Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Department of Pharmaceutical Physicochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Int J Pharm. 2012 Apr 15;426(1-2):302-306. doi: 10.1016/j.ijpharm.2012.01.022. Epub 2012 Jan 20.
The present study aimed to evaluate the physical stability on amorphous solid dispersion (SD) of cyclosporine A (CsA) employing hydroxypropyl cellulose (HPC). SD formulations (5-30% CsA) of CsA such wet-milled SD (WM/SD) and freeze-dried SD (FD/SD) were prepared, and both SD formulations were stored at 40 °C/75% relative humidity for 8 weeks. Transitions in morphology, dissolution behavior, crystallinity and thermal behavior of CsA were evaluated. There was at least 84-fold improvement in initial dissolution rate of SD formulations compared with that of amorphous CsA powder, although their dissolution rate was gradually decreased under accelerated conditions. In particular, aged FD/SD with a drug load of 30% exhibited highly limited dissolution as evidenced by 40% reduction of solubility after 8 weeks of storage. In contrast, aged WM/SD exhibited less reduction in dissolution rate compared with FD/SD. No significant changes were seen in crystallinity and thermal behavior after aging of SD formulations for 8 weeks; however, electron microscopic observations revealed aggregation of drug molecules/particles in the aged FD/SD, possibly leading to the reduced dissolution. From these findings, stability on CsA-loaded SD might be variable depending on the preparation methodology, and the wet-milling approach could be a viable option for preparing efficacious SD formulations with improved stability.
本研究旨在评价采用羟丙纤维素（HPC）制备的环孢素 A（CsA）无定形固体分散体（SD）的物理稳定性。制备了 CsA 的湿磨 SD（WM/SD）和冻干 SD（FD/SD）等 SD 配方（5-30%CsA），并将两种 SD 配方在 40°C/75%相对湿度下储存 8 周。评估了 CsA 的形态、溶解行为、结晶度和热行为的转变。与无定形 CsA 粉末相比，SD 配方的初始溶解速率至少提高了 84 倍，尽管在加速条件下其溶解速率逐渐降低。特别是载药量为 30%的老化 FD/SD 表现出高度受限的溶解，在储存 8 周后溶解度降低了 40%。相比之下，老化 WM/SD 的溶解速率降低程度小于 FD/SD。SD 配方老化 8 周后，结晶度和热行为没有明显变化；然而，电子显微镜观察显示老化 FD/SD 中药物分子/颗粒聚集，可能导致溶解减少。从这些发现可以看出，载药 SD 的稳定性可能因制备方法而异，湿磨法可能是制备具有改善稳定性的有效 SD 配方的可行选择。
