申亚静, 覃蕾, 衡伟利, 张建军, 钱帅, 高缘. 他达拉非-达泊西汀共无定形物的形成及其溶出度与稳定性的评价J. 药学学报, 2018,53(7): 1162-1168. doi: 10.16438/j.0513-4870.2018-0260
引用本文: 申亚静, 覃蕾, 衡伟利, 张建军, 钱帅, 高缘. 他达拉非-达泊西汀共无定形物的形成及其溶出度与稳定性的评价J. 药学学报, 2018,53(7): 1162-1168. doi: 10.16438/j.0513-4870.2018-0260
SHEN Ya-jing, QIN Lei, HENG Wei-li, ZHANG Jian-jun, QIAN Shuai, GAO Yuan. Preparation of tadalafil-dapoxetine coamorphous complex with evaluation of dissolution and physical stabilityJ. Acta Pharmaceutica Sinica, 2018,53(7): 1162-1168. doi: 10.16438/j.0513-4870.2018-0260
Citation: SHEN Ya-jing, QIN Lei, HENG Wei-li, ZHANG Jian-jun, QIAN Shuai, GAO Yuan. Preparation of tadalafil-dapoxetine coamorphous complex with evaluation of dissolution and physical stabilityJ. Acta Pharmaceutica Sinica, 2018,53(7): 1162-1168. doi: 10.16438/j.0513-4870.2018-0260

他达拉非-达泊西汀共无定形物的形成及其溶出度与稳定性的评价

Preparation of tadalafil-dapoxetine coamorphous complex with evaluation of dissolution and physical stability

  • 摘要: 他达拉非(TD)为5型磷酸二酯酶抑制剂,主要用于治疗男性勃起功能障碍,极低的水溶性导致其生物利用度较差。本研究将其与治疗早泄的药物达泊西汀通过减压旋转蒸发法制成摩尔比为1:1的共无定形物,以提高TD的溶解度和溶出度。差示扫描量热法(DSC)、粉末X射线衍射法(PXRD)和傅里叶变换红外光谱(FTIR)等表征表明共旋蒸产物为共无定形物。与单纯TD晶体相比,共无定形物中TD在水、0.01 mol·L-1 HCl、pH 4.5磷酸盐缓冲液等不同介质中的溶解及溶出度均有显著提高(2~4倍)。在25℃/60%相对湿度(RH)条件下放置90天后共无定形物无转晶现象;40℃/75% RH条件下放置30天无转晶,而放置90天后有转晶现象。

     

    Abstract: Tadalafil (TD), a phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, has a low oral bioavailability due to its extremely poorly aqueous solubility. The aim of this study was to enhance its solubility and dissolution by coamorphization with dapoxetine (DP), a selective serotonin reuptake inhibitor to manage premature ejaculation. Coamorphous TD-DP (molar ratio, 1:1) was prepared by solvent-evaporation method and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The supersaturated dissolution of TD from coamorphous TD-DP was investigated in various aqueous media and compared to that of crystalline TD. In addition, physical stability of coamorphous system was also evaluated under the conditions of 40℃/75% relative humidity (RH) and 25℃/60% RH for 90 days. DSC thermogram and PXRD pattern indicated the formation of the coamorphous TD-DP. In comparison to original TD crystal, the dissolution of TD from coamorphous system were significantly enhanced in various media (water, 0.01 mol·L-1 HCl and pH 4.5 phosphate buffer). In addition, no crystallization phenomenon of the prepared coamorphous system was observed until 90 days' storage under 25℃/60% RH. However, when temperature and humidity were increased to 40℃/75% RH, the coamorphous TD-DP was recrystallized easily.

     

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