Preparation And Bioequivalence Evaluation Of Chrysanthemum Morfolium Sustained-release Tablets

The present study prepared the CME (Chrysanthemum morifolium extract) sustained-release tablets by utilizing hydroxy-propyl methyl cellulose (HPMC) and 10 % polyvinylpyrrolidone (PVP) alcoholic solution as the excipient. UV method was used to evaluate the release characteristics of CME sustained-release tablets in vitro during screening of the prescription. The orthogonal experiment and artificial neural network(ANN) were applied to optimize and predict the formulations of sustained release tablets. The paper also studied the factors which influenced the release of CME sustained-release tablets. The results indicated that HPMC and 10%PVP alcoholic solution block the release of CME from the tablets. And the release velocity could be adjusted by altering the ratio of HPMC and PVP in the prescription. The release results of the optimized prescription showed that the CME sustained-release tablets fitted the estimation, and the dissolution of CME sustained release tablets in pure water was in agreement with Higuchi equation.To evaluate the dissolution of CME sustained -release tablets in vitro more credible, UV method by analysis of total flavonoids and HPLC method by measuring of effective components (luteolin and apigenin) were developed and validated, and the release results of CME sustained-release tablets by these two methods were compared. The results showed that the two methods had good linearity, satisfactory recovery and accuracy and could be applied to evaluate the release of sustained-release tablets. By using the developed methods, the release of CME sustained-release tablets was coupled action of diffusion and erosion mechanism. The sustained-release tablets behavior was appraisedaccording 12 hours in the distilled water, which fitted the demand of China Pharmacopoeia (2005).An HPLC method was developed and validate to determine the mian effectiveconstitutes of CME------luteolin and apigenin in plasma of pigs . The method wasapplied to study the release characteristic and bioequivalence of CME sustained-release tablets in vivo. The study selected the CME normal tablets as reference preparation, and was made by two preparations two cycles crossing trial design.The bioequiavailability test showed that AUCo-oo of luteolin and apiginin between normal tablets and sustained-release tablets had no significant difference according to t test(P>0.05),and the F of luteolin in CME normal tablets and CME sustained-release tablets were 88.8% and 88.0% respectively,both of them was among 80-125%, so it can be concluded that the two preparations were bioequiavalence;The results of the pharmacokinetics trial in six pigs indicated that the k of luteolin in CME normal tablets and CME sustained-release tablets were 0.382±0.241/h and 0.116±0.0391/h respectively;the Cmax of sustained-release tablets were 0.361±0.17ug/mL for sustained-release tablets and 0.582±0.37ug/mL for reference tablets;Tpeak of sustained-release tablets and reference tablets were 7.00±2.1h and 5.92±3.7h, respectively. MRTo-oo of sustained-release tablets and reference tablets were 9.16±l.lh and 8.92±1.2h, respectively;The k of apigenin in CME reference tablets and sustained-released tablets were 0.0912±0.0481/h and 0.0668±0.0291/^respectively;the average max comcentration values of sustained-release tablets was 0.368 times lower than that of ordinary tablets(0.123±0.056ug/mL and 0.334±0.044ug/mL);Tpeakof sustained-release tablets and ordinary tablets were 5.67±2.0 h and 4.22±2.2 h respectively. MRT o-co of sustained-release tablets and ordinary tablets were 9.16±l.lh and 8.77±0.84 h respectively;and the CME sustained-release tablets had the sustained features. Tpeak of luteolin and apiginin between the two preparations had significant difference according to t test(P<0.05), k of luteolin and apiginin between the two preparations had significant difference according to NPAR1WAY test(P<0.05), The results of the phamacokinetics study in the pigs indicated that the CME sustained-release tablets retention time prolongs and the tablets had the sustained-release characteristics, the sustained-release tablets was bioequivalence as the reference tablets .The present study also studied in vivo-in vitro correlation (IVIVC) test of luteolin andapigenin in the CME sustained-release tablets by Wagner-Nelson method. The regression equation between in vivo absorption and in vitro release was obtained as following:F(a)=0.918 X Mt+0.0735, r=0.9652 (according to luteolin)F(a)=0.845XMt+0.0676, r=0.9628 (according to apigenin)In the above equation, Fa means absorption fraction, Mt means release rate.The result showed that the Fa of CME sustained-release tablets in vivo was positive regression with the release in vitro.