Yu Anan, Lv Jieqiong, Yuan Fang, Xia Zihua, Fan Kaiyan, Chen Gang, Ren Jialin, Lin Cuicui, Wei Shijie, Yang Fan
Department of Pharmaceutics.
Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
Int J Nanomedicine. 2017 Nov 21;12:8353-8362. doi: 10.2147/IJN.S145488. eCollection 2017.
This study aimed to develop a novel methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelle drug delivery system to improve lamotrigine (LTG) distribution in the hippocampus.
LTG-loaded mPEG-PLA/TPGS mixed micelles and LTG-loaded mPEG-PLA micelles were formulated, and their characteristics, particle size, surface morphology, and release behavior in vitro were researched. Then, a microdialysis sampling technique coupled with two validated chromatographic systems was developed for the continuous measurement of the protein-unbound form of LTG in the rat plasma and hippocampus after administering two kinds of micelles and LTG solution intranasally.
The drug loading and mean size of LTG-loaded micelles and LTG-loaded mixed micelles prepared with optimal formulation were 36.44%±0.14%, 39.28%±0.26%, 122.9, and 183.5 nm, respectively, with a core-shell structure. The cumulative release rate in vivo of LTG-loaded mixed micelles was 84.21% at 24 hours and showed more sustained release while that of LTG-loaded micelles was 80.61% at 6 hours. The and area under concentration-time curve from zero to time of last quantifiable concentration of LTG solution, LTG-loaded micelles, and LTG-loaded mixed micelles were 55, 35, and 15 minutes and about 5,384, 16,500, and 25,245 (min⋅μg)/L in the hippocampus, respectively.
The results revealed that LTG-loaded mPEG-PLA/TPGS mixed micelles enhanced the absorption of LTG at the nasal cavity and reduced the efflux of LTG in the brain, suggesting that the function of TPGS inhibited P-glycoprotein and LTG-loaded mPEG-PLA/TPGS mixed micelles had the potential to overcome refractory epilepsy.
本研究旨在开发一种新型的甲氧基聚（乙二醇）-聚（丙交酯）（mPEG-PLA）/D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）混合胶束药物递送系统，以改善拉莫三嗪（LTG）在海马体中的分布。
制备了载LTG的mPEG-PLA/TPGS混合胶束和载LTG的mPEG-PLA胶束，并研究了它们的特性、粒径、表面形态和体外释放行为。然后，开发了一种微透析采样技术，结合两种经过验证的色谱系统，用于在鼻内给予两种胶束和LTG溶液后，连续测量大鼠血浆和海马体中未与蛋白结合形式的LTG。
用最佳配方制备的载LTG胶束和载LTG混合胶束的载药量和平均粒径分别为36.44%±0.14%、39.28%±0.26%、122.9和183.5nm，具有核壳结构。载LTG混合胶束在体内24小时的累积释放率为84.21%，显示出更持续的释放，而载LTG胶束在6小时的累积释放率为80.61%。LTG溶液、载LTG胶束和载LTG混合胶束在海马体中的达峰时间和从零到最后可定量浓度的浓度-时间曲线下面积分别为55、35和15分钟，以及约5384、16500和25245（min⋅μg）/L。
结果表明，载LTG的mPEG-PLA/TPGS混合胶束增强了LTG在鼻腔的吸收，并减少了LTG在脑内的外排，提示TPGS的功能抑制了P-糖蛋白，载LTG的mPEG-PLA/TPGS混合胶束有克服难治性癫痫的潜力。
