花旗松素纳米给药系统的研究
摘要
花旗松素是二氢黄酮醇类化合物,是红蓼、土茯苓等中药的主要有效成分,也广泛存在于柑橘、葡萄等水果中。药理学研究表明花旗松素具有显著的抗氧化、抗肿瘤等作用。但因其水溶性小,生物利用度低,口服吸收不规则,故很大程度上限制了其临床应用。本实验将花旗松素制成固体脂质纳米粒和脂质体,并对两者在小鼠体内的药代动力学特征进行了初步研究,为花旗松素的进一步开发奠定基础。
采用溶剂注入法分别制备花旗松素固体脂质纳米粒和花旗松素脂质体,通过星点设计-效应面优化法(RSM-CCD)优化花旗松素固体脂质纳米粒的处方,通过单因素实验筛选花旗松素脂质体的处方用量。根据优化后的处方及制备工艺分别制备三批花旗松素固体脂质纳米粒及脂质体,结果显示,固体脂质纳米粒平均包封率80.9±3.5%,载药量13.9±2.0%,激光动态散射仪分析,纳米粒平均粒径125.0±1.5nm,zeta电位-24.3±6.1mV,透射电镜观察显示,纳米粒呈圆整均匀的类球形粒子；花旗松素脂质体包封率68.1±4.5%,平均粒径166.4±2.9nm,zeta电位-32.3±4.9mV,透射及扫描电镜观察显示,颗粒圆整均匀。
建立小鼠血浆中花旗松素的HPLC分析方法。以花旗松素溶液剂为对照,研究小鼠静脉注射花旗松素固体脂质纳米粒混悬液、花旗松素脂质体混悬液后的体内药动学过程,并计算药动学参数。花旗松素制剂在小鼠体内血药药代动力学过程符合三房室模型。血药药代动力学参数为(每个采血点n=3)：溶液剂组：AUC(0-∞)15.745mg／L*h,t1／2β0.021h,Cmax 31.02mg／l,Tmax 0.083h,CL3.176L／h／kg；脂质体组：AUC(0-∞)20.962mg／L*h,t1／2p 0.279h,Cmax 15.30mg／l,Tmax 0.083h,CL 2.385L／h／kg；固体脂质纳米粒组：AUC(0-∞)17.61mg／L*h,t1／2β0.116h,Cmax 18.60mg/l,Tmax 0.083h,CL 2.839L／h／kg。实验结果表明,花旗松素脂质体及纳米粒在小鼠体内的AUC较溶液剂组有较大的提高,消除速度减少,可见,花旗松素脂质体及纳米粒能有效地延长花旗松素在体内存留时间,延缓药物的代谢及排泄。花旗松素溶液剂组、脂质体组、纳米粒组的Cmax分别为：31.02mg/l,15.30 mg/l,18.60 mg/l,可见,溶液剂在体内的分布要快于其他两种制剂。
Taxifolin is widely distributed in many Chinese herbs, such as the rhizome of Smilax glabra, a Liliaceae plant and Hypericum perforatum, also have been found in many citrus fruits, especially grapefruit and orange. It has been reported that taxifolin has many activities in anti-bacteria, anti-oxidative, anti-inflammation, anti-cancer, as well as hepato-protection. However, Taxifolin has poor water-solubility and low bioavailability for oral administration due to slow drug dissolution and decomposition in the stomach and intestine. Therefore, the development of the new formulation of Taxifolin that enables quick availability to the body is in great need. In this study, solid lipid nanoparticles (SLN) and liposomes of Taxifolin were prepared.
Taxifolin liposomes and solid lipid nanoparticles(DHQ-SLN) were prepared by solvent injection method. Central composite design-response surface methods were used to obtain the optimum prescription of SLN. The single factor experiment results were applied to have taxifolin liposomes. Three batches of DHQ-SLN were prepared using the optimized formulation. From the transmission electron microscope observation, the nanoparticles were spherically shaped, the encapsulation efficiency was 80.9±3.5%, and drug loaded capacity was 13.9±2.0%, the average diameter was 125.0±1.5nm, zeta potential was -24.3±6.1mv. The liposomes with spherical or ellipsoidal shape featured the encapsulation efficiency of 68.1±4.5%, the mean partical size of 166.4±2.9 nm, and Zeta potential of -32.3±4.9mV.
An HPLC method was developed for the detemination of taxifolin in mice plasma. Intravenous pharmacokinetic behaviors of taxifolin solution, taxifolin liposomes and DHQ-SLN suspension were investigated in mice. The plasma concentration-time profiles of taxifolin were fitted to the three compartment model. The plasma pharmacokinetic parameters were obtained as following(n=3):solution:AUC(0-∞) 15.745mg/L*h, t1/2β0.021h, Cmax 31.02mg/l, Tmax 0.083h, CL 3.176L/h/kg; liposomes:AUC(0-∞) 20.962mg/L*h, t1/2β0.279h, Cmax 15.30mg/l, Tmax 0.083h,CL 2.385L/h/kg; DHQ-SLN:AUC(0-∞) 17.61mg/L*h, t1/2β0.116h, Cmax 18.60mg/l, Tmax 0.083h, CL 2.839L/h/kg. The results showed that the AUC(0-∞) of taxifolin liposomes and DHQ-SLN were higher than that of solution, and less elimination. Solution, liposome, nanoparticle group Cmax were:31.02mg/l,15.30 mg/l,18.60 mg/l, showed the distribution of solution in the body faster than the other two preparations.
采用溶剂注入法分别制备花旗松素固体脂质纳米粒和花旗松素脂质体,通过星点设计-效应面优化法(RSM-CCD)优化花旗松素固体脂质纳米粒的处方,通过单因素实验筛选花旗松素脂质体的处方用量。根据优化后的处方及制备工艺分别制备三批花旗松素固体脂质纳米粒及脂质体,结果显示,固体脂质纳米粒平均包封率80.9±3.5%,载药量13.9±2.0%,激光动态散射仪分析,纳米粒平均粒径125.0±1.5nm,zeta电位-24.3±6.1mV,透射电镜观察显示,纳米粒呈圆整均匀的类球形粒子；花旗松素脂质体包封率68.1±4.5%,平均粒径166.4±2.9nm,zeta电位-32.3±4.9mV,透射及扫描电镜观察显示,颗粒圆整均匀。
建立小鼠血浆中花旗松素的HPLC分析方法。以花旗松素溶液剂为对照,研究小鼠静脉注射花旗松素固体脂质纳米粒混悬液、花旗松素脂质体混悬液后的体内药动学过程,并计算药动学参数。花旗松素制剂在小鼠体内血药药代动力学过程符合三房室模型。血药药代动力学参数为(每个采血点n=3)：溶液剂组：AUC(0-∞)15.745mg／L*h,t1／2β0.021h,Cmax 31.02mg／l,Tmax 0.083h,CL3.176L／h／kg；脂质体组：AUC(0-∞)20.962mg／L*h,t1／2p 0.279h,Cmax 15.30mg／l,Tmax 0.083h,CL 2.385L／h／kg；固体脂质纳米粒组：AUC(0-∞)17.61mg／L*h,t1／2β0.116h,Cmax 18.60mg/l,Tmax 0.083h,CL 2.839L／h／kg。实验结果表明,花旗松素脂质体及纳米粒在小鼠体内的AUC较溶液剂组有较大的提高,消除速度减少,可见,花旗松素脂质体及纳米粒能有效地延长花旗松素在体内存留时间,延缓药物的代谢及排泄。花旗松素溶液剂组、脂质体组、纳米粒组的Cmax分别为：31.02mg/l,15.30 mg/l,18.60 mg/l,可见,溶液剂在体内的分布要快于其他两种制剂。
Taxifolin is widely distributed in many Chinese herbs, such as the rhizome of Smilax glabra, a Liliaceae plant and Hypericum perforatum, also have been found in many citrus fruits, especially grapefruit and orange. It has been reported that taxifolin has many activities in anti-bacteria, anti-oxidative, anti-inflammation, anti-cancer, as well as hepato-protection. However, Taxifolin has poor water-solubility and low bioavailability for oral administration due to slow drug dissolution and decomposition in the stomach and intestine. Therefore, the development of the new formulation of Taxifolin that enables quick availability to the body is in great need. In this study, solid lipid nanoparticles (SLN) and liposomes of Taxifolin were prepared.
Taxifolin liposomes and solid lipid nanoparticles(DHQ-SLN) were prepared by solvent injection method. Central composite design-response surface methods were used to obtain the optimum prescription of SLN. The single factor experiment results were applied to have taxifolin liposomes. Three batches of DHQ-SLN were prepared using the optimized formulation. From the transmission electron microscope observation, the nanoparticles were spherically shaped, the encapsulation efficiency was 80.9±3.5%, and drug loaded capacity was 13.9±2.0%, the average diameter was 125.0±1.5nm, zeta potential was -24.3±6.1mv. The liposomes with spherical or ellipsoidal shape featured the encapsulation efficiency of 68.1±4.5%, the mean partical size of 166.4±2.9 nm, and Zeta potential of -32.3±4.9mV.
An HPLC method was developed for the detemination of taxifolin in mice plasma. Intravenous pharmacokinetic behaviors of taxifolin solution, taxifolin liposomes and DHQ-SLN suspension were investigated in mice. The plasma concentration-time profiles of taxifolin were fitted to the three compartment model. The plasma pharmacokinetic parameters were obtained as following(n=3):solution:AUC(0-∞) 15.745mg/L*h, t1/2β0.021h, Cmax 31.02mg/l, Tmax 0.083h, CL 3.176L/h/kg; liposomes:AUC(0-∞) 20.962mg/L*h, t1/2β0.279h, Cmax 15.30mg/l, Tmax 0.083h,CL 2.385L/h/kg; DHQ-SLN:AUC(0-∞) 17.61mg/L*h, t1/2β0.116h, Cmax 18.60mg/l, Tmax 0.083h, CL 2.839L/h/kg. The results showed that the AUC(0-∞) of taxifolin liposomes and DHQ-SLN were higher than that of solution, and less elimination. Solution, liposome, nanoparticle group Cmax were:31.02mg/l,15.30 mg/l,18.60 mg/l, showed the distribution of solution in the body faster than the other two preparations.
引文
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