阿奇霉素干混悬剂的制备及体内外评价  

Preparation and in vitro-in vivo Evaluation of Azithromycin Dry Suspension

作　　者：史红娟 欧阳旭 王瑞强 王中彦[1] SHI Hongjuan;OUYANG Xu;WANG Ruiqiang;WANG Zhongyan(Shenyang Pharmaceutical University,Shenyang 110016;Beijing YOUCARE Pharmaceutical Technology Co.,Ltd.,Beijing 102600)

机构地区：[1]沈阳药科大学,辽宁沈阳110016 [2]北京悦康科创医药科技股份有限公司,北京102600

出　　处：《中国医药工业杂志》2023年第8期1216-1223,共8页Chinese Journal of Pharmaceuticals

摘　　要：该研究基于质量源于设计(QbD)理念,开发阿奇霉素(1)干混悬剂的处方和工艺。采用二步制粒法制备1干混悬剂,并通过Box-Behnken设计,以制粒时间、外加蔗糖比例、混合时间为自变量,以含量均匀度为因变量优化工艺,所得优化工艺为制粒时间14 min,外加蔗糖比例40%,混合时间44 min。采用优化工艺制备了3批工艺验证样品,其含量均匀度均值为2.3,且在pH 2.0、4.5、6.0的介质中溶出行为与参比制剂相似。以三周期部分重复交叉设计进行了自制制剂和参比制剂在健康志愿者体内的生物等效性研究。结果显示,空腹状态下口服自制和参比制剂的c_(max)分别为114.675、114.917 ng/mL,AUC_(0→t)分别为552.41、594.87 h·ng·mL^(–1);餐后c_(max)分别为37.755、32.945 ng/mL,AUC0→t分别为276.66、257.87 h·ng·mL^(–1),参比制剂标定的生物等效性(RSABE)或平均生物等效性(ABE)统计分析结果显示自制与参比制剂生物等效。该研究制备的1干混悬剂质量和疗效与参比制剂一致。This study developed the formulation and preparation of azithromycin(1)dry suspension based on the concept of quality by design(QbD).First,1 and trisodium phosphate were granulated to improve the taste,then 1 particles and sucrose(grinding)were granulated,followed by mixing with the added sucrose.The second-step granulation and mixing process were optimized by Box-Behnken design with granulation time,adding sucrose ratio after granulation,and mixing time as independent variables and content uniformity as the dependent variable.The optimal process was as follows:granule time was 14 min,adding sucrose ratio was 40%,and mixing time was 44 min.Three batches of process validation samples prepared according to the optimized parameters had an average content uniformity of 2.3.And the dissolution behaviors of self-made preparations(T)and reference preparations(R)were similar in media with pH values of 2.0,4.5,and 6.0.The bioequivalence between T and R was studied through a three-cycle partially repeated crossover design in healthy volunteers.The results showed that under fasting conditions,the c_(max)of T and R were 114.675 and 114.917 ng/mL,the AUC_(0→t)were 552.41 and 594.87 h·ng·mL^(–1);under fed conditons,the c_(max)of T and R were 37.755 and 32.945 ng/mL,the AUC_(0→t)were 276.66 and 257.87 h·ng·mL^(–1).The statistical analysis results of reference-scaled average bioequivalence(RSABE)or average bioequivalence(ABE)showed that T and R were bioequivalent.The quality and efficacy of the 1 dry suspension prepared in this study were consistent with the reference.

关 键 词：阿奇霉素 干混悬剂 制粒 生物等效性 高变异药物 BOX-BEHNKEN设计 

分 类 号：R944.27[医药卫生—药剂学]