【作者】 张修宇；

【导师】 邓英杰； 赵春杰；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2006， 硕士

【摘要】 β-榄香烯（β-elemene，）是从温莪术（Curcuma wenyujin Chen et C．Ling）的根茎中分离提取得到的抗癌有效单体，属于倍半萜烯类成分，具有抗肿瘤和提高机体免疫力的作用，是一种高效、低毒、有别于传统化疗药的新型抗癌药。PVP作为一种两亲性聚合物，可用作脂质体立体保护剂，可增加体内滞留时间、阻止药物渗漏。因此作者在β-榄香烯普通脂质体的基础上制备了PVP包覆的β-榄香烯口服脂质体，以期进一步提高其口服给药的生物利用度。 本文建立了β-榄香烯的气相色谱分析方法及PVP包覆β-榄香烯脂质体包封率的测定方法。实验证实β-榄香烯质量浓度在0.1250～8.018g·L^-1的范围内线性关系良好，线性方程为y=1.384 ρ-0.0047（r=1.000）。考察了不同的包封率测定方法，最终选用的微柱离心法测定包封率各实验步骤的精密度、重现性均符合要求，磷脂及其他辅料均对结果无影响。 在PVP包覆β-榄香烯脂质体制备与处方优化试验中正交试验结果表明利用1％PVP-k30包覆，载药量为0.5％，磷脂用量为6％，磷脂与胆固醇比例为6：1（质量比）为最佳处方。制备工艺的各因素考察结果表明在50℃、搅拌速度30r·min^-1下采用乙醇注入法制得的脂质体粒径较小和包封率比较高。 PVP包覆β-榄香烯脂质体粒径为162nm左右，而普通β-榄香烯脂质体粒径为147nm左右。透射电镜照片显示PVP已形成了对脂质体的包覆。 分别考察了β-榄香烯原料药和PVP包覆β-榄香烯脂质体制剂的稳定性，β-榄香烯原料药在常用有机溶剂中比较稳定；制剂在光照和高温下包封率下降较为明显，加速试验证明在4℃避光保存条件下比较稳定。因此本制剂应在低温避光条件下保存。 以市售榄香烯口服乳剂和普通β-榄香烯脂质体作为参比制剂考察了本制剂灌胃给药后在大鼠体内的药物动力学行为。结果显示市售榄香烯口服乳剂生物利用度很低，仅能检测4个时间点的血药浓度，利用统计矩方法和3P87的双室模型拟和后计算的药动参数证明β-榄香烯普通脂质体和PVP包覆后的脂质体的体内行为无明显差异，但PVP包覆后的生物利用度为普通脂质体的1.4倍左右，经3P87计算后的数据与文献相比t1／2α有明显增加，但t1／2β无明显变化。更多还原

【Abstract】 β-elemene is a sesquiterpene ingredient extracted from one of the traditional Chinese herbal medicine Curcuma wenyujin Chen et C. Ling. Recent studies have shown that β-elemene possesses specific cytotoxicity. As a broad-spectrum anti-tumor agent, β-elemene exhibits pharmacological effects including anti-tumor, antibacterial, antivirus, improving immunity, inhibiting platelet aggregation and improving microcirculation, etc. PVP （pyrrolidone） is one kind of amphipathic macromolecule material, which could be used as protectant in liposomes. PVP has the potential of prolonging resident time in vivo. PVP-coated β-elemene liposomes were prepared to improve oral bio-availability.To investigate the envelop efficiency of β-elemene liposomes coated by pyrrolidone, GC analysis method was developed. Linear equation was y =1.384 p-0.0047 （r =1.000） in the concentration between 0.1250 and 8.018 g . L^-1. Minicolumn centrifugation method was selected to detect envelop efficiency after comparing of others. Precision and accuracy answered for the requirement.The orthogonal test showed that the optimal composition contained 1% PVP-k30, 0.5%β-elemene, 6% phospholipid and 1% cholesterol. Particle size and envelop efficiency was satisfied with 30 r . min^-1 agitating on 50 ℃.Diameter of PVP-coated β-elemene liposome was 162nm on average compared that the β-elemene liposome was 147 nm. Result of TEM confirmed the envelop structure.Stability of β-elemene crude drug and preparation was investigated separately. β-elemene crude drug was steady in all four organic solvents, preparation was steady in acceleration test on 4℃. While in condition of illumination and high temperature β-elemene liposomes degraded apparently. Therefore PVP-coated β-elemene liposomes should be conserved in low temperature and avoid of light.The pharmacokinetics of PVP-coated β-elemene liposomes were studied compared with conventional liposomes and elemene emulsion. The concentration in plasma handled by statistical moment method and 3P87 showed no obvious disparity. The bioavailability of PVP coated β-elemene liposomes was 140. 2 ± 7. 5% compared with conventional liposomes.更多还原