脂蟾毒配基PLGA-TPGS纳米粒的处方筛选及稳定性考察
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摘要
目的:本研究以脂蟾毒配基(resibufogenin,RBG)为模型药物,以自制的乙交酯丙交酯共聚物-维生素E聚乙二醇1000琥珀酸酯(polylactide-co-glycolide-D-α-tocopheryl polyethylene glycol 1000 succinate,PLGA-TPGS)为载体材料,采用正交试验筛选制备脂蟾毒配基PLGA-TPGS纳米粒(RBG-loaded PLGA-TPGS nanoparticles,RPTN)的最佳处方和制备工艺,并对RPTN进行体外稳定性考察。方法:采用超声乳化-溶剂挥发法制备RPTN,用单一因素法分别考察主药与载体配比、TPGS水溶液浓度、超声功率、超声时间对RPTN的粒径、载药量和包封率的影响。根据单一因素考察的试验结果,设定因素水平表,通过正交试验筛选制备RPTN的最佳处方和制备工艺。采用影响因素、加速、长期试验考察RPTN的体外稳定性。结果:通过正交试验筛选出制备RPTN的最佳处方和制备工艺,即主药与载体比例为3∶10(W∶W),0.05%TPGS水溶液为乳化剂,超声功率250 W下超声10 min。6批RPTN的平均粒径、载药量和包封率分别为(152.3±2.5)nm、(18.4±0.3)%和(79.3±1.2)%(n=6)。在稳定性考察中,RPTN在影响因素、加速、长期试验中均表现出良好的稳定性。结论:筛选出制备RPTN的最佳处方和制备工艺,自制RPTN粒径较小、载药量和包封率较高,体外具有良好的稳定性。
OBJECTIVE To formulate resibufogenin(RBG)-loaded polylactide-co-glycolide-D-α-tocopheryl polyethylene glycol 1000 succinate(PLGA-TPGS)nanoparticles(RPTN)with RBG as model drug and PLGA-TPGS as polymer matrix,the best prescription and preparation technology of nanoparticles were chosen by orthogonal tests,in vitro stability of RPTN was evaluated.METHODS RPTN was prepared by the ultrasonic emulsification-solvent evaporation method.The determination of the best prescription and preparation technology of nanoparticles:influence on preparative conditions(such as size,drug loading and entrapment efficiency)with different ratios of RBG to polymer matrix,different concentrations of TPGS aqueous solution,different ultrasonic power and time were estimated by appraisal method.Then factors and levels of the orthogonal design were established and the best prescription and preparation technologies of nanoparticles were selected.The in vitro stability of RPTN was examined by the stress testing,acceleration testing and long term testing.RESULTS According to orthogonal tests,the best prescription and preparation technologies of RPTN were selected:3∶10(W∶W)was selected as the best ratio of RBG to PLGA-TPGS with 0.05% TPGS aqueous solution as emulsifier,then the mixed solution was sonicated for 10 min at250 W.The average particle size,DL and EE of RPTN were(152.3±2.5)nm,(18.4±0.3)% and(79.3±1.2)%(n=6),respectively.The nanoparticles showed good stability under the conditions of the stress testing,acceleration testing and long term testing.CONCLUSION The best prescription and preparation technologies of RPTN are selected.RPTN produces smaller particle size,higher DL and EE,and good in vitro stability.
OBJECTIVE To formulate resibufogenin(RBG)-loaded polylactide-co-glycolide-D-α-tocopheryl polyethylene glycol 1000 succinate(PLGA-TPGS)nanoparticles(RPTN)with RBG as model drug and PLGA-TPGS as polymer matrix,the best prescription and preparation technology of nanoparticles were chosen by orthogonal tests,in vitro stability of RPTN was evaluated.METHODS RPTN was prepared by the ultrasonic emulsification-solvent evaporation method.The determination of the best prescription and preparation technology of nanoparticles:influence on preparative conditions(such as size,drug loading and entrapment efficiency)with different ratios of RBG to polymer matrix,different concentrations of TPGS aqueous solution,different ultrasonic power and time were estimated by appraisal method.Then factors and levels of the orthogonal design were established and the best prescription and preparation technologies of nanoparticles were selected.The in vitro stability of RPTN was examined by the stress testing,acceleration testing and long term testing.RESULTS According to orthogonal tests,the best prescription and preparation technologies of RPTN were selected:3∶10(W∶W)was selected as the best ratio of RBG to PLGA-TPGS with 0.05% TPGS aqueous solution as emulsifier,then the mixed solution was sonicated for 10 min at250 W.The average particle size,DL and EE of RPTN were(152.3±2.5)nm,(18.4±0.3)% and(79.3±1.2)%(n=6),respectively.The nanoparticles showed good stability under the conditions of the stress testing,acceleration testing and long term testing.CONCLUSION The best prescription and preparation technologies of RPTN are selected.RPTN produces smaller particle size,higher DL and EE,and good in vitro stability.
引文
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[3]蒋洁君,周婧,马宏跃,等.蟾酥对豚鼠离体心脏的毒性作用和物质基础研究[J].中国实验方剂学杂志,2011,17(17):233-237.
[4]Qi F,Li A,Inagaki Y,et al.Antitumor activity of extracts and compounds from the skin of the toad Bufo bufo gargarizans Cantor[J].Int Immunopharmacol,2011,11(3):342-349.
[5]张飞春,孙文革,高晓玲,等.蟾酥乙醇提取物抗肿瘤剂量效应关系实验研究[J].药物研究,2011,20(16):23-24.
[6]王传社,李燕燕,陈娜,等.脂蟾毒配基对人宫颈癌Hela裸鼠移植瘤生长的抑制作用[J].北京中医药大学学报,2006,29(3):184-187.
[7]刘丹,祝林,奉建芳.蟾酥中蟾毒配基类成分的分离纯化及其体外抗肿瘤活性的研究[J].中成药,2010,32(6):937-939.
[8]肖义秀,张瑾峰,吴白燕.脂蟾毒配基诱导人肝癌细胞凋亡作用的研究[J].中国生物工程杂志,2006,26(6):36-39.
[9]方晓玲.药剂学[M].北京:人民卫生出版社,2007,370-371.
[10]Bao X,Gao M,Xu H,et al.A novel oleanolic acid-loaded PLGATPGS nanoparticle for liver cancer treatment[J].Drug Development and Industrial Pharmacy,2015,41(7):1193-1203.
[11]Liu H,Gao M,Xu H,et al.A promising Emodin-loaded poly(lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol1000 succinate nanoparticles for liver cancer therapy[J].Pharm Res,2016,33:217-236.
[12]Ma Y,Zheng Y,Liu K,et al.Nanoparticles of Poly(LactideCo-Glycolide)-d-a-Tocopheryl Polyethylene Glycol 1000 Succinate Random Copolymer for Cancer Treatment[J].Nanoscale Res Lett,2010,5(7):1161-1169.
[13]段晓颖,李强.HPLC法测定益肝康胶囊中华蟾酥毒基与脂蟾毒配基的含量[J].中国药房,2009,20(30):2364-2366.
[14]宋莉,李亚君,王春侠.基于综合评分参数归一化法筛选愈溃单向释药膜成型处方[J].中国医院药学杂志,2015,35(24):2170-2175.
[15]段晓颖,韩红玉,高卫芳.熊果酸脂肪乳注射液的制备及体外评价[J].中国医院药学杂志,2016,36(18):1550-1555.
[16]中国药典.四部[S].2015:353-355.
[17]Feng SS,Zhao L,Zhang Z,et al.Chemotherapeutic engineering:Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for168 h in vivo[J].Chem Eng Sci,2007,62(23):6641-6648.