| Object: Divalproex sodium was one of the preferred antiepileptic drugs, it also could treat the bipolar disorder and prevent migraine. Divalproex sodium which have characteristics of hygroscopicity small, solid stability, mild gastrointestinal adverse reaction could overcome the shortcomings in the preparation of sodium valproate.Divalproex sodium would be prepared into sustained-release tablets in the study. It coud maintain steady plasma-drug concentration, extend the time of drug action and effect,reduce the frequency of administration, improve the compliance of patients.Methods:(1) we established content, release determination method by HPLC and related substances determination method by GC.(2) We observed and studied single factor influence of drug release in vitro containing all accessories and technological conditions. Significant influencing factors of divalproex sodium sustained-release tablets were screened by Plackett-Burman design. The optimal formulation was obtained by Plackett-Burman design and central composite design-response surface methodology. The regression equation of pharmaceutics was deduced by analyzing drug release data combination of zero-order equation, one-order equation, Higuchi modal,and Ritger-Peppas formula.(3) we discussed the stability of divalproex sodium sustained-release tablets we designed in heat, light, high humidity, the accelerated and long-term tests.(4) The LC-MS method which determinated the divalproex sodium concentration in Beagle was established. The concentration of divalproex sodium had excellent linear relationship in range of 0.202~50.5μg/m L. The relative recoveries of valproate sodium in Beagle dog plasma was more than 90%, the absolute recoveries of valproate sodium in Beagle dog plasma was more than 85.94%. As the divalproex sodium sustained-release tablets of Abbott being reference, we study the bioavailability and bioequivalence after single dose of self-made divalproex sodium sustained-release tablets(Hefei Industrial Pharmaceutical Institute Co.,Ltd.).Results:(1)In content, Peak area of divalproex sodium in mobile phase had fine linear relation with its concentration in range of 66.42~664.16μg/m L, the linear coefficient was 0.99995. The recovery in high, medium, low concentration were 99.97%, 99.46%and 99.17%, RSD were 0.22%, 0.95% and 0.71% respectively. In release media A, peak area of divalproex sodium has good linear relation with its concentration in range of6.33~316.3μg/m L, the linear coefficient was 0.9990. In release media B, peak area of divalproex sodium has exceeding good linear relation with its concentration in range of6.12~305.9 μg/m L, the linear coefficient was 0.9999. Finally, related substances determination method using GC was established according to U.S.P.(2) The result of Plackett-burman indicated that significant influencing factors which influenced drug release were the level of HPMC K100 M, HPMC K15 M, Ethanol concentration. Central composite design-response surface methodology was carried out to optimize formulation. The 1000 pieces of divalproex sodium sustained-release tablets contained divalproex sodium 250 g, HPMC K100 M 286.72 g, HPMC K15 M 16.96 g, lactose 96 g.Formulation and process verification test showed that the release curve of divalproex sodium sustained-release tablets in difference release media were similar with reference listed drug. Formulation and process were stable and highly reproducible. The regression equation of pharmaceutics was deduced by analyzing drug release data combination of zero-order equation, one-order equation, Higuchi modal, and Ritger-Peppas formula. We found that the designed drug preferably fitted zero-order equation. Divalproex sodium sustained-release tablets we designed has remarkably sustained-release action.(3) We discussed the stability of divalproex sodium sustained-release tablets we designed in heat, light, and high humidity. Results showed that the tablet was stable to heat, light and high humidity, its shape and properties,content, release and related substances almost had no significant change. The accelerated and long-term tests made clear that in corresponding condition each indicators of divalproex sodium had nearly no changed. Divalproex sodium sustained-release tablets were in conformity with the quality standards.(4) For divalproex sodium sustained-release tablets we designed after single dose the main pharmacokinetic parameters are: t1/2=6.07±0.94 h, Cmax=20.63±2.93μg/m L,Tmax=4.0±1.6h, AUC0-24= 142.28±22.17μg × h/m L, MRT0-t=8.81±1.31 h, AUC0 ~ ∞=152.77±25.98μg×h/m L; for divalproex sodium tablets commercially available the main pharmacokinetic parameters are: t1/2=7.49±2.03 h, Cmax=18.97±3.24μg/m L,Tmax=3.7±1.6h, AUC0-24=146.06±35.67μg × h/m L, MRT0-t=11.20±1.75 h,AUC0~∞=165.41±41.26μg×h/m L. While divalproex sodium sustained-release tablets we designed comparing to divalproex sodium sustained released tablets commercially available, In single dose, its relative bioavailabilty are 100.1%±14.9%. It suggest that divalproex sodium sustained-release tablets we designed have sustained features. They have bioequivalence between divalproex sodium sustained-release tablets commercially available and divalproex sodium sustained-release tablets that we designed.Conclusion: In this study, we had researched divalproex sodium sustained release tablets of 24 hours steady release with a combination of single factor, Plackett-burman design, central composite design- response surface optimization and easy industrialization; The methods of quality control were simple,accurate and reproductive.It laid a solid foundation for pharmaceutical quality production control. |
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