槲皮素肠溶PLGA纳米粒各肠段的吸收特性研究

摘要

Objective To study the absorption characteristics of quercetin enteric coated PLGA nanoparticles in the intestine. Methods The quercetin PLGA nanoparticles were prepared successfully by double emulsion solvent evaporation method and high pressure homogenization method. Various quercetin PLGA nanoparticles that were pre-pared with different enteric coating materials such as Eudragit L100, Eudragit L100-55, Eudragit S10, HP55 and HP50 mixed with different concentrations of PLGA. The in vitro drug release rate was studied in artificial gastric and intestinaljuice. Nanoparticle's morphology and size were investigated, and entrapment efficiency was also determined. The preparation process was optimized. The absorption site, drug concentration and flow rate of various quercetin enteric coated PLGA nanoparticles in different intestinal segments were studied through in situ single pass perfusion tech-nique. Results Among various quercetin PLGA nanoparticles that were prepared with five enteric coating materials, there was no statistical significance difference in encapsulation efficiency and particle size index (P>0.05). There were large particles precipitated at PLGA concentrations of 100 mg/mL and 50 mg/mL. In artificial intestinal juice, querce-tin release rate [(84.6 ± 9.8)%] of artificial PLGA nanoparticles was significantly higher than that in gastric juice of (64.7±4.6)%, and the difference was statistically significant (t=5.81, P<0.05). When quercetin concentrations were 1μg/mL, 10μg/mL and 20.0μg/ml, the drug absorption rates constant were (6.6±1.6) Ka/h, (3.5±1.5) Ka/h and (2±0.4) Ka/h re-spectively. The drug absorption rate constant of denum and jejunum was (7.5 ± 2.5) Ka/h;The drug absorption rate con-stant of Ileum and colon was (2.7±1.4);When filling flow velocity was at 0.2 mL/min and 0.8 mL/min, the drug absorp-tion rate constant was (15.5+3.5) Ka/h and (26.5±1.7) Ka/h. The drug absorption rate appeared to inhibit itself concentra-tion at the concentration range of 10~20 μg/mL. The drug absorption rate constant in the duodenum and jejunum was sig-nificantly higher than that in ileum and colon segment. Moreover, the drug absorption rate constant increased as perfu-sion rate increased gradually, and the difference was statistically significant (P<0.05). Conclusion The querce-tin-poly-lactic acid (QC-PLGA) nanoparticles can significantly improve the anti-tumor effect through drug sustained re-lease, and has broad prospects in the field of mass-tumor resection.%目的 研究槲皮素肠溶PLGA纳米粒各肠段的吸收特性.方法 采用高压均质法结合复乳-溶剂挥发法等方法制备槲皮素PLGA纳米粒,进行纳米粒形态学分析与粒径考察及包封率的测定,并优化制备工艺;考察药物在人工胃液、人工肠液不同介质中的槲皮素PLGA纳米粒的释放度;分别以Eudragit L100、Eudragit L100-55、Eudragit S10、HP55、HP50等肠溶包衣材料与PLGA以一定比例量制备槲皮素纳米粒,比较粒径、包封率,筛选肠溶材料及制备方法;分别于人工胃液及人工肠液中测定不同槲皮素肠溶PLGA纳米粒释放度,与槲皮素PLGA纳米粒比较;从吸收部位、药物质量浓度、灌流速度三个方面对槲皮素肠溶PLGA纳米粒的各肠段吸收特性进行考察.结果 5种不同肠溶包衣材料与PLGA以一定比例量制备槲皮素纳米粒的包封率、粒径等指标比较差异均无统计学意义(P>0.05),且在PLGA浓度为100 mg/mL和50 mg/mL时析出大颗粒沉淀;在人工肠液中的槲皮素PLGA纳米粒释放度明显高于人工胃液中,差异有统计学意义(P<0.05);在人工肠液中的槲皮素PLGA纳米粒释放度为(84.6±9.8)%,明显高于人工胃液中的(64.7±4.6)%,差异有统计学意义(t=5.81,P<0.05);质量浓度为1μg/mL时,药物吸收速率常数为(6.6±1.6)Ka/h,质量浓度为10μg/ml时,药物吸收速率常数为(3.5±1.5)Ka/h,质量浓度为20.0μg/mL时,药物吸收速率常数为(2.0±0.4)Ka/h,十二指肠、空肠中的药物吸收速率常数为(7.5±2.5)Ka/h,回肠、结肠中的药物吸收速率常数为(2.7±1.4)Ka/h;灌流速度为0.2 mL/min时,药物吸收速率常数为(15.5±3.5)Ka/h;灌流速度为0.8 mL/min时,药物吸收速率常数为(26.5±1.7)Ka/h;药物吸收速率在质量浓度10~20μg/mL范围内出现了自身浓度抑制;在十二指肠、空肠的药物吸收速率常数明显高于回肠、结肠段,且药物吸收速度常数随着灌流速度的增高而逐渐增高,差异均有统计学意义(P<0.05).结论 制备槲皮素-聚乳酸-羟基乙酸(QC-PLGA)纳米粒可显著提高抗肿瘤的缓释作用,在质量肿瘤切除术后残留癌灶方面前景广阔.