替比培南匹酯颗粒的制备及体内外评价

Preparation and in vitro-in vivo evaluation of tebipenem pivoxil granules

目的制备替比培南匹酯颗粒并测定其体外溶出曲线,考察其在Beagle犬体内的药动学特征。方法先用湿法制粒制备含药内核颗粒,再用流化床进行底喷包衣,考察不同包衣层(隔离层、掩味层、矫味层)增重对产品体外溶出的影响,确定各层最佳增重;采用正交实验法确定掩味层中各包衣组分(乙基纤维素水分散体、尤特奇NE30、羟丙基甲基纤维素E6)的最佳比例;以替比培南匹酯颗粒为参比制剂,进行体外溶出行为和Beagle犬体内药动学对比实验。结果自制制剂和参比制剂体外溶出行为相似,在犬体内的AUC_(0~∞)、t_(max)和C_(max)分别为(4678±652)和(4215±897)h·μg·L^(-1)、(1.5±0.55)和(1.17±0.41)h、(1838±179)和(1915±402)μg·L^(-1),差异均无统计学意义(P>0.05)。以AUC_(0~t)计算得自制制剂的相对生物利用度为(118.67±14.57)%。结论本文研究出的替比培南匹酯颗粒处方工艺可行,质量稳定,与参比制剂相似,可为其仿制研究提供依据。

Objective To prepare tebipenem pivoxil granules and determine its dissolution curve in vitro,then to investigate their pharmacokinetics in Beagle dogs.Methods First,drug-containing core particles were prepared by wet granulation,and then coating was sprayed at the bottom of a fluidized bed.The effect of weight gain due to different coating layers(the isolation layer,tastemasking layer,and taste-correcting layer)on the in vitro dissolution of the product was istudied to determine the best weight of each layer.Orthogonal test was used to determine the best proportion of each coating component in the taste-masking layer(ethyl cellulose aqueous dispersion,Eudragit NE30,hypromellose E6).Tebipenem pivoxil granules were taken as the reference preparation,and the in vitro dissolution behavior and the pharmacokinetics in beagle dogs were compared.Results The in vitro dissolution behavior of the self-made preparation and the reference preparation were similar.The AUC_(0~∞),t_(max) and C_(max) of the self-made and reference preparations in the dogs were(4678±652)and(4215±897)h·μg·L^(-1),(1.5±0.55)and(1.17±0.41)h,(1838±179)and(1915±402)μg·L^(-1),with no significant difference(P>0.05).The relative bioavailability of the self-made preparations calculated by AUC_(0~t) was(118.67±14.57)%.Conclusion The formulation technology of tebipenem pivoxil granules in this paper is feasible,with stable quality,which is similar to that of the reference preparation,which can provide a basis for its imitation research.