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Published ahead of print on September 28, 2005, doi:10.1164/rccm.200410-1414OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 1497-1504, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200410-1414OC

Original Article

Regional Lung Deposition and Bronchodilator Response as a Function of {beta}2-Agonist Particle Size

Omar S. Usmani, Martyn F. Biddiscombe and Peter J. Barnes

National Heart and Lung Institute, Imperial College London; Royal Brompton Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Omar S. Usmani, M.D., Department of Thoracic Medicine, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail: o.usmani{at}imperial.ac.uk

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-µg dose) of 1.5-, 3-, and 6-µm 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-µg dose) and 200 µg metered-dose inhaler (MDI) albuterol.

Results: Smaller particles achieved greater total lung deposition (1.5 µm [56%], 3 µm [50%], and 6 µm [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-µg dose) were more efficacious and achieved greater bronchodilation than 200 µg MDI albuterol ({Delta}FEV1[ml]: 6 µm [551], 3 µm [457], 1.5 µm [347], MDI [494]). Small particles were exhaled more (1.5 µm [22%], 3 µm [8%], 6 µm [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.

Key Words: aerosol • asthma • {beta}-adrenergic agonists • particle size • radionuclide imaging




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