Across the pulmonary epithelial barrier: integration of physicochemical properties and human cell models to study pulmonary drug formulations

During the process of inhalable formulation drug development a deep knowledge of the physicochemical characteristics of the drug and formulation components and their relationship with the biological properties of the airways is necessary. 
For example, the solubility and lipophilicity of a drug may affect therapeutic efficacy by changing the residence time of the inhaled microparticles at the airways surface. Furthermore, the properties of aerosol drug particles, such as shape, size and density, as well as the diseases of the respiratory tract, delivery device and inhalation manoeuvre will have an impact on where these microparticles are deposited.

The airway epithelium is involved in the pathogenesis and treatment of several respiratory diseases. Epithelial cells are directly exposed to the environment and respond to xenobiotics such as medical therapies. In some cases the epithelial cells are the site of action for drug molecules or the drug molecules might need to be transported across the epithelium to arrive at the site of action (β2-agonists are transported across the epithelium to target underlying smooth muscle cells). The drug particles, which are deposited on the respiratory epithelia, have to interact with the mucus lining, dissolve and get transported through this layer. Despite advances in in vitro testing of respiratory epithelial permeability, there is little known about how and where drugs are absorbed at a cellular level and how long they reside in the lung. Therefore, pulmonary permeability assessment of drug particles, and the influence of formulation parameters on drug uptake at the epithelia, may provide insights that will allow formulations to be developed with optimised therapeutic outcomes.
This review focuses on the integration of these physicochemical characteristics with the biological factors to provide a better understanding of the fate of drug microparticles after deposition on the epithelial cells