槲皮素磷脂复合物固体分散体增强对氧化损伤小鼠视网膜的保护作用

Quercetin-phospholipid Solid Dispersion Enhances Protective Effects on Oxidative Damage Retina in Mice

目的：研究槲皮素磷脂复合物固体分散体对氧化损伤模型小鼠视网膜的保护作用。方法：采用溶剂挥发法制备槲皮素磷脂复合物固体分散体,测定槲皮素的溶解性、溶出度和大鼠口服的生物利用度;采用高脂饮食结合氢醌制作小鼠视网膜氧化损伤模型,25只C57BL/6小鼠随机分为年龄对照组、溶媒对照组、药物治疗组（包括槲皮素、磷脂复合物和固体分散体组,给药量均为槲皮素400 mg·kg（-1）·d（-1））,灌胃给药,1次/d,持续3个月,电镜观察小鼠视网膜并进行RPE下沉积物半定量评定及Bruch膜厚度测量。结果：槲皮素磷脂复合物固体分散体在水和氯仿中的溶解性显著好于原药和磷脂复合物（P〈0.01）;槲皮素、磷脂复合物和固体分散体的累计溶出率分别为：31.4%、46.1%和80.2%,槲皮素从固体分散体中的溶出速率和程度明显大于原药和磷脂复合物;槲皮素、磷脂复合物和固体分散体在大鼠体内的AUC_（0→∞）分别为5.461、8.074、12.015μg·h/m L,固体分散体中槲皮素的生物利用度显著高于原药（P〈0.01）和磷脂复合物（P〈0.05）;与溶媒对照组比较,槲皮素对氧化损伤模型小鼠RPE下沉积物及Bruch膜厚度没有明显影响,磷脂复合物、固体分散体可显著减少RPE下沉积物（P〈0.05、P〈0.01）,固体分散体作用优于磷脂复合物（P〈0.05）,磷脂复合物及其固体分散体均可减轻Bruch膜增厚（P〈0.05）,两者作用没有显著性差异。结论：固体分散技术能显著改善槲皮素的溶解性和溶出率,提高其生物利用度;槲皮素磷脂复合物固体分散体能增强对氧化损伤小鼠视网膜的保护作用。

Objective： To study the protective effects of quercetin-phospholipid solid dispersion（ Q-P SD） on oxidative injury retina of mice. Methods： Q-P SD was prepared by solvent evaporation. The solubility,dissolution and oral bioavailability of quercetin were measured. Mice model of retinal oxidative damage was made by high-fat diet combined with hydroquinone. Twenty-five C57 BL/6 mice were randomly divided into aging control,vehical control and treatment groups（ drugs including quercetin,phospholipids complex and solid dispersion,dosage of quercetin： 400 mg · kg（-1）·d（-1））,and then were given relevant medicines intragastrically once a day for 3 successive months. Transmission electron microscopy was used to evaluate sub-RPE deposit formation and Bruch membrane（ Br M） thickness and the semi-quantitative grading of deposit severity was performed. Results： The solubility of Q-P SD in water and chloroform was significantly better than that of the pure quercetin and phospholipid complex（ P 〈 0. 01）. The cumulative dissolution rates of quercetin,phospholipids complex and solid dispersion were 31. 4%,46. 1% and 80. 2% respectively. Q-P SD showed a significantly higher solubility and dissolution rate than those of quercetin and phospholipid complex. The AUC_（0→∞） values of quercetin,phospholipids complex and solid dispersion were 5. 461 μg · h/m L,8. 074 μg · h/m L and 12. 015μg·h/m L respectively. The pharmacokinetic parameters clearly showed enhanced bioavailability of Q-P SD as com-pared to quercetin（ P 〈 0. 01） and phospholipids complex（ P 〈 0. 05）. Compared with vehical control group,quercetin had no significant effects on sub-RPE deposit formation and thickening of Br M in model mice. The quercetin phospholipids complex and its solid dispersion can significantly inhibit sub-RPE deposit formation（ P 〈 0. 05,P 〈 0. 01）. The solid dispersion showed a significantly better effects than that of phospholipid complex（ P 〈 0. 05）. Quercetin phospholipid complex and its solid dispersion can reduce thickening of Br M in mice（ P 〈 0. 05） and there was no significant difference between two groups. Conclusion： The solid dispersion technique markedly improves the solubility,dissolution rate and bioavailability of quercetin. Q-P SD enhances protective effects on oxidative damage retina in mice.