Studies On Double-layer Sustained Release Tablets Of Metformin Hydrochloride

Metformin hydrochloride (MH) reduces blood glucose levels, predominantly by improving hepatic and peripheral tissues sensitivity to insulin without affecting the secretion of this hormone. Rosiglitazone Maleate(Rg-M) is a highly selective peroxisome proliferator-activated receptor y agonist and exerts its glucose-lowering effects by increasing insulin sensitivity. Combination of the two agents is used to relieve symptoms of non-insulin-dependent diabetes mellitus (NIDDM or type-2 diabetes). The fixed dose combination of the double-layer tablets with the immediately release layer of Rg-M and sustained release layer of MH was prepared.Firstly, basic physicochemical properties of MH and Rg-M were investigated, and then the in vitro analytical methods of MH and Rg-M were developed. Ultraviolet (UV) spectro-photometry method and High performance liquid chromatographic method were developed for the measurements of drug dissolution、cumulative released(%) from tablets and the content of MH and Rg-M in tablets.Until now, there were no reports about compound metformin hydrochloride/rosiglitazone maleate sustained release preparations in the research area of pharmacy. On the basis of single-factor tests about the influence factors on disintegration time, optimal formulation was obtained. In this paper, soluble MH was selected as a model drug to study the effect of three different matrix materials HPMC, Kollidon(?)SR and Sodium Alginate on drug release. Sustained release tablets were prepared using the three different polymers as matrix materials. Similarity factors (f2) between drug release profile of self-prepared tablet and that of reference product were employed as the evaluation standard to optimize the formulation. The results indicated that drug release profile of the optimal formulation were similar to that of reference product. The quality studies on self-prepared sustained release tablets showed the good release homogeneity, repeatability and less influence on drug release behavior by the in vitro release conditions. By the analysis of release data using different equations, MH released mainly by drug diffusion.The results of preliminary stability experiments indicated that compound MH sustained release tablets had no changes in release percentage and content under other conditions except that moisture might cause some changes in tablets weight.With two-crossover design, the pharmacokinetics of MH and Rg-M of self-made tablets in dogs were studied comparing with the reference tablets by UPLC-ESI-MS/MS. Compared with reference tablets, the relative bioavailability of MH and Rg-M of self-made tablets were (130.18±69.50)% and (108.60±16.00)%, respectively. The results of analysis of variance and two one-sided t-test demonstrated that the sustained release part of self-made tablets was not bioequivalent, but immediately release part of self-made tablets was bioequivalent comparing with the reference tablets.