PLH自微乳給藥系統(tǒng)及其大鼠體內(nèi)藥動學(xué)評價(jià)
發(fā)布時(shí)間：2019-01-03 11:02
【摘要】：本研究的主要目的為制備PLH(Pranlukast hydrate,PLH)自微乳給系統(tǒng)(Self-Microemulsions Drug Delivery System,SMEDDS),并進(jìn)行質(zhì)量評價(jià)、體外溶出度考察和大鼠體內(nèi)藥動學(xué)研究。PLH是最早被研究的一個(gè)白三烯受體抑制劑,水溶性小,口服生物利用度低。為增加藥物的溶解度、提高口服生物利用度,本文研制了PLH-SMEDDS。本文首先建立了PLH體外含量測定的紫外分光光度法和高效液相色譜法(high performance liquid chromatography,HPLC),并對其進(jìn)行了方法學(xué)考察。結(jié)果表明所建立的方法精密度、準(zhǔn)確度及穩(wěn)定性均良好。在此基礎(chǔ)上,進(jìn)行了PLH溶解度、油水分配系數(shù)和穩(wěn)定性等處方前研究。本文結(jié)合藥物在各輔料中的溶解度和輔料相容性試驗(yàn),通過繪制偽三元相圖進(jìn)行PLH-SMEDDS處方的初步篩選。選擇自微乳區(qū)域面積較大的處方組成,采用星點(diǎn)設(shè)計(jì)-效應(yīng)面法對油、乳化劑及助乳化劑比例進(jìn)行了優(yōu)化,采用多元線性回歸擬合最優(yōu)處方,按預(yù)測最優(yōu)處方制備PLH-SMEDDS,并對其進(jìn)行驗(yàn)證。經(jīng)處方驗(yàn)證,實(shí)測值與預(yù)測值接近。結(jié)果表明星點(diǎn)設(shè)計(jì)-效應(yīng)面能夠較好優(yōu)化PLH-SMEDDS處方。另外,本文采用最優(yōu)處方考察了SMEDDS形成微乳的影響因素,最終確定的處方為載藥量為4%的PLH-SMEDDS,其組成為油酸乙酯:Cremophol EL:三乙醇胺:無水乙醇=40:18:10:22。本文對所制備的PLH-SMEDDS進(jìn)行了制劑學(xué)評價(jià),采用透射電鏡觀測了納米粒的表面形態(tài),PLH-SMEDDS形態(tài)為規(guī)整的類圓球形;采用粒度分析儀測定PLH-SMEDDS在蒸餾水、0.1mol·L-1的HCl、pH=6.8的磷酸緩沖液等不同介質(zhì)中的粒徑、粒徑分布(PDI),以及在蒸餾水中的Zeta電位;PLH-SMEDDS粒徑依次為70.3±2.1、85.9±2.2、74.0±0.5 nm;PDI依次為0.310±0.016、0.320±0.015、0.296±0.024;Zeta電位為(-24.97±1.34mv);采用目測及粒徑評價(jià)的方式考察了PLH-SMEDDS的自微乳化效率,PLH-SMEDDS的自微乳化迅速,其自微乳化時(shí)間小于1min,所形成的微乳粒徑較小,約為70nm。本文建立了PLH自微乳制劑體外溶出度測定的HPLC法,并進(jìn)行了方法學(xué)驗(yàn)證,結(jié)果表明該方法準(zhǔn)確度高、精密度好、穩(wěn)定性好。在此基礎(chǔ)上考察了PLH在不同介質(zhì)中的溶出情況,確定了PLH-SMEDDS的體外溶出度方法,比較自微乳制劑、PLH原料藥、原料藥加空白自微乳混合物的體外溶出情況。結(jié)果表明PLH-SMEDDS 30min內(nèi)溶出度可達(dá)80%以上,而原料藥及原料藥加空白自微乳混合物30min內(nèi)釋放量低于80%,結(jié)果表明PLH-SMEDDS明顯改善了PLH的體外溶出速率。建立了PLH大鼠血藥濃度測定的HPLC法,考察了PLH-SMEDDS與PLH原料藥混懸液在大鼠體內(nèi)的藥動學(xué)差異。應(yīng)用一室模型對藥動學(xué)參數(shù)進(jìn)行了分析,采用雙側(cè)t檢驗(yàn)分析評價(jià)。結(jié)果表明以一室模型計(jì)算,與PLH原料藥混懸液相比,PLH-SMEDDS的Tmax、Cmax、AUC分別為PLH原料藥混懸液的0.76、2.72、2.44倍,表明PLH-SMEDDS在一定程度上提高了大鼠體內(nèi)血藥濃度,增加了藥物體內(nèi)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 鹵2.1 渭 m 85.9 鹵2.2 nm;PDI and 74.0 鹵0.5 nm;PDI, respectively, and the Zeta potential was (-24.97 鹵1.34mv) 0.320 鹵0.015 鹵0.296 鹵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.
【學(xué)位授予單位】：廣東藥科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R943;R965
本文編號：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 鹵2.1 渭 m 85.9 鹵2.2 nm;PDI and 74.0 鹵0.5 nm;PDI, respectively, and the Zeta potential was (-24.97 鹵1.34mv) 0.320 鹵0.015 鹵0.296 鹵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.
【學(xué)位授予單位】：廣東藥科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R943;R965
【相似文獻(xiàn)】
相關(guān)碩士學(xué)位論文 前1條
1 馬薇;PLH自微乳給藥系統(tǒng)及其大鼠體內(nèi)藥動學(xué)評價(jià)[D];廣東藥科大學(xué);2016年
，本文編號：2399285
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