Pulmonary drug delivery and retention: A computational study to identify plausible parameters based on a coupled airway-mucus flow model
Aranyak Chakravarty, Mahesh V. Panchagnula, Alladi Mohan, Neelesh A. Patankar
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.
Introduction
The lung is one of the most exposed organs of the human body [1]. The dichotomous branching structure of the lung—starting from the trachea and culminating in the alveolar sacs—provides a mechanism by which air from the surrounding atmosphere is drawn into the lungs during inhalation and expired out during exhalation. Pulmonary drug delivery systems take advantage of the respiration process to deliver drug molecules to the lung through inhalation. The drug molecules may be in the form of dry powders or liquid aerosols, and are administered in a non-invasive manner with the help of aerosol generators such as inhalers, nebulisers etc. [2, 3]. Once inhaled, the powdered/aerosolised drugs are transported along the respiratory tract where they deposit depending on their physio-chemical properties as well as breathing characteristics and physiological conditions. Thus, drugs can be delivered locally to a targeted region of the lung for treatment of respiratory diseases, such as asthma or COPD [3]. Such targeted delivery can potentially lead to smaller overall drug dose and reduced side effects. Systemic drug delivery can also be achieved by targeting delivery to the alveolar region of the lung where the drugs can be easily absorbed into the systemic blood circulation through the thin blood-gas barrier and the large alveolar surface area [1].
Methods
Idealisation of the lung geometry
The physiological dichotomous branching network of human lungs is approximated in this work by a one-dimensional trumpet model (Fig 1). While this model cannot account for the effects of heterogeneity in the lungs, it is still a tractable model for the whole lungs in order to capture key trends.
Results and discussion
Drug-laden aerosols are deposited in the respiratory mucus primarily during inhalation. The deposited drug molecules diffuse in the mucus layer and are transported upstream (towards the mouth) via mucociliary advection. To obtain the key deposition and washout trends, simulations were done assuming that drug-laden aerosols are entering the lungs for five breaths, i.e., exposure time τexp = 5. Extrapolation to longer exposure times and its impact on drug retention will be discussed separately. It is seen that the (scaled) drug concentration in the mucus (ϕd), at the end of the exposure duration (τ = 5), qualitatively follows aerosol deposition Sd ( ; see Fig 2A).
Citation: Chakravarty A, Panchagnula MV, Mohan A, Patankar NA (2022) Pulmonary drug delivery and retention: A computational study to identify plausible parameters based on a coupled airway-mucus flow model. PLoSComputBiol 18(6): e1010143. https://doi.org/10.1371/journal.pcbi.1010143
Editor: Alison L. Marsden, Stanford University, UNITED STATES
Received: January 13, 2022; Accepted: April 26, 2022; Published: June 2, 2022
Copyright: © 2022 Chakravarty et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: This work was supported in part by the Ministry of Human Resource Development (now Ministry of Education), Government of India under the SPARC programme (https://sparc.iitkgp.ac.in/), grant SPARC/2018-2019/P838/SL to MVP. The funders had no role in study design, data collection and analysis, or decision to publish.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010143#abstract0
