Studies On Pharmaceutics Of Sustained-Release And Conventional Tablets Of Las

LAS is a member of a series of functionalized amino molecules that have been screened for anticonvulsant properties.To prepare the LAS gel-matrix sustained-release tablets which can sustained-release for24h, several character of LAS were examined before prescription. In the establishing HPLC method for determination of LAS, we selected the best HPLC system by evaluating indicators of the tailing factor, the number of impurities, resolution and the number of theoretical plates. Separation was obtained on a Symmetry(?) C18(5μm,4.6×150mm), the mobile phase is:acetonitrile:water (0.1%formic acid)(40:60, V/V); using an excitation wavelength of205nm; the flow rate is1.0ml/min; column temperature is30℃. The basic physicalchemical properties of LAS, drug release performance and drug content of tablets were determined by HPLC,which can satisfy and analytical requirement in this study correctly and conveniently. The solubilities of LAS in solutions of different pH were investigated, the results show that LAS is soluble both in the water and the phosphate buffers at different pH condition. Investigating the n-octyl alcohol-water partition coefficient (1gP) of LAS, we used a shake flask-HPLC method to determine the drug concentration of LAS in the aqueous phase, and thus calculated the oil-water partition coefficient of LAS. The results showd that the logP of LAS is small in the entire pH range.Based on the references, using the disintegration time of traditional tablet as evaluation index, we got the content of disintegrant. We achieved to the optimum formulation in which the content of MCC, L-HPC, PVPP, SiO2and magnesium stearate was40%,12.7%,6.3%,0.5%and0.5%, respectively. LAS gel-matrix sustained-release tablets were designed and prepared according to addenda XIXD of CHP2010. LAS gel-matrix sustained-release tablets were compressed by direct compression. According to the release profile in vitro, the specifications and amount of HPMC and the content of filler as well as compression pressure was selected for the excellent drug release character in this article. Because of they may effect the release of LAS gel-matrix sustained-release tablets. Prescription for the final choice was as followed:HPMC K4M-DC:16.67%, Prosolv(?) SMCC:50%, magnesium stearate:1%. When the compression pressure was110-130N, the products get better result. A similar factor (f2) was adopted for the similarity determine. The cumulative release percentage of LAS from gel-matrix sustained-release tablet was20%～40%、40%～60%、over80%and90%～100%at2h,6h,12h and16h, respectively. Some kinetic equations, such as zero-order-, first-order-, Higuchi-equation and Ritger-Peppas equation, were employed to attempt to fit in vitro release profile LAS gel-matrix sustained-release tablet. The results showed that the profile was consistent with the theory of anomalous transport by Ritger-Peppas equation. The release law of LAS sustained-release tablet in the water was the coupled action of the Fick diffusion and the gel matrix erosion mechanism.The HPLC-MS/MS method which determinates the LAS concentration in the beagle dog plasma and could satisfy the need of bioavailability study in the beagle dog was established and the method was certificated. As the LAS traditional beingthe reference preparation, the bioavailability study of LAS sustained-release tablet in the beagle dog was made by two preparations two cycles crossing trial design. The pharmacokinetics parameters of LAS in traditional tablet and gel-matrix sustained-release tablets analyzed by non-compartment model theory were Tmax1.00±0.55h,3.33±1.63h; Cmax8331.7±1577.7ng/mL,3311.7±778.5ng/mL; AUC0-∞40696.5±13147.9ng·h/mL,26925.9±10130.3ng·h/mL; MRT3.98±1.18h,6.11±1.77h. The relative bioavailability was65.94±76.09%. While sustained-release tablet comparing to the reference preparation, its Cmax decreases, Tmax increases, MRT prolongs and it has sustained features. It indicate that the LAS sustained-release tablet retention time prolongs, the release decreases and the purpose of once daily designed by the research was achieved.The paper discussed the common pathway of the development and manufacture of the sustained-release preparation which could release twenty-four hours continuously, explored the formula optimization by the instruction of the in vivo-in vitro study results, and provided the idea and method for the designment and the screening of the sustained-release preparation formula by the instruction of biopharmaceutics and pharmacokinetics theory.