青蒿素长循环脂质体的制备及体外性质评价  

Preparation and in vitro evaluation of artemisinin loaded long-circulating liposomes

作　　者：余荧蓝 郑智元 伊宸辰 周沐野 涂家生[1] 孙春萌[1] YU Ying-lan;ZHENG Zhi-yuan;YI Chen-chen;ZHOU Mu-ye;TU Jia-sheng;SUN Chun-meng(Center for Research Development and Evaluation of Pharmaceutical Exeipients and Generic Drugs, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China)

机构地区：[1]中国药科大学,药用辅料及仿创药物研发评价中心,药学院,江苏南京210009

出　　处：《药学学报》2018年第6期1002-1008,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81501579,81673364); 江苏省自然科学基金资助项目(BK20150702)

摘　　要：青蒿素(artemisinin,ART)由于溶解度差、稳定性低,限制了其应用。本研究采用长循环脂质体包裹青蒿素,增强其溶解度及稳定性。以粒径和包封率(entrapment efficiency,EE)等为评价指标,采用单因素试验及Box-Behnken响应面设计试验优化处方,考察最优处方制备得到脂质体的外观形态、粒径分布、zeta电位、放置稳定性、血清稳定性、体外释放和细胞毒性作用。结果表明,载青蒿素长循环脂质体的最优处方为:磷脂与胆固醇的质量比为5.22∶1,青蒿素与磷脂的质量比为1∶23.15,磷脂浓度为14.35 mg·m L-1,DSPE-m PEG摩尔含量为2%。按优化后处方制备所得青蒿素长循环脂质体呈类球形,分布均匀,粒径为(113.3±4.7)nm,多分散系数(polydispersity index,PDI)为0.227±0.022,zeta电位为(-12.9±2.6)m V,包封率为(95.88±4.8)%,在4℃条件下放置15天稳定性良好,血清中24 h内无明显聚集。体外释放实验表明青蒿素长循环脂质体具有缓释作用;细胞毒性实验证实脂质体载体本身安全性较高,载药脂质体制剂在高浓度时的细胞毒性作用低于游离青蒿素。本研究表明,优化得到的青蒿素长循环脂质体具有简便的制备方法、适宜的理化性质和较高的安全性,具有广阔的临床应用前景。The therapeutic application of artemisinin （ART） is restricted in application due to its poor water solubility and stability. In this study, the long-circulating liposomes （L-Lip） were constructed to improve the solubility and stability of ART. The preparation method, physicochemical properties, serum stability, in vitro release profile and cytotoxicity of the ART loaded long-circulating liposomes were investigated. Using the particle size and entrapment efficiency （EE） as the evaluation index, the preparation procedure was optimized by the Box-Behnken response surface design based on the single factor screening method. The ART loaded long-circulating liposomes were prepared by filming rehydration method, and evaluated with particle size and entrapment efficiency. The optimal formulation was as follows：lipid-cholesterol=5.22：1 （mass ratio）, drug-lipid=1：23.15 （mass ratio）, lipid concentration=14.35 mg·mL-1, and molar percentage of mPEG=2%. The morphology of L-Lip was uniformly spherical shape according to optimal formulation. The mean size and polydispersity index （PDI） were about （113.3 ±4.7） nm and 0.227 ±0.022 respectively, the zeta potential was （-12.9 ±2.6） mV, and the entrapment efficiency （EE） of ART was （95.88 ±4.8）%. The L-Lip had good stability at 4℃ for 15 days and the particle sizes did not exhibit significant variations in 50% rat plasma over 24 h at 37℃. The in vitro release study of formulation showed a sustained release. Moreover, the cytotoxicity exhibited that blank liposomes were of great safety. Compared with the free ART, the liposome formulation achieved lower cytotoxicity at the high concentration. The L-Lip successfully prepared by a simple filming-rehydration method exhibited ideal physicochemical properties and were enhanced safety, which may sever as a promising nanoplatform for clinical application.

关 键 词：青蒿素 长循环脂质体 处方优化 理化性质 细胞毒性 

分 类 号：R943[医药卫生—药剂学]