Preparation And Characterization Of Silybin Sustained Release Tablets

SLB is well known that it is effective in prevention and treatment of hepatic damage. It can protect liver cells from harmful effects caused by smoking, drinking, environmental contaminants, or liver-damaging drugs. Datas show that SLB has excellent activities in treating Hyperlipidemia and ischemia reperfusion , inhibiting the free radical and lipid peroxidation. However, the bioavailability of SLB was low for the poorly water-dissolution. The thesis presented here focuses mainly on the preparation of the SLB sustained-release tablets （SRT） containing soild dispersion, and its pharmakinetics in dogs, which may be divided into the following five parts.Part one: ReviewsThis reviews could be divided into two parts: in the first part, the advanced progresses of SLB were described, includes the physical and chemical properties of silybin, the absorption in vivo and the high bioavailability preparations. In the second part, we introduced the preparation methods of solid sustained-release preparations, such as: matrix preparations、osmotic pump preparations、film coated preparations、sustained release solid dispersion、sustained release inclusion compounds, and so on.Part two: Preparation of SLB solid dispersion and the pharmaceutical charactersThe solid dispersion using PVP as carriers was prepared with solvent method. The influences of the carriers, the lecithin and IVcrylic acid resin on the solubility, the dissolution rate of the solid dispersion were observed. Based on this observation, the best prescription that SLB:PVP:lecithin=l:2:0.5 was obtained. The pharmceutical characters of the solid dispersion were evaluated: during a Period of 2h, accumulated release percentage was about 55%; solubility was increased to be about 2.2, 1.6, 5.8, 9.9-fold in simulated gastric juice、enteric juice、water and pH6.8 0.1%SLS solution respectively compared with plain drug. Then the pharmaceutical properties of the dispersion were studied. The results indicated that the critical relative humidity（CRH） and angle of response of solid dispersion powder was 63% and 53.18°respectively. The results of X-ray and DSC showed that drug remained in the non-crystalline state. Part three: Preparation of sustained release tabletsHPMC was used as the main sustained release matrix material in SLB SRT. The effect of the pressure, the adhesive、the release promoter、the dosage of HPMC and Eudrgit E100 was studied. The best prescription was optimized by orthogonal design: solid dispersion （SLB: PVP: lecithin: IVcrylic acid resin= 1:2:0.5:0.3） : HPMC: L-HPC=0.7:0.1:0.2. 70% syrups was used as adhesive. The best pressure was 6Kg.To increase the stability, we have also got the SRT coated. The prescription of the coating solution was obtained by the moisture proof test: HPMC: PEG: crylic acid resin: ethanol: water=2.5: 0.7: 4: 75.8: 18（W/W）. The dissolution effects show that the coat didn’t influence the dissolution rate.Part four: In vitro evaluation of the sustained release tabletsIn this part, the determination methods of SLB with UV and HPLC were established, the friability, the content and the reaccuracy of the release in vitro and the stability of the SRT were evaluated. The results showed that the friability and the content were up to the standard。The results of the dissolution in vitro indicated that the cumulative release percentages in 2h, 6h and 12h were 18%, 45%, 90% respectively and the release data was fitted to zero-order kinetics equation. A well reaccuracy of the release in vitro was found. The SRT stored at 4℃, CRH=75% were found to be stable at least for 3 months.Part five: Pharmacokinetics of the sustained release tablets in dogsWe estanlished the determination methods of total silybin in plasma with HPLC. The SLB concentration was determined after single oral dose of SRT and capsule separately taken by the five dogs in a randomized cross-over test. The total concentration AUC of SRT and capsule were 6179.63 ng·h·mL^-1, 5157.87ng·h·mL^-1 respectively. The relative bioavailabilities of the sustained release tablets were 121.4%. The two one-side test results of single oral administration showed that the sustained release tablets improved the bioavailability and that C_max, T_max of SRT were lower, longer than that of capsule repectively. The results of deconvolution showed that the in vitro release of SRT was correlative well with absorption fraction in vivo.