The Demonstration of Bronchodilator Effects of Salbutamol Formulated in Chlorofluorocarbon and Hydrofluoroalkane-134a Metered Dose Inhalation Devices on Leukotriene D 4 -Induced Pulmonary Responses in the Guinea Pig

ABSTRACT

The demonstration of bronchodilator effects of β₂-adrenergic agonists delivered by metered dose inhalation (MDI) devices can be useful in the development of new therapies for asthma or assessing the effects of a formulation. MDI formulations of hydrofluoroalkane (HFA)-134a (a chlorofluorocarbon [CFC]-free propellant), salbutamol in the HFA-134a propellant, CFC-P11/P12 propellant, and salbutamol and formoterol in the CFC propellant were evaluated for their ability to reduce leukotriene D₄ (LTD₄)-induced bronchoconstriction in guinea pigs using the Konzett-Rossler method. LTD₄ challenges were made at various times up to 6 hours after MDI treatment. Neither the placebo vehicle propellants nor the drug formulations affected basal airflow. Only the salbutamol/CFC, formoterol/CFC, and salbutamol/HFA MDI formulations inhibited LTD₄-induced bronchoconstriction. One actuation of the MDI device containing salbutamol or formoterol in the CFC propellant produced ∼100% inhibition of LTD₄-induced effects following a 5-minute pretreatment period at doses greater than or equal to 10 μg per actuation. A single actuation of salbutamol (100 μg per actuation) was required to show significant inhibition 30 minutes after aerosol drug delivery (∼50% inhibition) and was inactive 1 hour after drug delivery. Inhibition with formoterol was observed at 30 minutes after aerosol delivery at 25 μg per actuation and for up to 6 hours at 100 μg per actuation. Results of this study indicate that the bronchodilator activity of MDI-delivered β₂-adrenergic agonists could be demonstrated using either CFC or HFA propellants in a standard preclinical animal model.