万龙,王晓帆,王可可,梁宇,李晓红,姜明燕
WAN Long,WANG Xiaofan,WANG Keke,LIANG Yu,LI Xiaohong,JIANG Mingyan

• 1:中国医科大学附属第一医院药学部
• 2:中国医科大学药学院
• 3:中国医科大学附属第四医院药学部

摘要(Abstract)：

目的研究三维有序大孔碳及叶酸(folic acid,FA)修饰的三维有序大孔碳对于难溶性药物羟基喜树碱溶出速率和溶出度的提高,考察具有不同表面性质的两种载体的体外释药特性。方法研究以聚苯乙烯微球(polystyrene,PS)作为胶晶模板制备三维有序大孔碳载体,采用湿法氧化将羧基引入到三维有序大孔碳载体表面,通过酰胺键将叶酸接枝在载体表面。采用场发射扫描电子显微镜(scanning transmission electron microscopy,SEM)对载体的形貌及孔道结构进行观察,Zeta电位分析仪及傅里叶变换红外分析仪(fourier transform infrared spectrometer,FT-IR)用于考察载体表面基团的变化。通过溶剂挥干法将羟基喜树碱载入载体的孔道之中,差示扫描量热仪用于考察药物在载体中的存在状态。结果 PS胶晶模板与蔗糖为碳源制得的三维有序大孔碳呈微米级块状,内部为均一的相互连通的三维立体蜂窝状孔道,叶酸接枝增加了载体的亲水性,载药量为25%时,制备的两种给药体系均呈现无定型。叶酸修饰的载药体系展现了最快的释放速率,15 min内体外累积释放度为72. 7%。结论 PS作为模板、蔗糖作为碳源成功制备了三维有序大孔碳,叶酸修饰可以增加载药体系的亲水性,显著提高难溶性药物羟基喜树碱的溶出速率及溶出度。
Objective Researching the improvement of dissolution rate and accumulated release of 3-dimensionally ordered macroporous carbon( 3 DOM C) carriers with or without folic acid( FA) modification loaded insoluble drug hydroxycamptothecine( HCPT),to investigate the in vitro release characteristics of two kinds of carriers with different surface properties. Methods 3 DOM C carriers were fabricated through hard template method with polystyrene( PS) as colloidal crystal template. Carboxyl groups were introduced onto the surface of 3 DOM C by wet oxidation,and folic acid was grafted onto the surface of the support by amide bond. Field emission scanning electron microscope( SEM) was used to observe the morphology and pore structure of 3 DOM C. Zeta potential analyzer and Fourier transform infrared analyzer( FT-IR) were used to investigate the changes of the surface groups of the carrier. HCPT was loaded into the pore channels of carriers by "solvent evaporation ". The existing status of drugs in carriers was researched by differential scanning calorimeter. Results The morphology of fabricated 3 DOM C carriers is micrometer-nubby and the inner pore structure is uniformly interconnected three-dimensional honeycomb. FA modification increases the hydrophilcity of carriers. The two drug delivery systems are amorphous when drug loading is 25%. The drug delivery system with FA modification possesses the fastest dissolution rate and the accumulated release reach up to 72. 7% in 15 min. Conclusion 3 DOM C carriers are fabricated successfully with PS as colloidal crystal template and sucrose as carbon source. FA modification could increase the hydrophilcity of carriers and observably improve the dissolution rate and accumulated release of the insoluble drug HCPT.

关键词(KeyWords)： 叶酸;三维有序大孔碳;羟基喜树碱;溶出度
folic acid;3-dimensionally ordered macroporous carbon;hydroxycamptothecine;dissolution

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金青年基金资助项目(81703427);; 辽宁省科学技术计划资助项目(2014226033);; 中国医科大学校内课题基金(XZR20160007);; 中国医科大学附属第一医院院内基金资助项目(FSFH201717)

作者(Author): 万龙,王晓帆,王可可,梁宇,李晓红,姜明燕
WAN Long,WANG Xiaofan,WANG Keke,LIANG Yu,LI Xiaohong,JIANG Mingyan

DOI: 10.14066/j.cnki.cn21-1349/r.2018.10.001

参考文献(References)：

• [1] HU Y,ZHENG X,WANG J,et al. 3-D macroporous silica and 2-D mesoporous silica as carriers for improved delivery of poorly w ater-soluble drugs:a comparative study[J]. Journal of Controlled Release,2013,172(1):81.
• [2] ZHANG Y,ZHANG H,CHE E,et al. Development of novel mesoporous nanomatrix-supported lipid bilayers for oral sustained delivery of the w ater-insoluble drug,lovastatin[J]. Colloids&Surfaces B Biointerfaces,2015,128:77-85.
• [3] HU Y,ZHI Z,ZHAO Q,et al. 3D cubic mesoporous silica microsphere as a carrier for poorly soluble drug carvedilol[J]. M icroporous&M esoporous M aterials,2012,147(1):94-101.
• [4] WANG Y,ZHAO Q,HU Y,et al. Ordered nanoporous silica as carriers for improved delivery of w ater insoluble drugs:a comparative study betw een three dimensional and tw o dimensional macroporous silica[J]. International Journal of Nanomedicine,2013,8(1):4015.
• [5] ZHANG Y,WANG H,GAO C,et al. Highly ordered mesoporous carbon nanomatrix as a new approach to improve the oral absorption of the w ater-insoluble drug,simvastatin[J]. European Journal of Pharmaceutical Sciences,2013,49(5):864-872.
• [6] CHEN A,SHI Y,YAN Z,et al. Dosage form developments of nanosuspension drug delivery system for oral administration route[J]. Current Pharmaceutical Design,2015,21(29):4355-4365.
• [7] BALA V,RAO S,BATEMAN E,et al. Enabling oral sn38-based chemotherapy w ith a combined lipophilic prodrug and self-microemulsifying drug delivery system[J]. M olecular Pharmaceutics,2016,13(10):3518-3525.
• [8] ELNAKAT H,RATNAM M. Distribution,functionality and gene regulation of folate receptor isoforms:implications in targeted therapy[J]. Advanced Drug Delivery Review s,2004,56(8):1067-1084.