Nifeviroc和F18复合微乳凝胶阴道杀微生物剂的临床前应用研究

发布时间：2018-05-20 02:19

本文选题：高效液相色谱法 + 尼非韦罗　；参考：《南京大学》2013年硕士论文

【摘要】：F18是calanolide A(吡喃型香豆素类化合物)的含氯衍生物,作为一种新型的艾滋病毒非核苷类逆转录酶抑制剂(NNTIs),正处于相关临床研究中；尼非韦罗为合成的小分子CCR5(人CC趋化因子受体5)拮抗剂,具有良好的抑制HIV-1感染的效果,其已经作为杀微生物剂在中国完成了临床前研究,申请进行人体临床试验。通过两个或者两个以上药物混合起来的杀微生物剂被认为将有效提高阻断HIV-1性传播的效率,从而降低传播率。尼非韦罗是有效的CCR5侵入抑制剂,而F18能高效抑制病毒的逆转录,二者有望在抗感染上形成良好的互补,配伍为复合杀微生物剂。但是F18和尼非韦罗都具有水溶性差的特点(溶解度都小于100μg·ml-1).本文旨在研究增溶剂Solutol HS15同时溶解F18和尼非韦罗的药剂学分析,同时探索液相条件使之能够有效的区分这两种化合物。用十八烷基硅烷键合硅胶为填充剂(4.60 *250mm,5μm);采用甲醇(A相)-复方醋酸缓冲液(B相,pH 4.5)为洗脱系统流动相。A相和B相比例为65：35,流速为1m1·min-1。检测波长为272nm,柱温为30度,进样量为20μ1。相邻两峰的分离度不小于1.5。对F18和尼非韦罗的微乳以及凝胶的相关性质进行基本的分析,研究结果初步显示混和微乳凝胶有良好的稳定性和体外实验毒性,3mg/ml的体外毒性仍在轻微刺激的范围内,所形成的的复合微乳的微乳区域也满足了稳定性的要求,复合微乳各组分的比例为表面活性剂：助表面活性剂：油相：水相=35：15：40：10。本研究为复合微乳凝胶的应用提供一个全新的可行性方案,研究出一个相对稳定的复合微乳制剂原型,为后续的研究奠定基础。
[Abstract]:F18 is a chlorinated derivative of calanolide A, a novel inhibitor of HIV non-nucleoside reverse transcriptase, which is currently in clinical study. As a synthetic antagonist of small molecule CCR5 (human CC chemokine receptor 5), Nifeverol has a good inhibitory effect on HIV-1 infection. It has completed preclinical research as a microbicide in China and applied for human clinical trial. Microbicides combined with two or more drugs are considered to increase the efficiency of blocking HIV-1 sexual transmission and thus reduce the transmission rate. Nifeverol is an effective inhibitor of CCR5 invasion, while F18 can inhibit retrovirus effectively. They are expected to complement each other in anti-infection, and their compatibility is a compound microbicide. However, both F18 and Nifevero have the characteristics of poor water solubility (solubility less than 100 渭 g / ml ~ (-1). The aim of this paper is to study the pharmacological analysis of solubilization of F18 and nifeverol by Solutol HS15 and to explore the liquid phase conditions to distinguish the two compounds effectively. Octadecyl silane bonded silica gel was used as filler (4.60 ~ 250mm ~ (-1) 渭 m ~ (-1). The mobile phase, phase A and phase B were used as elution system. The ratio of phase A to phase B was 65: 35, and the flow rate was 1m1 min-1. The detection wavelength is 272 nm, the column temperature is 30 degrees, and the injection amount is 20 渭 1. The separation degree of the two adjacent peaks is not less than 1.5. The properties of F18 and Nifevero microemulsions and gel were analyzed. The results showed that the mixed microemulsion gel had good stability and in vitro toxicity of 3 mg / ml was still within the range of slight stimulation. The microemulsion region of the composite microemulsion also meets the requirements of stability. The proportion of each component of the composite microemulsion is surfactant: cosurfactant: oil phase: water phase 35: 15: 40: 10. This study provides a new feasible scheme for the application of composite microemulsion gel, and develops a relatively stable prototype of composite microemulsion preparation, which lays a foundation for further research.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.91

【共引文献】