抄録
Particles of poorly water-soluble drugs with high dry powder inhalation (DPI) performance were developed. A spray drying (SD) technique utilizing a three-fluid nozzle was applied in this research to realize such DPI particles. The particles of cyclosporine (Cyc) as a poorly water-soluble model drug were dispersed in the aqueous solution of the dispersing agents and pulverized into nanometer-sized particles by a wet bead milling technique using a conventional stirrer reported before. The combination of polyvinylpyrrolidone (PVP) and sodium lauryl sulfate (SLS) was used to strengthen the milling efficiency. The resultant aqueous nanosuspension of Cyc was supplied to the spray-drying process to obtain the dried powder. In this process, l-leucine (Leu), as an anti-adhering agent, was co-formulated in the spray fluid to prepare the DPI particles to avoiding their inter-particulate cohesion. The Cyc nanosuspension and Leu solution were co-sprayed in various manners through the three-fluid nozzle, which has two liquid-supply lines and one air-supply line. The aerodynamic performance of the dried composite particles was evaluated with an Andersen Cascade Impactor. It was found that the incorporation of Leu successfully improved the cohesive behavior of Cyc, leading to enhanced aerosol dispersion. In particular, the particles produced from the concentric double-structured droplets, which consisted of an inner Cyc nanosuspension and outer Leu solution, showed the highest inhalation characteristics. This result suggested that Leu was dominantly accumulated on the surface of the particles, and such a structure positively promoted the detachment among particles in the air flow. The drug release test through a filter revealed that the composite particles drastically improved the in vitro dissolution behavior of Cyc, which was attributable to the huge surface area of individual milled particles and their hydrophilicity from PVP and SLS.
