均匀设计法制备硝酸益康唑纳米粒滴眼液及应用兔眼后的药代动力学研究

发布时间：2018-04-01 00:05

本文选题：均匀设计　切入点：硝酸益康唑　出处：《河南大学》2011年硕士论文

【摘要】：目的均匀设计法优化制备硝酸益康唑纳米粒滴眼液并测定其粒径、电荷、包封率及载药量等基本性质;高效液相法检测硝酸益康唑纳米粒滴眼液应用兔眼后房水和角膜中的药物浓度变化并分析其药代动力学特征。方法单因素初选制备条件,测定硝酸益康唑纳米粒胶体液在自然光、避光、暴露于空气中及60℃真空干燥5小时后的吸光度,分析其不同制备环境下纳米粒的稳定性;用纯化水与PBS缓冲液超滤稀释纳米粒,比较两者对粒径和电荷的影响,在纳米粒中添加透明质酸钠,聚乙烯醇,甘油,聚乙二醇,考察不同辅料添加下纳米粒粒径和电荷的变化,在PH值等于5.00和7.50之间考察纳米粒粒径和电荷,确定合适的酸碱度。在6个因素8个水平下制定均匀设计表,将测试结果综合评分,总分与影响因素多元线性回归,按回归方程确定制备条件并描述均匀设计法优选工艺下制备的硝酸益康唑纳米粒滴眼液的外观形态、电镜、粒径、电荷、包封率和载药量。取健康无眼疾白色日本长耳兔,随机分成纳米粒组和混悬液组,将用Vivaflow 50超滤器浓缩的0.3%硝酸益康唑纳米粒滴眼液作为试验药物,0.3%硝酸益康唑混悬液作为对照药物。在单剂量组中:试验药物和对照药物分别单次50μl滴于兔眼,在突击剂量组中:试验药物和对照药物每次50μl滴于兔眼,连续3次,每次间隔3min;均于最后一次给药后在5min、15min、30min、45min、60min、90min、120min、180min、240min和300min 10个时间点抽取房水,剖取角膜组织。样品处理后,采用反相高效液相色谱法(RP-HPLC)测定样品组织中益康唑的浓度,比较不同时间点兔眼房水和角膜的药物浓度变化和经时过程,分析其药代动力学特征,药动学参数处理采用3p97药动学软件。结果均匀设计法优选制备的ECZ-RS100-NP滴眼液外观呈现淡蓝色乳光,电镜照片显示颗粒分散均匀一致,所得粒径为50.47nm,电荷为+31.04mV。包封率为87.63%,载药量为25.18%。在单剂量组中,房水中5min,角膜中5min、15min、30min、45min、60min、90min和120min时间点纳米粒滴眼液组药物浓度均高于对照组,且两者比较具有显著性差异(P0.01)。在突击剂量组,房水在5 min、15 min、30 min、45 min和120 min时间点,角膜在时间点5 min,15 min,30 min纳米粒滴眼液组药物浓度均高于对照组,且两者比较具有显著性差异(P0.01或P0.05)。在房水中,单剂量点眼后实验组和对照组的达峰时间T_(max)分别为5.0min和60min,实验组和对照组的半衰期t1/2分别为47.38min和51.95min,在0-300min的药物浓度-时间曲线下面积(AUC)分别为10.76(μg/ml)·min和86.47(μg/ml)·min。突击剂量点眼后实验组和对照组的达峰时间T_(max)均为45.0min,实验组和对照组的半衰期t1/2分别为91.54min和150.35min,在0-300min的药物浓度-时间曲线下面积(AUC)分别为87.89(μg/ml)·min和241.74(μg/ml)·min。在角膜中,单剂量点眼后实验组和对照组的达峰时间T_(max)均为5min;达峰浓度分别为:28.18μg/g和22.09μg/g;半衰期t1/2分别为44.68min和30.55min,在0-300min的药物浓度-时间曲线下面积(AUC)分别为555.48(μg/mg)·min和830.96(μg/mg)·min,突击剂量点眼后实验组和对照组的达峰时间T_(max)分别为30min和45min;达峰浓度分别为:31.73μg/g和28.44μg/g;半衰期t1/2分别为58.26min和57.79min,在0-300min的药物浓度-时间曲线下面积(AUC)分别为2162.13 (μg/mg)·min和2446.27 (μg/mg)·min。结论均匀设计法安排实验科学、合理、有效,所优选制备的硝酸益康唑纳米粒滴眼液粒径较小,Zeta电位较高,包封率和载药量均理想。单剂量组兔眼角膜检测出的益康唑浓度比较,试验药物组浓度较高,,突击剂量组,在45min前,试验组房水中的浓度高于对照组,角膜中的浓度在15min前高于对照组。硝酸益康唑纳米粒滴眼液具有较大的眼部应用前景。
[Abstract]:The purpose of the uniform design method to optimize the preparation of econazole nitrate nanoparticles eye drops and determine the particle size, charge, encapsulation efficiency and drug loading and other basic properties; HPLC detection of econazole nitrate nanoparticles eyedrops application of rabbit after real concentrations of water and of the cornea and analyze its pharmacokinetics dynamic characteristics.
The primary method of single factor preparation conditions, determination of econazole nitrate Nanoparticles Colloids in natural light, light, was exposed to the air and vacuum drying at a temperature of 60 DEG C after 5 hours, the different preparation conditions of stability of nanoparticles; with purified water and PBS buffer dilution ultrafiltration nanoparticles, compared to grain size and charge the effects of adding sodium hyaluronate in nanoparticles, polyvinyl alcohol, glycerol, polyethylene glycol, the effects of different excipients added nano particle size and charge changes in pH value is equal to 5 and 7.50 to investigate the particle size and charge, determine the appropriate pH. Making the uniform design table in 8 level 6 a factor, the results of the test score, total score and the influence factors of multiple linear regression to determine the preparation conditions and describe the uniform design optimization process for preparation of econazole nitrate nanoparticles eye drops according to the regression equation Morphology, SEM, particle size, charge, encapsulation efficiency and drug loading. The healthy eye white Japanese long ear rabbits were randomly divided into nanoparticles group and suspension group, will use 0.3% of econazole nitrate Vivaflow 50 ultrafiltration concentrated conazole nanoparticle eyedrops as test drug, 0.3% ecz mixed suspension as a control drug. In single dose group: test drug and the control drug were administered 50 L drops in the rabbit eyes in loading dose group: an experimental drug and the control drug every 50 L drops in the rabbit eyes 3 times in a row, a time interval of 3min; at last after administration in 5min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240Min and 300min 10 time points from the real water, cut out the corneal tissue. The sample treated by reversed-phase high performance liquid chromatography (RP-HPLC). The ecz concentrations of the drug concentration at different time points in rabbits aqueous humor and corneal changes The pharmacokinetic characteristics were analyzed and the pharmacokinetic parameters were treated by 3P97 pharmacokinetic software.
Results the ECZ-RS100-NP eye drops prepared by uniform design showed the appearance of pale blue. The electron microscope images showed that the particles were uniformly distributed. The particle size was 50.47nm, the entrapment efficiency of +31.04mV. was 87.63%, and the drug loading was 25.18%..
In the single dose group, aqueous 5min, 15min, 30min in the corneal 5min, 45min, 60min, 90min and 120min time point nanoparticles eyedrop group concentration were higher than the control group, and both had significant differences (P0.01). In the assault group, the real water at 5 min, 15 min. 30 min, 45 min and 120 min time points, the cornea at time 5 min, 15 min, 30 min nanoparticles eyedrop group concentrations were higher than the control group, and both had significant differences (P0.01 or P0.05).
In real water, the peak time of T_ experimental group and control group in the single dose group (max) were 5.0min and 60min, the half-life of t1/2 experimental group and control group were 47.38min and 51.95min, in the area of drug concentration time profiles of 0-300min (AUC) were 10.76 (g/ml) and min 86.47 (g/ml) - min. T_ peak time of the experimental group and the control group loading dose group (max) was 45.0min, the half-life of t1/2 experimental group and control group were 91.54min and 150.35min, in the area of drug concentration time profiles of 0-300min (AUC) were 87.89 (g/ml) - min and 241.74 (g/ml) - min.
In the cornea, the peak time of T_ experimental group and control group in the single dose group (max) were 5min; peak concentrations were 28.18 g/g and 22.09 g/g 44.68min respectively; half-life of t1/2 and 30.55min, in the area of drug concentration time profiles of 0-300min (AUC) were 555.48 (g/mg - min) and 830.96 (g/mg) - min T_, assault the peak time of the experimental group and the control group dose group (max) were 30min and 45min; peak concentrations were 31.73 g/g and 28.44 g/g 58.26min respectively; half-life of t1/2 and 57.79min, in the area of drug time curve the concentration of 0-300min (AUC) were 2162.13 (g/mg) min and 2446.27 (g/mg) - min. conclusion uniform design experimental science, reasonable, effective, the optimized preparation of econazole nitrate nanoparticles eye drops has smaller particle size and higher Zeta potential, entrapment efficiency and drug loading ideal. The single dose group of rabbit eyes The concentration of econazole in the test group was higher than that in the control group. The concentration of the aqueous solution in the experimental group was higher than that in the control group before 45min. The concentration of cornea in 15min group was higher than that in the control group. Econazole nitrate nanoparticle eye drops had great potential for eye application.

【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R96

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