苦参碱脂质立方液晶纳米粒凝胶的制备及体外评价

Preparation and in Vitro Evaluation of Matrine Lipid-based Cubic Liquid Crystalline Nanoparticle Gels

目的:制备苦参碱脂质立方液晶纳米粒(MAT-LLCN)凝胶并考察其体外释放规律与经皮吸收行为。方法:以包封率为指标,在明确单油酸甘油酯(GMO)与泊洛沙姆407(P407)最佳比例的基础上,以极端顶点混料设计法筛选MAT-LLCN最佳处方,并对其载药量进行考察。以预溶胀的卡波姆940为凝胶基质,与MAT-LLCN混合均匀,制得MAT-LLCN凝胶。采用偏光显微镜(PLM)及小角X射线散射(SAXS)对MAT脂质立方液晶(MAT-LLC)进行结构表征。采用改良Franz扩散池法比较MAT-LLCN凝胶及其普通凝胶的体外释放及透皮吸收特性,通过苏木素-伊红(HE)染色观察二者作用于皮肤不同时间所引起的皮肤结构变化情况。结果:MAT-LLCN凝胶最佳处方为GMO-P407(9∶1)质量分数5.5%,MAT质量分数1%~6%,卡波姆9400.6%,加水至足量。制得的MAT-LLC为体心型LLC。制备的MAT-LLCN凝胶体外释放符合Weibull方程(R^(2)=0.9540),释药机制为Fick扩散。体外透皮试验显示,MAT-LLCN凝胶中MAT的累积释放率、稳态释放速率及大鼠皮肤滞留量均明显高于普通凝胶(P<0.05)。皮肤HE染色结果表明,MAT-LLCN凝胶能够使皮肤角质层细胞排列疏松,同时能够维持真皮层细胞结构的稳定。结论:制得的MAT-LLCN凝胶可通过快速打开皮肤角质层屏障,加快药物跨皮肤转运,并在真皮层中形成药物贮库,提示LLC在药物经皮给药领域具有良好的应用前景。

Objective:To prepare matrine lipid-based cubic liquid crystalline nanoparticle(MATLLCN)gels and investigate its in vitro release and transdermal absorption behavior.Method:Taking entrapment efficiency as the index,the optimal formulation of MAT-LLCN was screened by extreme vertex mixture method based on the optimal ratio of glycerol monooleate(GMO)to poloxamer 407(P407),and its drug loading was investigated.MAT-LLCN gels was prepared by mixing MAT-LLCN with pre-swelled carbomer940 as the gel matrix.The structure of MAT-lipid-based cubic liquid crystalline(LLC)was characterized by polarized light microscopy(PLM)and small angle X-ray scattering(SAXS).The in vitro release and transdermal absorption properties of MAT-LLCN gels and MAT ordinary gels were compared by modified Franz diffusion cell method,skin structure changes caused by them were observed by hematoxylin-eosin(HE)staining.Result:The optimal formulation of MAT-LLCN gels was 5.5% of GMO-P407(9∶1),1%-6% of MAT,0.6% of carbomer 940,adding water to sufficient amount.The prepared MAT-LLC was confirmed as body-centered(Im3m)LLC.The in vitro release behavior of MAT-LLCN gels was in accordance with the Weibull equation(R^(2)=0.9540),and the release mechanism was the Fick diffusion.In vitro transdermal test showed that all the parameters of MAT-LLCN gels were higher than those of MAT ordinary gels(P<0.05),including cumulative release rate,steady-state release rate and the amount of drug retention in skin.HE staining results showed that MAT-LLCN gels could loose the cellular arrangement of skin stratum corneum,and maintain the stability of the cell structure of the dermis.Conclusion:The prepared MAT-LLCN gels can accelerate the transdermal drug transport and form drug storage in the dermis by rapidly opening the skin stratum corneum barrier,suggesting that LLC has good application prospects in the field of transdermal drug delivery.