本文選題：均勻設(shè)計(jì)　切入點(diǎn)：硝酸益康唑　出處：《河南大學(xué)》2011年碩士論文

【摘要】：目的均勻設(shè)計(jì)法優(yōu)化制備硝酸益康唑納米粒滴眼液并測(cè)定其粒徑、電荷、包封率及載藥量等基本性質(zhì);高效液相法檢測(cè)硝酸益康唑納米粒滴眼液應(yīng)用兔眼后房水和角膜中的藥物濃度變化并分析其藥代動(dòng)力學(xué)特征。 方法單因素初選制備條件,測(cè)定硝酸益康唑納米粒膠體液在自然光、避光、暴露于空氣中及60℃真空干燥5小時(shí)后的吸光度,分析其不同制備環(huán)境下納米粒的穩(wěn)定性;用純化水與PBS緩沖液超濾稀釋納米粒,比較兩者對(duì)粒徑和電荷的影響,在納米粒中添加透明質(zhì)酸鈉,聚乙烯醇,甘油,聚乙二醇,考察不同輔料添加下納米粒粒徑和電荷的變化,在PH值等于5.00和7.50之間考察納米粒粒徑和電荷,確定合適的酸堿度。在6個(gè)因素8個(gè)水平下制定均勻設(shè)計(jì)表,將測(cè)試結(jié)果綜合評(píng)分,總分與影響因素多元線性回歸,按回歸方程確定制備條件并描述均勻設(shè)計(jì)法優(yōu)選工藝下制備的硝酸益康唑納米粒滴眼液的外觀形態(tài)、電鏡、粒徑、電荷、包封率和載藥量。取健康無(wú)眼疾白色日本長(zhǎng)耳兔,隨機(jī)分成納米粒組和混懸液組,將用Vivaflow 50超濾器濃縮的0.3%硝酸益康唑納米粒滴眼液作為試驗(yàn)藥物,0.3%硝酸益康唑混懸液作為對(duì)照藥物。在單劑量組中:試驗(yàn)藥物和對(duì)照藥物分別單次50μl滴于兔眼,在突擊劑量組中:試驗(yàn)藥物和對(duì)照藥物每次50μl滴于兔眼,連續(xù)3次,每次間隔3min;均于最后一次給藥后在5min、15min、30min、45min、60min、90min、120min、180min、240min和300min 10個(gè)時(shí)間點(diǎn)抽取房水,剖取角膜組織。樣品處理后,采用反相高效液相色譜法(RP-HPLC)測(cè)定樣品組織中益康唑的濃度,比較不同時(shí)間點(diǎn)兔眼房水和角膜的藥物濃度變化和經(jīng)時(shí)過(guò)程,分析其藥代動(dòng)力學(xué)特征,藥動(dòng)學(xué)參數(shù)處理采用3p97藥動(dòng)學(xué)軟件。 結(jié)果均勻設(shè)計(jì)法優(yōu)選制備的ECZ-RS100-NP滴眼液外觀呈現(xiàn)淡藍(lán)色乳光,電鏡照片顯示顆粒分散均勻一致,所得粒徑為50.47nm,電荷為+31.04mV。包封率為87.63%,載藥量為25.18%。 在單劑量組中,房水中5min,角膜中5min、15min、30min、45min、60min、90min和120min時(shí)間點(diǎn)納米粒滴眼液組藥物濃度均高于對(duì)照組,且兩者比較具有顯著性差異(P0.01)。在突擊劑量組,房水在5 min、15 min、30 min、45 min和120 min時(shí)間點(diǎn),角膜在時(shí)間點(diǎn)5 min,15 min,30 min納米粒滴眼液組藥物濃度均高于對(duì)照組,且兩者比較具有顯著性差異(P0.01或P0.05)。 在房水中,單劑量點(diǎn)眼后實(shí)驗(yàn)組和對(duì)照組的達(dá)峰時(shí)間T_(max)分別為5.0min和60min,實(shí)驗(yàn)組和對(duì)照組的半衰期t1/2分別為47.38min和51.95min,在0-300min的藥物濃度-時(shí)間曲線下面積(AUC)分別為10.76(μg/ml)·min和86.47(μg/ml)·min。突擊劑量點(diǎn)眼后實(shí)驗(yàn)組和對(duì)照組的達(dá)峰時(shí)間T_(max)均為45.0min,實(shí)驗(yàn)組和對(duì)照組的半衰期t1/2分別為91.54min和150.35min,在0-300min的藥物濃度-時(shí)間曲線下面積(AUC)分別為87.89(μg/ml)·min和241.74(μg/ml)·min。 在角膜中,單劑量點(diǎn)眼后實(shí)驗(yàn)組和對(duì)照組的達(dá)峰時(shí)間T_(max)均為5min;達(dá)峰濃度分別為:28.18μg/g和22.09μg/g;半衰期t1/2分別為44.68min和30.55min,在0-300min的藥物濃度-時(shí)間曲線下面積(AUC)分別為555.48(μg/mg)·min和830.96(μg/mg)·min,突擊劑量點(diǎn)眼后實(shí)驗(yàn)組和對(duì)照組的達(dá)峰時(shí)間T_(max)分別為30min和45min;達(dá)峰濃度分別為:31.73μg/g和28.44μg/g;半衰期t1/2分別為58.26min和57.79min,在0-300min的藥物濃度-時(shí)間曲線下面積(AUC)分別為2162.13 (μg/mg)·min和2446.27 (μg/mg)·min。結(jié)論均勻設(shè)計(jì)法安排實(shí)驗(yàn)科學(xué)、合理、有效,所優(yōu)選制備的硝酸益康唑納米粒滴眼液粒徑較小,Zeta電位較高,包封率和載藥量均理想。單劑量組兔眼角膜檢測(cè)出的益康唑濃度比較,試驗(yàn)藥物組濃度較高,,突擊劑量組,在45min前,試驗(yàn)組房水中的濃度高于對(duì)照組,角膜中的濃度在15min前高于對(duì)照組。硝酸益康唑納米粒滴眼液具有較大的眼部應(yīng)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.

【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2011
【分類號(hào)】：R96

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