Choi Jin-Seok, Kwon Soon-Hyung, Lee Sang-Eun, Jang Woo Suk, Byeon Jong Chan, Jeong Hyeong Mo, Park Jeong-Sook
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
IL-YANG Pharmaceutical Co., 110, Hagal-ro, Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
Int J Pharm. 2017 Jun 30;526(1-2):77-87. doi: 10.1016/j.ijpharm.2017.04.056. Epub 2017 Apr 24.
The purpose of this study is to improve the solubility, in vitro dissolution, and oral bioavailability in rats of tadalafil (TDF) by using SD technique with a weak acid and a copolymer. TDF-SD was prepared via solvent evaporation, coupled with the incorporation of an acidifier and solubilizer. Tartaric acid enhanced the solubility of TDF over 5-fold in DW, and Soluplus enhanced the solubility of TDF over 8.7-fold and 19.2-fold compared to that of TDF (pure) in DW and pH 1.2 for 1h, respectively. The optimal formulation of TDF-SD3 was composed of TDF vs Tartaric acid vs Soluplus vs Aerosil=1:1:3:3. The in vitro dissolution rate of TDF-SD3 in DW, pH 1.2 and pH 6.8 buffer (51.5%, 53.3%, and 33.2%, respectively) was significantly higher than that of the commercial product (Cialis) powder (16.5%, 15.2%, and 14.8%, respectively). TDF was completely transformed to an amorphous form as shown in SEM, DSC and PXRD data. The stability of TDF-SD3 included drug contents and in vitro dissolution for 1 month were similar to those of Cialis, and the amorphous form of TDF-SD3 was well maintained for 6 months. The TDF-SD3 formulation improved the relative bioavailability (BA) and peak plasma concentration (C) compared to that of Cialis powder after oral administration in rats as 117.3% and 135.7%, respectively. From the results, we found that the acidifier increased the wettability of TDF, and the solubilizer improved solubility through hydrogen bonding with TDF, thereby increasing the solubility, dissolution and oral bioavailability of TDF in TDF-SD3.
本研究的目的是通过使用含有弱酸和共聚物的固体分散技术来提高他达拉非（TDF）在大鼠体内的溶解度、体外溶出度和口服生物利用度。通过溶剂蒸发法制备TDF-固体分散体，并加入酸化剂和增溶剂。酒石酸使TDF在去离子水中的溶解度提高了5倍以上，与TDF（纯品）相比，Soluplus使TDF在去离子水和pH 1.2条件下1小时的溶解度分别提高了8.7倍和19.2倍。TDF-固体分散体3的最佳配方为TDF:酒石酸:Soluplus:Aerosil = 1:1:3:3。TDF-固体分散体3在去离子水、pH 1.2和pH 6.8缓冲液中的体外溶出率（分别为51.5%、53.3%和33.2%）显著高于市售产品（希爱力）粉末（分别为16.5%、15.2%和14.8%）。扫描电子显微镜（SEM）、差示扫描量热法（DSC）和粉末X射线衍射（PXRD）数据显示，TDF完全转变为无定形形式。TDF-固体分散体3的稳定性包括药物含量和1个月的体外溶出度与希爱力相似，且TDF-固体分散体3的无定形形式在6个月内保持良好。与希爱力粉末相比，TDF-固体分散体3制剂在大鼠口服给药后的相对生物利用度（BA）和血浆峰浓度（C）分别提高至117.3%和135.7%。从结果中我们发现，酸化剂提高了TDF的润湿性，增溶剂通过与TDF形成氢键提高了溶解度，从而提高了TDF-固体分散体3中TDF的溶解度、溶出度和口服生物利用度。
