PLH自微乳给药系统及其大鼠体内药动学评价
发布时间：2019-01-03 11:02
【摘要】：本研究的主要目的为制备PLH(Pranlukast hydrate,PLH)自微乳给系统(Self-Microemulsions Drug Delivery System,SMEDDS),并进行质量评价、体外溶出度考察和大鼠体内药动学研究。PLH是最早被研究的一个白三烯受体抑制剂,水溶性小,口服生物利用度低。为增加药物的溶解度、提高口服生物利用度,本文研制了PLH-SMEDDS。本文首先建立了PLH体外含量测定的紫外分光光度法和高效液相色谱法(high performance liquid chromatography,HPLC),并对其进行了方法学考察。结果表明所建立的方法精密度、准确度及稳定性均良好。在此基础上,进行了PLH溶解度、油水分配系数和稳定性等处方前研究。本文结合药物在各辅料中的溶解度和辅料相容性试验,通过绘制伪三元相图进行PLH-SMEDDS处方的初步筛选。选择自微乳区域面积较大的处方组成,采用星点设计-效应面法对油、乳化剂及助乳化剂比例进行了优化,采用多元线性回归拟合最优处方,按预测最优处方制备PLH-SMEDDS,并对其进行验证。经处方验证,实测值与预测值接近。结果表明星点设计-效应面能够较好优化PLH-SMEDDS处方。另外,本文采用最优处方考察了SMEDDS形成微乳的影响因素,最终确定的处方为载药量为4%的PLH-SMEDDS,其组成为油酸乙酯:Cremophol EL:三乙醇胺:无水乙醇=40:18:10:22。本文对所制备的PLH-SMEDDS进行了制剂学评价,采用透射电镜观测了纳米粒的表面形态,PLH-SMEDDS形态为规整的类圆球形;采用粒度分析仪测定PLH-SMEDDS在蒸馏水、0.1mol·L-1的HCl、pH=6.8的磷酸缓冲液等不同介质中的粒径、粒径分布(PDI),以及在蒸馏水中的Zeta电位;PLH-SMEDDS粒径依次为70.3±2.1、85.9±2.2、74.0±0.5 nm;PDI依次为0.310±0.016、0.320±0.015、0.296±0.024;Zeta电位为(-24.97±1.34mv);采用目测及粒径评价的方式考察了PLH-SMEDDS的自微乳化效率,PLH-SMEDDS的自微乳化迅速,其自微乳化时间小于1min,所形成的微乳粒径较小,约为70nm。本文建立了PLH自微乳制剂体外溶出度测定的HPLC法,并进行了方法学验证,结果表明该方法准确度高、精密度好、稳定性好。在此基础上考察了PLH在不同介质中的溶出情况,确定了PLH-SMEDDS的体外溶出度方法,比较自微乳制剂、PLH原料药、原料药加空白自微乳混合物的体外溶出情况。结果表明PLH-SMEDDS 30min内溶出度可达80%以上,而原料药及原料药加空白自微乳混合物30min内释放量低于80%,结果表明PLH-SMEDDS明显改善了PLH的体外溶出速率。建立了PLH大鼠血药浓度测定的HPLC法,考察了PLH-SMEDDS与PLH原料药混悬液在大鼠体内的药动学差异。应用一室模型对药动学参数进行了分析,采用双侧t检验分析评价。结果表明以一室模型计算,与PLH原料药混悬液相比,PLH-SMEDDS的Tmax、Cmax、AUC分别为PLH原料药混悬液的0.76、2.72、2.44倍,表明PLH-SMEDDS在一定程度上提高了大鼠体内血药浓度,增加了药物体内生物利用度。
[Abstract]:The main purpose of this study was to prepare PLH (Pranlukast hydrate,PLH) self-emulsion feed system (Self-Microemulsions Drug Delivery System,SMEDDS) and evaluate its quality. Dissolution in vitro and pharmacokinetics in rats. PLH is one of the earliest leukotriene receptor inhibitors studied, which has low water solubility and low oral bioavailability. In order to increase the solubility of drugs and improve the oral bioavailability, PLH-SMEDDS. was prepared in this paper. In this paper, UV spectrophotometry and high performance liquid chromatography (high performance liquid chromatography,HPLC) were established for the determination of PLH in vitro, and its methodology was investigated. The results show that the precision, accuracy and stability of the method are good. On this basis, the PLH solubility, oil and water partition coefficient and stability were studied before prescription. Based on the solubility and compatibility test of drugs in various excipients, the pseudo-ternary phase diagram was used to screen the formulation of PLH-SMEDDS. The composition of prescription with large area of self-microemulsion was selected. The proportion of oil, emulsifier and co-emulsifier was optimized by star design-effect surface method. The optimum formulation was fitted by multivariate linear regression, and the PLH-SMEDDS, was prepared according to the predicted optimum prescription. And verify it. The measured value is close to the predicted value. The results show that the star design-effect surface can better optimize the formulation of PLH-SMEDDS. In addition, the optimal formulation was used to investigate the factors affecting the formation of microemulsion of SMEDDS. The final formulation was PLH-SMEDDS, with a drug loading of 4%. Its composition was ethyl oleate: Cremophol EL: triethanolamine: anhydrous ethanol = 40: 18: 10: 22: 22. In this paper, the preparation of PLH-SMEDDS was evaluated. The surface morphology of the nanoparticles was observed by transmission electron microscope. The morphology of PLH-SMEDDS was spherical and regular. The particle size, particle size distribution (PDI),) and Zeta potential of PLH-SMEDDS in distilled water, HCl,pH=6.8 buffer solution of 0.1mol L-1 were measured by particle size analyzer. The particle size of PLH-SMEDDS was 70.3 卤2.1 渭 m 85.9 卤2.2 nm;PDI and 74.0 卤0.5 nm;PDI, respectively, and the Zeta potential was (-24.97 卤1.34mv) 0.320 卤0.015 卤0.296 卤0.024 1.34mv; The self-microemulsification efficiency of PLH-SMEDDS was investigated by visual measurement and particle size evaluation. The self-micro-emulsification of PLH-SMEDDS was rapid, and the self-microemulsification time was less than 1 min. The size of the microemulsion was about 70 nm. In this paper, a HPLC method for the determination of dissolution of PLH self-microemulsion in vitro was established, and the method was validated. The results showed that the method had high accuracy, good precision and good stability. On this basis, the dissolution of PLH in different media was investigated, the dissolution rate of PLH-SMEDDS in vitro was determined, and the dissolution in vitro of self-microemulsion, PLH raw drug, raw drug and blank self-microemulsion mixture was compared. The results showed that the dissolution rate of PLH-SMEDDS 30min was more than 80%, while the release amount of 30min was lower than that of the mixture of raw material and drug plus blank self-microemulsion. The results showed that PLH-SMEDDS could obviously improve the dissolution rate of PLH in vitro. A HPLC method for the determination of blood drug concentration in PLH rats was established. The pharmacokinetic differences of PLH-SMEDDS and PLH raw drug suspensions in rats were investigated. The pharmacokinetic parameters were analyzed by one-compartment model and evaluated by bilateral t-test. The results showed that compared with PLH drug suspension, the Tmax,Cmax,AUC of PLH-SMEDDS was 0.76 ~ 2.72 ~ 2.44 times of that of PLH, which indicated that PLH-SMEDDS could improve the blood drug concentration of rats to some extent. Increased bioavailability of drugs in vivo.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943;R965
本文编号：2399285
[Abstract]:The main purpose of this study was to prepare PLH (Pranlukast hydrate,PLH) self-emulsion feed system (Self-Microemulsions Drug Delivery System,SMEDDS) and evaluate its quality. Dissolution in vitro and pharmacokinetics in rats. PLH is one of the earliest leukotriene receptor inhibitors studied, which has low water solubility and low oral bioavailability. In order to increase the solubility of drugs and improve the oral bioavailability, PLH-SMEDDS. was prepared in this paper. In this paper, UV spectrophotometry and high performance liquid chromatography (high performance liquid chromatography,HPLC) were established for the determination of PLH in vitro, and its methodology was investigated. The results show that the precision, accuracy and stability of the method are good. On this basis, the PLH solubility, oil and water partition coefficient and stability were studied before prescription. Based on the solubility and compatibility test of drugs in various excipients, the pseudo-ternary phase diagram was used to screen the formulation of PLH-SMEDDS. The composition of prescription with large area of self-microemulsion was selected. The proportion of oil, emulsifier and co-emulsifier was optimized by star design-effect surface method. The optimum formulation was fitted by multivariate linear regression, and the PLH-SMEDDS, was prepared according to the predicted optimum prescription. And verify it. The measured value is close to the predicted value. The results show that the star design-effect surface can better optimize the formulation of PLH-SMEDDS. In addition, the optimal formulation was used to investigate the factors affecting the formation of microemulsion of SMEDDS. The final formulation was PLH-SMEDDS, with a drug loading of 4%. Its composition was ethyl oleate: Cremophol EL: triethanolamine: anhydrous ethanol = 40: 18: 10: 22: 22. In this paper, the preparation of PLH-SMEDDS was evaluated. The surface morphology of the nanoparticles was observed by transmission electron microscope. The morphology of PLH-SMEDDS was spherical and regular. The particle size, particle size distribution (PDI),) and Zeta potential of PLH-SMEDDS in distilled water, HCl,pH=6.8 buffer solution of 0.1mol L-1 were measured by particle size analyzer. The particle size of PLH-SMEDDS was 70.3 卤2.1 渭 m 85.9 卤2.2 nm;PDI and 74.0 卤0.5 nm;PDI, respectively, and the Zeta potential was (-24.97 卤1.34mv) 0.320 卤0.015 卤0.296 卤0.024 1.34mv; The self-microemulsification efficiency of PLH-SMEDDS was investigated by visual measurement and particle size evaluation. The self-micro-emulsification of PLH-SMEDDS was rapid, and the self-microemulsification time was less than 1 min. The size of the microemulsion was about 70 nm. In this paper, a HPLC method for the determination of dissolution of PLH self-microemulsion in vitro was established, and the method was validated. The results showed that the method had high accuracy, good precision and good stability. On this basis, the dissolution of PLH in different media was investigated, the dissolution rate of PLH-SMEDDS in vitro was determined, and the dissolution in vitro of self-microemulsion, PLH raw drug, raw drug and blank self-microemulsion mixture was compared. The results showed that the dissolution rate of PLH-SMEDDS 30min was more than 80%, while the release amount of 30min was lower than that of the mixture of raw material and drug plus blank self-microemulsion. The results showed that PLH-SMEDDS could obviously improve the dissolution rate of PLH in vitro. A HPLC method for the determination of blood drug concentration in PLH rats was established. The pharmacokinetic differences of PLH-SMEDDS and PLH raw drug suspensions in rats were investigated. The pharmacokinetic parameters were analyzed by one-compartment model and evaluated by bilateral t-test. The results showed that compared with PLH drug suspension, the Tmax,Cmax,AUC of PLH-SMEDDS was 0.76 ~ 2.72 ~ 2.44 times of that of PLH, which indicated that PLH-SMEDDS could improve the blood drug concentration of rats to some extent. Increased bioavailability of drugs in vivo.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943;R965
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1 马薇;PLH自微乳给药系统及其大鼠体内药动学评价[D];广东药科大学;2016年
，本文编号：2399285
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