目的采用铜离子梯度法制备盐酸米托蒽醌脂质体(Mit-lipo)，将其与盐酸米托蒽醌游离药(Mit-free)进行了药效学和药动学对比研究。方法采用正交设计法，以包封率为考察指标，优化盐酸米托蒽醌脂质体的制备工艺和处方。采用L1210/BDF1小鼠腹水瘤模型探讨盐酸米托蒽醌脂质体的抗肿瘤作用;KM小鼠单次静脉给予盐酸米托蒽醌脂质体和盐酸米托蒽醌游离药观察药动学参数变化。结果最佳处方和工艺条件为:采用铜离子梯度法制备脂质体，药脂比为1∶10，内相溶液为0.3mol·L-1，pH7.5的硫酸铜溶液，孵育温度为60℃，孵育时间为30min。盐酸米托蒽醌脂质体的平均粒径为(99.5±1.9)nm，包封率为(95.0±0.6)%。药动学实验结果表明，与盐酸米托蒽醌游离药相比，盐酸米托蒽醌脂质体在小鼠体内的AUC和t1/2更高，盐酸米托蒽醌脂质体具有长循环的特点。药效实验结果表明，盐酸米托蒽醌脂质体可显著延长荷瘤鼠的生存时间，且毒性小于盐酸米托蒽醌游离药。结论铜离子梯度法制备得到的盐酸米托蒽醌脂质体具有较高包封率，与盐酸米托蒽醌游离药相比在体内的动力学参数发生了改变，可以提高治疗指数。
Abstract
OBJECTIVE To prepare mitoxantrone-loaded liposomes using copper ion gradient method and compare the pharmacodynamics (PD) and pharmacokinetics (PK) of liposomal mitoxantrone (Mit-lipo) with free mitoxantrone (Mit-free). METHODS Orthogonal design was adopted to screen the preparation process and formulation of Mit-lipo,using encapsulation efficiency (EE) as the evaluation index. The antineoplastic effect of Mit-lipo was evaluated in L1210/ BDF1 ascites tumor model. The PK study of Mit-lipo and Mit-free was performed in KM mice followed a single intravenous injection. RESULTS The optimal preparation process and formulation were as follows: the weight proportion of mitoxantrone to HSPC was 1∶10. Mit-lipo was prepared by copper ion gradient method using 0.3 mol·L-1 copper sulfate (pH 7.5) as the inner phase solution. The drug loading process was performed at 60 ℃ for 30 min. The particle size of Mit-lipo was (99.5±1.9) nm,and the EE was (95.0±0.6)%. The PK study showed that the AUC and t1/2values of Mit-lipo were higher than those of Mit-free in KM mice,suggesting Mit-lipo had a long circulation characteristic. The PD study showed that Mit-lipo could significantly prolong the survival time of tumor-bearing mice with lower toxicity than Mit-free. CONCLUSION The developed preparation method for Mit-lipo has a high EE. The PK of Mit-lipo changes obviously compared to Mit-free,resulting in an increase of the therapeutic index.
关键词
米托蒽醌 /
脂质体 /
制备 /
药效学 /
药动学
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Key words
mitoxantrone /
liposome /
preparation /
pharmacodynamics /
pharmacokinetics
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中图分类号：
R944
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参考文献
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脚注
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基金
国家重点基础研究发展计划(973计划)资助项目(2010CB735603)
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