Post-marketing reevaluation of bioequivalence of metformin hydrochloride enteric-coated tablets / 中国药学杂志

ABSTRACT

OBJECTIVE: To reevaluate the bioequivalence of marked metformin hydrochloride enteric-coated tablets. METHODS: Using method 2 described in the appendix X D and apparatus 1 described in the appendix X C in Chinese Pharmacopoeia(edition 2010), the in vitro release of metformin hydrochloride enteric-coated tablets from different pharmaceutical factories (A, B, C, and D) was investigated. The contents were measured by utlraviolet (UV) spectroscopy. Generic tablets from factory A and D were chosen to be test 1 and test 2 preparations, with the innovative metformin hydrochloride tablets (Glucophage) as the reference preparation. In a randomized, three-way crossover study, 21 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 release of metformin hydrochloride enteric-coated tablets from factory B, C and D met the standard of Chinese Pharmacopoeia(the supplement edition of 2010) while that of the tablets from factory A did not. Metformin hydrochloride enteric-coated tablets from factory A and D were chosen to be test 1 and test 2 preparations, respectively. The F0-t and F0-∞ were (72.8 ± 9.7)% and (73.2 ± 10.0)% for test 1 preparation, and (45.5 ± 16.2)% and (46.2 ± 16.0)% for test 2 preparation, respectively. It was failed to conclude that test 1 and reference preparation were bioinequivalent. Test 2 and reference preparation were bioinequivalent, and the two test preparations were also bioinequivalent. CONCLUSION: The bioinequivalence risk of metformin hydrochloride enteric-coated tablets is high. For metformin hydrochloride enteric-coated tablets, not only conducting pre-marketing bioequivalence study with proper reference preparation, but also enhancing post-marketing surveillance and reevaluation of bioequivalence are very important for maintaining the consistency of drugs quality. Copyright 2012 by the Chinese Pharmaceutical Association.