本文選題：康普瑞汀脂肪酸酯 + 脂質(zhì)體　； 參考：《第二軍醫(yī)大學(xué)》2017年碩士論文

【摘要】：藥物的釋放對其療效的提高以及毒副作用的降低具有很大影響,特別是母藥從前藥中的釋放或者轉(zhuǎn)化對其活性藥物的藥效發(fā)揮有著至關(guān)重要的作用。本研究選擇新型抗腫瘤藥物康普瑞汀(Combretastatin A4,CA4)作為模型藥物,通過將其制成一系列前藥,來研究前藥的釋放或轉(zhuǎn)化速率對其活性藥物體內(nèi)外性質(zhì)的影響,從而為篩選出可以提高康普瑞汀抗腫瘤活性的前藥制劑打下基礎(chǔ)。本文研究內(nèi)容分為五個(gè)部分:(1)康普瑞汀脂肪酸酯的合成與處方前研究,包括康普瑞汀不同鏈長脂肪酸酯化合物的合成,采用不同方法對合成的化合物進(jìn)行結(jié)構(gòu)鑒定以及處方前研究;(2)康普瑞汀脂肪酸酯脂質(zhì)體的制備與表征,包括康普瑞汀脂肪酸酯脂質(zhì)體處方優(yōu)化以及脂質(zhì)體的釋放;(3)康普瑞汀脂肪酸酯脂質(zhì)體體外性質(zhì)研究,包括血漿中穩(wěn)定性和體外細(xì)胞毒性考查;(4)康普瑞汀脂肪酸酯脂質(zhì)體體內(nèi)藥代動(dòng)力學(xué)特征和組織分布研究;(5)康普瑞汀脂肪酸酯脂質(zhì)體體內(nèi)藥效學(xué)研究和安全性評價(jià)。第一部分,通過脂肪酰氯與康普瑞汀直接進(jìn)行一步酯化反應(yīng)生成康普瑞汀脂肪酸酯。通過低分辨質(zhì)譜、高分辨質(zhì)譜、核磁共振氫譜和核磁共振碳譜對合成的化合物進(jìn)行結(jié)構(gòu)鑒定,說明康普瑞汀脂肪酸酯成功合成。并且對康普瑞汀脂肪酸酯進(jìn)行處方前研究。第二部分,采用薄膜分散法制備康普瑞汀脂肪酸酯脂質(zhì)體,即康普瑞汀己酸酯脂質(zhì)體(CA4-6-L)、康普瑞汀癸酸酯脂質(zhì)體(CA4-10-L)、康普瑞汀肉豆蔻酸酯脂質(zhì)體(CA4-14-L)、康普瑞汀棕櫚酸酯脂質(zhì)體(CA4-16-L)、康普瑞汀硬酯酸酯脂質(zhì)體(CA4-6-L)。通過單因素實(shí)驗(yàn)考察不同DSPE-PEG2000、不同藥脂比和不同磷脂與膽固醇之比對康普瑞汀脂肪酸酯脂質(zhì)體粒徑、PDI、Zeta電位和包封率的影響,并篩選出最終處方為:DSPE-PEG2000用量為0.2%,磷脂與藥物之比為9:1,磷脂與膽固醇之比為9:1。通過反向透析法考察康普瑞汀脂質(zhì)體在體外的釋放行為,結(jié)果表明隨著修飾CA4的脂肪鏈的增長,前藥在體外釋放越緩慢。第三部分,首先考察康普瑞汀脂肪酸酯脂質(zhì)體在大鼠血漿中的穩(wěn)定性,即前藥轉(zhuǎn)化為母藥的速度,研究表明,在體外釋放越慢的康普瑞汀脂肪酸酯脂質(zhì)體在血漿中轉(zhuǎn)化為母藥的速度也越慢。其次通過CCK8法,對康普瑞汀脂肪酸酯脂質(zhì)體體外細(xì)胞毒性進(jìn)行考察,細(xì)胞毒性結(jié)果為CA4-6-LCA4-10-LCA4-14-LCA4-16-LCA4-18-L,即在體外釋放越慢,在血漿中轉(zhuǎn)化為母藥越慢,其體外細(xì)胞毒性越小。第四部分,采用HPLC分析CA4-6-L、CA4-10-L、CA4-18-L和CA4P大鼠體內(nèi)藥代動(dòng)力學(xué)特征,發(fā)現(xiàn)活性藥物釋放慢的CA4-18-L能夠延緩活性藥物CA4的清除,而在體外釋放較快的康普瑞汀脂肪酸酯脂質(zhì)體在體內(nèi)則極易被清除。與其他給藥組相比,CA4-18-L能夠極大的增加CA4的T1/2和AUC,T1/2是其他組的2-4倍,AUC約是其他組的9倍。建立荷S180昆明小鼠模型,評價(jià)CA4-10-L、CA4-18-L和CA4P在體內(nèi)的分布情況,表明CA4-18-L可以增加CA4腫瘤部位的藥物濃度。第五部分,首先對CA4P溶液、CA4-10-L和CA4-18-L在荷瘤昆明小鼠體內(nèi)抗腫瘤活性進(jìn)行研究,結(jié)果顯示在相同劑量下CA4P溶液、CA4-10-L和CA4-18-L的抑瘤率分別為57.87%,43.06%和94.44%,進(jìn)一步證明藥物的釋放、以及母藥從前藥中的釋放對藥物的體內(nèi)性質(zhì)有顯著影響,釋放慢的藥物,體內(nèi)滯留時(shí)間長,體內(nèi)藥效好。其次也發(fā)現(xiàn)CA4-18-L的體內(nèi)藥效顯著好于正處于臨床研究的CA4P。另外考察了CA4-18-L的體外溶血性和刺激性,結(jié)果顯示CA4-18-L未出現(xiàn)溶血現(xiàn)象和刺激性反應(yīng)。
[Abstract]:The release of drugs has a great effect on the improvement of its efficacy and the decrease in side effects, especially the release or transformation of the maternal antidrug to its active drug effect. This study chose the new antitumor drug Combretastatin A4 (CA4) as a model drug and made it by making it. A series of prodrugs to study the effect of the release or transformation rate of the prodrug on the internal and external properties of its active drug, which is the basis for screening the antineoplastic agents that can improve the antineoplastic activity of coprine. This study is divided into five parts: (1) the synthesis and pre prescription study of the fatty acid esters of coprine, including the different coprine Synthesis of chain long fatty acid esters, structural identification of synthetic compounds and pre formulation studies by different methods; (2) preparation and characterization of coprine fatty acid ester liposomes, including optimization of liposome formulation and release of liposomes; (3) in vitro research on the liposomes of coprine fatty acid ester liposomes It includes plasma stability and cytotoxicity in vitro; (4) pharmacokinetic characteristics and tissue distribution of corpine liposome in liposomes; (5) pharmacodynamic study and safety evaluation of corpine liposome in vivo. The first part is a direct esterification of fatty acid chloride and corprine. The synthesis of compound was identified by low resolution mass spectrometry, high resolution mass spectrometry, nuclear magnetic resonance and magnetic resonance carbon spectroscopy. The successful synthesis of kangpristin fatty acid ester. And the pre - prescription study of the kangpristin fatty acid ester. Second parts were prepared by thin film dispersion method. Ester liposomes, namely, CA4-6-L, CA4-10-L, CA4-10-L, CA4-14-L, CA4-10-L, and CA4-6-L liposome of connecticuline palmitate (CA4-6-L). The effects of different phospholipids and cholesterol on the particle size, PDI, Zeta potential and encapsulation efficiency of the liposome liposome were compared, and the final prescription was selected as: the dosage of DSPE-PEG2000 was 0.2%, the ratio of phospholipid to drug was 9:1, and the ratio of phospholipid to cholesterol was 9:1. through reverse dialysis to investigate the release behavior of the liposome in vitro. The results show that the release of the prodrug in vitro is slower with the increase of the fat chain of the modified CA4. The third part, first inspects the stability of the liposome in the rat plasma, that is, the rate of the prodrug conversion into the mother drug. The study shows that the slower the release of the liposome of the propretine fatty acid ester in vitro is converted into a mother drug in the plasma. The slower the cytotoxicity of the liposome in vitro was examined by the CCK8 method. The cytotoxicity of the liposomes was CA4-6-LCA4-10-LCA4-14-LCA4-16-LCA4-18-L, the slower the release in vitro, the slower the plasma in the plasma, the smaller the cytotoxicity in vitro. The fourth part, using HPLC to analyze CA4-6-L, CA4-10-L The pharmacokinetic characteristics of CA4-18-L and CA4P rats showed that the slow release of CA4-18-L from the active drug delayed the removal of the active drug CA4, while the fast releasing conopertin fatty acid ester liposomes were easily removed in the body. Compared with other drug groups, CA4-18-L could greatly increase the T1/2 and AUC of CA4, T1/2 is the other. 2-4 times of the group, AUC is about 9 times that of the other groups. Establish a S180 Kunming mouse model, evaluate the distribution of CA4-10-L, CA4-18-L and CA4P in the body, indicating that CA4-18-L can increase the concentration of drug in the CA4 tumor site. Fifth, first of all, CA4P solution, CA4-10-L and CA4-18-L in the tumor bearing Kunming mice anti-tumor activity in the body, the results showed that The inhibition rates of CA4P solution at the same dose, CA4-10-L and CA4-18-L were 57.87%, 43.06% and 94.44%, respectively. The release of drugs was further demonstrated, and the release of the drug in the maternal drug had a significant effect on the properties of the drug in vivo, the slow release of the drug, the long retention time in the body and the good efficacy in the body. Secondly, the efficacy of CA4-18-L in vivo was also found. Yu Zheng, who was in the CA4P. clinical study, also examined the hemolysis and irritation of CA4-18-L in vitro. The results showed that CA4-18-L did not appear hemolysis and irritation.

【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943

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