氟比洛芬酯眼用纳米乳-离子敏型原位凝胶的研究

设计新型纳米乳-离子敏感型原位凝胶 (nanoemulsion-in situ gel, NE-ISG), 以氟比洛芬酯 (flurbiprofen axetil, FBA) 为模型药物, 研究药物在家兔眼部的房水药动学特征, 并对其流变学特征、微观形态、角膜损伤效果和角膜滞留特性等进行了评价。采用剪切均质工艺制备氟比洛芬酯纳米乳 (flurbiprofen axetil nanoemulsion, FBA/NE), 与离子敏感型凝胶材料 (结冷胶) 混合后制得氟比洛芬酯纳米乳-原位凝胶 (flurbiprofen axetil  nanoemulsion-in situ gel, FBA/NE-ISG)。流变学结果显示, FBA/NE-ISG发生胶凝后, 黏度和弹性模量分别增加2 Pa·s和5 Pa, 胶凝能力强。透射电镜结果表明, FBA/NE-ISG中乳滴粒度分布均匀, 胶凝前后无明显变化。角膜损伤评价显示, FBA/NE-ISG无角膜刺激性。角膜滞留特性评价结果显示, NE-ISG角膜滞留时间显著延长, NE-ISG和溶液组的消除速率常数分别为0.008 5 min⁻¹和0.105 2 min⁻¹。房水药动学结果显示, FBA/NE-ISG组AUC_{0→12 h} (126.8 µg·min·mL⁻¹) 和MRT (12.3 h) 分别是氟比洛芬钠滴眼液组 (flurbiprofen sodium eye drop, FB-Na) 的2.9倍和2.7倍, 眼部生物利用度显著提高。FBA/NE-ISG能够显著延长药物的眼表滞留时间, 发挥缓释作用, 提高药物的眼部生物利用度, 并有效降低原形药物氟比洛芬 (flurbiprofen, FB) 的眼部刺激性。

Ion-sensitive nanoemulsion-in situ gel system for ophthalmic delivery of flurbiprofen axetil

The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE- ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention.  Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG.  Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa·s and 5 Pa respectively when mixed with     artificial tear at the ratio of 40∶7.  TEM images suggested no significant changes in particle morphology of the pre and post gelation.  Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination.  In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea   retention time significantly since K_NE-ISG (0.008 5 min⁻¹) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the K_{Eye drops} was 0.105 2 min⁻¹, indicated that the cornea retention time of NE-ISG was prolonged significantly.  Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC_{0→12 h} (126.8 µg·min·mL⁻¹) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flrubiprofen sodium eye drops respectively, which meant that the ocular bioavailability was improved greatly by the novel preparation.  Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly.  What’s more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.