PEG修饰姜黄素固体脂质纳米粒的制备、表征及溶出特征
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摘要
目的制备具有缓释作用的姜黄素固体脂质纳米粒(curcumin solid lipid nanoparticles,Cur-SLN)和长循环固体脂质纳米粒(long-circulating solid lipid nanoparticles,LSLN),并对2种纳米粒的理化性质进行考察。方法采用乳化-超声法制备Cur-SLN,并对最优处方下制备的Cur-SLN进行包封率和载药量的测定,采用后插法制备Cur-LSLN,并考察Cur-SLN和Cur-LSLN的粒径、Zeta电位,差示扫描量热法(DSC)分析姜黄素在纳米粒中的存在状态,透射电镜观察两者的形态,透析法进行体外释放实验。结果最优处方下制备的Cur-SLN和Cur-LSLN的外观为球形及类球形,包封率分别为(89.15±0.66)%、(92.97±0.27)%,载药量分别为(1.72±0.08)%、(1.98±0.08)%,粒径分别为(144.5±4.1)、(155.0±2.6)nm,Zeta电位分别为(-23.6±0.2)、(-47.8±1.8)m V,通过DSC检测,可确定纳米粒中的Cur已转变为无定形态,体外释放实验结果显示,2种制剂的药物释放分为突释期和缓释期,均在12 h内释放较快,Cur-SLN在96 h累积释放86.63%,Cur-LSLN在96h累积释放76.98%,Cur-LSLN表现出更好的缓释效果。结论采用乳化-超声法可成功制备Cur-SLN和Cur-LSLN,PEG修饰后的纳米粒有更好的缓释性能,可延长药物在体内存在的时间,为靶向药物的开发做了铺垫。
Objective The sustained release curcumin solid lipid nanoparticles(Cur-SLN) and long circulating solid lipid nanoparticles(LSLN) were prepared, and the physicochemical properties of the two nanoparticles were investigated. MethodsCur-SLN was prepared by emulsification ultrasonic method, and then the entrapment efficiency and drug loading of Cur-SLN prepared under the optimal formulation were determined. Cur-LSLN was prepared by back-extrapolation method, and the physicochemical properties of Cur-SLN and Cur-LSLN were evaluated by entrapment efficiency, drug loading, particle size, and Zeta potential; DSC was used to analyze, in vitro release characteristics and the transmission electron microscope(TEM) was used to observe particle appearance. Results Based on the optimal conditions, TEM showed that the appearance of Cur-SLN and Cur-LSLN were spherical or nearly spherical, the entrapment efficiency respectively were(89.15 ± 0.66)% and(92.97 ± 0.27)%, drug loading were(1.72 ± 0.08)% and(1.98 ± 0.08)%, average diameters of particles were(144.5 ± 4.1) nm and(155.0 ± 2.6) nm, and the mean Zeta potential were(-23.6 ± 0.2) mV and(-47.8 ± 1.8) mV. Through DSC detection, it can be determined that Cur in nanoparticles had been transformed into amorphous state. In vitro release test showed that the drug release of the two preparations was divided into two stages: burst release phase and sustained released stage, the release rate was fast in 12 h, and the cumulative release of Cur-SLN in 96 h was 86.63%, and Cur-LSLN was 76.98%, so Cur-LSLN showed better sustained-release effect. ConclusionCur-SLN and Cur-LSLN can be successfully prepared by emulsification ultrasonic method, and PEG modified nanoparticles have better sustained-release properties and prolong the time of the presence of drug in vivo, providing reference for the development of targeted drugs.
Objective The sustained release curcumin solid lipid nanoparticles(Cur-SLN) and long circulating solid lipid nanoparticles(LSLN) were prepared, and the physicochemical properties of the two nanoparticles were investigated. MethodsCur-SLN was prepared by emulsification ultrasonic method, and then the entrapment efficiency and drug loading of Cur-SLN prepared under the optimal formulation were determined. Cur-LSLN was prepared by back-extrapolation method, and the physicochemical properties of Cur-SLN and Cur-LSLN were evaluated by entrapment efficiency, drug loading, particle size, and Zeta potential; DSC was used to analyze, in vitro release characteristics and the transmission electron microscope(TEM) was used to observe particle appearance. Results Based on the optimal conditions, TEM showed that the appearance of Cur-SLN and Cur-LSLN were spherical or nearly spherical, the entrapment efficiency respectively were(89.15 ± 0.66)% and(92.97 ± 0.27)%, drug loading were(1.72 ± 0.08)% and(1.98 ± 0.08)%, average diameters of particles were(144.5 ± 4.1) nm and(155.0 ± 2.6) nm, and the mean Zeta potential were(-23.6 ± 0.2) mV and(-47.8 ± 1.8) mV. Through DSC detection, it can be determined that Cur in nanoparticles had been transformed into amorphous state. In vitro release test showed that the drug release of the two preparations was divided into two stages: burst release phase and sustained released stage, the release rate was fast in 12 h, and the cumulative release of Cur-SLN in 96 h was 86.63%, and Cur-LSLN was 76.98%, so Cur-LSLN showed better sustained-release effect. ConclusionCur-SLN and Cur-LSLN can be successfully prepared by emulsification ultrasonic method, and PEG modified nanoparticles have better sustained-release properties and prolong the time of the presence of drug in vivo, providing reference for the development of targeted drugs.
引文
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[21]张新科,陈英,李鹏,等.PEG包衣左氧氟沙星脂质体的制备及性质[J].山东大学学报:医学版,2017,55(8):42-47.
[22]Dong Z,Guo J,Xing X,et al.RGD modified and PEGylated lipid nanoparticles loaded with puerarin:Formulation,characterization and protective effects on acute myocardial ischemia model[J].Biomed Pharmacother,2017,89:297-304.
[23]林巧平,郭仁平,许向阳,等.注射用姜黄素脂质体的制备及其质量评价[J].中国天然药物,2007,5(3):207-210.
[24]卞龙艳.柚皮素固体脂质纳米粒制剂的制备、表征及药动学评价[J].中国新药杂志,2016,25(12):1424-1430.
[25]Jose S,Anju S S,Cinu T A,et al.In vivo pharmacokinetics and biodistribution of resveratrolloaded solid lipid nanoparticles for brain delive[J].Int JPharm,2014,474(1/2):6-13.
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[27]万小敏,丁宇翔,赵兵杰,等.载葛根素的PEG修饰介孔硅纳米粒的制备及其对急性心肌缺血大鼠的保护作用[J].中草药,2018,49(8):1789-1795.
[28]Torchilin V P,Weissig V,Deng Y,et al.Liposome[M].2nded.Beijing:Chemical Industry Press,2007.
[29]Gabizon A,Shmeeda H,Horowitz A T,et al.Tumor cell targeting of liposome-entrapped drugs with phospholipidanchored folic acid-PEG conjugates[J].Adv Drug Deliv Rev,2004,56(8):1177-1192.
[30]Li C L,Cui J X,Wang C X,et al.Development of pegylated liposomal vinorelbine formulation using“postinsertion”technology[J].Int J Pharm,2010,391(1/2):230-236.
[31]陶慧,余楚钦,黄劲恒,等.姜黄素的增溶及稳定性研究[J].食品与发酵工业,2016,42(8):160-165.
[32]张卿,张良珂,袁佩,等.和厚朴酚固体脂质纳米粒的制备及性质研究[J].中草药,2011,42(4):691-693.
[2]郝东明,张丽.姜黄素联合伊立替康对结肠癌SW620细胞的体外抑制作用[J].现代药物与临床,2016,31(6):731-735.
[3]胡晨,汪玉馨,孟长虹.姜黄素下调NF-κB信号通路抑制化学缺氧诱导的U87细胞炎症反应[J].药物评价研究,2018,41(11):1989-1993.
[4]杨雪梅,邱红梅,田蜜,等.姜黄素对人过氧化物酶体增殖物激活受体γ1激活作用的研究[J].中草药,2017,48(15):3122-3126.
[5]韩伟,雷勇胜.姜黄素治疗泌尿生殖系统癌症的作用机制研究进展[J].现代药物与临床,2016,31(2):260-264.
[6]常明向,吴梅梅,李瀚旻.姜黄素与甘草次酸联用对肝癌Hep G-2细胞增殖的抑制作用[J].药物评价研究,2017,40(1):42-47.
[7]赵爽,程学敏,黎海娟,等.姜黄素干预中枢神经系统疾病生物学机制研究进展[J].中草药,2016,47(3):512-518.
[8]Yoichi S,Yasufumi K,Koji H,et al.Clinical applications of curcumin[J].Pharm Nutr,2015,3(4):131-135.
[9]Schiborr C,Kocher A,Frank J.Curcumin fundamentals of absorption and metabolism[J].Ernahrungs Umschau,2015,62(11):M636-M642.
[10]Ketan H,Goutham R.A,Kanchan H,et al.Indomethacinloaded solid lipid nanoparticles for ocular delivery:Development,characterization,and in vitro evaluation[J].J Ocul Pharmacol Ther,2013,29(2):216-228.
[11]Liu K P,Wang L F,Li Y,et al.Preparation,pharmacokinetics,and tissue distribution properties of icariin-loaded stealth solid lipid nanoparticles in mice[J].Chin Herb Med,2012,4(2):170-174.
[12]邓向涛,阮晓东,郝海军.马钱子碱固体脂质纳米粒凝胶骨架缓释片的研制[J].中草药,2018,49(22):5298-5304.
[13]Shelma R,Sharma C P.Acyl modified chitosan derivatives for oral delivery of insulin and curcumin[J].JMater Sci Mater Med,2010,21(7):2133-2140.
[14]Shamji M F,Hwang P,Bullock R W,et al.Release and activity of anti-TNF alpha therapeutics from injectable chitosan preparations for local drug delivery[J].J Biomed Mater Res B Appl Biomater,2009,90(1):319-326.
[15]Ping Y,Yu L,Hu Y Q,et al.Study on targeting and in vitro anti-oxidation of baicalin solid lipid nanoparticles[J].Chin Herb Med,2012,4(4):336-340.
[16]谭梅娥,姜雯,曾诚,等.田蓟苷固体脂质纳米粒的优化及其在Caco-2细胞模型中的吸收和转运研究[J].中草药,2017,48(10):2051-2060.
[17]Paolino D,Accolla M L,Cilurzo F,et al.Interaction between PEG lipid and DSPE/DSPC phospholipids:An insight of PEGylation degree and kinetics of de-PEGylation[J].Colloids Surf B Biointerfaces,2017,155:266-275.
[18]刘娟,郭宇,胡孟洋,等.葛根素固体脂质纳米粒制备工艺研究[J].黑龙江医药科学,2016,39(1):1-5.
[19]黄霞,朱婷婷,罗晴,等.新藤黄酸纳米脂质载体制备及其药剂学性质研究[J].中草药,2013,44(11):1400-1406.
[20]李静静,贾运涛,田睿,等.柚皮素纳米结构脂质载体的处方优化和初步评价[J].中草药,2015,46(2):211-215.
[21]张新科,陈英,李鹏,等.PEG包衣左氧氟沙星脂质体的制备及性质[J].山东大学学报:医学版,2017,55(8):42-47.
[22]Dong Z,Guo J,Xing X,et al.RGD modified and PEGylated lipid nanoparticles loaded with puerarin:Formulation,characterization and protective effects on acute myocardial ischemia model[J].Biomed Pharmacother,2017,89:297-304.
[23]林巧平,郭仁平,许向阳,等.注射用姜黄素脂质体的制备及其质量评价[J].中国天然药物,2007,5(3):207-210.
[24]卞龙艳.柚皮素固体脂质纳米粒制剂的制备、表征及药动学评价[J].中国新药杂志,2016,25(12):1424-1430.
[25]Jose S,Anju S S,Cinu T A,et al.In vivo pharmacokinetics and biodistribution of resveratrolloaded solid lipid nanoparticles for brain delive[J].Int JPharm,2014,474(1/2):6-13.
[26]Wen Z,Su J Q,Chen Q,et al.Characterization and properties of solid lipid nanoparticles modified with polyethylene glycol-2000-1,2-distearoyl-sn-glycero-3-phosphoethanolamine[J].Sci Adv Mater,2016,8(8):1617-1627.
[27]万小敏,丁宇翔,赵兵杰,等.载葛根素的PEG修饰介孔硅纳米粒的制备及其对急性心肌缺血大鼠的保护作用[J].中草药,2018,49(8):1789-1795.
[28]Torchilin V P,Weissig V,Deng Y,et al.Liposome[M].2nded.Beijing:Chemical Industry Press,2007.
[29]Gabizon A,Shmeeda H,Horowitz A T,et al.Tumor cell targeting of liposome-entrapped drugs with phospholipidanchored folic acid-PEG conjugates[J].Adv Drug Deliv Rev,2004,56(8):1177-1192.
[30]Li C L,Cui J X,Wang C X,et al.Development of pegylated liposomal vinorelbine formulation using“postinsertion”technology[J].Int J Pharm,2010,391(1/2):230-236.
[31]陶慧,余楚钦,黄劲恒,等.姜黄素的增溶及稳定性研究[J].食品与发酵工业,2016,42(8):160-165.
[32]张卿,张良珂,袁佩,等.和厚朴酚固体脂质纳米粒的制备及性质研究[J].中草药,2011,42(4):691-693.