Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size.
BACKGROUND
Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways.


OBJECTIVE
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-microg dose) of 1.5-, 3-, and 6-microm 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-microg dose) and 200 microg metered-dose inhaler (MDI) albuterol.


RESULTS
Smaller particles achieved greater total lung deposition (1.5 microm [56%], 3 microm [50%], and 6 microm [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-microg dose) were more efficacious and achieved greater bronchodilation than 200 microg MDI albuterol (deltaFEV1 [ml]: 6 microm [551], 3 microm [457], 1.5 microm [347], MDI [494]). Small particles were exhaled more (1.5 microm [22%], 3 microm [8%], 6 microm [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 beta2-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.
Usmani
Omar S
OS
Department of Thoracic Medicine, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. o.usmani@imperial.ac.uk
Biddiscombe
Martyn F
MF
Barnes
Peter J
PJ
D000280:Administration, Inhalation; D000420:Albuterol / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001249:Asthma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D010316:Particle Size; D011877:Radionuclide Imaging; D012137:Respiratory System / Q000000981:diagnostic imaging / Q000378:metabolism*; D016896:Treatment Outcome
D001993:Bronchodilator Agents; D000420:Albuterol