【作者】 胡向青；

【导师】 杜青；

【作者基本信息】 河北医科大学 ， 药剂学， 2005， 硕士

【摘要】 目的:辛伐他汀(Simvastatin)是一种新型的高效降血脂药,文献资料表明,它能够降低血清、肝脏、主动脉中胆固醇(TC)的含量,能降低极低密度脂蛋白胆固醇(VLDL-C)、低密度脂蛋白、胆固醇(LDL-C)的水平。其适应症非常广泛,对于各型高胆固醇血症、高脂血症及其引起的冠心病均有良好的治疗效果。该药是一种前体药物,其活性代谢产物辛伐他汀酸在体内迅速消除,其血浆半衰期短,吸收快,血药浓度波动大,有一定的不良反应,且该药在水中几乎不溶,基于以上原因考虑,本研究将其制成缓释滴丸,能够在控制药物释放的同时增加药物溶解度,以增加药物吸收,稳定血药浓度,达到长效和高效的目的。方法:在文献和预试验的基础上初步确定辛伐他汀缓释滴丸的制备处方,选择硬脂酸、单硬脂酸甘油酯、PEG6000和PEG12000 为基质,在预试验的基础上考察影响缓释滴丸成形的各个因素,在单因素考察的基础上通过三因素三水平的正交实验,以圆整度合格率、丸重差异相对标准偏差为评价指标,综合考察冷却方式、料液温度和滴速的影响,确定缓释滴丸的制备工艺。然后在对缓释滴丸制备过程中各种影响药物释放的因素进行单因素考察的基础上,通过三因素三水平的正交实验,以0.2% SDS 磷酸盐缓冲液为释放介质,进行溶出实验,选用Higuchi 缓释模型拟合参数r 以及关键时间点的释放度作为指标,对各个处方进行筛选、评分,并更多还原

【Abstract】 Objectives: Simvastatin is a new highly effective bloodgrease-lowering agent. Documents data showed that it couldreduce cholesterol in serum, main artery and liver ,anddecrease the levels of very-low-density lipoprotein (VLPL-C),low-density lipoprotein and cholesterol. It is widely used in thetreatment of hypercholesterolemia and coronary heart disease.It is a prodrug, and simvastatin acid is its active metabolitewhich is absorbed and eliminated quickly in vivo, it has a shorthalf-time in plasma and widely scope of the drug concentrationin blood. In order to improve its absorption, stability andbioavailabitity, simvastatin was made into sustained-releasedropping pills that can increase solubility and control release ofdrug in this study.Methods: On the basis of scientific literatures and pretesting,stearic acid, glycery monostearate, PEG6000 and PEG12000were adopted as matrix to make up sustained-release droppingpills. At first, on the basis of pretesting,we analyzed the factorsthat influenced shape of sustained-release dropping pills.Thenthrough the orthogonal experiment of three influencing factorsand three levels,we analyzed the effects of freezing temperature,temperature of drug liquid and dropping rate to select theoptimal technology. In the course of that, the spherical degreeand relative standard deviation of pills weight difference wereselected as evaluation indexes. Then based on the analysis ofthe factors that influenced the drug release behavior, in 0.2%SDS phosphate buffer, the orthogonal experiment L9(33) wasused to select the optimal fomula. The parameters ofsustained-release model and accumulative release percentagewere used to score every prescription.The release behavior of sustained-release dropping pills wasstudied by cylindrical basket method. The release medium was0.2% SDS phosphate buffer with 100r/min at a temperature of37±0.5℃,Samples were obtained at set time and quantitied at238nm with UV spectrophotometer. We calculated theconcentration of simvastatin by standard curve, then obtainedaccumulative release percentage of sustained-release droppingpills. Three batches of sustained-release dropping pills wereprepared and studied by dissolution test and detecting drugcontent to confirm the stability of preparation. The release datawere analyzed with three models. Its related substances weredetected with HPLC and solid dispersion was identified withDifferential Scanning Calorimeter.The chemical and physical stability of optimal formula wasinvestigated under following circumstances: high humidity,high temperature, strong light and long natural store condition.We took the dissolution test and obtain the accumulativerelease percentage to examine in stability of sustained-releasedropping pills.Pharmacokinetics study in vivo of rabbits: We selected therabbits as laboratory animals and divided them into 2 groups inrandom. One group was given market tablets and the other wasgiven sustained-release dropping pills. Crossover experimentwas taken after two weeks. Plasma samples were obtained atdifferent times. High-performance Liquid Chromatograph withUltraviolet detector was adopted in examining concentration ofplasma in which lovastatin was used as the internal standard.Results: The optimal technology and formula were definedthrough simple factor test and two orthogonal experiments.Sustained-release dropping pills made from the optimalformula was white and smooth with good spherical degree andsuitable rigidity. The range analysis of orthogonal experimentshowed that dosage of stearic acid and glycery monostearatehad much more influence on drug release than any others. Theaccumulative release percentage of three batches sustained-release dropping pills was: 2h: 31.44%; 6h: 60.00%; 10h:86.52%. The release data were analyzed with three models:Higuchi equation, Zero and First order kinetics, the correlationcoefficients were:Higuchi equation: r=0.9971;Zero order kinetics: r=0.9913;First order kinetics: r=0.9555.In related substances inspection, the percentage of impuritypeak areas except lovastatin in total peak areas was 0.257%.The product was up to standard. Analysis of DSC showed thatsimvastatin was amorphous material in matrix and formingsolid dispersion.Stability experiment: The results of high humidity test(92.5%)showed that the weight increased more than 5% after 5 days. Inhumidity of 75%, the weight increased less than 5%.Sustained-release dropping pills became soft in 60℃.The dataof cumulative release percentage and drug content did notchange markedly in 40℃and strong light after 5 and 10 days.The results of long-term experiment showed that the data werenot significantly different from before.Pharmacokinetics study: We take the experiment accordingto defined HPLC condition. The chromatograms showed thatall the peaks could be separated well from each other, andsimvastatin complied with single compartment model in vivo.The pharmacokinetics parameters of sustained-releasedropping pills and market conventional tablet were respectivelyas following:Sustained-release dropping pills:T1/2(ke):4.79±0.81h T1/2(ka):1.54±0.43hTmax:6.31±0.54h Cmax:73.79±13.51ng·ml-1AUC:976.4±155.3h·ng·ml-1 MRT:12.76±1.48hMarket conventional tablet:T1/2(ke):2.81±0.36h T1/2(ka):0.66±0.19hTmax:2.93±0.39h Cmax:114.7±7.2ng·ml-1AUC:804.7±69.1h·ng·ml-1 MRT:7.08±0.83h更多还原