基于CRITIC权重赋值的Box-Behnken响应面法优化甘草黄酮纳米海绵制备工艺
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摘要
采用搅拌-冷冻干燥法制备甘草黄酮纳米海绵(LF-NSP),在单因素基础上,以搅拌温度、搅拌时间以及搅拌速度为自变量,载药量、粒径以及总评"归一值"为响应值,采用CRITIC权重赋值结合Box-Behnken响应面法优化制备工艺。采用扫描电子显微镜(SEM),傅里叶变换红外光谱法(FT-IR)和差式扫描量热法(DSC)对纳米海绵的性质进行表征,并考察其体外释放行为。结果表明,甘草黄酮纳米海绵的最优制备工艺为药辅比1∶2,交联剂DPC与β-CD比例4∶1,搅拌温度45℃,搅拌时间4. 8 h,搅拌速度245 r·min-1。所制备甘草黄酮纳米海绵的综合评分为94. 78;傅里叶变换红外光谱和差式扫描量热均表明甘草黄酮纳米海绵的形成,扫描电子显微镜表明其形态为球形颗粒。体外释放实验中甘草黄酮纳米海绵240 min的累积释放度为81. 8%,而原料药仅为31. 5%;纳米海绵可以明显提高甘草黄酮的溶出度。
In this paper,nano-sponges of flavonoids from Glycyrrhizae Radix et Rhizoma( LF-NSP) were prepared by agitationfreeze drying method. Box-benhnken design and response surface method based on the single factor experiment was used to optimize the preparation process,with the stirring temperature as well as stirring time and speed as the independent variables,while with drug loading,particle size and the generalized " normalized value" as the response values. In addition,the nano-sponges were characterized by scanning electron microscope( SEM),infraredspectroscopy( FT-IR) and differential scanning calorimetry( DSC),and its release in vitro was also investigated. The results showed that the optimum preparation conditions for glycyrrhizin nano-sponges were as follows:The proportion of main drug and auxiliary drug was 1∶ 2; the proportion of crosslinking agent DPC and β-CD was 4∶ 1; stirring temperature 45 ℃ for 4. 8 h at 245 r·min-1. The comprehensive score of LF-NSP prepared under these conditions was 94. 78. FT-IR and DSC results indicated the formation of Glycyrrhiza flavonoids nano-sponges,and SEM showed that they were spherical particles in shape. In release experiment in vitro,the cumulative release of glycyrrhizin flavonoids nano-sponges for 240 min was 81. 8%,while that of crude drug was only 31. 5%. Nano-sponges can significantly improve the dissolution of flavonoids from Glycyrrhizae Radix et Rhizoma.
In this paper,nano-sponges of flavonoids from Glycyrrhizae Radix et Rhizoma( LF-NSP) were prepared by agitationfreeze drying method. Box-benhnken design and response surface method based on the single factor experiment was used to optimize the preparation process,with the stirring temperature as well as stirring time and speed as the independent variables,while with drug loading,particle size and the generalized " normalized value" as the response values. In addition,the nano-sponges were characterized by scanning electron microscope( SEM),infraredspectroscopy( FT-IR) and differential scanning calorimetry( DSC),and its release in vitro was also investigated. The results showed that the optimum preparation conditions for glycyrrhizin nano-sponges were as follows:The proportion of main drug and auxiliary drug was 1∶ 2; the proportion of crosslinking agent DPC and β-CD was 4∶ 1; stirring temperature 45 ℃ for 4. 8 h at 245 r·min-1. The comprehensive score of LF-NSP prepared under these conditions was 94. 78. FT-IR and DSC results indicated the formation of Glycyrrhiza flavonoids nano-sponges,and SEM showed that they were spherical particles in shape. In release experiment in vitro,the cumulative release of glycyrrhizin flavonoids nano-sponges for 240 min was 81. 8%,while that of crude drug was only 31. 5%. Nano-sponges can significantly improve the dissolution of flavonoids from Glycyrrhizae Radix et Rhizoma.
引文
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[21]陆瑾,于雪娥,付廷明,等.响应面法优化PLA-α-细辛脑纳米粒的制备工艺[J].中国现代应用药学,2018,35(2):182.
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[24]洪军辉,乡世健,曹思玮,等.甘草总黄酮微海绵的制备及体外释放度评价[J].中国实验方剂学杂志,2017,23(14):12.
[25] Mognetti B,Barberis A,Marino S,et al. In vitro enhancement of anticancer activity of paclitaxel by a Cremophor free cyclodextrinbased nanosponge formulation[J]. J Incl Phenom Macro,2012,274(1/4):201.
[2] Yang R,Wang L Q,Yuan B C,et al. The pharmacological activities of licorice[J]. Planta Med,2015,81(18):1654.
[3] Yang R,Yuan B C,Ma Y S,et al. The anti-inflammatory activity of licorice,a widely used Chinese herb[J]. Pharm Biol,2017,55(1):1.
[4]曹玲娟,颜苗,李焕德,等.雷公藤致肝损伤及与甘草配伍减毒机制的研究进展[J].中国中药杂志,2015,40(13):2537.
[5] Huo X,Liu D,Li G,et al. Flavonoids extracted from licorice prevents colitis-associated carcinogenesis in AOM/DSS mouse model[J]. Int J Mol Sci,2016,17(9):1343.
[6] Tang Z H,Li T,Tong Y G,et al. A systematic review of the anticancer properties of compounds isolated from licorice(Gancao)[J]. Planta Med,2015,81(18):1670.
[7]景晶,赵金英,华冰,等.甘草总黄酮抑制硫代乙酰胺诱导肝纤维化大鼠肝组织中TGF-β-1及Caspase-3的表达[J].中国中药杂志,2015,40(15):3034.
[8]吴超群,李小芳,严敏嘉,等.甘草黄酮纳米混悬剂的制备及其体外溶出率[J].中成药,2017,39(11):2279.
[9]刘圣,谢军,陈象青,等.反射线直角单纯形法优化甘草黄酮阿魏酸乳膏配方[J].中国中药杂志,2010,35(4):449.
[10]王娜,孟子嫣,星星·巴哈努尔,等.甘草黄酮纳米乳的制备及其稳定性研究[J].畜牧与饲料科学,2016,37(3):22.
[11]孙芸,江钰,单丽娟,等.甘草黄酮脂质体的制备及理化性质考察[J].现代中药研究与实践,2011,25(3):55.
[12]梁旭霞,刘莉,张文新,等.甘草黄酮-β-CD包合物的制备及增溶作用研究[J].中国实验方剂学杂志,2010,16(7):1.
[13] Brewster M E,Loftsson T. Cyclodextrins as pharmaceutical solubilizers[J]. Adv Drug Delivery Rev,2007,59(7):645.
[14] Swaminathan S,Pastero L,Serpe L,et al. Cyclodextrin-based nanosponges encapsulating camptothecin:physicochemical characterization,stability and cytotoxicity[J]. Eur J Pharm Biopharm,2010,74(2):193.
[15]邓凤,徐才兵,贾运涛,等.和厚朴酚环糊精纳米海绵的制备及表征研究[J].中国药学杂志,2016,51(16):1390.
[16]黄潇,刘婧,付小梅,等.基于CRITIC法计算权重系数的BoxBehnken响应面法优化栀子炭微波炮制工艺研究[J].中草药,2017,48(6):1133.
[17] Anandam S,Selvamuthukumar S. Optimization of microwave-assisted synthesis of cyclodextrin nanosponges using response surface methodology[J]. J Porous Mat,2014,21(6):1015.
[18]熊友香,汤红霞,马瑞,等.去甲斑蝥素/粉防己碱双载药脂质体的制备工艺及体外释放性质考察[J].中国中药杂志,2018,43(12):2531.
[19]贾成友,李微,张传辉,等.基于多指标权重分析和正交设计法优选白黄泄热止痢片复方提取工艺[J].中草药,2016,47(6):917.
[20]徐江慧.环糊精纳米海绵及其蒿甲醚载药系统研究[D].合肥:安徽中医药大学,2017.
[21]陆瑾,于雪娥,付廷明,等.响应面法优化PLA-α-细辛脑纳米粒的制备工艺[J].中国现代应用药学,2018,35(2):182.
[22] Coviello V,Sartini S,Quattrini L,et al. Cyclodextrin-based nanosponges for the targeted delivery of the anti-restenotic agent DB103:a novel opportunity for the local therapy of vessels wall subjected to percutaneous intervention[J]. Eur J Pharm Biopharm,2017,117:276.
[23] Anandam S,Selvamuthukumar S. Fabrication of cyclodextrin nanosponges for quercetin delivery:physicochemical characterization,photostability,and antioxidant effects[J]. J Mater Sci-Mater El,2014,49(23):8140.
[24]洪军辉,乡世健,曹思玮,等.甘草总黄酮微海绵的制备及体外释放度评价[J].中国实验方剂学杂志,2017,23(14):12.
[25] Mognetti B,Barberis A,Marino S,et al. In vitro enhancement of anticancer activity of paclitaxel by a Cremophor free cyclodextrinbased nanosponge formulation[J]. J Incl Phenom Macro,2012,274(1/4):201.