【作者】 陈祝康；

【导师】 吴伟；

【作者基本信息】 复旦大学 ， 药剂学， 2008， 硕士

【摘要】 辛伐他汀（Simvastatin）是一种新型的高效降血脂药,为甲基羟戊二酰辅酶A（HMG-CoA）还原酶抑制剂。于1988年在瑞典首次上市,1991年12月获得美国FDA批准,是治疗原发性高胆固醇血症的药物。辛伐他汀为美国默克公司的专利产品,1997年由杭州默沙东制药引入我国（商品名:舒降之）。目前,国内企业获准生产的主要包括原料药、胶囊、片剂和滴丸。由于辛伐他汀脂溶性很强,水中几乎不溶,这很大程度上影响了药物在体内的吸收,导致口服吸收差,生物利用度低,从而影响其临床疗效。自微乳化释药系统（SMEDDS）由于其独特的作用机制,可作为难溶性、口服吸收差、生物利用度低的药物载体,成为提高难溶性药物口服生物利用度的新工具。本文将辛伐他汀制成SMEDDS,以提高其生物利用度。第一部分考察了油-吐温-醇-水体系伪三元相图在自微乳化给药系统研究中的应用。通过滴定法绘制伪三元相图,比较了三种油相（亚油酸乙酯、中链甘油三酯、单亚油酸甘油酯）和六种助乳化剂（无水乙醇、丙三醇、1,2-丙二醇、PEG-400、双甘醇单乙醚、异丙醇）对自微乳形成的影响。结果表明相同条件下以亚油酸乙酯为油相的体系,相图中自微乳区面积远大于以中链甘油三酯和单亚油酸甘油酯为油相的体系;助乳化剂中,PEG400和甘油有较大的自微乳区域,也有较大的凝胶区,两者从Km值为1:6到6:1均有自微乳无限稀释区,且同Km条件下,甘油较PEG400大,但是,若以甘油为助乳化剂,在未加水时,有较大的区域是浑浊的。用其他试剂作为助乳化剂时,都是当Km达到1:1时才出现自微乳无限稀释区域。相对于PEG400和甘油,其他自微乳区域和凝胶区域较小。同一K_m条件下,油相/（乳化剂+助乳化剂）越小越易形成自微乳。第二部分进行了辛伐他汀SMEDDS的处方制备及基本特性研究,辛伐他汀SMEDDS的基本组成为油相（亚油酸乙酯）、表面活性剂（吐温-80）、助表面活性剂（PEG-400）、稳定剂（维生素E）。最终选择Km为2:1,油/混合乳化剂为1:9,所选处方的SMEDDS于37℃、室温、-4℃下放置90天自微乳化能力和药物含量无明显变化,稳定性好。SMEDDS处方以不同介质稀释,粒径无明显变化。SMEDDS通常被设计为单剂量的胶囊剂。其内容物有液体和固体两种,现在比较多的是液体内容物制备成软胶囊的形式。本文将辛伐他汀SMEDDS制成软胶囊,并对SMEDDS胶囊在在光照（4500±500Lx）、高湿（RH75%、RH92.5%）和高温（40℃）影响因素条件下考察5天和10天,结果光照和高湿条件下,胶囊及内容物的性状、含量无明显变化,高温（40℃）条件下,内容物发生浑浊,含量下降。表明该制剂在高温下不稳定,应低温贮藏。第三部分进行了辛伐他汀自微乳化给药系统的Beagle犬体内生物利用度评价。建立了狗血浆中辛伐他汀含量的RP—HPLC测定法。经方法学考察,符合体内药物分析的要求。单剂量口服剂量为40mg,同时比较了SMEDDS和混悬剂的体内药动学参数。结果SMEDDS和混悬剂在犬体内的药动学均符合二室模型,SMEDDS的血药浓度达峰时间略有提前,最高血药浓度增大,达峰时间(t_max)为0.84±0.26h,峰浓度(C_max)为39.73±9.11ng/ml,而混悬剂的t_max为0.99±0.32h,C_max为28.54±7.76ng/ml;AUC_0～∞为混悬剂的184.84%。更多还原

【Abstract】 Simvastatin,an inhibitor of HMG-CoA deoxidization enzyme,has been used as a kind of highly effective therapeutic agent for hypercholesterolaemia.Now,domestic simvastatin is marketed in dosage forms of capsules,tablets and dripping pills.Due to its poor water solubility and poor absorption after p.o.adminstration,low bioavailability limits its clinical therapeutic effect.In recent years,much attention has been paid to self-microemulsifying drug delivery system（SMEDDS） to improve the bioavailability of poorly soluble drugs.In this study,simvastatin SMEDDS was prepared to improve its bioavailability.In the first part,pseudo-ternary phase diagrams were prepared by titrating the mixture of oil,surfactant and cosurfactant with distilled water in 37℃water bath., ethyl linoleate,median-chain glycerides and 2-monolinolein were used as oil phase, tween-80 as surfactant and ethanol,isopropanol,1,2-propanediol,glycerol, di（ethylene glycol） ethyl ether and PEG 400 as cosurfactants,respectively.The results showed that the self-emulsifying region area in the diagrams for the systems using ethyl linoleate as oil phase was bigger than those systems using mean-chain glyceride and 2-monolinolein as oil phase under same conditions.The self-emulsifying region aera and gel aera in the diagrams for the systems using PEG 400 or propanetriol as cosurfactants was bigger than those systems using other cosurfactants under same congditions.Both of them have infinite dilution area from Km of 1:6 to 6:1.The infinite dilution area for the systems using propanetriol was bigger than the systems using PEG 400 under same Kin.But when use glycerol as cosurfactants,there was a turbid area before adding water.In the second part,simvastatin SMEDDS formulation was screened and the basic characteristics were studied.The optimum SMEDDS formulation was composed of ethyl linoleate,tween80,PEG400 and vitamin E.The stability and self-microemulsified ability of SMEDDS was good after 90 days of storage at 37℃, room temperature and -4℃.Diluted by various solvents,the particle size change little.Usually the SMEDDS were designed as single dose capsules.In this study we make simvastatin into the soft capsule.The soft capsules have been stored under stress testing conditions:light illumination（4500±500 Lx）,high humidity（RH75%, RH92.5%） and heat（40℃） for 5 days and 10 days.The results showed that the appearance and drug content of the capsules under strong light and high humidity did not change obviously.But for the capsules stored under 40℃,the content turned turbid and drug content decreased.The soft capsule was not stable under high temperature and it should be stored under low temperature.In the third part,the pharmacokinetics of self-microemulsifying drug delivery system of simvastatin（SV-SMEDDS） was evaluated in beagle dogs.Plasma simvastatin was determined by RP-HPLC with solid-phase extraction using Waters OASIS^? HLB cartridge.The pharmacokinetics of SV-SMEDDS was evaluated after a single oral dose of 40 mg of simvastain in a two-period crossover experiment design compared with simvastatin suspension（SV-Sus）.The pharmacokinetics of both SV-SMEDDS and SV-Sus can be fitted to two-compartment model.SV-SMEDDS showed slightly shortened peak time and increased peak concentration of simvastatin with t_max of 0.84±0.26 h and C_max of 39.73±9.11 ng·mL^-1,while SV-Sus showed t_max of 0.99±0.32 h and C_max of 28.54±7.76 ng·mL^-1.AUC_0→∞ of simvastatin SMSDDS was 184.84%that of simvastatin suspension.SMEDDS is able to increase the absorption and bioavailability of simvastatin.更多还原