The Study Of Tetramethylpyrazine Phosphate Solid Dispersion Sustained Release Tablets

Solid dispersion is a high dispersion system which mixed by drug and carrier. In recent years, sustained-release solid dispersion has been made by insolubility polymer, intestine dissolubility polymer, lipid material and so on as carrier which developed a new way for preparation of extended release dosage system.Tetramethylpyrazine Phosphate(TMPP) which is water-soluble was chosen as a model drug. Sustained-release solid dispersion was preparated by insolubility polymer (EC) as carrier and water solubility polymer(PVP) as release conditioner. Tablets which made by these solid dispersion powder could reduce the frequency of administration, improve bioavailability and offered a feasible method of water-soluble pharmacal sustained release dosage form's investigation.According to the literature, UV spectrophotometry was developed for in vitro assay of physicochemical properties, content and drug release. High-performance liquid chromatography (HPLC) was applied in the determination of plasma concentration in dogs.TMPP concentration in rat intestinal perfusion solution was determined by HPLC. Rat single pass intestinal perfusion (SPIP) was employed to investigate the effects of different flow rate, pH of perfusion solution and testinal segments.The influence of different viscosity and proportional of EC and different kinds and proportional of release conditioner on the dissolution of TMPP was examined. In addition, basing on the results of single-factor tests, orthogonal design test was carried out to optimize the formulation of solid dispersion. The DSC curves prove that after forming the solid dispersion, the thermal characteristic of TMPP was sheltered. X-Ray powder diffraction analysis exhibits that the solid dispersion of TMPP-EC-PVP k30 was in an amorphous form.During the study of preparing TMPP solid dispersion sustained-release tablets, the formulation and technology were determined by investigating the kinds and dosage of loading and disintegrating agent and the methods and pressure of preparing tablets. The curve of cumulative drug release was accorded with the Higuchi equation.TMPP conventional tablet was used as a comparison to study the pharmacokinetics and bioavailability of solid dispersion sustained-release tablet in dogs' plasma. The results showed that concentration- time curve was explained by compartment model, which was accorded with oral single-compartment. Compared with conventional tablet, T_max and MRC were prolonged and C_max was reduced significantly, at the level of 0.01. In addition, AUC value was increased remarkably, at the level of 0.05. The relative bioavailability value was 125.4%.The results showed that the test tablet can better the bioavailability and delay the release of TMPP, compared to the reference tablet. Validated by Warner-Nelson method, the release of solid dispersion sustained-release tablet in vitro was correlated well with the absorption fraction in vivo.