雷公藤内酯醇固体脂质纳米粒的制备及理化性质

目的：以聚乙二醇单硬脂酸酯表面修饰材料结合到固体脂质纳米粒（solid lipid nanoparticles，SLN），以雷公藤内酯醇（triptolide，TPL）为模型药，制备一种具有良好亲水亲脂性的雷公藤内酯醇固体脂质纳米粒。方法：采用熔融-乳化法制备固体脂质纳米粒。通过单因素考察、中心复合设计（central composite design，CCD），考察脂质材料、聚山梨醇酯-80和PEG-stearate（PEG-SA）三个因素对TPL-SLN粒径、包封率和载药量的影响。通过透射电镜、热分析和X-射线衍射考察TPL-SLN的理化性质，并考察其固体脂质纳米粒的稳定性以及体外释放情况。用MTT法测定其对人正常肝L02细胞和肝癌细胞HepG2的增殖抑制作用并计算其IC₅₀。结果：最优的处方：脂质材料为7.5%，聚山梨醇酯80（Tween 80）为2%和PEG-SA为2%，其粒径（193.43±6.07）nm，包封率（87.63±0.09）%，载药量（0.33±0.01）%。透射电镜观察所制备的纳米粒的形态近似于球形，DSC分析和X-射线衍射证实TPL以非晶型的形式存在于固体脂质纳米粒中。稳定性考察发现纳米粒粒径在一个月的贮存期基本没有变化（P>0.05），体外释放表明TPL-SLN具有体外缓释特性。TPL-SLN对肿瘤细胞的抑制作用强于正常肝细胞。结论：雷公藤内酯醇聚乙二醇修饰固体脂质纳米粒有望开发为临床口服用药新剂型。

Preparation and physicochemical characterization of triptolide-loaded solid lipid nanoparticles

OBJECTIVE Triptolide-loaded solid lipid nanoparticles (SLN) coated with polyethylene glycol (PEG) derivatives were prepared, and its physicochemical properties were investigated.METHODS The optimized TPL-SLN was prepared for further evaluation. The solid lipid nanoparticles (SLN) of TPL were prepared by melt emulsification. Single factor, five-level central composite design (CCD) was applied to explore the optimum levels of independent variables such as particle size, encapsulation efficiency (EE) and drug loading (DL). Physicochemical properties of TPL solid lipid nanoparticles were studied, included the morphology, particle size distribution, Zeta potential, entrapment efficiency, drug-loading rate and release characteristics in vitro. MTT method was used to determine its antitumor activity in vitro.RESULTS The optimal formulation was as follows:lipid 7.5%, Tween 80 2% and PEG-stearate 2%. The particle size, EE, and DL were (193.43±6.07) nm, (87.63±0.09)% and (0.33±0.01)%, respectively. The optimized TPL-SLN was in good agreement with predicted values. Shape and surface morphology determined by TEM revealed fairly spherical shape of nanoparticles. The results of DSC and XRD showed that TPL was not present in a crystalline state dispersed into SLNs. In vitro release studies demonstrated that TPL-SLN possessed a controlled release over a period of 12 hrs. No significant change was observed in particle size, Zeta potential or entrapment efficiency over a period of one month (P>0.05), indicating the developed SLN was fairly stable. TPL-SLN had more obvious inhibition of liver cancer HepG2 than L02 cells.CONCLUSION Triptolide-loaded solid lipid nanoparticles coated with polyethylene glycol (PEG) derivatives can be used as candidate pharmaceutical dosage form for anticancer therapy.