目的 制备甘氨胆酸缓释微丸（glycocholic acid sustained-release pellets，GA-SRP），优化包衣处方、考察体外释放度及其在大鼠体内的药动学特征。方法 采用挤出滚圆法制备甘氨胆酸载药微丸，再以苏丽丝^®水分散体为包衣材料通过流化床技术制得GA-SRP；以包衣增重、E5 LV羟丙甲纤维素（HPMC E5）用量和老化温度作为处方考察因素，以缓释微丸2、4、8 h的累积释放率为评价指标，通过Box-Behnken设计-响应面法（Box-Behnken design-response surface method，BBD-RSM）优化GA-SRP包衣处方。对微丸进行表征分析并结合模型拟合初步探讨GA-SRP体外释药机制。健康SD雄性大鼠随机分为2组：甘氨胆酸原料药组和GA-SRP组，以卡马西平为内标，测定不同时间血药浓度，运用Das 3.0软件计算药动学参数。结果 最优缓释微丸包衣处方为包衣增重9.0%，HPMC E5用量7.5%，老化温度40.0 ℃，2、4、8 h的累积释放率分别为23.95%、50.64%、77.94%；其体外释药机制符合一级释药模型；GA-SRP与原料药相比，相对生物利用度为178.61%。结论 GA-SRP制备工艺重现性良好，体内外缓释效果明显且释药平稳，性质稳定，生物利用度显著提高，为甘氨胆酸缓释制剂的研究提供了基础。

Objective To prepare glycocholic acid sustained-release pellets (GA-SRP), optimizate coating formula, investigate its in vitro release rate and pharmacokinetic characteristics in rats. Methods Glycocholic acid-loaded micropellets were prepared by extrusion rounding method, and then GA-SRP were produced by fluidized bed technology using Surelease^® aqueous dispersions as coating materials. The weight gain of the coating, the amount of HPMC E5, and the aging temperature were used as the factors of the prescription, and the cumulative release rate of the sustained-release micropellets at 2, 4, 8 h were used as the evaluation indexes to optimize the prescription of the coating materials of GA-SRP by Box-Behnken design-response surface method (BBD-RSM). Characterization analysis was conducted on the microspheres, and a model fitting was employed to preliminarily explore the in vitro drug release mechanism of GA-SRP. Healthy SD male rats were randomly divided into two groups: glycocholic acid raw material group and GA-SRP group. Carbamazepine was used as an internal standard to measure blood concentration at different time, and pharmacokinetic parameters were calculated using Das 3.0 software. Results The optimal coating formulation for the sustained-release pellets was determined to be a coating weight gain of 9.0%, an HPMC E5 amount of 7.5%, and an aging temperature of 40.0 ℃, with cumulative release rates of 23.95%, 50.64%, and 77.94% at 2, 4, and 8 h, respectively; The in vitro drug release mechanism was found to conform to a first-order release model; The relative bioavailability of GA-SRP compared to the raw material was 178.61%. Conclusion The preparation process of GA-SRP has good reproducibility, with significant sustained-release effects both in vitro and in vivo, stable properties, and significantly improved bioavailability, providing a foundation for the study of glycocholic acid sustained-release preparations.

R283.6

内蒙古自治区科技重大专项（2021ZD0017）;辽宁省科技计划联合计划-应用基础研究项目（2023JH2/101700206）;辽宁中医药大学校级重点项目（2021LZY047）