透明质酸修饰的载紫杉醇脂质体的研究

发布时间：2019-05-14 00:39

【摘要】：研究目的：建立载紫杉醇脂质体体外含量以及包封率测定方法；制备载紫杉醇阳离子脂质体,通过单因素考察筛选最优处方；制备透明质酸修饰的载紫杉醇脂质体,对其理化性质、体外释放、体内药效学及药物动力学进行初步评价。 研究方法：采用HPLC法建立载紫杉醇脂质体体外紫杉醇含量测定方法和包封率的测定方法,并进行方法学考察；采用薄膜分散法进行载紫杉醇阳离子脂质体的制备,并对影响脂质体成形的因素进行单因素考察,获得最优处方；负电性透明质酸包裹到荷正电的载紫杉醇阳离子脂质体上,透射电镜观察其形态,激光粒度分析仪测定粒径,电势分析仪测定Zeta电位值；采用动态膜透析法对透明质酸修饰的载紫杉醇脂质体进行体外释放行为的考察；采用小鼠进行药物动力学评价,荷瘤小鼠进行体内药效学评价。 研究结果：成功建立载紫杉醇脂质体体外含量以及包封率测定方法,方法学考察符合要求。成功制备载紫杉醇阳离子脂质体,通过单因素考察进行处方优化,获得最优处方,最优处方的粒径、电位、包封率和载药量分别为(162.1±4.59)nm、(27.04±5.88)mV、(97.63±1.47)%、(4.05±0.08)%成功制备透明质酸修饰的载紫杉醇脂质体,最优处方的粒径、电位、包封率和载药量分别为(237.87±6.63) nm、(-29.99±0.61) mV、(89.44±3.80)%、(3.60±0.15)%；体外释放结果显示泰素(?)组的释放行为拟合的数学方程为lnln(1/(1-Q/100))=0.96321nt-2.3540(r=0.9970),符合韦伯方程；透明质酸修饰的载紫杉醇脂质体组的释放行为拟合的数学方程为100-Q=45.9567e-0.2010t+54.8828e-0.0026t,符合Bioexponential数学模型；体内药物动力学试验结果发现透明质酸修饰的载紫杉醇脂质体组血药浓度迅速降低,30min后血药浓度均低于泰素(?)组；药物动力学参数计算结果显示,透明质酸修饰的载紫杉醇脂质体K10为2.163±0.20732h-1,显著低于泰素(?)组(P0.001)；体内药效学结果显示载紫杉醇阳离子脂质体组小鼠的瘤体积变化与泰素(?)组相似,而透明质酸修饰的载紫杉醇脂质体组小鼠瘤体积显著小于泰素(?)组(P0.001)。 结论：经透明质酸修饰的载紫杉醇脂质体是一种制备工艺简单,理化性质稳定,抑瘤效果明显,并具有一定缓释作用的制剂。
[Abstract]:Objective: to establish a method for the determination of paclitaxel-loaded liposomes in vitro and entrapment efficiency, to prepare Taxol-loaded cationic liposomes, and to screen the optimal prescription by single factor investigation. The physicochemical properties, in vitro release, pharmacokinetics and pharmacokinetics of hyaluronic acid modified paclitaxel liposomes were evaluated. Methods: the determination method of paclitaxel content in vitro and the entrapment efficiency of paclitaxel-loaded liposomes were established by HPLC method, and the methodology was investigated. The preparation of Taxus alcohol cationic liposomes was carried out by thin film dispersion method, and the factors affecting the formation of liposomes were investigated by single factor, and the optimal prescription was obtained. The negative hyaluronic acid was wrapped on the positively charged Taxus alcohol cationic liposomes, the morphology was observed by transmission electron microscope, the particle size was measured by laser particle size analyzer, and the potential value of Zeta was measured by potential analyzer. The release behavior of hyaluronic acid modified paclitaxel liposomes in vitro was investigated by dynamic membrane dialysis, and the pharmacokinetics of paclitaxel liposomes modified by hyaluronic acid was evaluated by pharmacokinetics in mice and in vivo by tumor bearing mice. Results: a method for the determination of paclitaxel-loaded liposomes in vitro and entrapment efficiency was successfully established, and the methodological investigation met the requirements. Taxol cationic liposomes were successfully prepared and optimized by single factor investigation. The optimal prescription was obtained. The particle size, potential, entrapment efficiency and drug loading of the optimal prescription were (162.1 卤4.59) nm, (27.04 卤5.88) mV, respectively. Paclitaxel liposomes modified by hyaluronic acid were successfully prepared by (9763 卤1.47)% and (4.05 卤0.008)% hyaluronic acid modified paclitaxel liposomes. The optimal prescription particle size, potential, entrapment efficiency and drug loading were (237.87 卤6.63) nm, (- 29.99 卤0.61) mV, respectively. (89.44 卤3.80)%, (3.60 卤0.15)%; The results of in vitro release showed that Taxol (?) The mathematical equation of the release behavior of the group was lnln (1 / (1-Q/100) = 0.96321nt-2.3540 (r 鈮，

本文编号：2476304