葛根素微乳的制备及生物利用度的研究
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摘要
葛根素(Puerarin)为豆科葛属植物葛根异黄酮的主要有效成分之一,临床疗效确切。因其在水中溶解度较低,口服生物利用度仅为3.779%;临床上主要将其溶解于1,2—丙二醇中制备注射剂,然而关于葛根素注射液临床应用不良反应的报道较多,因此研究高生物利用度口服葛根素微乳制剂具有重要意义。本课题以微乳为药物载体制备高载药量葛根素口服给药系统,通过前期组份筛选、相图制备确定微乳处方,以市售片剂为对照考察微乳中药物在不同介质中的溶出特征,采用Caco-2细胞模型考察微乳体系中药物转运特性,动物体内考察葛根素微乳药物动力学特征并对制剂体内外相关性进行初步研究。
处方前研究中,建立了葛根素在甲醇—水,人工胃液、人工肠液和30%乙醇环境中的HPLC-UV含量测定方法并对方法进行系统评价,结果表明分析方法准确、灵敏、快速,符合测试要求。测定葛根素在不同表面活性剂、助表面活性剂和油相、水相中的溶解度,葛根素在油相中基本不溶;在不同pH水相中微溶,随pH上升溶解度增大;在Brij-96v中溶解度较大。对葛根素12h内在人工胃液和人工肠液中的稳定性进行考察,在考察时间范围内(12h),药物稳定性良好。
通过溶解度实验、处方配伍实验和伪三元相图的绘制,以乳化时间、色泽和粒径的大小为指标,筛选油相、表面活性剂、助表面活性剂的最佳搭配和处方配比。微乳的最佳处方确定为IPM(10%),Brij-96V(32.5%),Ethanol(32.5%),Water(25%)。葛根素在微乳中的溶解度最高可达77mg/ml,PUE-ME的粒径为(16.46±2.95)nm,自微乳化时间＜1 min。以市售片剂为对照,进行了葛根素的体外药物释放试验。在pH 1.2和pH 6.8两种介质中,葛根素微乳的体外释药速度和程度明显大于市售片剂,12h累积释药量达90%。同一处方在模拟肠液中的释药速度比在模拟胃液中稍快。在葛根素微乳体外释药机制的考察实验中,葛根素微乳在两种介质中的释药机制分别符合一级动力学和Ritger-peppas动力学方程。
Caco-2细胞模型的建立是通过细胞接种于Millicell插入式培养皿中,培养21天后,测定碱性磷酸酶活性、跨膜电阻、荧光素钠透过量以检验细胞的极化现象和致密程度验证细胞模型特性。以Caco-2细胞模型进行葛根素微乳制剂中药物的细胞摄取、跨膜转运的研究,结果表明微乳和微乳稀释液中葛根素的吸收、分泌和摄取均较对照组显著增加;P糖蛋白抑制剂—环孢菌素可抑制对照液和微乳液中葛根素在Caco-2细胞的分泌而对转运影响较小。
大鼠血浆中葛根素的测定采用UltimateXB-C18柱(250~*4.6,5μm),柱温:40℃,流动相:甲醇-水为22:78,检测波长:250nm,采用蛋白沉淀法处理血浆,在40～2000ng/ml的范围内线性关系良好(r~2=0.9986)。定量下限为40ng/ml,回收率和精密度符合生物样品的测定要求。方法可用于大鼠血浆中葛根素的含量测定和药动学研究。
SD大鼠分别以30mg/kg的剂量灌胃给予葛根素微乳,以葛根素原料药配制混悬液为对照,3P87软件计算药动学参数。微乳组口服给药后大鼠体内血药浓度和曲线下面积均显著增加,微乳组AUC是对照组的7.99±1.99倍,C_(max)约是对照组的7倍,T_(max)稍有推后。以Cmax/AUC评价药物的吸收速度,结果为微乳＞原料药。
Puerarin is a major effective ingredient extracted from the traditional Chinese medicine Ge-gen.It has been reported that puerarin exhibits many pharmacological effect of cardiact blood vascular diseases.It has poor solubility and totally only 3.799% of puerarin can be absorbed by oral administration.However its clinical applications have been hindered by its low solubility.Puerarin is currently solubilized in 50% 1,2-propanediol as clinincal formulation.But this method bring many adverse effects. So our purpose is to develop the formulation of microemulsion drug delivery system for Puerarin.The uptake and transport of Puerarin-Microemulsion in Caco-2 cells were investigated.Finally,the studies on pharmacokinetics of Pue-ME were determined.
The HPLC methods for in vitro analysis of puerarin were set up among methanol-water,0.1MHCL,PBS and ethanol-wter.The method was accuracy,sensitive and suitable for the determination of puerarin.The solubility of Puerarin in various vehicles was measured such as surfactant,cosurfactant,oilphase,aqueous media. Studies on stability of Puerarin were carried out in 0.1M HCL and PBS for 12h.
The optimum formulation of PUE-ME was screened by solubility experiments, compatibility tests and pseudo-ternary phase diagrams,with the time of formulating microemulsion,the consequence of visual examination and particle size as parameters. The optimum formulation was composed of IPM(10%),Brij-96V(32.5%),ethanol (32.5%) and water(25%).The particle diameter was(16.46±2.95)nm.The content of puerarin in the optimum formulation was 77.11mg/ml.Forming time less 1 min.The release of puerarin from microemulsion was significantly faster than that of the conventional tablet in simulated gastric and intestinal fluid.Results indicated that release of puerarin was more than 90%at 12h.Release in PBS was much faster than that in 0.1M HCL.Release profile of puerarin from tablet and microemulsion followed first-order kinetics and Ritger-peppas model,respectively.
Caco-2 cell monolayer model was established according to Caco-2 cell cultivated in millicell plate for 21d.The morphological and growth characters of the monolayer were examined.The polarization and compactification of the monolayer was determined by the alkaline phosphatase activity,transepithelial electrical resistance and apical-to-basolateral of sodium fluorescein across cell monolayer.The Caco-2 cell model was used to study the uptake,transport of Pue-ME.The effect of ME on the transport of drug was investigated.The results indicted that ME could significantly improve the uptake,transport and efflux kinetics of Puerarin(P＜0.05),especially when ME was diluted.In the presence of CsA,potent inhibitors of P-glycoprotein,P_(appAP-BL) /P_(appBL-AP) ratio was decreased in ME but have no effectent on transport.
A specific and accurate HPLC method was developed for the determination of puerarin in SD rats plasma.Puerarin was extracted by protein precipitation and then the supematant was injected into a UltimateXB-C18 column(250×4.6mm,5μm).The detection wavelength was set at 250nm and the mobile phase consisted of methanol: water(22:78) at a flow rate of 1.0ml/min.The blank plasma had no interference on the determination of puerarin.A good linear relationship was obtained between the peak area of puerarin and the concentration of puerarin over the range of 40 to 2000 ng/ml. The LLOQ was 40ng/ml and the total chromatographic analysis time was within 10 min. The method is precise and fast for the determination of puerarin in plasma after oral administration of Pue-ME to healthy SD rats.
The pharmacokinetic parameters of Puerarin in suspension and dilusion-ME were investigated after oral administration to rats at a single dose of 30mg/kg.The date was disposed using the program 3P87.The C_(max) of purerarin from D-ME is greater than that of the puerarin suspension.The AUC_(0.24h) of puerarin from D-ME is about 7-fold higher than that of puerarin from suspension.Compared with the puerarin suspension,the relative bioavailability of D-ME was 783%.The D-Me possessed later Tmax.This study suggested that the oral bioavaiability of Pue ME was greater than Pue suspension.
处方前研究中,建立了葛根素在甲醇—水,人工胃液、人工肠液和30%乙醇环境中的HPLC-UV含量测定方法并对方法进行系统评价,结果表明分析方法准确、灵敏、快速,符合测试要求。测定葛根素在不同表面活性剂、助表面活性剂和油相、水相中的溶解度,葛根素在油相中基本不溶;在不同pH水相中微溶,随pH上升溶解度增大;在Brij-96v中溶解度较大。对葛根素12h内在人工胃液和人工肠液中的稳定性进行考察,在考察时间范围内(12h),药物稳定性良好。
通过溶解度实验、处方配伍实验和伪三元相图的绘制,以乳化时间、色泽和粒径的大小为指标,筛选油相、表面活性剂、助表面活性剂的最佳搭配和处方配比。微乳的最佳处方确定为IPM(10%),Brij-96V(32.5%),Ethanol(32.5%),Water(25%)。葛根素在微乳中的溶解度最高可达77mg/ml,PUE-ME的粒径为(16.46±2.95)nm,自微乳化时间＜1 min。以市售片剂为对照,进行了葛根素的体外药物释放试验。在pH 1.2和pH 6.8两种介质中,葛根素微乳的体外释药速度和程度明显大于市售片剂,12h累积释药量达90%。同一处方在模拟肠液中的释药速度比在模拟胃液中稍快。在葛根素微乳体外释药机制的考察实验中,葛根素微乳在两种介质中的释药机制分别符合一级动力学和Ritger-peppas动力学方程。
Caco-2细胞模型的建立是通过细胞接种于Millicell插入式培养皿中,培养21天后,测定碱性磷酸酶活性、跨膜电阻、荧光素钠透过量以检验细胞的极化现象和致密程度验证细胞模型特性。以Caco-2细胞模型进行葛根素微乳制剂中药物的细胞摄取、跨膜转运的研究,结果表明微乳和微乳稀释液中葛根素的吸收、分泌和摄取均较对照组显著增加;P糖蛋白抑制剂—环孢菌素可抑制对照液和微乳液中葛根素在Caco-2细胞的分泌而对转运影响较小。
大鼠血浆中葛根素的测定采用UltimateXB-C18柱(250~*4.6,5μm),柱温:40℃,流动相:甲醇-水为22:78,检测波长:250nm,采用蛋白沉淀法处理血浆,在40～2000ng/ml的范围内线性关系良好(r~2=0.9986)。定量下限为40ng/ml,回收率和精密度符合生物样品的测定要求。方法可用于大鼠血浆中葛根素的含量测定和药动学研究。
SD大鼠分别以30mg/kg的剂量灌胃给予葛根素微乳,以葛根素原料药配制混悬液为对照,3P87软件计算药动学参数。微乳组口服给药后大鼠体内血药浓度和曲线下面积均显著增加,微乳组AUC是对照组的7.99±1.99倍,C_(max)约是对照组的7倍,T_(max)稍有推后。以Cmax/AUC评价药物的吸收速度,结果为微乳＞原料药。
Puerarin is a major effective ingredient extracted from the traditional Chinese medicine Ge-gen.It has been reported that puerarin exhibits many pharmacological effect of cardiact blood vascular diseases.It has poor solubility and totally only 3.799% of puerarin can be absorbed by oral administration.However its clinical applications have been hindered by its low solubility.Puerarin is currently solubilized in 50% 1,2-propanediol as clinincal formulation.But this method bring many adverse effects. So our purpose is to develop the formulation of microemulsion drug delivery system for Puerarin.The uptake and transport of Puerarin-Microemulsion in Caco-2 cells were investigated.Finally,the studies on pharmacokinetics of Pue-ME were determined.
The HPLC methods for in vitro analysis of puerarin were set up among methanol-water,0.1MHCL,PBS and ethanol-wter.The method was accuracy,sensitive and suitable for the determination of puerarin.The solubility of Puerarin in various vehicles was measured such as surfactant,cosurfactant,oilphase,aqueous media. Studies on stability of Puerarin were carried out in 0.1M HCL and PBS for 12h.
The optimum formulation of PUE-ME was screened by solubility experiments, compatibility tests and pseudo-ternary phase diagrams,with the time of formulating microemulsion,the consequence of visual examination and particle size as parameters. The optimum formulation was composed of IPM(10%),Brij-96V(32.5%),ethanol (32.5%) and water(25%).The particle diameter was(16.46±2.95)nm.The content of puerarin in the optimum formulation was 77.11mg/ml.Forming time less 1 min.The release of puerarin from microemulsion was significantly faster than that of the conventional tablet in simulated gastric and intestinal fluid.Results indicated that release of puerarin was more than 90%at 12h.Release in PBS was much faster than that in 0.1M HCL.Release profile of puerarin from tablet and microemulsion followed first-order kinetics and Ritger-peppas model,respectively.
Caco-2 cell monolayer model was established according to Caco-2 cell cultivated in millicell plate for 21d.The morphological and growth characters of the monolayer were examined.The polarization and compactification of the monolayer was determined by the alkaline phosphatase activity,transepithelial electrical resistance and apical-to-basolateral of sodium fluorescein across cell monolayer.The Caco-2 cell model was used to study the uptake,transport of Pue-ME.The effect of ME on the transport of drug was investigated.The results indicted that ME could significantly improve the uptake,transport and efflux kinetics of Puerarin(P＜0.05),especially when ME was diluted.In the presence of CsA,potent inhibitors of P-glycoprotein,P_(appAP-BL) /P_(appBL-AP) ratio was decreased in ME but have no effectent on transport.
A specific and accurate HPLC method was developed for the determination of puerarin in SD rats plasma.Puerarin was extracted by protein precipitation and then the supematant was injected into a UltimateXB-C18 column(250×4.6mm,5μm).The detection wavelength was set at 250nm and the mobile phase consisted of methanol: water(22:78) at a flow rate of 1.0ml/min.The blank plasma had no interference on the determination of puerarin.A good linear relationship was obtained between the peak area of puerarin and the concentration of puerarin over the range of 40 to 2000 ng/ml. The LLOQ was 40ng/ml and the total chromatographic analysis time was within 10 min. The method is precise and fast for the determination of puerarin in plasma after oral administration of Pue-ME to healthy SD rats.
The pharmacokinetic parameters of Puerarin in suspension and dilusion-ME were investigated after oral administration to rats at a single dose of 30mg/kg.The date was disposed using the program 3P87.The C_(max) of purerarin from D-ME is greater than that of the puerarin suspension.The AUC_(0.24h) of puerarin from D-ME is about 7-fold higher than that of puerarin from suspension.Compared with the puerarin suspension,the relative bioavailability of D-ME was 783%.The D-Me possessed later Tmax.This study suggested that the oral bioavaiability of Pue ME was greater than Pue suspension.
引文
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