黄体酮共晶制备及其体内安全性研究
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篇名: 黄体酮共晶制备及其体内安全性研究
TITLE: Study on preparation and in vivo safety of progesterone cocrystal
摘要: 目的 制备黄体酮-2-氯-4-硝基苯胺(CNA)共晶以提高黄体酮的水溶性,并初步评价其体内安全性。方法选用黄体酮为共晶主体,CNA为共晶配体,采用溶剂挥发法制备黄体酮-CNA共晶。通过单晶X射线衍射、粉末X射线衍射、差示扫描量热、红外光谱等技术对共晶进行表征,并对比共晶与黄体酮原料药、黄体酮与CNA物理混合物之间的溶出度差异。将48只雌性KM小鼠随机分为正常组(含0.1%二甲基亚砜的磷酸盐缓冲液)、黄体酮组(16mg/kg)、CNA组(9mg/kg)和黄体酮-CNA共晶低、中、高剂量组(6、12.5、25mg/kg),每组8只;肌内注射相应药物/溶剂,每天给药1次,连续14d。通过测定/观察小鼠体质量、脏器指数、组织形态、血常规及肝肾功能指标变化来初步评价共晶的安全性。结果单晶X射线衍射实验结果中新晶型结构的出现、粉末X射线衍射图谱里新特征峰的出现、差示扫描量热检测结果中熔点的改变以及红外光谱图中3500~2750、1700~1250cm-1范围内特征峰位置的改变,均表明黄体酮-CNA共晶制备成功,且所制共晶的溶出速率比黄体酮原料药提高了1倍以上。体内安全性实验结果显示,各组小鼠死亡率均为零。与正常组比较,黄体酮组及黄体酮-CNA共晶各剂量组小鼠子宫指数均显著升高(P>0.05),子宫内膜也有所增厚;各组小鼠体质量、肝肾功能、肝脏指数、肾脏指数以及白细胞、淋巴细胞、中性粒细胞数量差异均无统计学意义(P>0.05),肝肾组织形态无差异;黄体酮组小鼠红细胞数量显著减少(P<0.05),但黄体酮-CNA共晶各剂量组小鼠红细胞数量差异均无统计学意义(P>0.05)。结论成功制备了黄体酮-CNA共晶,提高了黄体酮原料药的水溶性,且所制黄体酮-CNA共晶的体内安全性较好。
ABSTRACT: OBJECTIVE To prepare progesterone-2-chloro-4-nitroaniline cocrystal (CNA) so as to improve the solubility of progesterone and primarily evaluate the safety of the progesterone cocrystal in vivo. METHODS Using progesterone as the main body and CNA as the ligand, progesterone-CNA cocrystal was prepared with solvent evaporation method. The cocrystal was characterized by X-ray single crystal diffraction, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (IR). The dissolution rate of cocrystal was compared with those of progesterone and physical mixture. Forty-eight female KM mice were randomly divided into normal group (phosphate buffer containing 0.1% dimethyl sulfoxide), progesterone group (16 mg/kg), CNA group (9 mg/kg), progesterone-CNA cocrystal low-dose, medium- dose and high-dose groups (6, 12.5, 25 mg/kg), with 8 mice in each group. They were given relevant medicine/solvent intramuscularly, once a day, for consecutive 14 d. The safety of cocrystal was evaluated primarily by determining/observing the changes in body weight, organ index, tissue morphology, blood routine indicators, and liver and kidney function indicators. RESULTS The new crystal structure in the X-ray single crystal diffraction results, the new characteristic peak in the XRPD pattern, the change of melting point in the DSC results, and the change of the characteristic peak position in the range of 3 500- 2 750 cm-1 and 1 700-1 250 cm-1 in the infrared spectrum all Δ 基金项目国家重点研发计划项目(No.2022YFC3502100) indicated that progesterone-CNA cocrystal was successfully *第一作者 硕士研究生 。研究方向 :药物制备技术与工艺 。 prepared, and the dissolution rate of cocrystal was more than E-mail:SWB_1221@163.com # 通信作者教授,硕士生导师,博士。研究方向:药物制备技术与 twice that of the progesterone raw material drug. The results of 工艺。E-mail:wuxx-415@126.com in vivo safety experiments showed that the mortality rate of all 中国药房 2023年第34卷第13期 China Pharmacy 2023 Vol. 34 No. 13 · 1567 · groups was zero. Compared with normal group, uterine indexes of mice in progesterone group and progesterone-CNA cocrystal groups were significantly increased (P>0.05), and endometrium was also thickened; there was no statistical difference in the changes of body mass, liver and kidney function, liver index, kidney index, the number of leukocyte, lymphocyte and neutrophil in routine blood test among those groups (P>0.05), and the morphology of liver and kidney tissue has also no significant difference. However, the number of plasma red blood cells in the progesterone group decreased significantly (P<0.05), and there was no statistical significance in the number difference of red blood cells among progesterone-CNA cocrystal groups (P>0.05). CONCLUSIONS The progesterone-CNA cocrystal is successfully prepared with good safety in vivo, which significantly improve the solubility of progesterone.
期刊: 2023年第34卷第13期
作者: 石文博;李嫚;曾华辉;张慧;赵文文;武香香
AUTHORS: SHI Wenbo,LI Man,ZENG Huahui,ZHANG Hui,ZHAO Wenwen,WU Xiangxiang
关键字: 黄体酮;共晶;表征分析;体内安全性
KEYWORDS: progesterone; cocrystal; characterization analysis; safety in vivo
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