紫杉醇-索拉非尼-聚乳酸-羟基乙酸载药栓塞微球的制备及体外释药特性研究
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篇名: 紫杉醇-索拉非尼-聚乳酸-羟基乙酸载药栓塞微球的制备及体外释药特性研究
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摘要: 目的:制备紫杉醇-索拉非尼-聚乳酸-羟基乙酸(PLGA)载药栓塞微球,建立其含量的测定方法,并考察其体外释药特性。方法:采用乳化-溶剂挥发法制备紫杉醇-索拉非尼-PLGA载药栓塞微球。采用高效液相色谱法测定微球中紫杉醇、索拉非尼的含量并计算载药量及包封率,色谱柱为Agilent TC-C18,流动相为水-乙腈(40 ∶ 60,V/V),流速为1.0 mL/min,检测波长为228 nm,柱温为28 ℃,进样量为10 μL。采用光学显微镜、扫描电镜观察微球的形态,采用激光粒度仪测定微球的粒径;采用高效液相色谱法测定生理温度(37 ℃)下紫杉醇、索拉非尼的释放度;采用阿伦尼乌斯方程预测37 ℃下的反应速率常数,并与实测(37 ℃)值进行比较。结果:紫杉醇、索拉非尼的检测质量浓度线性范围均为2.0~400.0 μg/mL(r均为0.999 6);定量限分别为1.902 6、1.890 2 μg/mL,检测限分别为0.985 5、1.264 5 μg/mL;精密度、稳定性、重复性试验的RSD均小于2%;回收率分别为99.00%~102.91%(RSD=1.12%,n=9)、98.39%~102.96%(RSD=1.94%,n=9)。所得微球形态圆整,表面光滑无粘连、无突起,平均粒径为(139±1.16)μm;紫杉醇、索拉非尼的载药量分别为1.12%、0.85%,包封率分别为73.11%、58.65%;在37 ℃下,41 d内累积释放度分别为(71.83±3.96)%、(81.44±6.02)%;紫杉醇、索拉非尼预测反应速率常数与实测值相对标准偏差的RSD<10%,相似因子分别为83.53、73.95。结论:成功制得紫杉醇-索拉非尼-PLGA载药栓塞微球,其形态较好,且具有较好的缓释作用;预测释放度曲线与实测释放度曲线相关性较好;所建含量测定方法操作简便、稳定性较好。
ABSTRACT: OBJECTIVE: To prepare Paclitaxel-sorafenib-PLGA-loaded embolic microspheres, and to establish a method for the content determination and investigate their in vitro drug release characteristics. METHODS: Paclitaxel-sorafenib-PLGA-loaded embolic microspheres were prepared by emulsification-solvent evaporation method. HPLC method was used to determine the contents of paclitaxel and sorafenib in Paclitaxel-sorafenib-PLGA-loaded embolic microspheres; drug-loading amount and encapsulation efficiency were calculated. The determination was performed on Agilent TC-C18 column with mobile phase consisted of water-acetonitrile (40 ∶ 60,V/V) at the flow rate of 1.0 mL/min. The detection wavelength was set at 228 nm, and column temperature was 28 ℃. The sample size was 10 μL. The morphology of the microspheres was observed by optical microscopy and scanning electron microscopy. The particle size and granularity distribution of microspheres were measured by laser granularity analyzer. The release rates of paclitaxel and sorafenib were determined by HPLC under physiological temperature (37 ℃). The reaction rate constants were predicted by Arrhenius equation at 37 ℃, and compared with the measured value (37 ℃). RESULTS: The linear range of paclitaxel and sorafenib were 2.0-400.0 μg/mL (both r=0.999 6). The quantitative limits were 1.902 6 and 1.890 2 μg/mL, and detection limits were 0.985 5 and 1.264 5 μg/mL, respectively. RSDs of precision, stability and reproducibility tests were all lower than 2%. The recoveries were 99.00%-102.91% (RSD=1.12%, n=9) and 98.39%-102.96% (RSD=1.94%, n=9). The surface of the microspheres were spherical, smooth and no protuberance and no adhesions. The average particle size was (139±1.16) μm. Drug-loading amounts of paclitaxel and sorafenib were 1.12% and 0.85%, respectively. The encapsulation efficiency were 73.11% and 58.65%, respectively. Accumulative release rates were (71.83±3.96)% and (81.44±6.02)% within 41 d at 37 ℃. RSDs for relative standard deviation of prediction reaction rate constant to measured value were less than 10% for paclitaxel and sorafenib. The similarity factors were 83.53 and 73.95. CONCLUSIONS: Paclitaxel-sorafenib-PLGA-loaded embolic microspheres are successfully prepared. The microspheres have good morphology and sustained release. The predicted release curve is well correlated with the measured release curve. Established determination method is simple and stable.
期刊: 2019年第30卷第10期
作者: 陈鑫,李翔,罗晓健,刘微
AUTHORS: CHEN Xin,LI Xiang,LUO Xiaojian,LIU Wei
关键字: 紫杉醇;索拉非尼;聚乳酸-羟基乙酸;载药栓塞微球;体外释药
KEYWORDS: Paclitaxel; Sorafenib; PLGA; Drug-loaded embolic microspheres; Drug release in vitro
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