Studies On Metformin Hydrochloride Sustained-Release Tablets

Metformin hydrochloride (MH) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM or type-2 diabetes). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissues sensitivity to insulin without affecting the secretion of this hormone. It also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity. In this paper, metformin hydrochloride (MH) was selected as the model drug to prepare sustained-release tablets. Combining with other filers, a sustained release tablet of once daily administration was prepared by using hydropropyl methylcellulose (HPMC) and ethylcellulose (EC) both as basic matrix materials. Then the drug release character and mechanism were studied. At last, the Pharmacokinetics study of MH sustained-release tablets was performed.Basic physicalchemical properties and the stability of MH were investigated. MH was easily soluble in phosphate buffers at physiologyical pH condition and stable at high temperature and light. It was shown that the drug was sensitive to moisture.MH sustained-release tablets were prepared by HPMC and EC as the matrix materials. The effects of the viscosity and amount of HPMC, amount of EC, amount of lubricant and the preparation methods on the release of MH from matrix tablets were observed. On the basis of pharmaceutical preformulation studies, the preparation technique and optimized formulation of MH sustained-release tablets were determined according to cumulative percent of drug release. The release mechanism is properly characterized by diffusion.High performance liquid chromatography method was developed to determine content, accumulated release and related substance of MH sustained-release tablets.The quality criteria of MH sustained-release tablets including character, identification, related substance, content and accumulated release was developed. The results of quality studies on self-prepared MH sustained-release tablets showed the homogeneity of one batch and the repeatability of three batches were good. Three batches tablets complied with the standard. Stress' testing, accelerated testing and long-term testing were carried out to investigate the stability of MH sustained-release tablets. Character, content, related substance and accumulated release were studied. The results showed that light and temperature had little effect on sustained-release tablets, but moisture should pay attention to.A sensitive and rapid HPLC method was developed to determine MH levels in human plasma. The testing tablets and reference tablets of single and repeated dose were orally administrated to healthy volunteers in randomized crossover design. Atenolol was used as an internal standard. After single oral dose of 1000 mg MH of the testing tablets and reference tablets, the AUC_0-24 of testing tablets was (10983.1±1552.5) ng·h·mL^-1 and the AUC_0-24 of reference tablets was (10437.7±2484.9) ng·h·mL^-1. The relative bioavailability of testing tablets was (110.2±26.7)%. The results indicated that testing tablets were bioequivalent to reference tablets. After repeated oral dose of 1000 mg MH of the testing tablets, the relative bioavailability of testing tablets was calculated to be (77.0±16.1)%.