基于马来酰亚胺基团的肠道黏附纳米粒对改善药物口服生物利用度的研究

Investigation of maleimide groups-based intestinal adhesive nanoparticles for improving oral bioavailability of drugs

目的探索基于马来酰亚胺与肠道黏蛋白共价结合的肠道黏附纳米粒对药物口服生物利用度的影响,构建新型纳米载体用于增强药物口服吸收。方法通过乳化溶剂挥发法制备包载荧光剂香豆素6的马来酰亚胺肠道黏附纳米粒,对制备的黏附纳米粒与非黏附聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]纳米粒的外观、粒径进行了表征,通过香豆素6考察了纳米粒的体外释放、肠灌流及体内药动学。结果制备的马来酰亚胺肠道黏附纳米粒呈类球形,粒径为(139.8±2.650)nm,PDI为(0.071±0.062),Zeta电位为(-5.793±0.737)mV。在4℃条件下放置30 d稳定性良好,体外释放实验表明马来酰亚胺纳米粒释放缓慢,没有突释效应。药动学实验表明香豆素6马来酰亚胺纳米粒的体内消除半衰期(t1/2)和药时曲线下面积(AUC0-t)分别是香豆素6非黏附对照纳米粒组的1.17倍和1.42倍,药时曲线下面积(AUC0-t)是香豆素6溶液剂的1.76倍。结论基于马来酰亚胺与肠道黏蛋白共价结合的肠道黏附纳米粒能延长药物肠道滞留时间,增加口服吸收,提高药物口服生物利用度。

Objective To explore the effect of nanoparticles,which are intestinal adhesive by the covalent binding of maleimide groups to intestinal mucin,on the oral bioavailability of drugs,and to construct novel nanocarriers for enhancing drug penetration and oral absorption.Methods The maleimide groups-based intestinal adhesive nanoparticles coated with the fluorescent agent coumarin 6 were prepared by emulsion solvent evaporation method.The morphology and particle size of the prepared adhesive and non-adhesive nanoparticles were characterized.The particle size,physical stability,in vitro release and pharmacokinetics of the nanoparticles were investigated.Results The prepared maleimide groups-based intestinal adhesion nanoparticles were spherical,the particle size was(139.8±2.650) nm with PDI about(0.071±0.062),the Zeta potential was(-5.793±0.737) mV,respectively.After 30 days′ incubation at 4 ℃,the stability was good.The in vitro release experiments showed that the maleimide groups-based nanoparticles released slowly and there was no burst effect.The in vivo pharmacokinetic study revealed that C6-PLGA-SA-PEG-MAL NPs exhibited a significantly higher bioavailability(AUC0-t,1.76-fold) compared with C6 solution.It also exhibited a longer C6 plasma half-life(t1/2,1.17-fold) and a higher bioavailability(AUC0-t,1.42-fold) compared with C6-PLGA-SA-PEG NPs.Conclusions Intestinal adhesive nanoparticles based on the covalent binding of maleimide groups with intestinal mucin can prolong the intestinal retention time of the drug,increase oral absorption,and improve the oral bioavailability of the drug.