目的 制備甘氨膽酸緩釋微丸（glycocholic acid sustained-release pellets，GA-SRP），優(yōu)化包衣處方、考察體外釋放度及其在大鼠體內(nèi)的藥動學(xué)特征。方法 采用擠出滾圓法制備甘氨膽酸載藥微丸，再以蘇麗絲^®水分散體為包衣材料通過流化床技術(shù)制得GA-SRP；以包衣增重、E5 LV羥丙甲纖維素（HPMC E5）用量和老化溫度作為處方考察因素，以緩釋微丸2、4、8 h的累積釋放率為評價指標(biāo)，通過Box-Behnken設(shè)計-響應(yīng)面法（Box-Behnken design-response surface method，BBD-RSM）優(yōu)化GA-SRP包衣處方。對微丸進行表征分析并結(jié)合模型擬合初步探討GA-SRP體外釋藥機制。健康SD雄性大鼠隨機分為2組：甘氨膽酸原料藥組和GA-SRP組，以卡馬西平為內(nèi)標(biāo)，測定不同時間血藥濃度，運用Das 3.0軟件計算藥動學(xué)參數(shù)。結(jié)果 最優(yōu)緩釋微丸包衣處方為包衣增重9.0%，HPMC E5用量7.5%，老化溫度40.0 ℃，2、4、8 h的累積釋放率分別為23.95%、50.64%、77.94%；其體外釋藥機制符合一級釋藥模型；GA-SRP與原料藥相比，相對生物利用度為178.61%。結(jié)論 GA-SRP制備工藝重現(xiàn)性良好，體內(nèi)外緩釋效果明顯且釋藥平穩(wěn)，性質(zhì)穩(wěn)定，生物利用度顯著提高，為甘氨膽酸緩釋制劑的研究提供了基礎(chǔ)。

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

內(nèi)蒙古自治區(qū)科技重大專項（2021ZD0017）;遼寧省科技計劃聯(lián)合計劃-應(yīng)用基礎(chǔ)研究項目（2023JH2/101700206）;遼寧中醫(yī)藥大學(xué)校級重點項目（2021LZY047）