亚麻酸-壳聚糖载多柔比星口服胶束的制备和表征及大鼠在体肠吸收  

Preparation and characterization of linolenic acid-chitosan micelle for doxorubicin oral delivery and its in situ intestinal absorption in rats

作　　者：杨宇涵 林世源 陈卉 李典鹏[2] 奉建芳 吴卫[1] 张玮[1,2] YANG Yu-han;LIN Shi-yuan;CHEN Hui;LI Dian-peng;FENG Jian-fang;WUWei;ZHANGWei(School of Pharmacy,Guilin Medical University,Guilin 541004,China;Guangxi Institute of Botany,Chinese Academy of Sciences,Guilin 541006,China;School of Pharmacy,Guangxi University of Chinese Medicine,Nanning 530200,China)

机构地区：[1]桂林医学院药学院,广西桂林541004 [2]广西壮族自治区中国科学院广西植物研究所,广西桂林541006 [3]广西中医药大学药学院,广西南宁530200

出　　处：《药学学报》2022年第9期2857-2863,共7页Acta Pharmaceutica Sinica

基　　金：广西自然科学基金资助项目(2020GXNSFAA297133);广西科技基地和人才专项(桂科AD19110070);广西高等学校千名中青年骨干教师培育计划(桂教师范〔2019〕47号).

摘　　要：本研究通过制备亚麻酸修饰的壳聚糖胶束(linolenic acid-modified chitosan,CS-LA),以多柔比星(doxorubicin,DOX)为模型药物,构建了CS-LA@DOX胶束给药系统以提高DOX口服生物利用度,并研究其大鼠在体肠吸收情况。透析法制备CS-LA@DOX,通过核磁共振氢谱、傅里叶红外光谱等对聚合物进行表征;测定载药胶束的粒径、zeta电位、包封率(entrapment efficiency,EE)、载药量(drug loading,DL)和临界胶束浓度(critical micelle concentration,CMC)等理化参数,并考察胶束粒子的微观形态及载药的多晶型现象;透析法考察胶束的体外释放;以盐酸多柔比星水溶液为对照,通过大鼠在体肠循环实验考察胶束的促吸收作用。动物福利和实验过程均遵循桂林医学院动物伦理委员会的规定。结果表明,CS与LA通过酰胺键共价结合,DOX以无定型态包载于胶束内核,CS-LA@DOX胶束zeta电位为+12.1 mV,平均粒径为(119.2±2.1)nm,聚合物分散指数(polymer dispersity index,PDI)为0.190±0.08;CS-LA的CMC为51.75μg·mL^(-1);EE和DL分别为(70.23±0.74)%、(8.77±0.02)%;本胶束体外释放较市售的盐酸多柔比星有明显的缓释作用;CS-LA@DOX胶束对DOX在大鼠小肠的吸收具有明显的促进作用。In this study,a novel oral drug delivery system based on linolenic acid-modified chitosan(CS-LA)micelle was developed to improve the oral bioavailability of doxorubicin(DOX),which was proven by its in vivo intestinal absorption in rats.The DOX-loaded CS-LA micelles(CS-LA@DOX)were prepared by the dialysis method.The synthesized micelle material was identified by proton nuclear magnetic resonance spectroscopy(1H-NMR)and Fourier transform infrared spectroscopy(FT-IR).A series of the micelle properties,including particle size distribution,zeta potential,encapsulation efficiency(EE),drug loading(DL),micromorphology,polymorphy,and critical micelle concentration(CMC)were characterized or tested.The in vitro release of micelles was observed by the dialysis method,and the absorption-promoting effect of micelles was investigated by intestinal circulation experiments in rats.The animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Guilin Medical University.The results of 1H-NMR and FT-IR showed that CS and LA were covalently bound via an amide linkage.The DOX encapsulated in the micelle core was in an amorphous state.The as-prepared micelles in the transmission electron microscope(TEM)image showed regular spherical shapes and uniform sizes with a series of excellent characteristics including(119.2±2.1)nm of mean particle size[polymer dispersity index(PDI),0.190±0.08],+12.1 mV of zeta potential,(70.23±0.74)%of EE,(8.77±0.02)%of DL and 51.75μg·mL^(-1)of CMC.Compared with the reference,DOX hydrochloride,the proposed micelle drug delivery system showed an obvious sustained-release effect in vitro release;and enhanced drug absorption in the small intestine of rats.

关 键 词：亚麻酸 壳聚糖胶束 多柔比星 在体单向肠灌流模型 吸收 

分 类 号：R943[医药卫生—药剂学]