Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

抄録

Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.