Studies On Fluvastatin Sodium Sustained Release Tablets

Fluvastatin, the first synthetic HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types Ⅱa and Ⅱb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration.The plain capsules of fluvastatin is usually administered twice daily. Frequent adminstrations lead to fluctuation in blood drug concentration and high incidence of adverse effects. Therefore, sustained release formulations are highly needed. In this thesis, a sustained release tablet (SRT) for administration once a day was thereby formulated using hydroxypropyl methyl-cellulose (HPMC) as basic matrix material combined with other filers,.An accurate and quick high-performance liquid chromatograpy (HPLC) method was developed for in vitro assay of drug release, relative substent, content and the determination of plasma concentration in Beagle dogs. In the preformulation studies, the drug solubility in various mediums and hygroscopicity were determinded. Stability studies of fluvastatin sodium showed that light, temperature and moisture had significant effects on the character and content of the drug. The orthogonal design test was carried out to optimize the formulations and the influences of HPMC strength, compressing and releasing condition on the drug release profiles were investigated with the accumulative drug release over10h as a standard. Stability studies showed that the tablets had good stability.Using Lescol (?)XR tablets as control, in vivo pharmacokinetics in Beagle dogs of the drug in this tablet was investigated and the pharmacokinetics parameters were calculated. The Cmax values of the fluvastatin sodium sustained tablets prepared in this work and the controlled tablet were5379.0±3580.7ng ml-13683.2±1389.6ng ml-1, and their AUC (0-t) values were16105.3±9891.7ng.h.ml-1and13424.3±4541.1ng.h.ml-1, respectively. The relative bioavailability was119.97%. According to the statistical analysis of Cmax, AUC and individual differences, it is concluded that the two preparations are bioequivalent.