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 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg 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 beta2-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.

In Vitro Evaluation of Positive Expiratory Pressure Devices Attached to Nebulizers

“…Drugs that target receptors in the large airways would benefit from larger particles. 15 Laube et al reported a significant increase in intrapulmonary deposition in small and medium size aerosols when a slow inhalation maneuver was used. 11 The limitations of this study are related to its in vitro nature and the methodology.…”

“…In addition, the change of aerosol particle size could affect the deposition location and therefore increase systemic absorption and decrease the therapeutic response. 15 …”

In vitro and in vivo aspects of cascade impactor tests and inhaler performance: A review

“…Studies with a similar protocol were undertaken in mild to moderate asthmatics, 82,83 using monodisperse albuterol aerosols of 1.5 μm, 3 μm, and 6 μm. The results of the first of the investigations, by Usmani et al, 83 differed from those of Zanen et al, [79][80][81] because bronchodilator response was found to be higher for 3 μm and 6 μm aerosols than for the 1.5 μm aerosol.…”

Which factors affect the choice of the inhaler in chronic obstructive respiratory diseases?

“…In particular, it is still unknown what is the optimal particle size able to provide greater improvements in lung function. In this regard, the discrepancy between the study from Zanen et al [13] and that from Usmani et al [14] which specifically addressed the clinical benefit as a function of the particle size of the inhaled bronchodilator, could be only apparent, since the asthmatic volunteers differed in terms of magnitude of airway obstruction. Findings with this methodology generally replicate those obtained with the Andersen impactor device.…”