白藜芦醇三个不同载体材料纳米口服给药系统的研究
摘要
白藜芦醇(Resveratrol，Res)是从植物中提取的一种天然二苯乙烯类化合物。现代药理学研究表明白藜芦醇具有确切的抗癌、保护心血管、调节血脂代谢及抗炎等多种生理活性。但白藜芦醇水不溶性的物理化学性质使其普通制剂难以通过口服给药途径在体内发挥其良好的生物活性。
纳米给药系统(nanoparticaes drug delivery system，NDDS)是指药物与载体材料采用纳米技术制成的1～1000nm的药物输送系统。是近年来药剂学领域研究颇为活跃的一系列新型超微小给药系统的统称，其粒径大小多在10～1000nm之间。作为口服药物输送系统其提高药物胃肠吸收的机理可能包括以下几个方面：1)纳米粒可通过小肠的peyer’s结而进入循环系统，粒径小的纳米载体还可穿过肠系膜的细胞间通路进入循环；2)由于纳米粒高度的分散性和巨大的表面积，能增加难溶性药物的溶解度和溶出速度，也能增加与胃肠道壁的接触，从而增加吸收的机会，提高难溶性药物的生物利用度；3)纳米粒较之溶液剂，更能被十二指肠的微毛所捕获，并滞留较长时间，进一步延长药物与细胞壁接触时间，提高药物的吸收速率和吸收率；4)纳米载体可保护某些不稳定药物，使之不被酶或酸碱催化降解。因此，采用现代药剂学手段设计合理的药物纳米口服传输系统，是解决难溶性药物低口服生物利用度问题的一种有效途径。
本课题以中药抗癌生物活性成分白藜芦醇为模型药物，分别以天然新型载体材料小麦醇溶蛋白、单硬脂酸甘油脂及磷脂为载体材料，系统进行了白藜芦醇小麦醇溶蛋白纳米粒、固体脂质纳米粒及纳米脂质体3个不同载体材料的纳米给药系统的的制备工艺，制剂学性质、体外释药规律，大鼠在体小肠吸收动力学及大鼠药代动力学的研究，旨在为纳米给药系统提高难溶性药物生物利用度的可行性提供一定的依据。
依据白藜芦醇溶解性质及各制备方法的特点，采用简单、快速的乙醇注入法制备Res-LP。采用试验次数少但模型预测精度低的五因素二水平正交实验设计法初步确定了影响药物包封率和载药量的3个主要影响因素；在此基础上，采用模型预测精度高的星点设计-效应面法进一步优化，各指标与3个因素的关系均用多元三项式方程来描述，根据指标与因素的三维效应面和二维等高图筛选出最佳处方配比。结果，制备的Res-LP的粒径、PDI、包封率及载药量分别为95.3nm、0.279、84.48％及4.36％。另外，通过脂质体水分配系数的研究，探讨了Res-LP具有较高包封率的原因。
通过比较固体脂质纳米粒各种制备方法的特点，选用与乙醇注入法具有相似特点的水性溶剂扩散法制备Res-SLN。采用均匀设计联用星点设计-效应面法进行制备工艺处方的优化。以包封率、载药量及平均粒径为指标，以均匀实验设计法确定了3个影响指标的主要因素，再对这3个因素进一步以星点设计-效应面法进行优化，结果，Res-SLN优化工艺处方制备样品的平均粒径、包封率和载药量分别为170.5nm、0.223、56.77％及2.59％。为进一步提高药物的包封率，考察了增加药物包封率的方法，结果药物包封率的增加并未改善Res-SLN的体外释药行为。
结合Res-LP及Res-SLN制备方法的特点，依据文献研究及小麦醇溶蛋白的性质，采用溶剂非溶剂法制备Res-NP，在预实验的基础上，选择药脂比、有机相与水相体积比及水相表面活性剂浓度3个影响因素，采用星点设计效应面法进行优化，根据指标与因素的三维效应面和二维等高图筛选出最佳工艺处方。结果，Res-NP的粒径、包封率、载药量分别为178nm、0.294、71.4％、5.3％。在进行包封率测定方法的研究时，分别考察了柱分离法、超滤法及超速离心法等，结果建立的反相透析法是一种准确、经济、快速的用于Res-NP包封率测定的方法。
为解决三个纳米给药系统物理化学稳定性差、不易久贮等问题。以外观、色泽、再分散性等为指标，分别优选了Res-SLN及Res-NP冻干剂的处方，体外释药试验结果表明，Res-LP胶体分散液在人工胃液及人工肠液(pH=6.8)的释药曲线均可用Weibull模型拟合，Res-SLN胶体分散液在人工肠液的体外释放以Weibull模型拟合最好，而在人工胃液中则以一级动力学方程模型拟合较好，Res-NP胶体分散液在人工胃液及人工肠液中体外释放的最佳模型均为Weibull模型。体外释放研究结果表明，3个纳米给药系统的释放曲线前期释药有均有一定量的突释，但后期释药则具有一定的缓释特征。
采用大鼠原位灌注模型进行Res、Res-LP、Res-SLN及Res-NP的小肠吸收部位及小肠吸收动力学的研究，结果，Res-LP及Res-SLN均在回肠处有较高的吸收百分率，与其它肠段相比，差异具有显著性。Res-NP在小肠各段吸收的差异不显著，在十二指肠及结肠处的ka大于Res-LP及Res-SLN，差异具有显著性。大鼠整肠段的吸收结果表明，3个纳米给药系统作为白藜芦醇的载体可以促进其白藜芦醇在小肠的吸收。Res、Res-SLN、Res-LP及Res-NP的吸收机制表明，不同剂量的供试品在整肠段的吸收百分率无显著性差异，提示四者在小肠的吸收机制均为被动扩散。
大鼠体内药代动力学研究结果表明，Res、Res-LP、Res-SLN及Res-NP绝对生物利用度分别为1.83％、7.12％、6.83％及4.95％，3个不同载体材料的纳米给药系统的主要药动学参数与Res相比，具有显著性差异，因此，纳米给药系统具有增加药物的体内稳定性，延长药物在体内的滞留时间、促进药物经肠吸收作用，为纳米给药系统作为药物的载体提高难溶性药物生物利用度的可行性提供了一定的依据。
综上所述，本课题首次以白藜芦醇为模型药物，系统进行了以口服纳米给药系统作为药物的载体提高药物口服生物利用度的可行性研究。而有关白藜芦醇小麦醇溶蛋白纳米的制备、正交设计联用星点设计优化白藜芦醇脂质体的制备工艺及均匀实验设计联用星点设计优化白藜芦醇固体脂质纳米粒制备工艺等研究内容，国内外均未见相关的报道。因此，为纳米给药系统载体材料的选用、制备工艺实验方法的设计提供了新的研究思路，同时课题的研究成果也丰富了改善难溶性药物口服生物利用度的研究内容和方法。
Resveratrol (Res) is a natural compound extracted and purified from variousspermatophytes such as mulberries. Its activities of anti- platelet aggregation,anticancer, adjusting lipid metabolism and antibiosis were proved in modernpharmacological studies. However, the absorption of Res in common oraladministration was extremely poor due to its water insoluble properties, whichhampered the Res to educe its biological activity in vivo.
The study of nanopartical drug delivery system was defined as particlescomposed of drugs and materials prepared by nanotechnology and particle diameterranged from 10nm to 1000nm. The mechanisms of nanoparticles enhancing the oralabsorption of drugs may include: 1) The nanoparticles can enter the systemcirculation through the peyer's knot on small intestine or spaces between theintestine cells. 2) The high dispersivity and enormous surface area of thenanoparticles can increase the solubility and the dissolution of the water-insolubledrugs. 3) Comparing to the solution, nanoparticles were more prone to be capturedby the microtriche on the duodenal wall, which extended the contact time of the drugand cells. 4) Some unstable drugs can be protected in the carders. Generallydesigning nanoparticles drug delivery system for water insoluble drugs was aneffective method to solve the low bioavailability problem.
In present study, using Res as the model drug, three different carders includingnanoparticles, SLN, nanoliposomes were studied. Their preparation technologies,pharmaceutical properties, releasing mechanism in vitro, absorption mechanism of in-situ perfusate and pharmacokinetics of rats were studied.
Firstly, using orthogonal design to optimize the formulation from five factorsincluding concentration of SPC, drug-lipids ratio, organic solvent-water ratio,SPC-cholesterol ratio and concentration of mannitol, entrapment efficiency (EE),drug loading (DL), and OD values were selected to evaluate the results. On the baseof the results, three factors (concentration of SPC, drug-lipids ratio, organicsolvent-water ratio) were chosen by orthogonal design as the most significant factors.Secondly, using central composite design with three selected factors to optimize theformulation again, the response surfaces were delineated according to best-fitmathematic models to obtain the optimized formulation.
The ethanol injection method was used to prepare the nanoparticles accordingto the physico-chemical properties of Res. Firstly, using orthogonal design tooptimize the formulation from five factors in this formulation includingconcentration of SPC, drug-lipids ratio, organic solvent-water ratio, SPC-cholesterolratio and concentration of mannitol. Entrapment efficiency (EE), drug loading (DL),and OD values were selected to evaluate the results. Secondly, using centralcomposite design with three selected factors to optimize the formulation again, theresponse surfaces were delineated according to best-fit mathematic models to obtainthe optimized formulation. The optimized results of particle size, PDI、EE and DL,which were 95.3nm, 0.279, 84.48% and 4.36%, respectively.
According to the method described above, Res-SLN was prepared by solventdispersion method which was similar to the ethanol injection method.Thecombination uniform design with central composite design was used to optimize thepreparation technology. The optimized mean size, PDI, EE and DL of samples were170.5nm, 0.223, 56.77% and 2.59%, respectively.
The Res-NP was prepared by solvent-insolvent method according to thereferences and the properties of gliadin. Based on the results of the preliminaryexperiment, central composite design was utilized to gain the optimized results.Furthermore, then the response surfaces were delineated according to best-fitmathematic models to obtain the optimized formulation, the optimized results of particle size, PDI, EE and DL, which were 178nm, 0.294, 71.4% and 5.3%,respectively. Particularly, retrodialysis metod was used to determine the EE of theRes-NP, which is accurate, economic and convenient comparing to the othertraditional methods.
Freeze-drying technology was also applied to enhance the deposition stabilityof the nanoparticles. In vitro releasing experiments, the releasing profile of Res-LPin artificial gastric and intestinal juice can be fitted by Weibull model, whileRes-SLN in artificial gastric and intestinal juice were fitted by first-order kineticsequation and Weibull model; Res-NP fitted by Weibull model, respectively. Thereleasing profiles of the three kinds of nanoparticles demonstrated a fast release inthe beginning and a sustained release in the later period.
The absorption mechanism of the three nanoparticles was studied by in-situperfusate model on rats. The results showed that both Res-LP and Res-SLN had ahigher absorptive effect in ileum, which were significantly different from other partof the intestine. Res-NP had a relatively similar absorptive behavior in the wholeintestine. It can be concluded that three kinds of nanoparticles can enhance theabsorption of Res comparing to the solution and all of them were passively absorbeddue to no active transporting happened.
The results of pharmacokinetics study on rats showed that the absolutebioavailability of Res、Res-LP、Res-SLN and Res-NP were 1.83%, 6.83%, 7.11% and4.96%, respectively. The main pharmacokinetics parameters of the nanoparticleswere significantly different from the Res solution samples. So it can be concludedthat nanoparticle drug delivery system increased the stability of the drug in vivo,sustained the retention time and enhance the absorption of drugs. All theseadvantages may be applied to improve the bioavailability of the water insolubledrugs.
To sum up, in our study, three different kinds of nanoparticles were introducedto improve the low bioavailability of the Res which was used as the model drug.Another creative point was the combination of orthogonal or uniform design withcentral composite to optimize the preparation technology of the nanoparticles, which central composite to optimize the preparation technology of the nanoparticles, whichwas still not reported in international journals. The achievement of our studyprovided a new method to adopting the carrier materials and designing thepreparation technology, meanwhile, it also enriched the research contents andmethods to improve the bioavailability of water insoluble drugs in oraladministration.
纳米给药系统(nanoparticaes drug delivery system，NDDS)是指药物与载体材料采用纳米技术制成的1～1000nm的药物输送系统。是近年来药剂学领域研究颇为活跃的一系列新型超微小给药系统的统称，其粒径大小多在10～1000nm之间。作为口服药物输送系统其提高药物胃肠吸收的机理可能包括以下几个方面：1)纳米粒可通过小肠的peyer’s结而进入循环系统，粒径小的纳米载体还可穿过肠系膜的细胞间通路进入循环；2)由于纳米粒高度的分散性和巨大的表面积，能增加难溶性药物的溶解度和溶出速度，也能增加与胃肠道壁的接触，从而增加吸收的机会，提高难溶性药物的生物利用度；3)纳米粒较之溶液剂，更能被十二指肠的微毛所捕获，并滞留较长时间，进一步延长药物与细胞壁接触时间，提高药物的吸收速率和吸收率；4)纳米载体可保护某些不稳定药物，使之不被酶或酸碱催化降解。因此，采用现代药剂学手段设计合理的药物纳米口服传输系统，是解决难溶性药物低口服生物利用度问题的一种有效途径。
本课题以中药抗癌生物活性成分白藜芦醇为模型药物，分别以天然新型载体材料小麦醇溶蛋白、单硬脂酸甘油脂及磷脂为载体材料，系统进行了白藜芦醇小麦醇溶蛋白纳米粒、固体脂质纳米粒及纳米脂质体3个不同载体材料的纳米给药系统的的制备工艺，制剂学性质、体外释药规律，大鼠在体小肠吸收动力学及大鼠药代动力学的研究，旨在为纳米给药系统提高难溶性药物生物利用度的可行性提供一定的依据。
依据白藜芦醇溶解性质及各制备方法的特点，采用简单、快速的乙醇注入法制备Res-LP。采用试验次数少但模型预测精度低的五因素二水平正交实验设计法初步确定了影响药物包封率和载药量的3个主要影响因素；在此基础上，采用模型预测精度高的星点设计-效应面法进一步优化，各指标与3个因素的关系均用多元三项式方程来描述，根据指标与因素的三维效应面和二维等高图筛选出最佳处方配比。结果，制备的Res-LP的粒径、PDI、包封率及载药量分别为95.3nm、0.279、84.48％及4.36％。另外，通过脂质体水分配系数的研究，探讨了Res-LP具有较高包封率的原因。
通过比较固体脂质纳米粒各种制备方法的特点，选用与乙醇注入法具有相似特点的水性溶剂扩散法制备Res-SLN。采用均匀设计联用星点设计-效应面法进行制备工艺处方的优化。以包封率、载药量及平均粒径为指标，以均匀实验设计法确定了3个影响指标的主要因素，再对这3个因素进一步以星点设计-效应面法进行优化，结果，Res-SLN优化工艺处方制备样品的平均粒径、包封率和载药量分别为170.5nm、0.223、56.77％及2.59％。为进一步提高药物的包封率，考察了增加药物包封率的方法，结果药物包封率的增加并未改善Res-SLN的体外释药行为。
结合Res-LP及Res-SLN制备方法的特点，依据文献研究及小麦醇溶蛋白的性质，采用溶剂非溶剂法制备Res-NP，在预实验的基础上，选择药脂比、有机相与水相体积比及水相表面活性剂浓度3个影响因素，采用星点设计效应面法进行优化，根据指标与因素的三维效应面和二维等高图筛选出最佳工艺处方。结果，Res-NP的粒径、包封率、载药量分别为178nm、0.294、71.4％、5.3％。在进行包封率测定方法的研究时，分别考察了柱分离法、超滤法及超速离心法等，结果建立的反相透析法是一种准确、经济、快速的用于Res-NP包封率测定的方法。
为解决三个纳米给药系统物理化学稳定性差、不易久贮等问题。以外观、色泽、再分散性等为指标，分别优选了Res-SLN及Res-NP冻干剂的处方，体外释药试验结果表明，Res-LP胶体分散液在人工胃液及人工肠液(pH=6.8)的释药曲线均可用Weibull模型拟合，Res-SLN胶体分散液在人工肠液的体外释放以Weibull模型拟合最好，而在人工胃液中则以一级动力学方程模型拟合较好，Res-NP胶体分散液在人工胃液及人工肠液中体外释放的最佳模型均为Weibull模型。体外释放研究结果表明，3个纳米给药系统的释放曲线前期释药有均有一定量的突释，但后期释药则具有一定的缓释特征。
采用大鼠原位灌注模型进行Res、Res-LP、Res-SLN及Res-NP的小肠吸收部位及小肠吸收动力学的研究，结果，Res-LP及Res-SLN均在回肠处有较高的吸收百分率，与其它肠段相比，差异具有显著性。Res-NP在小肠各段吸收的差异不显著，在十二指肠及结肠处的ka大于Res-LP及Res-SLN，差异具有显著性。大鼠整肠段的吸收结果表明，3个纳米给药系统作为白藜芦醇的载体可以促进其白藜芦醇在小肠的吸收。Res、Res-SLN、Res-LP及Res-NP的吸收机制表明，不同剂量的供试品在整肠段的吸收百分率无显著性差异，提示四者在小肠的吸收机制均为被动扩散。
大鼠体内药代动力学研究结果表明，Res、Res-LP、Res-SLN及Res-NP绝对生物利用度分别为1.83％、7.12％、6.83％及4.95％，3个不同载体材料的纳米给药系统的主要药动学参数与Res相比，具有显著性差异，因此，纳米给药系统具有增加药物的体内稳定性，延长药物在体内的滞留时间、促进药物经肠吸收作用，为纳米给药系统作为药物的载体提高难溶性药物生物利用度的可行性提供了一定的依据。
综上所述，本课题首次以白藜芦醇为模型药物，系统进行了以口服纳米给药系统作为药物的载体提高药物口服生物利用度的可行性研究。而有关白藜芦醇小麦醇溶蛋白纳米的制备、正交设计联用星点设计优化白藜芦醇脂质体的制备工艺及均匀实验设计联用星点设计优化白藜芦醇固体脂质纳米粒制备工艺等研究内容，国内外均未见相关的报道。因此，为纳米给药系统载体材料的选用、制备工艺实验方法的设计提供了新的研究思路，同时课题的研究成果也丰富了改善难溶性药物口服生物利用度的研究内容和方法。
Resveratrol (Res) is a natural compound extracted and purified from variousspermatophytes such as mulberries. Its activities of anti- platelet aggregation,anticancer, adjusting lipid metabolism and antibiosis were proved in modernpharmacological studies. However, the absorption of Res in common oraladministration was extremely poor due to its water insoluble properties, whichhampered the Res to educe its biological activity in vivo.
The study of nanopartical drug delivery system was defined as particlescomposed of drugs and materials prepared by nanotechnology and particle diameterranged from 10nm to 1000nm. The mechanisms of nanoparticles enhancing the oralabsorption of drugs may include: 1) The nanoparticles can enter the systemcirculation through the peyer's knot on small intestine or spaces between theintestine cells. 2) The high dispersivity and enormous surface area of thenanoparticles can increase the solubility and the dissolution of the water-insolubledrugs. 3) Comparing to the solution, nanoparticles were more prone to be capturedby the microtriche on the duodenal wall, which extended the contact time of the drugand cells. 4) Some unstable drugs can be protected in the carders. Generallydesigning nanoparticles drug delivery system for water insoluble drugs was aneffective method to solve the low bioavailability problem.
In present study, using Res as the model drug, three different carders includingnanoparticles, SLN, nanoliposomes were studied. Their preparation technologies,pharmaceutical properties, releasing mechanism in vitro, absorption mechanism of in-situ perfusate and pharmacokinetics of rats were studied.
Firstly, using orthogonal design to optimize the formulation from five factorsincluding concentration of SPC, drug-lipids ratio, organic solvent-water ratio,SPC-cholesterol ratio and concentration of mannitol, entrapment efficiency (EE),drug loading (DL), and OD values were selected to evaluate the results. On the baseof the results, three factors (concentration of SPC, drug-lipids ratio, organicsolvent-water ratio) were chosen by orthogonal design as the most significant factors.Secondly, using central composite design with three selected factors to optimize theformulation again, the response surfaces were delineated according to best-fitmathematic models to obtain the optimized formulation.
The ethanol injection method was used to prepare the nanoparticles accordingto the physico-chemical properties of Res. Firstly, using orthogonal design tooptimize the formulation from five factors in this formulation includingconcentration of SPC, drug-lipids ratio, organic solvent-water ratio, SPC-cholesterolratio and concentration of mannitol. Entrapment efficiency (EE), drug loading (DL),and OD values were selected to evaluate the results. Secondly, using centralcomposite design with three selected factors to optimize the formulation again, theresponse surfaces were delineated according to best-fit mathematic models to obtainthe optimized formulation. The optimized results of particle size, PDI、EE and DL,which were 95.3nm, 0.279, 84.48% and 4.36%, respectively.
According to the method described above, Res-SLN was prepared by solventdispersion method which was similar to the ethanol injection method.Thecombination uniform design with central composite design was used to optimize thepreparation technology. The optimized mean size, PDI, EE and DL of samples were170.5nm, 0.223, 56.77% and 2.59%, respectively.
The Res-NP was prepared by solvent-insolvent method according to thereferences and the properties of gliadin. Based on the results of the preliminaryexperiment, central composite design was utilized to gain the optimized results.Furthermore, then the response surfaces were delineated according to best-fitmathematic models to obtain the optimized formulation, the optimized results of particle size, PDI, EE and DL, which were 178nm, 0.294, 71.4% and 5.3%,respectively. Particularly, retrodialysis metod was used to determine the EE of theRes-NP, which is accurate, economic and convenient comparing to the othertraditional methods.
Freeze-drying technology was also applied to enhance the deposition stabilityof the nanoparticles. In vitro releasing experiments, the releasing profile of Res-LPin artificial gastric and intestinal juice can be fitted by Weibull model, whileRes-SLN in artificial gastric and intestinal juice were fitted by first-order kineticsequation and Weibull model; Res-NP fitted by Weibull model, respectively. Thereleasing profiles of the three kinds of nanoparticles demonstrated a fast release inthe beginning and a sustained release in the later period.
The absorption mechanism of the three nanoparticles was studied by in-situperfusate model on rats. The results showed that both Res-LP and Res-SLN had ahigher absorptive effect in ileum, which were significantly different from other partof the intestine. Res-NP had a relatively similar absorptive behavior in the wholeintestine. It can be concluded that three kinds of nanoparticles can enhance theabsorption of Res comparing to the solution and all of them were passively absorbeddue to no active transporting happened.
The results of pharmacokinetics study on rats showed that the absolutebioavailability of Res、Res-LP、Res-SLN and Res-NP were 1.83%, 6.83%, 7.11% and4.96%, respectively. The main pharmacokinetics parameters of the nanoparticleswere significantly different from the Res solution samples. So it can be concludedthat nanoparticle drug delivery system increased the stability of the drug in vivo,sustained the retention time and enhance the absorption of drugs. All theseadvantages may be applied to improve the bioavailability of the water insolubledrugs.
To sum up, in our study, three different kinds of nanoparticles were introducedto improve the low bioavailability of the Res which was used as the model drug.Another creative point was the combination of orthogonal or uniform design withcentral composite to optimize the preparation technology of the nanoparticles, which central composite to optimize the preparation technology of the nanoparticles, whichwas still not reported in international journals. The achievement of our studyprovided a new method to adopting the carrier materials and designing thepreparation technology, meanwhile, it also enriched the research contents andmethods to improve the bioavailability of water insoluble drugs in oraladministration.
引文
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