【作者】 王娜；

【导师】 邓英杰；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2009， 硕士

【摘要】 本文建立了洛莫司汀的体外HPLC分析方法,测定了洛莫司汀在水和不同pH值缓冲液中的溶解度以及在正辛醇／水中的油水分配系数,为处方设计、工艺条件的确定以及体内分析方法的建立提供了依据。建立了HPLC测定洛莫司汀脂质体中药物含量的方法,微柱离心-HPLC法测定脂质体包封率。采用乙醇注入法制备了洛莫司汀脂质体,以包封率为指标,对磷脂种类和浓度、药脂比、缓冲液的pH值和制备温度、搅拌速度等处方及工艺进行单因素考察；通过正交设计优化处方,制备了包封率大于80%的普通脂质体。进一步制得洛莫司汀脂质体冻干品,对冻干工艺进行研究,重点考察了冻干保护剂的种类和配比,确定了最佳处方和工艺。考察了洛莫司汀冻干脂质体的理化性质,脂质体形状圆整,大小均一；冻干前体积径为(155±21)nm,冻干后体积径为(185±30)nm；两者pH值基本不变,接近7.4；冻干前后包封率分别为(82.06±1.1)%和(78.39±1.8)%；载药量分别为(2.22±1.4)%和(0.52±6.9)%。稳定性影响因素试验表明,洛莫司汀冻干脂质体易吸湿,对高温和强光照射敏感。加速试验和长期试验中,洛莫司汀冻干脂质体除过氧化值略有升高外,其它指标无明显变化,稳定性较好。以家兔为试验对象,对注射用洛莫司汀脂质体进行了安全性考察,结果表明洛莫司汀脂质体无刺激性,无溶血,满足静脉注射要求。建立了洛莫司汀在血浆和组织中的分析方法,比较了洛莫司汀混悬液和脂质体在小鼠体内的药物动力学和组织分布。药物动力学试验结果表明,两种制剂均符合双隔室模型,洛莫司汀脂质体在体内的消除减慢,半衰期和生物利用度均有所提高；组织分布试验结果表明,将洛莫司汀制成脂质体后能够明显提高肝、脾、肺、脑的靶向性。更多还原

【Abstract】 The HPLC analytical method for CCNU in vitro was developed. The solubilities of CCNU in water and PBS with different pH and the apparent partition coefficient in n-octyl alcohol/water was determined by HPLC. The HPLC method for the content of CCNU in liposomes was established. The entrapment efficiency of CCNU liposome was determined by microcolumn centrifuge-HPLC method.The CCNU liposome was prepared by ethanol injection method. The single factor investigation and the orthogonal design were adopted to obtain the optimized prescription, the entrapment efficiency of CCNU liposome was above 80%.To resolve the instability problem of liposome dispersion, freeze-drying (lyophilization) technique was utilized to prepare freeze-dried proliposome. The technology of freeze-dried especially on the kinds and ratio of cryoprotectants had been researched.The physicochemical properties of freeze-dried CCNU liposome were studied. The liposome was spheroidal and uniform, the volume diameters of CCNU liposome suspension and freeze-dried product were (155±21) nm and (185±30) nm respectively; the pH value was not changed notably, closed to 7.4; the entrapment efficiency of these were (82.06±1.1)% and(78.39±1.8)% differently; the drug loading capacity of these were (2.22±1.4)% and (0.52±6.9)%The results of stability tests indicated that the CCNU freeze-dried liposome was sensitive to high temperature and strong light. There was not significant change in the accelerated test and the long test.The security investigation indicated that the CCNU liposome injection was non-irritant and non-hematolytic, the preparation met the regulations of the i.v. administration.The HPLC method of CCNU liposome in blood plasma and tissues was established. After i.v. administrated CCNU suspension and liposomes to mice, respectively, the drug concentrations in different tissues were monitored by HPLC. The pharmacokinetic processes in mice for the two preparations were both accorded with two compartmental models. Compared with CCNU suspension, the liposome had longer half-life and higher bioavailability. The levels of CCNU liposome in liver, spleen, lung and brain were higher than that of suspension group.更多还原