交联环糊精金属有机骨架负载甲氨蝶呤缓释微粒的制备及体内外评价

Preparation and evaluation of methotrexate sustained-release particles using crosslinked cyclodextrin metal-organic frameworks

甲氨蝶呤(methotrexate,MTX)注射给药的半衰期短,毒副作用大。为了改善MTX注射给药的缺陷,本研究将MTX装载在交联环糊精金属有机骨架(crosslinked cyclodextrin metal-organic framework,COF)中,得到载药微粒MTX@COF,采用溶剂蒸发法将阳离子脂质材料(2,3-二油酰基-丙基)-三甲胺[(2,3-dioleyl-propyl)-trimethylamine,DOTAP]包裹在MTX@COF表面,MTX@COF@DOTAP的微粒形态没有显著改变,但具有不同的表面电荷特征。以水和磷酸盐缓冲液(pH 7.4)为释放介质考察缓释微粒的体外释放,并通过大鼠药代动力学评价其体内释放特征。体外释放结果显示,在水中MTX、MTX@COF和MTX@COF@DOTAP于6 h的累积释放量分别为92.70%、36.31%和18.19%;在磷酸盐缓冲液中MTX、MTX@COF和MTX@COF@DOTAP于4 h的累积释放量分别为90.82%、79.37%和58.30%,表明MTX@COF可显著延缓MTX的释放,经DOTAP修饰后的MTX@COF可进一步延缓MTX的释放。大鼠药代动力学研究结果显示,皮下注射MTX@COF@DOTAP组与MTX@COF组及MTX组相比,其平均滞留时间MRT_((0-t))和达峰时间T_(max)明显延长,且MTX@COF@DOTAP组的药时曲线下面积[AUC_((0-t))]是MTX组的1.8倍。本研究制备的MTX@COF@DOTAP微粒经皮下注射给药具有一定的缓释效果,并提高了MTX的生物利用度,为MTX的新剂型开发提供一个新的思路。

Methotrexate(MTX)injection has a short half-life and significant toxic side effects.In order to overcome the demerits of MTX injection,MTX@COF was prepared for subcutaneous injection by loading MTX in crosslinked cyclodextrin metal-organic framework(COF)in this study.The cationic lipid material(2,3-dioleoylpropyl)-trimethylamine(DOTAP)was then coated on the MTX@COF surface by solvent evaporation.Different surface charge characteristics were observed in the coated MTX@COF@DOTAP with no significant change in particle morphology.The in vitro release behaviors of sustained-release particles were investigated in water and phosphate buffer(pH 7.4),and the in vivo release characteristics were evaluated for pharmacokinetics in rats.The in vitro release results showed that the cumulative release of MTX,MTX@COF and MTX@COF@DOTAP within6 h was 92.70%,36.31%and 18.19%in water,respectively;the cumulative release of MTX,MTX@COF and MTX@COF@DOTAP within 4 h was 90.82%,79.37%and 58.30%in phosphate buffer,respectively;the results showed that MTX@COF can significantly delay the release of MTX,the modification to MTX@COF by DOTAP can further delay the release of MTX.Pharmacokinetic studies in rats showed that the mean retention time[MRT_(0-t)]and the time to peak(T_(max))of the subcutaneous injection of MTX@COF@DOTAP group were significantly prolonged compared with the MTX@COF group and the MTX group.The area under the concentration-time curve[AUC_(0-t)]of the MTX@COF@DOTAP subcutaneous injection group was 1.8 times high as that of the MTX group.In this study,MTX@COF@DOTAP particles had a certain sustained-release effect,and could prolong the bioavailability of MTX by subcutaneous injection,which provided a new idea for the development of new MTX dosage forms.