Assessing airways deposition, physiology and pharmacokinetics of monodisperse aerosols in obstructive lung disease

Abstract

Inhaled medication is standard therapy in asthma and COPD. However the amount of drug reaching the lung is influenced by several factors including aerosol particle size and upper airway morphology. While smaller sized aerosol particles may be transported to the small airways there is still a need to examine the systemic risk and efficacy associated with small particle aerosols. On one hand small particles can be transported to the lung periphery (small airways) where they can reduce small airways dysfunction. On the other hand small particles can increase plasma concentrations of the drug worsening systemic side effects. Aerosol particle size determines deposition throughout the whole of the respiratory tract including the upper airway and by altering aerosol delivery characteristics it is possible to avoid deposition in the upper airway. This thesis set out to investigate how to improve drug deposition in the lung by controlling aerosol delivery characteristics mainly particle size and flow rate and investigate how the filtering effects of the upper airway can be overcome. The specific aims of this thesis were: To quantify aerosol deposition in the upper airway both in vitro and in vivo with the hope of using in vitro techniques to predict what happens in vivo. Explore how aerosol particle size effects lung deposition and pulmonary bioavailability through pharmacokinetics. Investigate and evaluate novel tests of small and large airways function and see if these can detect physiological improvement following inhalation of small (1.5 µm) particles and large (6 µm) particles. In vitro tests on upper airway models somewhat predicted what happens in vivo. The increasing effect of both particle size and flow rate was shown to increase upper airway deposition. Tests of respiratory function and inflammation demonstrated greater between test variability than routine tests of lung function and warrant further evaluation. Improvements in small and large airway function were not associated with the deposition of small and large aerosol particles following one off dosing of an inhaled corticosteroid fluticasone propionate and a link between these tests and aerosol particle size warrants further investigation.