Niwa Toshiyuki, Mizutani Daisuke, Danjo Kazumi
Department of Industrial Pharmacy, Faculty of Pharmacy, Meijo University, Yagotoyama, Tempaku-ku, Nagoya, Japan.
Chem Pharm Bull (Tokyo). 2012;60(7):870-6. doi: 10.1248/cpb.c12-00208.
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.
为开发一种干粉吸入器（DPI），制备了难溶性药物颗粒。本研究采用了作者开发的使用四流体喷嘴（4N）的喷雾冷冻干燥（SFD）技术。分别使用环孢素和甘露醇作为难溶性模型药物和溶出促进载体。环孢素的有机溶液和甘露醇的水溶液通过4N分别同时雾化，两种溶液在喷嘴边缘尖端相互碰撞。喷雾雾滴立即在液氮中冷冻形成悬浮液。然后，将冰滴冷冻干燥以制备药物和载体的复合颗粒。由于叔丁醇（t-BuOH）的凝固点相对较高，因此用作有机喷雾溶剂。根据所得复合颗粒的形态和物理化学性质对其进行表征。颗粒中含有无定形环孢素和δ-结晶甘露醇。SFD颗粒特有的多孔结构可能有助于其良好的空气动力学性能。一系列具有相似尺寸分布和不同药物含量的颗粒表明，甘露醇的加入成功改善了环孢素的内聚行为，从而增强了气溶胶分散性。新建立了使用低体积介质的溶出试验方法，以模拟颗粒从沉积在支气管和肺粘膜表面的释放过程。亲水性甘露醇复合物结合SFD颗粒的多孔结构显著改善了环孢素的体外溶出行为。
