文献类型：期刊文献

中文题名：枸橼酸托法替布长效缓释微球的研制、表征及药动学研究

英文题名：Preparation,Characterization and Pharmacokinetics of Tofacitib Citrate Long-Acting Sustained-Release Microspheres

作者：杨群[1];张锴[2];李晓辉[1];李若琼[1];廖红德[1];殷芳雪[1];罗超[1]

机构：[1]绍兴文理学院元培学院,浙江绍兴312000;[2]绍兴震元中药饮片有限公司,浙江绍兴312000

年份：2021

卷号：56

期号：12

起止页码：988

中文期刊名：中国药学杂志

外文期刊名：Chinese Pharmaceutical Journal

收录：CSTPCD、、CSCD2021_2022、Scopus、北大核心、CSCD、PubMed、北大核心2020

基金：绍兴市科技计划项目资助(2018C30009);国家级大学生创新创业训练计划项目资助(201910349006);浙江省大学生科技创新活动计划暨新苗人才计划项目资助(2018R432017);大学生科技创新项目资助[绍市教高〔2017〕71号];2016年浙江省第八届大学生生命科学竞赛三等奖项目。

语种：中文

中文关键词：枸橼酸托法替布;长效缓释微球;扫描电镜法;傅里叶变换红外光谱法;X-射线衍射法;差示扫描量热法;接触角测定法;药动学

外文关键词：tolfretate citrate;long-acting sustained-release microsphere;scanning electron microscopy;Fourier transform infrared spectroscopy;X-ray diffraction;differential scanning calorimetry;contact angle measurement;pharmacokinetics

中文摘要：目的研制枸橼酸托法替布长效缓释微球,进行表征,研究其释药机制及药动学行为。方法以聚乳酸(PLA)、卵磷脂等为载体材料,采用溶剂-喷雾干燥法和乳化(W/O)-喷雾干燥法制备枸橼酸托法替布长效缓释微球;以2、48、144、240和336 h的释放度为指标,筛选长效缓释微球最佳处方和制备工艺;采用扫描电镜法(SEM)、傅里叶变换红外光谱法(FT-IR)、X-射线衍射法(XRD)、差示扫描量热法(DSC)和接触角测定法对微球进行表征;拟合释放动力学方程,考察释药机制;大鼠皮下注射枸橼酸托法替布长效缓释微球及其原料药,建立高效液相色谱法(HPLC)测定大鼠体内血药浓度,考察药动学行为。结果最佳工艺为乳化(W/O)-喷雾干燥法;微球最佳处方组成为枸橼酸托法替布-PLA-卵磷脂=0.2∶2.0∶1.8;SEM结果表明,制得微球为圆球形,大小均匀;DSC和XRD结果表明,药物以分子或无定形形式分散于微球中;FT-IR结果表明,药物与载体材料发生了氢键结合;制得长效缓释微球在0.1 mol·L^(-1)盐酸溶液、水、pH 7.4磷酸盐缓冲液中接触角分别为20.5°、23.5°和20.45°,润湿性良好;制得长效缓释微球2、48、144、240、336 h释放度分别为4.65%、22.95%、50.73%、73.44%和98.02%;枸橼酸托法替布长效缓释微球和枸橼酸托法替布的ρmax分别为(13.04±1.41)和(32.12±3.32)μg·mL^(-1),tmax分别为(4±0.42)和(4±0.38)h,AUC0-∞分别为(2159.45±208.32)和(431.84±42.66)μg·h·mL^(-1)。结论该微球在336 h内呈良好缓释特性,释放速度符合零级动力学方程,释放机制为降解控释机制,降低了血浓的波动,提高了生物利用度。

外文摘要：OBJECTIVE To develop and characterize tofacitinib citrate long-acting sustained-release microspheres,and study its release mechanism and pharmacokinetic behavior.METHODS Tofacitib citrate long-acting sustained-release microspheres were prepared by solvent-spray drying and emulsification(W/O)-spray drying methods with polylactic acid(PLA),lecithin,etc.as carrier materials.The best formulation and preparation process of long-acting sustained-release microspheres were screened with the release rates of 2,48,144,240 and 336 h as indicators.The microspheres were characterized by scanning electron microscopy(SEM),Fourier transform infrared spectroscopy(FT-IR),X-ray diffraction(XRD),differential scanning calorimetry(DSC)and contact angle measurement.The release kinetic equation was fitted and the drug release mechanism was investigated.Rats were injected subcutaneously with tofacitib citrate long-acting sustained-release microspheres and its raw materials,and established a high-performance liquid chromatography(HPLC)method to determine the blood drug concentration in rats to investigate the pharmacokinetic behavior.RESULTS The best process was the emulsification(W/O)-spray drying method;the optimal formulation composition of the microspheres was tofacitinib citrate-PLA-lecithin=0.2∶2.0∶1.8;SEM results showed that the microspheres were spherical and uniform in size;DSC and XRD results showed that the drug was dispersed in the microspheres in a molecular or amorphous form.FT-IR results showed that the drug was hydrogen bonded to the carrier material.The contact angles of the long-acting sustained-release microspheres were 20.5°,23.5°and 20.45°,respectively in 0.1 mol·L^(-1) hydrochloric acid solution,water and pH 7.4 phosphate buffer,with good wettability.The release rates of the long-acting sustained-release microspheres were 4.65%,22.95%,50.73%,73.44%and 98.02%,respectively at 2,48,144,240 and 336 h.The pharmacokinetics of tofacitinib citrate long-acting sustained-release microspheres and tofacitinib citrate were as follows:ρmax(13.04±1.41)μg·mL^(-1) vs(32.12±3.32)μg·mL^(-1),tmax(4±0.42)h vs(4±0.38)h,AUC0-∞(2159.45±208.32)μg·h·mL^(-1) vs(431.84±42.66)μg·h·mL^(-1).CONCLUSION The microspheres show good sustained-release characteristics within 336 h,and the release rate is in line with the zero-order kinetic equation.The release mechanism is a degradation controlled release mechanism,which could reduce the fluctuation of blood concentration and improve the bioavailability.