P1-修饰微乳液相色谱高通量测定药物亲脂性的研究

发布时间：2018-10-15 14:18

【摘要】：目的在本研究中，将P1和微乳结合作为流动相，使在流动相和固定相上引入P1分子，建立新的生物分配高效液相色谱，用于高通量筛选药物亲脂性和模拟药物与生物膜的相互作用。本研究建立的P1修饰微乳液相色谱利用logk建立模型预测logP（正辛醇/水分配系数的对数，用于描述化合物亲脂性），并且应用于电离和不电离药物亲脂性研究中。除了药物亲脂性，本研究还将利用P1修饰微乳液相色谱模拟药物通过血脑屏障的过程，利用logk建立模型预测logBB。研究方法 1. P1用量和表面活性剂类型的确定通过测定不同P1含量的P1修饰微乳溶液的相对粘度（25℃）和紫外吸收，选择相对粘度小的且P1含量多的体系，并且紫外吸收要弱，这样才符合液相色谱流动相的要求。 2.引入P1的微乳组成的筛选在引入P1前，要得到最佳的微乳组成。配制多种不同组成的微乳液相色谱流动相，通过logk-logP的相关性分析，选择相关性大的微乳组成作为用于引入P1的条件。 3. P1修饰微乳液相色谱的建立将P1引入最佳微乳条件，初步建立P1修饰微乳液相色谱。考察此色谱体系的稳定性和重现性。通过线性溶剂化方程描述分析物分子与色谱体系间的相互作用，用欧氏距离和主成分分析评价此色谱体系，并与文献报道的体系比较预测logP的能力。 4. P1修饰微乳液相色谱预测logP模型的建立在P1修饰微乳液相色谱体系条件下，建立logk-logP模型，并引入分子结构参数，，提高模型预测logP的能力。 5. P1修饰微乳液相色谱的优化在初步获得的P1修饰微乳液相色谱条件下，对其进行优化，并制备P1修饰微乳柱系统。通过logk-logP相关性分析评价优化的结果。 6.电离和不电离分析物在P1修饰微乳液相色谱的应用将优化后得到的P1修饰微乳液相色谱体系应用于电离和不电离分析物，建立预测药物亲脂性模型。比较logk-logP与logk-logD的相关性结果，并通过logk值的主成分分析将本研究所得体系与文献报道体系进行比较。 7. P1修饰微乳液相色谱预测logBB模型的建立在最佳P1修饰微乳液相色谱体系下，建立logk-logBB模型，并引入分子结构参数，提高模型预测logBB的能力。成果和结论通过确定P1用量、表面活性剂类型和筛选微乳组成实验和数据分析，初步建立P1修饰微乳液相色谱系统（流动相组成为0.08%P1-3.0%SDS-6.0%正丁醇-0.8%乙酸乙酯-90.2%水），并获得好的稳定性和重现性。线性溶剂化方程指出溶质体积和氢键碱度对分析物保留影响最大。通过欧氏距离和主成分分析证明此体系与正辛醇/水体系性质相似，可用于预测logP。建立logk-logP模型（R2=0.797），但通过逐步回归引入了摩尔体积（MV）参数至模型后，使得模型的预测能力有明显的提高(logP=2.168logkMP12+0.003MV+1.551, R2=0.856)。将初步获得的P1修饰微乳液相色谱流动相优化后，获得最佳流动相组成为0.2%P1-3.0%SDS-6.0%正丁醇-0.8%乙酸乙酯-90.0%水。P1修饰微乳柱色谱的logk-logP线性关系较差，预测logP能力弱。将优化后得到的P1修饰微乳液相色谱体系应用于电离和不电离分析物，比较发现logk-logD的相关性（logD7.0=2.030logkMP9+1.796, R2=0.673）比logk-logP好。通过与其他文献体系比较，P1修饰微乳液相色谱体系有好的预测logD能力。在最佳P1修饰微乳液相色谱体系下，建立logk-logBB模型，发现logk与logBB没有明显的线性关系，但将摩尔分子量（MW）大于250的药物剔除后，logk-logBB线性关系有明显的提高（R2=0.612），且在此基础上引入参数（MW），能获得好的预测logBB模型（logBB=0.347logk-0.002MW+0.352, R2=0.793）。
[Abstract]:Purpose In this study, P1 and microemulsion are combined as mobile phases, P1 molecules are introduced into the mobile phase and the stationary phase, and new biodistribution high performance liquid chromatography is established for high-throughput screening of drug lipophilic and simulated drugs and biofilm The P1 modified microemulsion chromatography established in this study uses the logk set up model to predict logP (the log of n-octanol/ water distribution coefficients for describing the lipophilic nature of the compound) and is applied to both ionization and non-ionization drug lipophilic research. in addition to that lipophilic nature of the drug, the study will use P1 to modify the microemulsion chromatography to simulate the process of the drug through the blood-brain barrier, and use the logk to establish the model prediction log. BB. Study Method 1. P1 Usage and Table Determination of surfactant type by measuring the relative viscosity (25.degree. C.) and ultraviolet absorption of P1-modified microemulsion solution with different P1 contents, with a relatively low viscosity and a higher P1 content. the system, and the ultraviolet absorption is weak, Requirements for liquid chromatography mobile phase. 2. Screening of Microemulsion Composition with P1 Before the introduction of P1, the optimal microemulsion composition was obtained. A variety of different compositions of microemulsion chromatography mobile phase were prepared. The correlation analysis of logk-logP was used to select the correlation. Large micro-emulsion composition as used for the introduction of P1 Conditions. 3. P1 Modified Microemulsion Gas Chromatography Establishment of P1 The optimal microemulsion condition was introduced, and P1 repair was initially established. The stability and reproducibility of the chromatographic system were investigated by gas chromatography. The interaction between the analyte molecules and the chromatographic system was described by the linear solvation equation. The chromatogram was evaluated by Euclidean distance and principal component analysis. The ability of logP to be compared with the system reported by the literature. 4.P1 Modified microemulsion chromatography to predict logP model was established under the condition of P1 modified microemulsion chromatography system, and logk-l was established. ogp model and the introduction of molecular structure parameters to improve the ability of the model to predict logp. 1, optimizing the micro-emulsion chromatographic conditions and preparing P 1. Modified micro-emulsion column system. Through logk-logP correlation analysis The results of evaluation optimization. 6. The application of ionization and non-ionization analytes in P1-modified microemulsion chromatography will be optimized. The P1 modified microemulsion chromatography system was applied to ionization and non-ionization analytes to establish a predicted drug lipophilic model. The phase of logk-logP and logk-logD was compared. Pass the results and analyze the study by the principal component analysis of the logk value A comparison was made between the system and the literature reporting system. 7. P1 modified microemulsion chromatography to predict the logBB model was established in the best P1 modified microemulsion phase color. under the spectrum system, The logk-logBB model was established and the molecular structure parameters were introduced to improve the ability of the model to predict logBB. Results and conclusions were established by determining P1 dosage, surfactant type and screening micro-emulsion composition experiment and data analysis, and initially establishing P1-modified microemulsion chromatography system (mobile phase composition was 0. 0 8% P1-3.0% SDS-6.0% n-butanol-0.8% ethyl acetate-90. 2% water) and good stability and reproducibility. Linear solvation equation indicates solute volume and hydrogen bond alkalinity It is proved that this system is similar to that of n-octanol/ water system by Euclidean distance and principal component analysis. It can be used to predict logP. The log-log P model (R2 = 0. 044) is established, but Moore volume (MV) parameter is introduced into the model by stepwise regression, so that the model can be predicted. There was a significant increase in the force (logP = 2.168logkMP12 + 0.003MV + 1.551, R2 = 0.9856). The optimum flow phase was 0.2% P1-3.0% SDS-6.0% n-butanol-0. 8% ethyl acetate-90. 0% water. The log-log P linear relation of P1 modified microemulsion column chromatography was poor, and the prediction log P was weak. The P1 modified microemulsion chromatography system obtained after optimization was applied to ionization and non-ionization analysis to find the phase of logk-logD. Off (logD7. 0 = 2. 030logkMP9 + 1. 796, R2 = 0. 6 73) It is better than logk-logP. By comparison with other literature systems, P1-modified microemulsion chromatography system has good predictive logD ability. Under the optimum P1 modified microemulsion chromatography system, the logk-logBB model is established. It is found that logk does not have a significant linear relationship with logBB, but the molar molecular weight (MW) is greater than 250. The linear relationship between logk-logBB and logk-logBB is obviously improved (R2 = 0.9612), and the parameters (MW) are introduced on this basis, which can be obtained.
【学位授予单位】：广东药学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R927

【参考文献】