Abstract
Cyclosporine A (CsA) has been widely used as an immunosuppressive agent, and recent outcomes from clinical studies are indicative of the potent therapeutic potential of CsA for chronic asthma and airway inflammation. The clinical use of CsA for airway inflammatory diseases is partly limited because of low oral bioavailability and severe systemic side effects. A number of CsA dosage forms have been proposed to overcome these drawbacks, for example, nebulizer formulation and metered-dose inhaler formulation for inhalation therapy, whereas these liquid formulations sometimes contain organic solvents and other solubilizers, leading to local irritant potency. In this context, our group developed a dry powder inhalation (DPI) system of CsA, employing a polymer-based amorphous solid dispersion (ASD) approach, for inhalation therapy on airway inflammations. There was marked improvement in dissolution behavior of the ASD formulation compared with that of an amorphous CsA. The new DPI system of CsA exhibited high dispersibility and suitable particle distribution for inhalation therapy. In vivo experiments demonstrated that inhaled DPI system of CsA attenuated inflammatory events in experimental asthma/chronic obstructive pulmonary disease (COPD) model rats as evidenced by a decrease of infiltrated granulocytes, and there was no excessive increase in systemic exposure of CsA at a pharmacologically effective dose, possibly leading to reduced systemic side effects. From these findings, combination use of CsA-loaded ASD and DPI systems might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.
