| To improve the stability of simvastatin, the present study was designed to prepare more stable and effective simvastatin tablets. In orer to decrease the fluctuation of drug plasma concentration and reduce the flushing and hepatic toxicity side-effects, this investigation developed 24 h sustained-release niacin tablets with good bioavailability and high stability. In addition, we also combined simvastatin and niacin as a compound preparation to enhance the curative effect and improve patients’compliance.UV, HPLC and HPLC-MS methods were established for both the in vitro and in vivo analysis of simple preparation as well as compound preparation. All the methods were validated to be accurate and credible. UV spectrophotometry was developed and validated for the determination of niacin release properties of sustained-release niacin tablets as well as compound tablets in vitro. Different HPLC methods were applied to determine the content of sustained-release niacin tablets as well as the dissolution, content and related substance of simvastatin in simple and compound tablets. The quantification of niacin in beagle dog plasma was also determined by HPLC. A specific HPLC-MS method was developed for quantification of simvastatin in dog plasma.HPMC was selected as the matrix material to prepare niacin sustained-release tablets. With the commercial niacin sustained-release tablets as the reference formulation, based on the single-factor tests, similarity factor (f2) was employed as the evaluation standard to optimize the formulation of the sustained-release tablets. The quality studies on self-made sustained release tablets showed that the drug release speed was influenced significantly by pH value of dissolution solution, but seldom affected by the dissolution methods and the rotation speed of the baskets. The mechanism of drug release in vitro was confirmed as the combination result of drug diffusion and matrix erosion.The amounts of related substances in simvastatin tablets under different conditions were determined as the evaluation standard to optimize the formulation of the simvastatin tablets. Based on the single-factor tests, MCC and a-starch were selected as the bulking agents and the direct compression technology was used to prepare simvaststin tablets. Comparing the dissolution rates of self-made tablets with those of commercially available tablets, it was concluded that the dissolution rates of simvastatin from self-made tablets were comparable with those of the commercially available tablets. The stability experiments showed that the self-made preparation were stable with the exception of high humidity.Simvastatin/niacin sustained-release tablets were prepared according to the formulation investigation of niacin sustained-release tablets and simvastatin tablets. With the commercial niacin sustained-release tablets and the commercial simvastatin tablets as the reference preparations, the pharmacokinetics of self-made compound tablets in vivo was examined with six beagle dogs. The pharmacokinetic parameters of niacin in both reference and test tablets were as follows:t1/2 were (4.77±2.19) h and (4.44±1.43) h, Tmax were (5.50±2.66) h and (5.67±2.40) h, Cmax were (183.09±102.55)μg·mL-1 and (168.62±66.79)μg·mL-1, AUC0-24 were (1801.5±734.1)μg·h·mL-1 and (2188.3±1192.5)μg·h·mL-1, AUC0-∞were (1866.8±678.3)μg·h·mL-1 and (2233.6±1192.5)μg·h·mL-1, respectively. The relative bioavailability of niacin was (139.57±77.22)%. The pharmacokinetic parameters of simvastatin in both reference and test preparations were as follows:t1/2 were (9.65±2.91) h and (8.74±4.01) h, Tmax were (1.17±0.68) h and (1.50±0.63) h, Cmax were (98.70±47.23) ng·mL-1 and (86.31±59.89) ng·mL-1, AUC0-24 were (328.95±255.14) ng·h·mL-1 and (384.25±222.19) ng·h·mL-1, AUC0-∞were (398.99±365.86) ng·h·ml-1 and (434.04±255.93) ng·h·mL-1, respectively. The relative bioavailability of simvastatin was (135.20±54.95)%. |
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