| Levetiracetam has been used as adjunctive therapy in the treatment of partial onse t seizures in adults and children4years of age and older with epilepsy, the mechanis m of action of which is involved in the neuronal synaptic vesicle protein SV2A. Leve tiracetam is rapidly and almost completely absorbed after oral administration, and the oral bioavailability of which is100%. Immediately released tablets, solution, sustained release tablets are the routinely used dosage forms. The most frequently reported adve rse reactions of levetiracetam were somnolence, asthenia, dizziness and infection, etc. The frequency of adverse events is proportional to the plasma concentration of levetira cetam. The levetiacetam bioadhesive sustained release tablets were expected to reduce adverse reactions and extend the gastrointestinal tract retention time. Systematic researc hes, such as formulation, release mechanism, the methods of quality control and stabili ty, were conducted as follows:UV spectrophotometry and biological adhesion measurement were developed and v alidated, which could be used for evaluation of extended release and adhesion force of levetiacetam bioadhesive sustained release tablets.The formulation and preparation method of levetiracetam bioadhesive sustained rel ease tablets were optimized. RSM plus CCD was used for the formulation, independen t variables were the amounts of HPMC and carpol, and in vitro cumulative releases a nd adhesion force were dependent variables. Multilinear and quadratic models were us ed to estimate the relationship between the dependent and the independent variables, a nd to delineate RSM and overlay contour plots in order to select the optimal formulat ions with the validation. The optimized formulations were composed of levetiracetam500mg and HPMC275mg over80mesh drug screen mixed, to which5%HPC-S L was added, over30mesh granulating. Wet particles in55℃vacuum were dried o ven for about1h. The dried particles were over the20mesh, which were blended w ith carpol84mg, silica gel0.430mg, magnesium stearate0.859mg over80mesh. T ableting and packaging were exercised by using12mm in diameter of die. Three bat ches of tablets were prepared for the validation, and the cumulative release of12h w as95.67±1.03%. The measured and predicted had no obvious difference (p>0.05). C ompared with Keppra XR and patent of CN102068414A, the release curve of bioadhe sive sustained release tablets were similar, but the adhesion performance was better th an the others (p<0.05).Several models were employed to simulate the release and Weibull equation descr ibed the release situation in2-12h. Releasing mechanism was a Fick diffusion (dru g diffusion and skeleton dissolution synergy), which was further verified by SEM.The methods with HPLC determination were developed for cumulative releases, i mpurities and content of levetiracetam bioadhesive sustained release tablets with the va lidation. The results showed that the established HPLC methods are accurate, strong s pecificity, high sensitivity, and can be used for the qualitycontrol.The influencing factor experiment revealed that the tablets were stable to high te mperature and strong light, however sensitive to high humidity. According to which, t he levetiracetam sustained release tablets should be packed in moisture-proof material and preserved under dry environment. The stability experiments results indicated that t he tablets were stable at25℃, RH60%and40℃,RH75%for three months.Compared with Keppra XR, the prepared levetiracetam bioadhesive sustained relea se tablets have similar characteristics of release in vitro, and better performance of ad hesion in vitro, which can extend residence time in the gastrointestinal tract. Furtherm ore, levetiracetam bioadhesive sustained release tablets werepromising for the treatment of epilepsy. |
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