Niwa Toshiyuki, Shimabara Hiroko, Danjo Kazumi
Department of Industrial Pharmacy, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan.
Chem Pharm Bull (Tokyo). 2010 Feb;58(2):195-200. doi: 10.1248/cpb.58.195.
Spray freeze-drying (SFD) technique using four-fluid nozzle (4N), which is a novel particle design technique previously developed by authors, has been further developed to expand its application in pharmaceutical industry. The organic solvent was utilized as a spray solvent to dissolve the poorly soluble drug instead of conventional aqueous solution. Acetonitrile solution of the drug and aqueous solution of the polymeric carrier were separately and simultaneously atomized through 4N, and collided each other at the tip of nozzle edge. The spray mists were immediately frozen in the liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier according to our proprietary method developed before. The resultant composite particles with phenytoin prepared by using acetonitrile (4N-SFD-MeCN system) were deeply characterized compared to those using aqueous solution (4N-SFD-aqua system) from morphological and physicochemical perspectives. The characteristic porous structure was observed in 4N-SFD-MeCN particles as well as 4N-SFD-aqua particles. However, it was found that the size and quantity of pore in 4N-SFD-MeCN particles were smaller than those of 4N-SFD-aqua particles. As a result, the former particles had 2- to 3-times smaller specific surface area than the latter particles independent of the type of carrier loaded. The slight difference of release profiles from the particles prepared between both systems was discussed from the microscopically structural viewpoint. In addition, ciclosporin was applied to organic solvent SFD system because this drug was poorly water soluble and cannot be applied to conventional aqueous SFD system. The release profiles from SFD particles were dramatically improved compared to the bulk material, suggesting that the new SFD technique using organic solvent has potential to develop the novel solubilized formulation for poorly water-soluble active pharmaceutical ingredients (APIs).
使用四流体喷嘴（4N）的喷雾冷冻干燥（SFD）技术是作者先前开发的一种新型颗粒设计技术，现已进一步发展以扩大其在制药行业的应用。使用有机溶剂作为喷雾溶剂来溶解难溶性药物，而不是传统的水溶液。药物的乙腈溶液和聚合物载体的水溶液通过4N分别同时雾化，并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，根据我们之前开发的专有方法将冷冻的液滴进行冷冻干燥，以制备药物和载体的复合颗粒。从形态学和物理化学角度对使用乙腈制备的苯妥英复合颗粒（4N-SFD-MeCN系统）与使用水溶液制备的复合颗粒（4N-SFD-水系统）进行了深入表征。在4N-SFD-MeCN颗粒以及4N-SFD-水颗粒中均观察到特征性的多孔结构。然而，发现4N-SFD-MeCN颗粒的孔径和数量比4N-SFD-水颗粒的小。结果，与所负载载体的类型无关，前一种颗粒的比表面积比后一种颗粒小2至3倍。从微观结构观点讨论了两种系统制备的颗粒释放曲线的细微差异。此外，环孢素被应用于有机溶剂SFD系统，因为这种药物水溶性差，不能应用于传统的水性SFD系统。与原料药相比，SFD颗粒的释放曲线有显著改善，这表明使用有机溶剂的新SFD技术有潜力开发用于难水溶性活性药物成分（API）的新型增溶制剂。
