Pulmonary drug delivery and retention: A computational study to identify plausible parameters based on a coupled airway-mucus flow model

Abstract

Pulmonary drug delivery systems rely on inhalation of drug-laden aerosols produced from aerosol generators such as inhalers, nebulizers etc. On deposition, the drug molecules diffuse in the mucus layer and are also subjected to mucociliary advection which transports the drugs away from the initial deposition site. The availability of the drug at a particular region of the lung is, thus, determined by a balance between these two phenomena. A mathematical analysis of drug deposition and retention in the lungs is developed through a coupled mathematical model of aerosol transport in air as well as drug molecule transport in the mucus layer. The mathematical model is solved computationally to identify suitable conditions for the transport of drug-laden aerosols to the deep lungs. This study identifies the conditions conducive for delivering drugs to the deep lungs which is crucial for achieving systemic drug delivery. The effect of different parameters on drug retention is also characterized for various regions of the lungs, which is important in determining the availability of the inhaled drugs at a target location. Our analysis confirms that drug delivery efficacy remains highest for aerosols in the size range of 1-5 μm. Moreover, it is observed that amount of drugs deposited in the deep lung increases by a factor of 2 when the breathing time period is doubled, with respect to normal breathing, suggesting breath control as a means to increase the efficacy of drug delivery to the deep lung. A higher efficacy also reduces the drug load required to be inhaled to produce the same health effects and hence, can help in minimizing the side effects of a drug.

Inhalation of virus-loaded droplets as a clinically plausible pathway to deep lung infection

“…The one-dimensional transport equation for droplets in the modelled LRT can be represented in a dimensionless manner as (Chakravarty et al, 2022)…”

“…Major droplet deposition mechanisms viz. diffusion, sedimentation and impaction have been taken into account while calculating droplet deposition in the LRT (see S1 Text of Chakravarty et al (2022) for details). The quantity L ′ D ϕ d quantifies dimensionless deposition of the droplets.…”

“…Once inhaled, the droplets are subjected to advective-diffusive transport in the respiratory tract through the breathing dynamics and may eventually deposit in the respiratory mucosa in different regions of the respiratory tract ( Mittal et al., 2020 ). SARS-CoV-2 has been observed to initially deposit and replicate in the upper respiratory tract (URT), particularly the nasopharynx ( Grant et al., 2021 ), although there remains a possibility of the deposition taking place directly in the lower respiratory tract (LRT) depending on the inhaled droplet size and flow conditions ( Madas et al., 2020 ; Chakravarty et al., 2022 ). It is, however, unlikely that the initial infection will be seeded in the LRT.…”

“…Extensive independent studies have been carried out over the years on all these aspects ( Baccam et al., 2006 ; Smith et al., 2008 ; Hofmann, 2011 ; Mauroy et al., 2011 ; Handel et al., 2018 ; Karamaoun et al., 2018 ; Jensen et al., 2019 ). A few studies have investigated the coupled nature of droplet and mucus transport ( Chakravarty et al., 2022 ) as well as virus transport and infection kinetics ( Quirouette et al., 2020 ). However, the nature of the phenomena requires simultaneous consideration of all the processes necessitating a fully coupled mathematical model taking into account the individual processes.…”

“…Such a model is being reported for the first time. This model is used within the framework of a Weibel-type model of the complete human LRT, with appropriate modifications ( Weibel, 1963 ; Chakravarty et al., 2022 ). Aerosolisation of nasopharyngeal mucosa is not explicitly considered in the present study.…”