目的对已上市的盐酸二甲双胍片进行人体生物等效性再评价。方法以原研药盐酸二甲双胍片（格华止）为参比制剂，采用转篮法考察格华止和国内8个厂家（A~H）的盐酸二甲双胍片的体外溶出度，并选择其中2个厂家的盐酸二甲双胍片作为受试制剂，进行人体生物等效性试验。24名健康男性受试者随机分组，于3个周期交叉服用受试制剂1、受试制剂2和参比制剂500mg，采用LC-MS/MS测定血浆样本中二甲双胍的浓度，计算药动学参数及2种受试制剂相对于参比制剂的平均相对生物利用度，采用（1-2α）置信区间法评价2种受试制剂与参比制剂的生物等效性，以及2种受试制剂之间的生物等效性。结果9个厂家的盐酸二甲双胍片的溶出度均符合2010年版《中国药典》中的规定，但B和H厂的盐酸二甲双胍片的溶出曲线与格华止的溶出曲线差异较大，选择B和H厂的盐酸二甲双胍片分别作为受试制剂1和受试制剂2。受试制剂1的平均相对生物利用度F0-t和F0-∞分别为（102.0±13.3）%、（101.9±13.3）%，受试制剂2的平均相对生物利用度F0-t和F0-∞分别为（94.6±14.7）%、（94.4±14.5）%。受试制剂1、受试制剂2和参比制剂的ρmax、AUC0-∞和AUC0-∞分别经对数转换后进行（1-2α）置信区间检验，2种受试制剂与参比制剂均具有生物等效性，2种受试制剂之间也具有生物等效性。结论盐酸二甲双胍片为生物不等效风险低的品种，可考虑根据体外溶出度试验豁免人体内生物等效性试验，即以体外溶出度评价代替上市前人体生物等效性评价或上市后人体生物等效性监测与再评价，以节约药品研发和监管成本，提高工作效率，减少人体不必要的药物暴露。
Abstract
OBJECTIVE To reevaluate the bioequivalence of post-marketing metformin hydrochloride tablets. METHODS With the original metformin hydrochloride tablets (Glucophage) as the reference preparation, the in vitro dissolution of Glucophage and generic metformin hydrochloride tablets from eight pharmaceutical factories (A-H) was investigated using method 1 described in the appendix X C in Chinese Pharmacopoeia (edition 2010), among which two generic products were chosen for the bioequivalence study as test 1 and test 2 preparations. In a randomized, three-way crossover study, 24 healthy male volunteers were given a single oral dose of test 1, test 2 and reference preparations containing 500 mg of metformin hydrochloride. Plasma concentrations of metformin were determined by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated. The bioequivalence between test 1 and reference preparation, test 2 and reference preparation, and the bioequivalence between the two test preparations were evaluated. RESULTS The in vitro dissolution of the metformin hydrochloride tablets from all the nine factories met the standard of Chinese Pharmacopoeia (edition 2010). Metformin hydrochloride tablets from factory B and H, of which the cumulative dissolution rate-time profiles were significantly different from that of Glucophage, were chosen to be test 1 and test 2 preparations, respectively. The F0-t and F0-∞ were (102.0±13.3)% and (101.9±13.3)% for test 1 preparation, and (94.6±14.7)% and (94.4±14.5)% for test 2 preparation to Glucophage. Both test 1 and test 2 preparations were bioequivalent with reference preparation, and the two test preparations were also bioequivalent. CONCLUSION The bioinequivalence risk of metformin hydrochloride tablets is low. Biowaivers can be granted for generic metformin hydrochloride tablets on the basis of in vitro dissolution evaluation, to save cost, improve efficiency in drug development and supervision, and reduce unnecessary drug exposure in human body.
关键词
盐酸二甲双胍片 /
体外溶出度 /
生物等效性 /
上市后再评价 /
生物不等效风险
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Key words
metformin hydrochloride tablet /
in vitro dissolution /
bioequivalence /
post-marketing reevaluation /
bioinequivalence risk
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中图分类号：
R969
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参考文献
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脚注
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基金
卫生部公益性行业科研专项(200902008)
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