目的 制备阿司匹林/埃索美拉唑镁复方肠溶微丸胶囊剂,并进行体内外释药评价。方法 采用挤出-滚圆法制备阿司匹林含药丸芯;采用流化床包衣上药法制备埃索美拉唑镁含药丸芯;采用流化床包衣法,将2种含药微丸分别外包肠溶层制得肠溶微丸,通过含量测定确定装量,将其灌装于1号胶囊中即得复方肠溶微丸胶囊剂;体外以释放百分率评价其释药性;体内以大鼠为研究对象,通过药物动力学参数评价其体内释药行为。结果 复方肠溶胶囊剂在0.1 mol·L^-1盐酸溶液中,2种药物在2 h内累积释放百分率均小于5%;在pH 6.8 PBS中,阿司匹林在45 min累积释放百分率大于70%,埃索美拉唑镁30 min累积释放百分率大于80%;体内阿司匹林血浆中代谢物水杨酸的t_1/2=9.47 h、MRT_0-∞=14.43 h、t_max=3.00 h、ρ_max=51.34 mg·L^-1、AUC _0-24=703.39 mg·h·L^-1、AUC _0-∞=860.52 mg·h·L^-1;埃索美拉唑镁的t_1/2=3.72 h 、MRT_0-∞=7.44 h、t_max=1.50 h、ρ_max=2.71 mg·L^-1、AUC _0-24=11.89 mg·h·L^-1 、AUC _0-∞=13.79 mg·h·L^-1。结论 复方肠溶微丸胶囊剂处方组成合理、制备工艺重现性良好,药物定位于肠道释放,埃索美拉唑镁拮抗阿司匹林胃肠道副作用,更好地发挥阿司匹林抗血栓的作用。

OBJECTIVE To prepare compound aspirin and esomeprazole magnesium enteric-coated pellet capsules and evaluate the drug release in vitro/in vivo. METHODS The aspirin pellet cores were prepared by using extrusion-spheronization method, and the esomeprazole magnesium-containing drug pellets were prepared with fluidized bed. By using fluidized bed coating method, the two kinds of drug-containing pellets were respectively coated with enteric layer to obtain enteric-coated pellets. After determining the loading capacity by measuring drug content, the two kinds of drug-containing pellets were filled into No.1 capsules. In vitro release was evaluated by measuring release percentage. The in vivo release behavior was evaluated by determination of pharmacokinetic parameters in rats. RESULTS The cumulative release percentage of the two drugs was less than 5% in 2 h in 0.1 mol·L^-1 hydrochloric acid solution. The cumulative release percentage of aspirin was more than 70% in 45 min in pH 6.8 PBS and it was more than 80% in 30 min for esomeprazole magnesium. Aspirin was metabolized to salicylic acid in plasma and its main pharmacokinetic parameters were as follows:t_1/2=9.47 h, MRT_0-∞=14.43 h, t_max=3.00 h, ρ_max=51.34 mg·L^-1, AUC _0-24=703.39 mg·h·L^-1, AUC _0-∞=860.52 mg·h·L^-1. The pharmacokinetic parameters for esomeprazole magnesium were as follows:t_1/2=3.72 h, MRT_0-∞=7.44 h, t_max=1.50 h, ρ_max=2.71 mg·L^-1, AUC_0-24=11.89 mg·h·L^-1, AUC_0-∞=13.79 mg·h·L^-1. CONCLUSION The formulation of compound enteric-coated pellet capsules is reasonable, and the preparation technology has good reproducibility. The drug release is located in the intestinal tract, thus esomeprazole magnesium can antagonize the gastrointestinal side effects of aspirin and aspirin can produce better antithrombotic effect .