【作者】 陶波；

【导师】 杨祥良；

【作者基本信息】 华中科技大学 ， 生物化学与分子生物学， 2011， 硕士

【摘要】 酪蛋白是一种天然的表面活性剂,可代替普通的表面活性剂,降低普通表面活性剂对胃肠道的刺激和毒副作用。固体自乳化制剂比液体乳液稳定,易于携带,可以增加药物的溶解性,提高难溶性药物的生物利用度。辛伐他汀能够有效的控制胆固醇含量预防心血管疾病。辛伐他汀水溶性差,口服生物利用度不到5%。本文利用酪蛋白作为表面活性剂,筛选了合适的油相,成功制备了稳定性、复溶性都很好的酪蛋白固体自乳化制剂。完成的主要研究工作有:（1）建立了能同时检测辛伐他汀和辛伐他汀酸的液相检测方法,辛伐他汀和辛伐他汀酸的峰面积与浓度在0.3-50μg·mL^-1范围内的线性关系良好,溶液稳定,精密度高,能够满足制剂过程中的检测需求。（2）对固体自乳化制剂中的油相,酪蛋白溶液的浓度、pH,水溶性载体,干燥工艺进行了筛选。选用了capryol 90和maisine 35^-1比例为1:1的混合油相来制备乳液,酪蛋白的浓度为50 mg·mL^-1,pH值为6.0,先用微射流法制备液态微乳,再用喷雾干燥法将液态乳液制成固体粉末。制备的固体乳液稳定,复溶性良好。（3）考察了辛伐他汀酪蛋白固体自乳化制剂的体外释药行为。体外溶出法表明乳剂的在人工肠液中的释放比片剂有了显著的提高,肠囊外翻实验说明水溶性载体不利于乳剂中药物的吸收。（4）建立了能同时检测血浆样品中辛伐他汀和辛伐他汀酸的液质检测方法,辛伐他汀和辛伐他汀酸在0.1 ng·mL^-1-150 ng·mL^-1范围内线性关系良好。辛伐他汀的回收率在70-80 %之间,辛伐他汀酸的回收率在65-75 %之间,辛伐他汀和辛伐他汀酸高中低三中浓度的日内、日间变异系数均小于10 % ,稳定性,紧密度均良好,测定方法符合生物样品检测要求。（5）研究了辛伐他汀不同剂型的药代动力学行为。对大鼠口服灌胃,检测不同时间点大鼠体内的血药浓度。以辛伐他汀片剂作为参比制剂,辛伐他汀原料药生物利用度最低;加了水溶性载体羟乙基淀粉的酪蛋白乳剂的生物利用度与片剂相比相差不大;不加水溶性载体的酪蛋白乳液的相对生物利用度最高,辛伐他汀达到184.08 %,辛伐他汀酸达到284.53 %,酪蛋白自乳化制剂促进了辛伐他汀在体内的吸收,提高了辛伐他汀的生物利用度。更多还原

【Abstract】 The casein is a kind of natural surfactant which is non-toxic and nonirritant compared with normal surfactant. The solid self-emusifying drug delivery system（SSEDDS） is more stability and portability than liquid self-emusifying drug delivery system（LSEDDS）. SSEDDS can increase the solubility of the drug and improve the bioavailability. Simvastatin can control the content of cholesterol and prevent cardiovascular disease efficiently. Simvastatin is a kind of poorly water soluble drug, the oral bioavailabilty is less than 5 %.In this paper, we use casein as surfactant, select the proper oil, prepared simvastatin SSEDDS which is stability and good solubility successfully. We have finished the research work as follow:（1） We have established the HPLC method for the detection of simvastatin and simvastatin acid simultaneously. Simvastatin and simvastatin acid had a good linear relationship in the scope of 0.3-50μg·mL^-1, the solution is stability. This method is accurate and can satisfy the requirements for the analysis of pharmaceutical process.（2） We have selected the oil phase, the concentration and pH of casein solution, the water solubility carrier and the drying processing. The combination of Capryol 90 and Maisine 35^-1 （1:1 proportions） was used as oily phase. The concentration of casein is 50mg?mL^-1, pH is 6.0. We prepare liquid microemulsion by microjet technology, then we transform LSEDDS to SSEDDS by Spray-drying technology. The solid self-emulsifying power is stability and have good redissolved ability.（3） We have researched the in vitro release of SSEDDS. The dissolution experiment indicate that the release amount and speed of SSEDDS is improved significantly than tablet. The experiment of everted intestine indicate that the water soluble carrier is bad for the absorb of the drug.（4） We have established the LC-MS/MS method for the detection of simvastatin and simvastatin acid simultaneously. Simvastatin and simvastatin acid had a good linear relationship in the scope of 0.1 ng·mL^-1-50 ng·mL^-1. The recovery of simvastatin is 70-80 %; the recovery of simvastatin acid is 65-75 %. The coefficient of variation of inter-day and intra-day samples of high, medium and low concentration of simvastatin and simvastatin acid are less than 10 % respectively, the accurate and stability are both well, this method can meet the requirement of the biological samples.（5） We have researched the pharmacokinetic of different formulation. We detected the concentration of drug of in the plasma at the different time point after intragastric infusion to rats, the tablet is the reference formulation. We find that the bioavailability of raw material drug is the lowest, the bioavailability of casein SSEDDS with water soluble carrier is almost the same as tablet. The bioavailability of casein SSEDDS without water soluble carrier is the highest. The relative bioavailability of simvastatin is 184.08 %, simvastatin acid is 284.53 %. The casein SSEDDS can promote absorption of simvastatin, improved the bioavailability of simvastatin.更多还原