酒石酸长春瑞滨脂质体注射液的制备及体内外评价  

Preparation of Vinorelbine Tartrate Liposomes Injection by Different Methods and Their Properties and Antitumor Effects

作　　者：王栋海 解李丽 张勇 杨清敏 

机构地区：[1]山东省注射用微粒给药新技术重点实验室,济南250108 [2]齐鲁制药(海南)有限公司,海口570314

出　　处：《中国药学杂志》2014年第15期1333-1337,共5页Chinese Pharmaceutical Journal

基　　金：重大新药创制国家科技重大专项(2010ZX09401-302-4-2)

摘　　要：目的 考察采用不同工艺制备的酒石酸长春瑞滨脂质体注射液（vinorelbine tartrate liposome injection,VLI）的药剂学性质及抗肿瘤效果。方法 采用pH梯度法、硫酸铵梯度法和蔗糖八硫酸酯三乙胺（SOS-TEA）梯度法,结合PEG外导入法,制备酒石酸长春瑞滨脂质体注射液-1、酒石酸长春瑞滨脂质体注射液-2、酒石酸长春瑞滨脂质体注射液-3;观察3种脂质体形态,并测定3种脂质体的粒径及Zeta电位、包封率、体外释放、稳定性等药剂学特性;以酒石酸长春瑞滨注射液（vinorelbine tartrate injection,VI）为对照,采用人结肠癌HT-29移植肿瘤模型,比较3种脂质体在裸鼠体内抑制肿瘤效果和一般毒性。结果 3种脂质体药物包封率均大于93%,平均粒径80~100 nm,Zeta电位约为-15 mV,2~8℃条件下放置6个月各样品的主要质量指标均未发生明显变化;3种脂质体均缓慢释放,以酒石酸长春瑞滨脂质体注射液-3药物释放速度最慢。冷冻透射电镜观察形态结果表明,酒石酸长春瑞滨脂质体注射液-1中药物以溶液形态存在于脂质体内部,而酒石酸长春瑞滨脂质体注射液-2和-3内部可观察到胶体状和针状结晶。药效学研究结果表明,采用酒石酸长春瑞滨脂质体注射液-3疗效优于酒石酸长春瑞滨脂质体注射液-2和酒石酸长春瑞滨脂质体注射液-1,而酒石酸长春瑞滨脂质体注射液-1和酒石酸长春瑞滨脂质体注射液-2疗效均略优于酒石酸长春瑞滨注射液。结论 酒石酸长春瑞滨脂质体注射液-3在抗肿瘤细胞生长方面与酒石酸长春瑞滨注射液相比具有显著优势,毒性低。OBJECTIVE To prepare vinorelbine tartrate liposomes injection （VLI） by three different methods and evaluate their properties and antitumor effects. METHODS Vinorelbine tartrate liposome injections were prepared by pH gradient method （ VLI- 1 ）, ammonium sulfate gradient method （ VLI-2 ） and sucrose octasulfate gradient method （ VLI-3 ）, respectively. PEG-DSPE （ an ex- tensively used peglipid） was added into liposomes using ＂post-insertion＂ technology to increase the entrapment efficiency （EE）. The morphology, diameter and Zeta potential of VLI were analyzed by cryo-transmission electron microscope （cryo-TEM） and laser particle sizer. A cation exchange resin centrifugalization method was used to determine the entrapment efficiency. The in vitro release rate and stability were also evaluated. The toxicity and antitumor effect of VLI were investigated in Human HT-29 xenograft tumor model and compared with the vinorelbine tartrate injection （VI）. RESULTS All EEs of the three VLIs were over 93%. The mean diameters, Zeta potentials and entrapment efficiencies of the three VLIs were similar. Meanwhile the three VLIs were stable in the long-term stability test. The cryo-TEM showed that almost all vesicles had spherical structure and uniform nanosize. Furthermore, some colloid substances and acicular crystal were found inside VLI-2 and VLI-3, respectively. The release rate of VLI-3 was slower, which indicated that the drug crystal probably influence the in vitro drug release. The pharmacodynamic test showed that the antitumor effect of VLI-3 was better than VLI-2 and VLI-1, while those of the latter two were superior to VI. CONCLUSION VLI-3 has advantages in antitumor effect with lower adverse reactions.

关 键 词：酒石酸长春瑞滨脂质体注射液 PH梯度法 硫酸铵梯度法 蔗糖八硫酸酯三乙胺 相对肿瘤生长抑制率 

分 类 号：R971.1[医药卫生—药品]