FNC脂質(zhì)體的制備及藥物動力學(xué)研究
發(fā)布時間：2018-07-24 20:38
【摘要】：FNC是一種新合成的抗病毒、抗腫瘤的核苷類似物。藥效學(xué)研究發(fā)現(xiàn)FNC具有抗艾滋病毒(HIV)和乙型肝炎病毒(HBV)生物活性的藥理作用。但由于其半衰期短,在體內(nèi)藥物濃度持續(xù)時間短,在一定程度上影響了藥效,增加藥物的半衰期從而延長藥物在體內(nèi)的作用時間,對FNC治療效果的提高有較大意義。 脂質(zhì)體作為一種新型載藥系統(tǒng),具有緩釋性、靶向性、降低藥物毒性和提高藥物穩(wěn)定性等多重優(yōu)勢。將藥物包載于脂質(zhì)體中,可減少腎排泄和代謝而延長藥物在血液中的滯留時間,使藥物在體內(nèi)緩慢釋放,延長藥物的作用時間,且將藥物包載于脂質(zhì)體中能明顯降低藥物的毒性。針對FNC的不足以及脂質(zhì)體的優(yōu)勢,本課題制備了FNC脂質(zhì)體,從而解決藥物半衰期短的問題,延長藥物在體內(nèi)的作用時間,降低毒性及不良反應(yīng),提高藥物的藥效。本文以磷脂和膽固醇為主要膜材,以FNC為模型藥物,制備了FNC脂質(zhì)體,并考察了其體內(nèi)外的性質(zhì)。具體研究內(nèi)容包括： 1.FNC體外分析方法的建立 建立了FNC的高效液相分析方法,且做了方法學(xué)驗(yàn)證,并選擇了透析法進(jìn)行包封率的測定,以高效液相法測定FNC脂質(zhì)體包封率的方法。 2.FNC脂質(zhì)體的制備 為了制備FNC脂質(zhì)體,本課題首先考察了制備脂質(zhì)體的幾種方法對制備FNC脂質(zhì)體的影響,確定逆向蒸發(fā)-凍融法制備FNC脂質(zhì)體,然后對FNC脂質(zhì)體的處方和制備工藝進(jìn)行了單因素考察,得出藥脂比、磷脂和膽固醇的質(zhì)量比和水相體積是影響較大的因素,在此基礎(chǔ)上以包封率、載藥量及平均粒徑為指標(biāo),采用星點(diǎn)設(shè)計(jì)對FNC脂質(zhì)體處方及工藝進(jìn)行了優(yōu)化,得到了FNC脂質(zhì)體制備的最優(yōu)處方,在此基礎(chǔ)上制備出FNC脂質(zhì)體,FNC脂質(zhì)體的包封率是42.75%,平均粒徑為104.7nm,載藥量為1.75%。 3.FNC脂質(zhì)體的藥劑學(xué)性質(zhì)、體外質(zhì)量評價和穩(wěn)定性考察 按照最優(yōu)處方制備了FNC脂質(zhì)體,對其藥劑學(xué)性質(zhì)進(jìn)行了考察,結(jié)果顯示FNC脂質(zhì)體呈均勻類球形,平均粒徑是104.7±44.46nm, Zeta電位為-30.7±6.03mv,在體外釋放減慢,其釋放行為符合Riger-Peppas的釋放模型。 4.FNC脂質(zhì)體的藥物動力學(xué)研究 以大鼠為研究對象,對FNC脂質(zhì)體和FNC溶液劑的藥物動力學(xué)進(jìn)行對比研究。采用高效液相-質(zhì)譜聯(lián)用技術(shù)測定大鼠血漿中FNC的含量,采用DAS2.0藥動學(xué)軟件對結(jié)果進(jìn)行分析處理。結(jié)果表明：FNC脂質(zhì)體和FNC溶液劑的體內(nèi)動力學(xué)過程均符合二室模型,將FNC包封于脂質(zhì)體中能明顯改善其體內(nèi)藥動學(xué)行為,與自制的FNC溶液劑相比,T1/21β由3.354h延長到8.459h,MRT由4.467h延長到6.327h;AUC提高了近2倍,CL由0.224L/h/Kg減小到0.093L/h/Kg;表明FNC脂質(zhì)體延長了FNC的作用時間具有緩釋作用,使FNC能在體內(nèi)較長時間維持較高的血藥濃度,提高了藥物生物利用度,從而提高了FNC的藥效。
[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 鹵44.46 nm and the Zeta potential was -30.7 鹵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.
【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943;R96
本文編號：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 鹵44.46 nm and the Zeta potential was -30.7 鹵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.
【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943;R96
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