Research Of Silybin Sustained-release Tablets

Silybin (SLB), the seeds extract of the milk thistle ( Silybum Marianum L. Gaertn ), was found effective clinically to treat a variety of liver disorders, including acute and chronic viral hepatitis, toxin- and drug-induced hepatitis and cirrhosis, and alcoholic liver disease. It was also found effective in treating certain cancers, such as breast, prostate, and skin cancers. However, the effectiveness of SLB as liver disease remedy was discounted by its poor water solubility and low bioavailability after oral administration. The immediate release preparations of SLB has been commercialized as a hepatoprotector, and it is required to be administrated three times a day, but the hepatitis and hyperlipemia patients needs long-term treatment, therefore, it is desired to develop SLB sustained-release tablet to increase the oral bioavailability and improve patients'compliance.It is reported that silybin-phospholipid complex (SLC) can improve the oral bioavailability of SLB obviously. Thus, in order to improve the solubility and bioavailability of SLB, SLC was prepared first. Then an in situ intestinal perfusion model was employed to study the absorption characteristics of SLC and SLB in rat intestine. The results showed that the absorption of SLC and SLB was a first-order process; Compared with SLB, the cumulative absorption percent and the absorptive rate constants(Ka) of SLC were increased significantly. The uptake and the permeability coefficient (Ke) of SLC from different intestinal segments (Duodenum,Jejunum,Ileum,Colon) kept at the same level (α=0.05, P>0.05). SLC can be absorbed in whole intestinal segments.SLB sustained-release tablets were prepared by direct powder compression, which is taken orally twice one day, using HPMC as matrix, PVPK30 as solubilizer, lactose as filler. The optimal formulation was obtained by orthogonal experimental design. In vitro release rate was observed to evaluate the formulation,the results showed that the optimal formulation release SLB 15-25% in 1 h, 35-45% in 4 h, 75-85% in 8 h, exceeding 90% in 12 h in disolution medium. The mechanism of SLB released from sustained-release tablets was investigated, which indicated that in vitro drug release characteristics appeared to be Peppas equation. Peppas equations is to be applied and the results showed erosion was the main release mechanism .The accelerated stability test of SLB sustained-release tablets was examined at the condition of RH 75% 40℃for 3 months. The results showed that the tablets had no significant changes in apperance. The content of SLB and the drug release were qualified.HPLC method was established for SLB determination in dog plasma. No interference was found and the two isomers were separated finely. This method is simple, sensitive and accurate. It can be widely used in the research of SLB . Take two-period and two-crossover experiment with commercial capsule as reference preparation and SLB sustained-release tablets as test preparation to study the pharmacokinetics and bioavailability of sustained-release tablet in beagle dogs by detecting the concentration of SLB in the plasma. The results showed that concentration- time curve was explained by compartment model,which was accorded with oral two-compartment and first-order absorption and first-order elimination. Compared with reference preparation, T_max and MRT were prolonged and C_max was reduced significantly. It indicates that SLB sustained-release tablets have good sustained-release effect. In addition, the relative bioavailability value was 75.9%. The results indicated that the sustained-release tablet was not bioequivalence as compared with reference preparation through double one-side t-test.