PEG修饰的盐酸吉西他滨脂质体的制备及质量研究
发布时间：2019-03-23 18:31
【摘要】：为得到制剂学特性优良,且高稳定性的盐酸吉西他滨脂质体,本论文以PEG修饰二硬脂酰磷脂酰乙醇胺(PEG2000-DSPE)、氢化大豆磷脂(HSPE)、胆固醇(Chol)为载体材料,采用改良薄膜法、冻融法制备PEG化盐酸吉西他滨脂质体。建立了盐酸吉西他滨含量测定的HPLC法,并进行了方法学验证。该方法专属性强,重复性良好(RSD2%),准确度高,盐酸吉西他滨在1~40μg/mL内线性关系良好。采用葡聚糖凝胶色谱法分离脂质体和游离药物,准确度较好,回收率高。对脂质体制备工艺进行了研究,通过对比薄膜分散法、乙醇注入法、逆相蒸发法、改良薄膜法、冻融法、硫酸铵梯度法以及PEG2000-DSPE掺入方式等制备方法对吉西他滨脂质体包封率的影响,最终确定采用改良薄膜法与冻融法相结合,PEG2000-DSPE后加制备PEG化盐酸吉西他滨脂质体;并通过单因素试验结合响应面分析法,对PEG化盐酸吉西他滨脂质体的处方和制备工艺进行优化;优化后的脂质体平均包封率71.8%,在透射电镜下呈球状、均匀完整、分散性较好;平均粒径为202.1±5.6 nm,多分散系数(PDI)为0.209±0.04,Zeta电位-17.9±0.73 m V。稳定性试验结果表明,在一定范围内,PEG化脂质体有一定的抗稀释和抗氧化作用;在4℃条件下能稳定存放30 d;在强酸、强碱、高温条件下不稳定。为达到长期保存目的,筛选了PEG化盐酸吉西他滨脂质体冻干粉针剂的处方和工艺。冻干后PEG化脂质体的药物保留率在90%以上,平均粒径为227.4±6.4 nm,PDI为0.223±0.05,Zeta电位为-17.4±0.86 mV,在4℃条件下能稳定存放3个月。体外释放结果表明,PEG化脂质体中药物的释放速率较游离药物和普通脂质体释放速率小;PEG外加法比内加法制备的脂质体释药速率小,且均具有一定的缓释作用。综上所述,本文制备了PEG化盐酸吉西他滨脂质体及其冻干制剂,并对其制备工艺、制剂学性质进行了研究,为以后深入研究盐酸吉西他滨以及其它水溶性药物脂质体制剂打下了良好的基础。
[Abstract]:In order to obtain gemcitabine hydrochloride liposomes with excellent properties and high stability, PEG modified distearyl phosphatidylethanolamine (PEG2000-DSPE) and hydrogenated soybean phospholipid (HSPE), cholesterol (Chol) were used as carrier materials. PEG gemcitabine hydrochloride liposomes were prepared by modified thin film method and freeze-thaw method. A HPLC method for the determination of gemcitabine hydrochloride was established and validated. The method has good specificity, good repeatability (RSD2%) and high accuracy. The calibration curve of gemcitabine hydrochloride is good in the range of 1 ~ 40 渭 g / mL. The separation of liposomes and free drugs by dextran gel chromatography showed good accuracy and high recovery. The preparation process of lipid system was studied by comparing film dispersion method, ethanol injection method, reverse phase evaporation method, modified thin film method, freeze-thaw method. The effects of ammonium sulfate gradient method and PEG2000-DSPE incorporation method on the entrapment efficiency of gemcitabine liposomes were studied. Finally, the modified thin film method combined with freeze-thaw method was used to prepare gemcitabine hydrochloride liposomes with PEG after PEG2000-DSPE. The formulation and preparation technology of PEG gemcitabine hydrochloride liposomes were optimized by single factor test and response surface analysis. The average entrapment efficiency of the liposomes was 71.8% and the average particle size was 202.1 卤5.6mV, (PDI) was 0.209 卤0.04, Zeta potential was-17.9 卤0.73 MV, and the average diameter of the liposomes was 202.1 卤5.6mmol / L, (PDI) was 0.209 卤0.04mV. the average entrapment efficiency of the liposomes was 71.8%. The stability test results show that PEG liposomes have certain anti-dilution and anti-oxidation effects within a certain range, can be stored stably at 4 鈩，
本文编号：2446122
[Abstract]:In order to obtain gemcitabine hydrochloride liposomes with excellent properties and high stability, PEG modified distearyl phosphatidylethanolamine (PEG2000-DSPE) and hydrogenated soybean phospholipid (HSPE), cholesterol (Chol) were used as carrier materials. PEG gemcitabine hydrochloride liposomes were prepared by modified thin film method and freeze-thaw method. A HPLC method for the determination of gemcitabine hydrochloride was established and validated. The method has good specificity, good repeatability (RSD2%) and high accuracy. The calibration curve of gemcitabine hydrochloride is good in the range of 1 ~ 40 渭 g / mL. The separation of liposomes and free drugs by dextran gel chromatography showed good accuracy and high recovery. The preparation process of lipid system was studied by comparing film dispersion method, ethanol injection method, reverse phase evaporation method, modified thin film method, freeze-thaw method. The effects of ammonium sulfate gradient method and PEG2000-DSPE incorporation method on the entrapment efficiency of gemcitabine liposomes were studied. Finally, the modified thin film method combined with freeze-thaw method was used to prepare gemcitabine hydrochloride liposomes with PEG after PEG2000-DSPE. The formulation and preparation technology of PEG gemcitabine hydrochloride liposomes were optimized by single factor test and response surface analysis. The average entrapment efficiency of the liposomes was 71.8% and the average particle size was 202.1 卤5.6mV, (PDI) was 0.209 卤0.04, Zeta potential was-17.9 卤0.73 MV, and the average diameter of the liposomes was 202.1 卤5.6mmol / L, (PDI) was 0.209 卤0.04mV. the average entrapment efficiency of the liposomes was 71.8%. The stability test results show that PEG liposomes have certain anti-dilution and anti-oxidation effects within a certain range, can be stored stably at 4 鈩，
本文编号：2446122
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