Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols

Abstract

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 μm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 μg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 μm, were significantly more potent bronchodilators than the 1.5-μm and placebo aerosols for FEV1and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-μg dose of the 6- and 3-μm aerosols produced FEV1bronchodilation comparable to that produced by 200 μg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal β2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.