国内3厂家环孢素软胶囊的体外溶出评价研究

Study on Dissolution in vitro of Cyclosporine Soft Capsules from 3 Domestic Manufacturers

目的:考察国内环孢素软胶囊仿制药与参比制剂(原研药)在6种溶出介质中体外溶出曲线的相似性。方法:采用桨法进行溶出度试验,以含2%十二烷基硫酸钠(SDS)的p H 1.2盐酸溶液、含2%SDS的水溶液、含2%SDS的pH 4.5醋酸盐缓冲溶液、含2%SDS的pH 5.5醋酸盐缓冲溶液、含2%SDS的p H 6.8磷酸盐缓冲溶液和含2%SDS的模拟胃液为溶出介质,转速为50 r/min;采用高效液相色谱法测定环孢素的含量,色谱柱为Agilent Eclipse XDB-C18,流动相为乙腈-水-磷酸溶液(73∶27∶0.25,V/V/V),流速为1.0 mL/min,检测波长为226 nm,柱温为60℃,进样量为20μL;通过绘制6种介质下的溶出曲线,并采用相似因子(f2)法考察国内3厂家样品(共5批)与1批原研药的相似性。结果:环孢素检测质量浓度线性范围为5~250μg/mL(r=0.999 6~0.999 9);方法学考察中精密度、稳定性(12 h)、重复性试验的RSD均<2.0%(n=6或7),回收率为98.4%~99.7%(RSD均小于2.0%,n=9);在含2%SDS的pH 1.2盐酸溶液以及含2%SDS的模拟胃液这2种介质中,6批样品15 min的累积溶出量均达到85%;5批仿制药与原研药溶出曲线的f2在含2%SDS的水溶液中分别为75、45、57、42、83,在含2%SDS的pH 4.5醋酸盐缓冲溶液中分别为44、76、38、32、76,在含2%SDS的pH 5.5醋酸盐缓冲溶液中分别为76、47、49、40、79,在含2%SDS的pH 6.8磷酸盐缓冲溶液中分别为52、49、55、48、80。结论:3个国内厂家5批环孢素软胶囊仿制制剂与原研药在体外溶出曲线相似性方面比较显示有差异。

OBJECTIVE:To investigate the similarity of in vitro dissolution curve between the generic drugs and the reference preparation(original drugs)of the domestic Cyclosporine soft capsules in 6 dissolution mediums. METHODS:The dissolution test was performed with paddle method. 2% SDS water solution,2% SDS p H 1.2 hydrochloric acid solution,2% SDS water solution,2% SDS pH 4.5 acetate buffer solution,2% SDS pH 5.5 acetate buffer solution,2% SDS pH 6.8 phosphate buffer solution and2% SDS simulated gastric fluid were used as the dissolution medium,and the rotation speed was 50 r/min. HPLC method was used. The determination was performed on Agilent Eclipse XDB-C18 column with mobile phase consisted of acetonitrile phosphate solution(73 ∶ 27 ∶ 0.25,V/V/V),the flow rate was 1.0 mL/min. The detection wavelength was set at 226 nm,the column temperature was 60 ℃,and sample size was 20 μL. The dissolution curves in 6 medium were drawn and the similarity factor(f2)was used to investigate the similarity between the samples from 3 domestic manufacturers(5 batches)and a batch of original drugs.RESULTS:The linear range of cyclosporine was 5-250 μg/mL(r=0.999 6-0.999 9);RSDs of precision,stability(12 h) and reproducibility tests were lower than 2.0%(n=6 or 7);the recoveries were 98.4%-99.7%(RSD<2.0%,n=9). The cumulative dissolution of 6 batches of samples within 15 min reached 85% in 2% SDS pH 1.2 hydrochloric acid solution and 2% SDS simulated gastric juice. f2 of the dissolution curve of 5 batches of generic and original drugs of Cyclosporine soft capsules were 75,45,57,42,83 in 2% SDS water solution and 44,76,38,32,76 in 2% SDS pH 4.5 acetate buffer solution 76,47,49,40,79 in 2% SDS pH 5.5 acetate buffer solution and 52,49,55,48,80 in 2% SDS pH 6.8 phosphate buffer solution,respectively.CONCLUSIONS:There have differences in the similarity of the dissolution curve between the domestic generic and the original drugs of 5 batches of Cyclosporin soft capsule from 3 domestic manufacturers.