FNC脂质体的制备及药物动力学研究
发布时间：2018-07-24 20:38
【摘要】：FNC是一种新合成的抗病毒、抗肿瘤的核苷类似物。药效学研究发现FNC具有抗艾滋病毒(HIV)和乙型肝炎病毒(HBV)生物活性的药理作用。但由于其半衰期短,在体内药物浓度持续时间短,在一定程度上影响了药效,增加药物的半衰期从而延长药物在体内的作用时间,对FNC治疗效果的提高有较大意义。 脂质体作为一种新型载药系统,具有缓释性、靶向性、降低药物毒性和提高药物稳定性等多重优势。将药物包载于脂质体中,可减少肾排泄和代谢而延长药物在血液中的滞留时间,使药物在体内缓慢释放,延长药物的作用时间,且将药物包载于脂质体中能明显降低药物的毒性。针对FNC的不足以及脂质体的优势,本课题制备了FNC脂质体,从而解决药物半衰期短的问题,延长药物在体内的作用时间,降低毒性及不良反应,提高药物的药效。本文以磷脂和胆固醇为主要膜材,以FNC为模型药物,制备了FNC脂质体,并考察了其体内外的性质。具体研究内容包括： 1.FNC体外分析方法的建立 建立了FNC的高效液相分析方法,且做了方法学验证,并选择了透析法进行包封率的测定,以高效液相法测定FNC脂质体包封率的方法。 2.FNC脂质体的制备 为了制备FNC脂质体,本课题首先考察了制备脂质体的几种方法对制备FNC脂质体的影响,确定逆向蒸发-冻融法制备FNC脂质体,然后对FNC脂质体的处方和制备工艺进行了单因素考察,得出药脂比、磷脂和胆固醇的质量比和水相体积是影响较大的因素,在此基础上以包封率、载药量及平均粒径为指标,采用星点设计对FNC脂质体处方及工艺进行了优化,得到了FNC脂质体制备的最优处方,在此基础上制备出FNC脂质体,FNC脂质体的包封率是42.75%,平均粒径为104.7nm,载药量为1.75%。 3.FNC脂质体的药剂学性质、体外质量评价和稳定性考察 按照最优处方制备了FNC脂质体,对其药剂学性质进行了考察,结果显示FNC脂质体呈均匀类球形,平均粒径是104.7±44.46nm, Zeta电位为-30.7±6.03mv,在体外释放减慢,其释放行为符合Riger-Peppas的释放模型。 4.FNC脂质体的药物动力学研究 以大鼠为研究对象,对FNC脂质体和FNC溶液剂的药物动力学进行对比研究。采用高效液相-质谱联用技术测定大鼠血浆中FNC的含量,采用DAS2.0药动学软件对结果进行分析处理。结果表明：FNC脂质体和FNC溶液剂的体内动力学过程均符合二室模型,将FNC包封于脂质体中能明显改善其体内药动学行为,与自制的FNC溶液剂相比,T1/21β由3.354h延长到8.459h,MRT由4.467h延长到6.327h;AUC提高了近2倍,CL由0.224L/h/Kg减小到0.093L/h/Kg;表明FNC脂质体延长了FNC的作用时间具有缓释作用,使FNC能在体内较长时间维持较高的血药浓度,提高了药物生物利用度,从而提高了FNC的药效。
[Abstract]:FNC is a newly synthesized antiviral, anti-tumor nucleoside analogue. Pharmacodynamic study showed that FNC had the pharmacological effect of anti-HIV (HIV) and hepatitis B virus (HBV). However, because of its short half-life and short duration of drug concentration in vivo, the drug effect is affected to a certain extent, and the half-life of the drug is increased, thus prolonging the time of action of the drug in vivo, which is of great significance to the improvement of the therapeutic effect of FNC. As a new drug delivery system, liposomes have many advantages, such as slow release, targeting, reducing drug toxicity and improving drug stability. Encapsulating drugs in liposomes can reduce renal excretion and metabolism, prolong the retention time of drugs in the blood, slow release of drugs in the body, and prolong the time of action of drugs. Drug encapsulation in liposomes can significantly reduce the toxicity of the drug. In view of the deficiency of FNC and the advantage of liposome, the FNC liposomes were prepared in order to solve the problem of short half-life of drugs, prolong the time of action of drugs in vivo, reduce toxicity and adverse reactions, and improve the efficacy of drugs. In this paper, liposomes of FNC were prepared by using phospholipid and cholesterol as main membrane materials and FNC as model drug. The properties of liposomes in vitro and in vivo were investigated. The main contents of this study are as follows: the establishment of 1.FNC in vitro analysis method, the establishment of high performance liquid phase analysis method for FNC, the validation of methodology, and the selection of dialysis method for the determination of entrapment efficiency. The preparation of FNC liposomes in order to prepare FNC liposomes, the effects of several methods of preparing liposomes on the preparation of FNC liposomes were investigated. The preparation of FNC liposomes by reverse evaporation-freeze-thaw method was determined. The formulation and preparation process of FNC liposomes were investigated. The results showed that the ratio of liposomes to liposomes, the mass ratio of phospholipid to cholesterol and the volume of water phase were the most important factors. On the basis of this, the formulation and process of FNC liposome were optimized by star design with encapsulation efficiency, drug loading and average particle size as indexes, and the optimal formulation of FNC liposome was obtained. On this basis, the encapsulation efficiency of FNC liposome was 42.75, the average diameter was 104.7 nm, and the drug loading capacity was 1.75. The pharmacological properties of 3.FNC liposome were obtained. The FNC liposomes were prepared according to the optimal formulation. The pharmacological properties of the liposomes were investigated. The results showed that the FNC liposomes were homogeneous globular. The average particle size was 104.7 卤44.46 nm and the Zeta potential was -30.7 卤6.03mv.The release behavior of 4.FNC liposomes was in accordance with the release model of Riger-Peppas. The pharmacokinetics of 4.FNC liposomes was studied in rats. The pharmacokinetics of FNC liposome and FNC solution was studied. The content of FNC in rat plasma was determined by high performance liquid phase mass spectrometry and the results were analyzed by DAS2.0 pharmacokinetic software. The results showed that the pharmacokinetic process of FNC liposomes and FNC liposomes was in accordance with the two-compartment model. Encapsulation of FNC in liposomes could significantly improve the pharmacokinetic behavior of the liposomes. Compared with the self-made FNC solution, the T1 / 21 尾 was prolonged from 3.354 h to 8.459h, and the AUC increased from 4.467 h to 6.327h, and the CL decreased from 0.224L/h/Kg to 0.093 L / h / kg, indicating that the FNC liposome prolonged the action time of FNC with slow release. FNC can maintain high blood concentration in vivo for a long time, improve the bioavailability of FNC, and improve the efficacy of FNC.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943;R96
本文编号：2142586
[Abstract]:FNC is a newly synthesized antiviral, anti-tumor nucleoside analogue. Pharmacodynamic study showed that FNC had the pharmacological effect of anti-HIV (HIV) and hepatitis B virus (HBV). However, because of its short half-life and short duration of drug concentration in vivo, the drug effect is affected to a certain extent, and the half-life of the drug is increased, thus prolonging the time of action of the drug in vivo, which is of great significance to the improvement of the therapeutic effect of FNC. As a new drug delivery system, liposomes have many advantages, such as slow release, targeting, reducing drug toxicity and improving drug stability. Encapsulating drugs in liposomes can reduce renal excretion and metabolism, prolong the retention time of drugs in the blood, slow release of drugs in the body, and prolong the time of action of drugs. Drug encapsulation in liposomes can significantly reduce the toxicity of the drug. In view of the deficiency of FNC and the advantage of liposome, the FNC liposomes were prepared in order to solve the problem of short half-life of drugs, prolong the time of action of drugs in vivo, reduce toxicity and adverse reactions, and improve the efficacy of drugs. In this paper, liposomes of FNC were prepared by using phospholipid and cholesterol as main membrane materials and FNC as model drug. The properties of liposomes in vitro and in vivo were investigated. The main contents of this study are as follows: the establishment of 1.FNC in vitro analysis method, the establishment of high performance liquid phase analysis method for FNC, the validation of methodology, and the selection of dialysis method for the determination of entrapment efficiency. The preparation of FNC liposomes in order to prepare FNC liposomes, the effects of several methods of preparing liposomes on the preparation of FNC liposomes were investigated. The preparation of FNC liposomes by reverse evaporation-freeze-thaw method was determined. The formulation and preparation process of FNC liposomes were investigated. The results showed that the ratio of liposomes to liposomes, the mass ratio of phospholipid to cholesterol and the volume of water phase were the most important factors. On the basis of this, the formulation and process of FNC liposome were optimized by star design with encapsulation efficiency, drug loading and average particle size as indexes, and the optimal formulation of FNC liposome was obtained. On this basis, the encapsulation efficiency of FNC liposome was 42.75, the average diameter was 104.7 nm, and the drug loading capacity was 1.75. The pharmacological properties of 3.FNC liposome were obtained. The FNC liposomes were prepared according to the optimal formulation. The pharmacological properties of the liposomes were investigated. The results showed that the FNC liposomes were homogeneous globular. The average particle size was 104.7 卤44.46 nm and the Zeta potential was -30.7 卤6.03mv.The release behavior of 4.FNC liposomes was in accordance with the release model of Riger-Peppas. The pharmacokinetics of 4.FNC liposomes was studied in rats. The pharmacokinetics of FNC liposome and FNC solution was studied. The content of FNC in rat plasma was determined by high performance liquid phase mass spectrometry and the results were analyzed by DAS2.0 pharmacokinetic software. The results showed that the pharmacokinetic process of FNC liposomes and FNC liposomes was in accordance with the two-compartment model. Encapsulation of FNC in liposomes could significantly improve the pharmacokinetic behavior of the liposomes. Compared with the self-made FNC solution, the T1 / 21 尾 was prolonged from 3.354 h to 8.459h, and the AUC increased from 4.467 h to 6.327h, and the CL decreased from 0.224L/h/Kg to 0.093 L / h / kg, indicating that the FNC liposome prolonged the action time of FNC with slow release. FNC can maintain high blood concentration in vivo for a long time, improve the bioavailability of FNC, and improve the efficacy of FNC.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943;R96
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