两性霉素B衍生物SW39长循环脂质体的制备、质量评价及药效学研究

Preparation, Quality Evaluation and Pharmacodynamics of Long-circulating Liposomes Loaded with Amphotericin B Derivative SW39

采用薄膜分散-高压均质法制备两性霉素B衍生物(SW39)的长循环脂质体。透射电镜观察到该脂质体呈球形,动态光散射法测得其粒径为(49.6±0.5)nm,ζ电位为(-19.5±0.5)mV,用葡聚糖凝胶柱色谱法测得包封率为(95±2)%;SW39的长循环脂质体在1%十二烷基硫酸钠水溶液中96h累积释放率为39.9%,释放速率比游离SW39(96h累积释放率为91%)缓慢。药效学试验表明,相同剂量(0.07 mg/kg)的SW39长循环脂质体与市售两性霉素B注射剂均有一定抗白色念珠菌活性,且抗菌活性相当,随着脂质体给药剂量增加,自制脂质体的抗菌作用增强,高剂量(0.20 mg/kg)SW39长循环脂质体组抗菌活性与市售注射剂(0.07 mg/kg)组相比有极显著差异(P<0.001)。

In this study, the long-circulating liposomes of an amphotericin B derivative(SW39) were prepared by thin film dispersion and high pressure homogenization method. Under the transmission electron microscope(TEM), the liposomes showed a uniform spherical form. The mean particle size of SW39 liposomes measured by dynamic light scattering(DLS) was(49.6±0.5)nm and the ζ potential of SW39 liposomes was(-19.5±0.5)mV. To determine the encapsulation efficiency(EE), Sephadex gel column chromatography was utilized, and the EE of SW39 liposomes was(95±2)%. In the 1% sodium lauryl sulfate solution, SW39 liposomes presented a cumulative release rate of 39.9% at 96 h, which was slower than that of free SW39(cumulative release rate of 91% at 96 h). The pharmacodynamics evaluation showed that both SW39 liposomes and commercial amphotericin B injection had remarkable antifungal activities against Candida albicans in the same dosage(0.07 mg/kg), and their antifungal activities were similar. Meanwhile, with the increase of liposome dosage, the antifungal effect of the SW39 liposomes was enhanced. There was extremely significant difference in antifungal activity between the high dose(0.20 mg/kg) group of SW39 liposomes and the commercial injection(0.07 mg/kg) group(P<0.001).