Effect of delayed pMDI actuation on the lung deposition of a fixed-dose combination aerosol drug

Abstract

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2 and 5 s and inhalation flow rate between 30 and 150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition.

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…Spray characterization of MDIs using CFD is challenging because of the several physical processes that include droplet formation, the large temperature gradient at the device orifice, high initial velocity values, and rapid evaporation of the propellant . Several studies have considered MDI delivery to the lungs using CFD, with varying physical treatments . Proper characterization of an MDI spray requires the careful selection of orifice boundary conditions because this process is crucial to understanding device differences.…”

“…However, experimental spray velocity measurements are not available directly at the orifice but ~20–50 mm downstream of the orifice, where some assumptions need to be made to specify orifice boundary conditions. For example, Farkas et al . used several downstream experimental spray velocity measurements to extrapolate to the orifice.…”

“…The expected large temperature gradient at the orifice and the rapid evaporation of propellant may significantly affect aerosol behavior and subsequently drug deposition, but there is no consensus in the literature for the manner in which these processes are modeled. Several studies have assumed that the temperature at the orifice is at the boiling point of the propellant, and conservation of mass was used to estimate the initial density . Oliveira et al .…”

“…considered heat transfer but did not describe the method. Regarding evaporation, several studies that model MDI delivery treat the initial aerosol state as a dry particle, with the inherent assumption that propellant evaporation is so rapid that it does not affect drug deposition . Longest et al .…”

“…showed good agreement with in vitro regional deposition data using this approach with a suspension‐based MDI. However, for studies that model solution‐based MDI delivery it is unclear whether this assumption is appropriate considering that ethanol, a common cosolvent in solution‐based MDIs, evaporates more slowly than the propellant . A few studies did consider evaporation, but details on model implementation were few.…”