白藜芦醇纳米乳的制备及大鼠体内的药动学研究
|
摘要
目的制备白藜芦醇纳米乳并探讨其在大鼠体内的药动学行为。方法以油酸乙酯作为油相,聚氧乙烯氢化蓖麻油RH40为乳化剂,无水乙醇为助乳化剂,采用滴定法绘制伪三元相图以优化纳米乳处方,对所制备的白藜芦醇纳米乳进行粒径、透射电镜及红外光谱测定等理化性质的表征。大鼠ig给药后,采用HPLC测定其血药浓度,计算其药动学参数,利用DAS软件分析其药动学特征。结果白藜芦醇纳米乳处方为药物-油相-混合乳化剂-水的质量比为1∶10∶24∶65,所制备纳米乳的粒径为40 nm左右,电镜观察其形态为圆形球状结构,红外光谱结果表明白藜芦醇以活性的反式结构存在于纳米乳的油相中。与白藜芦醇混悬剂相比,白藜芦醇纳米乳在大鼠体内的血药浓度时间曲线下面积(78.89 h·μg/mL)为混悬剂(54.42h·μg/mL)的1.45倍,达峰浓度(3.29μg/mL)是混悬剂(1.70μg/mL)的1.93倍,可以提高白藜芦醇口服给药的生物利用度。结论所制备的纳米乳制剂有希望为白藜芦醇的有效递送提供新的给药途径。
Objective To fabricate resveratrol nanoemulsions and probe their pharmacokinetics profiles in rats in vivo. Methods The nanoemulsions of resveratrol were tailored by using aethylis oleas as the oil phase, Cremophor RH40 as emulsifiers, absolute alcohol as co-emulsifiers, respectively. The formulation was optimized by pseudo-ternary phase diagrams and their physicochemical properties of nanoemulsions were characterized by particle size distribution, transmission electron microscope(TEM), and Fourier transform infrared spectroscopy(FTIR). The pharmacokinetics experiments were also performed in rats after gavage and the plasm concentration of resveratrol were determined by HPLC as well as the profiles of pharmacokinetic parameters were obtained by Drug and Statistics(DAS) software. Results The formula of nanoemulsions were as follows: the ratio of resveratrol-aethylis oleas-mixture surfactantdistilled water was 1∶10∶24∶65. The average particle size diameters of prepared resveratrol nanoemulsions were about 40 nm and the droplets of nanoemulsions were in spherical shape observed by TEM. The results of IR disclosed that the active trans-resveratrol presented in the oil droplet of the nanoemulsions. Compared with resveratrol suspensions, the bioavailability of resveratrol nanoemulsions was increased 1.45-fold, and Cmax reached to 1.93-fold. Conclusion These results indicated that nanoemulsions may be a promising tool for the delivery of resveratrol.
Objective To fabricate resveratrol nanoemulsions and probe their pharmacokinetics profiles in rats in vivo. Methods The nanoemulsions of resveratrol were tailored by using aethylis oleas as the oil phase, Cremophor RH40 as emulsifiers, absolute alcohol as co-emulsifiers, respectively. The formulation was optimized by pseudo-ternary phase diagrams and their physicochemical properties of nanoemulsions were characterized by particle size distribution, transmission electron microscope(TEM), and Fourier transform infrared spectroscopy(FTIR). The pharmacokinetics experiments were also performed in rats after gavage and the plasm concentration of resveratrol were determined by HPLC as well as the profiles of pharmacokinetic parameters were obtained by Drug and Statistics(DAS) software. Results The formula of nanoemulsions were as follows: the ratio of resveratrol-aethylis oleas-mixture surfactantdistilled water was 1∶10∶24∶65. The average particle size diameters of prepared resveratrol nanoemulsions were about 40 nm and the droplets of nanoemulsions were in spherical shape observed by TEM. The results of IR disclosed that the active trans-resveratrol presented in the oil droplet of the nanoemulsions. Compared with resveratrol suspensions, the bioavailability of resveratrol nanoemulsions was increased 1.45-fold, and Cmax reached to 1.93-fold. Conclusion These results indicated that nanoemulsions may be a promising tool for the delivery of resveratrol.
引文
[1]Hung C F,Chen J K,Liao M H,et al.Development and evaluation of emulsion-liposome blends for resveratrol delivery[J].J Nanosci Nanotechnol,2015,6(9/10):2950-2958.
[2]杜丽芬,胡建武,卢立,等.白藜芦醇对烟熏和脂多糖诱导大鼠慢性阻塞性肺疾病的改善及肺Derlin-1蛋白的调控作用[J].现代药物与临床,2018,33(8):1865-1869.
[3]刘顺,李赫宇,赵玲.白藜芦醇降血尿酸、抗炎作用研究进展[J].药物评价研究,2016,39(2):304-307.
[4]张黎媛.白藜芦醇及其代谢产物与类似物抗癌症转移作用机制研究进展[J].中草药,2017,48(20):4346-4352.
[5]Liu S,Zhang X X,Zhuang S,et al.Effect of Polygoni Cuspidati Rhizoma et Radix and its ingredient resveratrol on experimental autoimmune myasthenia gravis by suppressing immune response[J].Chin Herb Med,2016,8(3):251-258.
[6]张蕊,马寅仲,孙双勇,等.白藜芦醇对阿霉素诱导心脏毒性保护作用的研究进展[J].现代药物与临床,2017,32(4):752-756.
[7]卢佳倩,赵耀鑫,刘晓彤,等.白藜芦醇对糖尿病及其并发症作用机制的研究进展[J].药物评价研究,2018,41(2):334-339.
[8]张翠,王丹枫,张思琪,等.白藜芦醇对肾纤维化大鼠肾组织ORP150、GRP78、GRP94蛋白表达的影响[J].中草药,2018,49(2):406-413.
[9]Amri A,Chaumeil J C,Sfar S,et al.Administration of resveratrol:What formulation solutions to bioavailability limitations?[J].J Control Release,2012,158(2):182-193.
[10]Prévost S,Gradzielski M,Zemb T.Self-assembly,phase behavior and structural behavior as observed by scattering for classical and non-classical microemulsions[J].Adv Colloid Interface Sci,2017,247:374-396.
[11]张宽云,马燕.紫杉醇-油酸和鸦胆子油分子配型组装纳米乳给药系统研究[J].中草药,2017,48(8):1544-1552.
[12]Cerpnjak K,Zvonar A,Ga?perlin M,et al.Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs[J].Acta Pharm,2013,63(4):427-445.
[13]李文华,王英姿,骆声秀,等.苦参总碱纳米乳和苦参总碱纳米乳凝胶的透皮机制研究[J].中草药,2017,48(3):484-489.
[14]Mariarenata S,Maria Luisa B,Giovanna F,et al.Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems[J].Food Chem,2014,147(6):42-50.
[15]Padula C,TelòI,Di A I,et al.Microemulsion containing triamcinolone acetonide for buccal administration[J].Eur J Pharm Sci,2018,115(30):233-239.
[16]赵晶,金凯,宋光杰,等.水杨酸微乳的制备及其体外透皮吸收研究[J].中国药房,2015,26(1):112-114.
[17]Mamadou G,Charrueau C,Dairou J,et al.Increased intestinal permeation and modulation of presystemic metabolism of resveratrol formulated into selfemulsifying drug delivery systems[J].Int J Pharm,2017,521(1/2):150-155.
[18]Harun S,Nordin S A,Gani S S A,et al.Development of nanoemulsion for efficient brain parenteral delivery of cefuroxime:Designs,characterizations,and pharmacokinetics[J].Int J Nanomed,2018,13:2571-2584.
[19]Mehta S K,Kaur G,Mutneja R,et al.Solubilization,microstructure,and thermodynamics of fully dilutable U-type Brij microemulsion[J].J Colloid Interface Sci,2009,338(2):542-549.
[20]刘继勇,郝天龙,高申,等.白藜芦醇纳米乳的制备[J].中国医药工业杂志,2012,43(5):347-351.
[21]Zhou J,Zhou M,Yang F F,et al.Involvement of the inhibition of intestinal glucuronidation in enhancing the oral bioavailability of resveratrol by labrasol containing nanoemulsions[J].Mol Pharm,2015,12(4):1084-1095.
[22]Davidovpardo G,Mcclements D J.Nutraceutical delivery systems:Resveratrol encapsulation in grape seed oil nanoemulsions formed by spontaneous emulsification[J].Food Chem,2015,167:205-212.
[23]Koroleva M Y,Yurtov E V.Nanoemulsions:The properties,methods of preparation and promising applications[J].Russ Chem Rev,2012,81(1):21-43.
[2]杜丽芬,胡建武,卢立,等.白藜芦醇对烟熏和脂多糖诱导大鼠慢性阻塞性肺疾病的改善及肺Derlin-1蛋白的调控作用[J].现代药物与临床,2018,33(8):1865-1869.
[3]刘顺,李赫宇,赵玲.白藜芦醇降血尿酸、抗炎作用研究进展[J].药物评价研究,2016,39(2):304-307.
[4]张黎媛.白藜芦醇及其代谢产物与类似物抗癌症转移作用机制研究进展[J].中草药,2017,48(20):4346-4352.
[5]Liu S,Zhang X X,Zhuang S,et al.Effect of Polygoni Cuspidati Rhizoma et Radix and its ingredient resveratrol on experimental autoimmune myasthenia gravis by suppressing immune response[J].Chin Herb Med,2016,8(3):251-258.
[6]张蕊,马寅仲,孙双勇,等.白藜芦醇对阿霉素诱导心脏毒性保护作用的研究进展[J].现代药物与临床,2017,32(4):752-756.
[7]卢佳倩,赵耀鑫,刘晓彤,等.白藜芦醇对糖尿病及其并发症作用机制的研究进展[J].药物评价研究,2018,41(2):334-339.
[8]张翠,王丹枫,张思琪,等.白藜芦醇对肾纤维化大鼠肾组织ORP150、GRP78、GRP94蛋白表达的影响[J].中草药,2018,49(2):406-413.
[9]Amri A,Chaumeil J C,Sfar S,et al.Administration of resveratrol:What formulation solutions to bioavailability limitations?[J].J Control Release,2012,158(2):182-193.
[10]Prévost S,Gradzielski M,Zemb T.Self-assembly,phase behavior and structural behavior as observed by scattering for classical and non-classical microemulsions[J].Adv Colloid Interface Sci,2017,247:374-396.
[11]张宽云,马燕.紫杉醇-油酸和鸦胆子油分子配型组装纳米乳给药系统研究[J].中草药,2017,48(8):1544-1552.
[12]Cerpnjak K,Zvonar A,Ga?perlin M,et al.Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs[J].Acta Pharm,2013,63(4):427-445.
[13]李文华,王英姿,骆声秀,等.苦参总碱纳米乳和苦参总碱纳米乳凝胶的透皮机制研究[J].中草药,2017,48(3):484-489.
[14]Mariarenata S,Maria Luisa B,Giovanna F,et al.Bioavailability of encapsulated resveratrol into nanoemulsion-based delivery systems[J].Food Chem,2014,147(6):42-50.
[15]Padula C,TelòI,Di A I,et al.Microemulsion containing triamcinolone acetonide for buccal administration[J].Eur J Pharm Sci,2018,115(30):233-239.
[16]赵晶,金凯,宋光杰,等.水杨酸微乳的制备及其体外透皮吸收研究[J].中国药房,2015,26(1):112-114.
[17]Mamadou G,Charrueau C,Dairou J,et al.Increased intestinal permeation and modulation of presystemic metabolism of resveratrol formulated into selfemulsifying drug delivery systems[J].Int J Pharm,2017,521(1/2):150-155.
[18]Harun S,Nordin S A,Gani S S A,et al.Development of nanoemulsion for efficient brain parenteral delivery of cefuroxime:Designs,characterizations,and pharmacokinetics[J].Int J Nanomed,2018,13:2571-2584.
[19]Mehta S K,Kaur G,Mutneja R,et al.Solubilization,microstructure,and thermodynamics of fully dilutable U-type Brij microemulsion[J].J Colloid Interface Sci,2009,338(2):542-549.
[20]刘继勇,郝天龙,高申,等.白藜芦醇纳米乳的制备[J].中国医药工业杂志,2012,43(5):347-351.
[21]Zhou J,Zhou M,Yang F F,et al.Involvement of the inhibition of intestinal glucuronidation in enhancing the oral bioavailability of resveratrol by labrasol containing nanoemulsions[J].Mol Pharm,2015,12(4):1084-1095.
[22]Davidovpardo G,Mcclements D J.Nutraceutical delivery systems:Resveratrol encapsulation in grape seed oil nanoemulsions formed by spontaneous emulsification[J].Food Chem,2015,167:205-212.
[23]Koroleva M Y,Yurtov E V.Nanoemulsions:The properties,methods of preparation and promising applications[J].Russ Chem Rev,2012,81(1):21-43.