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 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.

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

“…Additionally, it has been reported that the engineered particles with a geometric diameter greater than 10 microns can extend drug retention time in the lungs due to the ability of the deposited particles to escape from macrophage phagocytosis [ 29 ]. According to a recent study by Longest et al, computational models demonstrated that nanoaggregates are favorable for higher drug absorption efficiency and dose uniformity in the lungs, compared to microparticles [ 30 ]. Furthermore, TFF can produce amorphous high-surface area powders with submicron primary particles, which can enhance the dissolution rate and subsequently improve the bioavailability of poorly water-soluble drugs like remdesivir in the lungs [ 31 ].…”

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

“…Additionally, it has been reported that the engineered particles with a geometric diameter greater than 10 microns can extend drug retention time in the lungs due to the ability of the deposited particles to escape from macrophage phagocytosis [28]. According to a recent study by Longest et al, computational models demonstrated that nanoaggregates are favorable for higher drug absorption efficiency and dose uniformity in the lungs, compared to microparticles [29]. Furthermore, TFF can produce amorphous high surface area powders with submicron primary particles, which can enhance the dissolution rate and subsequently improve the bioavailability of poorly water-soluble drugs like remdesivir in the lungs [30].…”

Use of computational fluid dynamics deposition modeling in respiratory drug delivery

“…An important aspect of coupled CFD and PK modeling is where to switch from the 3D resolved CFD approach to mechanistic 1D models and/or PK rate equations. Based on the findings of Longest and Hindle [14], illustrated in Figure 5, we propose that CFD simulation all the way through epithelial cell absorption has important implications to bioavailability that cannot be captured with 1D approximations or PK rate equations. Therefore, when PK metrics such as plasma drug concentration are of interest, we recommend that the protocol implemented by Rygg et al [177] be followed in which the PK model is applied after epithelial cell absorption occurs with a 3D or other mechanistic model.…”

“…Once inside the lung tissue, we view a PK model as valuable for determining tissue clearance and the prediction of plasma concentrations and distribution of drug throughout the body. Our assessment is that without CFD predictions through absorption, potentially important metrics such as the percentage of cells absorbing drug above a predefined threshold [14] cannot be accurately predicted.…”

“…Of this fraction, only a small percentage, which may be less than 1%, is typically deposited in an airway region, like the small tracheobronchial airways [13]. Absorption of the deposited drug then varies widely depending on the physicochemical properties of the drug molecule and formulation, and may be as low as 1% of the deposited dose for some hydrophobic medications [14, 15].…”