of cells receiving drug to approximately 43%. The Nanoaerosol treats nearly all cells (~92%) and further increases total absorption to approximately 90%.

Figure 7

Absorption enhancement factor (AEF) for microparticles with fast clearance for (a) BD and (b) FP. Values of AEF below 0.1 are not contoured (i.e., they are clear). AEF represents the local absorption in a 16×16 matrix of surface epithelial cells normalized by the total area-averaged absorption in the small airway geometry. An AEF of 1000 in a single element indicates 1000 times more ICS absorption in a 16×16 matrix of cells compared to the total dose per total area.

Figure 8

Absorption enhancement factor (AEF) for nanoaggregates with fast clearance for (a) BD and (b) FP. Values of AEF below 0.1 are not contoured.

Figure 9

Absorption enhancement factor (AEF) for nanoaerosols with fast clearance for (a) BD and (b) FP. Values of AEF below 0.1 are not contoured.

Figure 10

Absorption enhancement factor (AEF) including the effects of gravity and fast clearance for (a) microparticles and (b) nanoaerosol. Values of AEF below 0.1 are not contoured. Initial locations of the microparticles and orientation of the gravity vector are shown.