Evaluation of metered dose inhaler (MDI) formulations of ciclosporin.

Our purpose was to evaluate metered dose inhaler (MDI) formulations of cyclosporin (cyclosporine) for aerodynamic properties, chemical stability and bioactivity. Ciclosporin formulations (0.1, 0.5 and 1.0% w/w) were prepared in hydrofluoroalkane (HFA) propellants (134a and 227) containing 3 and 6% ethanol. Aerodynamic properties of the MDI formulations were analysed using an eight-stage Andersen cascade impactor and respirable mass and non-respirable mass, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined from the impaction profiles. The chemical stability of 0.1% ciclosporin in HFA 227 containing 3% ethanol formulation stored at room temperature and 40 degrees C was evaluated by HPLC at 0, 14, 30 and 90 days. The bioactivity of ciclosporin MDI formulations was evaluated by determining the ciclosporin-mediated inhibition of interleukin-2 (IL-2) release from human Jurkat cells stimulated with phorbol 12-myristate 13-acetate (PMA). As ethanol concentration increased from 3 to 6%, respirable mass decreased from 2.3 mg per five actuations to 0.04 mg per five actuations for HFA 227 formulations, and from 1.5 mg to 0.09 mg per five actuations for HFA 134a formulations. The MMAD for both HFA 134a and 227 formulations increased with an increase in ciclosporin concentration. HPLC analysis showed ciclosporin to be extremely stable in HFA 227 at room temperature and 40 degrees C. Stimulation of Jurkat cells with PMA released significant amounts of IL-2, which was inhibited by ciclosporin in a dose-dependent manner. This study shows the feasibility of developing chemically stable and bioactive HFA-based MDI formulations of ciclosporin.