Regional lung deposition and bronchodilator response as a function of β2-agonist particle size

Rationale: Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways. Objectives: We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. Methods: In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 +/- 11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30-mu g dose) of 1.5-, 3-, and 6-mu m mass median aerodynamic diameter, at slow (30-60 L/min) and fast(> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-mu g dose) and 200 mu g metered-dose inhaler (MDI) albuterol. Results: Smaller particles achieved greater total lung deposition (1.5 mu m [56%], 3 mu m [50%], and 6 mu m [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-mu g dose) were more efficacious and achieved greater bronchodilation than 200 mu g MDI albuterol (Delta FEV1[ml]: 6 mu m [551], 3 mu m [457], 1.5 mu m [347], MDI [494]). Small particles were exhaled more (1.5 mu m [22%], 3 mu m [8%], 6 mu m [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. Conclusions: Regional targeting of inhaled beta(2)-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.