烯丙孕素-β-环糊精水溶性衍生物包合物的制备及表征

为了提高难溶性药物烯丙孕素（altrenogest，ALT）的水溶性，本试验采用冷冻干燥法来制备烯丙孕素-羟丙基-β-环糊精（ALT-HP-β-CD）及其衍生物2，6-二甲基-β-环糊精（DIME-β-CD）包合物载药体系，并对ALT的线性关系和专属性、仪器的精密度以及包合物的回收率和稳定性进行了测定。以包合物的收率和包合物中ALT的包合率为评价指标，采用正交试验设计优选2种包合物的最佳制备条件，并使用傅里叶变换红外光谱法、热重分析法和显微镜成像法对所制得的ALT包合物进行表征分析，采用溶解度法测定包合物中ALT的溶解度。结果表明，ALT在1~12 μg/mL范围内具有较好的线性关系且专属性良好，仪器的精密度良好；加入0.1、0.2和0.3 mL ALT标准液的ALT-HP-β-CD包合物的平均回收率分别为97.78%、99.38%和99.90%，加入0.1、0.2和0.3 mL ALT标准液的ALT-DIME-β-CD包合物的平均回收率分别为93.86%、97.72%和94.93%；ALT-HP-β-CD包合物的最佳制备工艺为在55 ℃条件下，ALT与HP-β-CD的投料摩尔比为1∶7，包合时间为4 h，溶液pH为8，溶剂水的加入量为110 mL/g药物；ALT-DIME-β-CD包合物的最佳制备工艺为在55 ℃条件下，ALT与DIME-β-CD的投料摩尔比为1∶4，包合时间为4 h，溶液pH为9，溶剂水的加入量为100 mL/g；经傅里叶变换红外光谱法、热重分析法和显微镜成像法表征，证实成功制得包合物；溶解度试验得出包合物的溶解度分别约为ALT原药的1 012和1 354倍，表明两种包合物均可有效增加ALT的溶解度。本试验包合物的制备方法简单，条件温和，易于产业化生产。

Preparation and Characterization of Altrenogest-β-cyclodextrin Water-soluble Derivative Inclusion Complex

In order to improve the water solubility of the poorly soluble drug altrenogest(ALT), this experiment used freeze-drying to prepare altrenogest-hydroxypropyl-β-cyclodextrin (ALT-HP-β-CD) and its derivative 2, 6-dimethyl-β-cyclodextrin (DIME-β-CD) inclusion complex drug-carrying system, the linear relationship and specificity of ALT, the precision of the instrument, and the rate and stability of the inclusion complex were measured. Based on the yield of the inclusion complex and the inclusion rate of ALT in the inclusion complex, the orthogonal test design was used to optimize the optimal preparation conditions of the two types of inclusion complexes, and Fourier transform infrared spectroscopy, thermogravimetric analysis and microscopy imaging methods were used to characterize the prepared ALT inclusion complex, and the solubility method was used to determine the solubility of ALT in the inclusion complex. The results showed that:ALT had a good linear relationship in the range of 1~12 μg/mL, and the specificity was good, and the precision of the instrument was good. The average recoveries of ALT-HP-β-CD inclusion complex with 0.1, 0.2 and 0.3 mL ALT standard solution were 97.78%, 99.38% and 99.90%, respectively. The average recoveries of ALT-DIME-β-CD inclusion complex with 0.1, 0.2 and 0.3 mL of ALT standard solution were 93.86%, 97.72% and 94.93%, respectively. The best preparation process for the inclusion complex of ALT-HP-β-CD was at 55 ℃, the molar ratio of ALT to HP-β-CD was 1:7, the inclusion time was 4 h, the pH of the solution was 8, and the amount of solvent water added was 110 mL/g drug. The best preparation process of the inclusion complex of ALT-DIME-β-CD was at 55 ℃, the molar ratio of ALT to DIME-β-CD was 1:4, the inclusion time was 4 h, the pH of the solution was 9, and the amount of solvent water added was 100 mL/g drug. The inclusion complex was characterized by Fourier infrared spectroscopy, thermogravimetric analysis and microscopy imaging methods. The solubility test showed that the solubility of the inclusion complex was about 1 012 times and 1 354 times of the ALT drug, respectively, indicating that the two inclusion complexes could effectively increase the solubility of ALT. The preparation method of the inclusion complex was simple, the conditions were mild, and it was easy to industrialized production.