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二-（4-氯苯甲酰异羟肟酸）二正丁基合锡（DBDCT）脂质体的制备及其体内药代动力学研究
【作者】 王一婕；
【作者基本信息】 山西医科大学 ， 药物化学， 2009， 硕士
【摘要】 [二-(4-氯苯甲酰异羟肟酸)二正丁基合锡]( DBDCT )是一种新型的抗肿瘤化合物,课题组前期研究表明,该化合物有较高的抗癌活性,但其毒性较大,半衰期较短。脂质体作为一种新的剂型,不仅可以明显改善药物的药代动力学特征和体内分布,达到靶向和缓释的效果,还可降低药物的毒副作用。因此,本研究进行了DBDCT脂质体的研制,以期改善其药代动力学特性,并最终提高其治疗指数。为控制DBDCT的质量,建立了测定脂质体中DBDCT的高效液相色谱法(HPLC)和测定DBDCT脂质体(DBDCT-L)包封率的葡聚糖凝胶微柱离心法。通过测定得出DBDCT脂质体的包封率为67.2%。本实验采用薄膜分散法制备DBDCT脂质体,并在单因素实验的基础上,以包封率为指标综合评分,优化制备DBDCT脂质体的处方,其中胆固醇与卵磷脂质量比、卵磷脂用量和磷酸盐缓冲液的量这三个因素变化显著。对影响包封率的三个主要因素采用正交试验确定DBDCT脂质体的最佳制备处方为:胆固醇与卵磷脂质量比为1:6,卵磷脂用量为200mg,磷酸盐缓冲液的量为10ml。脂质体的粒径大小及其分布运用激光粒度仪进行了考察,用透射电镜观察其形态,结果显示,粒度分布均匀,平均粒径为121.3nm,电子显微镜下观察脂质体为均匀的球状或近球状小囊泡。通过对比脂质体溶液和DBDCT溶液之间的药动学参数和组织分布的数据,结果显示,脂质体组具有较大的血药浓度—时间曲线下面积,较低的清除率,药物在体内的消除半衰期明显延长;脂质体组在肝、脾、肺、肾中的分布也高于DBDCT溶液组,特别是在肝组织中的浓度最高。DBDCT脂质体制剂的药代动力学特征及组织分布的变化有利于提高其抗肿瘤活性。通过小鼠体内的急性毒性实验,测定了DBDCT脂质体(DBDCT-L)在小鼠体内的半数致死量(LD50),以及其体外的抗肿瘤活性,结果显示,与原料组相比,脂质体组LD50增大,对于移植性肿瘤(H22)的抑瘤率也提高。
【Abstract】 Di-n-butyl-di-(4-chlorobenzohydroxamato) tin (IV) (DBDCT) is a new antitumor compound with high activity and relatively low bioavailability. It could distribute and be eliminated rapidly in rat with a short half-time(T1/2) value. In this paper the liposome of DBDCT (DBDCT-L) was first prepared in order to improve the pharmacokinetics characteristics and finally to raise its therapeutic indexes.In order to control the quality of DBDCTL, the method for determination of DBDCT quality by HPLC and for determination of encapsulation efficiency of DBDCT-L by Sephadex G-50 minicolumn using centrifugation technique were established. The encapsulation efficiency was calculated by comparing the amount of drug present in the final liposome suspension with that present prior to the removal of the non-incorporated drug. The entrapping efficiency is 67.2%.Liposomes of DBDCT were prepared by thin film evaporation–extrusion technique. Orthogonal design was adopted to the formulation of DBDCT liposome on the basis of the score of the entrapment efficiency. According to the entrapment efficiency, various factors were studied. The orthogonal experimental design was chosen to optimize the condition of preparation DBDCT-L. The analysis showed (PC) 200mg, (PC/CH) 6:1, (PBS) 10ml, which were the optimal formulation.The size, size distribution and shape of all batches of liposomes were determined using dynamic light scattering and negative staining electron microscopy. The mean diameter of the liposomes loaded with DBDCT was 128.3nm.A comparison study of the pharmacokinetics and tissue distribution after intravenous administrations of the DBDCT-L with the corresponding free DBDCT to rats was investigated. Comparing with the free DBDCT, the DBDCT-L showed slower clearance, increased half-time and larger AUC value than those of the free DBDCT after intravenous administration to rats. Significant differences were observed in heart, liver, spleen, lung, kidney, brain and adrenal gland after administration of DBDCT-L and the free DBDCT. However, the distribution in the spleen, liver, lung and kidney of DBDCT-L was higher than those of the free DBDCT, especially the concentration distribution in liver is the highest which may be associated with the enhanced antitumor activity and indicated the possible target release of the drug.The acute toxicity studies showed that the LD50 value of the DBDCT-L is higher than that of the free DBDCT. The further in vivo antitumor tests in mice showed that DBDCT-L displayed higher in vivo antitumor activity against the hepatocellular carcinoma H22 than those of the free DBDCT, and indicated that the liposomes could prolong the action-time of DBDCT in the system circulation, change its distribution in rats in vivo, reduce the acute toxicity and finally raise the antitumor activity.