多西他赛人血白蛋白微球的制备及体外释药性质的评价
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摘要
目的:通过优选工艺条件制备多西他赛人血白蛋白微球,并考察其体外缓释特性。方法:以人血白蛋白为药物载体,采用乳化-化学交联法制备多西他赛蛋白微球,HPLC测定多西他赛的浓度,通过L16(45)正交设计试验考察药质比、交联剂用量、交联时间、搅拌转速、酸碱度等因素对微球载药量和包封率的影响,利用极差分析和方差分析优选最佳工艺条件;扫描电镜观察微球形态;以累积释药百分率为指标考察微球体外释药特性。结果:最佳工艺条件为药质比为1∶7、交联剂用量为2.0mL、交联时间为1.5h、搅拌转速为300r·min-1、反应介质pH值为7.5;以优化工艺制备的微球在扫描电镜下可见为表面光滑的类球体,平均粒径为36.16μm,载药量为(11.74±0.26)%,包封率为(65.24±1.24)%,体外释药模式符合Higuchi方程Q=14.34t1/2+0.21(r=0.994 5),48h体外累积释药百分率为82.8%。结论:本实验通过优化工艺条件,制备完成载药量、包封率和缓释性均较为理想的多西他赛人血蛋白微球。
OBJECTIVE To prepare docetaxel-albumin microsphere via optimized process before investigating slow releasing in vitro.METHODS Docetaxel-albumin microsphere was prepared with human serum albumin as carrier by emulsion-chemical crosslinking,the encapsulation efficiency and drug loading rate of microsphere were determined by HPLC.The optimal process was selected according to the ratio of m DT/m HSA,consumption of cross-linking agent,cross-linking period,speed of vortex and pH of solution,which were all analyzed via L16(45)orthogonal array design.The feature of microsphere was observed by electron microscope(SEM).Extracorporeal drug releasing characteristics were investigated by the cumulative drug releasing percentage.RESULTS The optimal process of preparing microsphere:docetaxel and albumin ratio of 1∶7,using 2.0mL of crosslinking agent for 1.5hour at the vortex speed of 300r·min1 in pH 7.5solution.The optimal microsphere was observed as smooth spheroid under the SEM,the mean particle size was 36.16μm,the drug loading rate was(11.74±0.26)% and the ecapsulation efficiency was(65.24±1.24)%.In vitro,drug release model was fitted to Higuchi formula Q=14.34t1/2+0.21(r=0.994 5)and cumulative drug releasing percentage was up to 82.8% after 48 hours.CONCLUSION Docetaxel-albumin microsphere is prepared by optimal process,with preferable drug loading rate,ecapsulation efficiency and slower releasing rate.
OBJECTIVE To prepare docetaxel-albumin microsphere via optimized process before investigating slow releasing in vitro.METHODS Docetaxel-albumin microsphere was prepared with human serum albumin as carrier by emulsion-chemical crosslinking,the encapsulation efficiency and drug loading rate of microsphere were determined by HPLC.The optimal process was selected according to the ratio of m DT/m HSA,consumption of cross-linking agent,cross-linking period,speed of vortex and pH of solution,which were all analyzed via L16(45)orthogonal array design.The feature of microsphere was observed by electron microscope(SEM).Extracorporeal drug releasing characteristics were investigated by the cumulative drug releasing percentage.RESULTS The optimal process of preparing microsphere:docetaxel and albumin ratio of 1∶7,using 2.0mL of crosslinking agent for 1.5hour at the vortex speed of 300r·min1 in pH 7.5solution.The optimal microsphere was observed as smooth spheroid under the SEM,the mean particle size was 36.16μm,the drug loading rate was(11.74±0.26)% and the ecapsulation efficiency was(65.24±1.24)%.In vitro,drug release model was fitted to Higuchi formula Q=14.34t1/2+0.21(r=0.994 5)and cumulative drug releasing percentage was up to 82.8% after 48 hours.CONCLUSION Docetaxel-albumin microsphere is prepared by optimal process,with preferable drug loading rate,ecapsulation efficiency and slower releasing rate.
引文
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[14]张智舟,姜守刚,祖元刚.多西紫杉醇白蛋白微球的制备及优化实验研究[J].植物研究,2011,31(3):381-384.
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[2]Cheetham P,Petrylak DP.Tubulin-targeted agents including docetaxel and cabazitaxel[J].Cancer J,2013,19(1):59-65.
[3]王庆利,彭健.吐温80的安全性研究进展[J].毒理学杂志,2006,20(4):262-264.
[4]Tan Q,Liu X,Fu X.Current development in nanoformulations of docetaxel[J].Expert Opin Drug Deliv,2012,9(8):975-990.
[5]Taguchi K,Chuang VT,Maruyama T,Pharmaceutical aspects of the recombinant human serum albumin dimer:structural characteristics,biological properties,and medical applications[J].J Pharm Sci,2012,101(9):3033-3046.
[6]杨峰,梁宏.人血清白蛋白及其复合物的结构基础[J].化学进展,2013,25(4):530-538.
[7]Urien S,BarréJ,Morin C,Paccaly A.Docetaxel serum protein binding with high affinity to alpha 1-acid glycoprotein[J].Invest New Drugs,1996,14(2):147-151.
[8]丁锐,纪宏,余立.人血白蛋白不溶性微粒检测方法的建立及测定结果[J].中国医院药学杂志,2010,30(14):1197-1200.
[9]McCann KB,Vucica Y,Wu J.Use of mep HyperCel for polishing of human serum albumin[J].J Chromatogr B Analyt Technol Biomed Life Sci,2014,969:241-248.
[10]Anraku M,Tsurusaki Y,Watanabe H.Stabilizing mechanisms in commercial albumin preparations:octanoate and N-acetyl-L-tryptophanate protect human serum albumin against heat and oxidative stress[J].Biochim Biophys Acta,2004,1702(1):9-17.
[11]伊春芳,王东凯.多西紫杉醇白蛋白微球的制备及性质[J].中国药剂学杂志,2014,12(5):160-166.
[12]Umashankar PR,Mohanan PV,Kumari TV.Glutaraldehyde treatment elicits toxic response compared to decellularization in bovine pericardium[J].Toxicol Int,2012,19(1):51-58.
[13]张良珂,侯世祥,宋相容.一种白蛋白纳米粒的制备与评价[J].中国药学杂志,2007,42(5):365-367.
[14]张智舟,姜守刚,祖元刚.多西紫杉醇白蛋白微球的制备及优化实验研究[J].植物研究,2011,31(3):381-384.
[15]Simionescu A,Simionescu D,Deac R.Lysine-enhanced glutaraldehyde crosslinking of collagenous biomaterials[J].J Biomed Mater Res,1991,5(12):1495-1505.
[16]Langer K,Balthasar S,Vogel V,Optimization of the preparation process for human serum albumin(HSA)nanoparticles[J].Int J Pharm,2003,257(1-2):169-180.