【作者】 王倩；

【导师】 黄亚东；

【作者基本信息】 暨南大学 ， 微生物与生化药学， 2010， 硕士

【摘要】 aFGF具有多种生物学活性,但由于稳定性差,对温度、pH以及金属离子敏感,极易失活等众多缺点,极大限制了其临床应用的范围。目的：以阳离子脂质体作为药物aFGF的载体,以实现制剂对aFGF的有效保护作用和制剂缓释作用为目标,研究制备工艺,建立其质量评价体系,并进行体外释药动力学及大鼠体内药动学研究。方法：①pH梯度法制备aFGF阳离子脂质体,以包封率为考察指标单因素筛选aFGF阳离子脂质体最佳制备工艺,并考察该工艺的重现性。②采用低温电镜和激光散射法测定aFGF阳离子脂质体的理化性质,并进行了稳定性考察。③采用透析法研究aFGF阳离子脂质体体外释药动力学,考察其与aFGF溶液组的差别及释放介质对其释药的影响。④从静脉与腹腔注射两种给药方式,研究aFGF阳离子脂质体体内药动学,并观察aFGF溶液与aFGF脂质体药动学的差别。结果：①筛选最佳制备工艺为：十八胺用量为0.02g,柠檬酸缓冲液浓度为0.03mol／L,aFGF投药量为0.04 mg/mL,内外水相ΔpH为3.5,孵育温度为35℃,孵育时间为15 min,制备的aFGF阳离子脂质体包封率为(78.82±2.56)%。②aFGF阳离子脂质体平均粒径为124.03 nm,ζ电位为9.68 mV,在温度25℃以上不稳定,宜低温4℃保存。③体外释药动力学研究结果表明,与aFGF原液相比,aFGF阳离子脂质体,在不同释放介质中均具有一定的缓释作用。④无论腹腔还是静脉注射,药动学结果表明,aFGF阳离子脂质体明显延长了体内半衰期,且与体外释药存在良好相关性。结论：制备出一种aFGF阳离子脂质体,具有包封率高,理化性质稳定,及显著的体内缓释作用。更多还原

【Abstract】 As we know aFGF (acid fibroblast growth factor) plays an important role in organism for its numerous bioactivity.However, aFGF is unstable and sensitive to temperature, pH and metal ion, it still has a bottle neck on clinical application.Objective: In this study, we made cationic liposome as a drug carrier for aFGF in order to effectively protect aFGF from unstabilizing factors, established the quality assessment system of aFGF cationic liposome,and researched on its release kinetics in vitro and pharmacokinetic in vivo.Methods:AFGF cationic liposomes were prepared by pH-gradient, the formulation and preparation were optimized by single-factor test with encapsulation efficiency of liposomes as the parameter, and the reproducibility of the best preparation was studied.The physical and chemistry properties of aFGF cationic liposome was identified by Cryo transmission electron microscopy and laser light scattering, and its stability was also researched. The vitro release kinetics of aFGF cationic liposome was investigated by Dialysis method. Observed the influence of drug release between different release medium, and also researched the difference with aFGF solution. Studied pharmacokinetic of aFGF cationic liposomes after intravenous and intraperitoneal administration in rats, and discussed the difference with aFGF solution.Results:Optimization experiments to determine the optimal formulation and process conditions, stearylamine (0.02 g), citric acid buffer (0.03 mol/L), aFGF (0.04 mg/mL), ApH (3.5), incubation temperature (35℃), incubation time (15 min), the preparation of aFGF cationic liposome encapsulation efficiency was (78.82±2.56)%.The mean diameter of aFGF cationic liposomes was 124.03nm, Zeta potential was 9.68mV. Stability studies indicated that aFGF liposome should be stored at low temperature 4℃, it was unstable above 25℃.In vitro release kinetics study showed that, aFGF cationic liposome had some sustained release compared to aFGF solution, similar behavior in various release medium.Pharmacokinetic results had showned that aFGF cationic liposomes obvious prolonged the half-life in vivo, compared with aFGF solution. And there is a good correlation between the release characters in vivtro with the release in vitro.Conclusion:Research indiated, aFGF cationic liposomes had high encapsulating efficiency, physical chemical stability, and sustained release in vivo.更多还原