Abstract
Mucus is the first biological component inhaled drugs encounter on their journey towards their pharmacological target in the upper airways. Yet, how mucus may influence drug disposition and efficacy in the lungs has been essentially overlooked. In this study, a simple in vitro system was developed to investigate the factors promoting drug interactions with airway mucus in physiologically relevant conditions. Thin layers of porcine tracheal mucus were prepared in Transwell® inserts and initially, the diffusion of various fluorescent dyes across those layers was monitored over time. A deposition system featuring a MicroSprayer® aerosolizer was optimized to reproducibly deliver liquid aerosols to multiple air-facing layers and then exploited to compare the impact of airway mucus on the transport of inhaled bronchodilators. Both the dyes and drugs tested were distinctly hindered by mucus with high logP compounds being the most affected. The diffusion rate of the bronchodilators across the layers was in the order: ipratropium ≈ glycopyronnium > formoterol > salbutamol > indacaterol, suggesting hydrophobicity plays an important role in their binding to mucus but is not the unique parameter involved. Testing of larger series of compounds would nevertheless be necessary to better understand the interactions of inhaled drugs with airway mucus.
Highlights
Development efforts in pulmonary drug delivery have primarily focused on advancing device technologies and formulations in order to improve aerosol deposition in the respiratory system as well as patients’ compliance [1]
Mucus-drug interactions are difficult to investigate in vivo, which incentivizes us to develop a model of airway mucus based on thin layers of native porcine tracheal mucus coating the semi-permeable membrane of Transwell® inserts [11]
We assessed the role of compound physico-chemical characteristics on their permeation through porcine tracheal mucus layers, adapted our previously described deposition system [11] for production of liquid aerosols and exploited this to study the interactions of inhaled bronchodilators with airway secretions
Summary
Development efforts in pulmonary drug delivery have primarily focused on advancing device technologies and formulations in order to improve aerosol deposition in the respiratory system as well as patients’ compliance [1]. Study protocols have typically involved 400 μm to several mm thick mucus layers exposed to relatively large volumes of drug preparations to reproduce conditions in the gastro-intestinal tract [6,7]. Such experimental designs are not pertinent to aerosolized drugs which, in the clinic, directly land onto the airway mucosa
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