甘草酸二铵半乳糖化壳寡糖纳米粒的制备及体外释放考察

Preparation and release characteristics of diammonium glycyrrhizinate chitosan galactosyl oligosaccharide nanoparticles in vitro

目的合成具有肝靶向特性的半乳糖化壳寡糖,以甘草酸二铵为模型药物,制备肝靶向纳米粒,并考察其外观、粒径及其体外释药特性。方法用化学方法合成了2-亚氨基-2-甲氧基乙基-1-硫代-β-D-半乳吡喃糖苷(IME-thio-galactopyranoside),并对壳寡糖的氨基进行半乳糖化修饰制备了半乳糖化壳寡糖。使用半乳糖化壳寡糖作为载体材料,以span-80为乳化剂、甘油为助乳化剂、硫酸钠为胶凝剂,采用微乳化-胶凝法制备甘草酸二铵壳寡糖纳米粒;采用HPLC法测定甘草酸二铵含量并计算其在不同介质中的累积释放度。结果按最佳处方制得的壳寡糖纳米粒呈球形或类球形,平均粒径为64.12nm,平均包封率为87.5%,载药量为17.8%。在去离子水中,纳米粒释放缓慢,10min内突释量为16%,然后释放缓慢,48h内仅释放38%;在pH=7的磷酸盐缓冲溶液(PBS,150mmol·L-1)中,48h内能够完全释放(91%)。结论微乳化凝胶法适用于甘草酸二铵壳寡糖纳米粒的制备,释药递质对释药程度影响显著,呈离子强度依赖性。

Objective To synthesize liver-targeted galactosyl chitosan oligosaccharide(GAL-COS), prepare diammonium glycyrrhizinate loaded chitosan oligosaccharide nanoparticles and investigate the in vitro release of the nanoparticles. Methods 2-Imino-2-methoxyethly-1-thio-galactose was synthesized from galactose by a series of reactions including acetylation, bromization,condensation,substitution and addition of methanol, and then it was used to modify chitosan oligosaccharide. Using span-80 as emulsifying agent, glycerol as co-emulsifier, diammonium glycyrrhizinate-loaded nanoparticles were prepared by dropping sodium sulfate solution into COS microemulsion. The characteristics and release mechanism of COS-NPs were investigated. Results DG-COS-NPs with DG loading 17.8% were obtained by using chitosan oligosaccharide (COS; MW=10 000; 85% deacetylated) 30 g·L-1 and agglomerated by 40 g·L-1 Na2SO4. The average particle size of the nanoparticles was 64.12 nm and the encapsulation ratio was 87.15 %. In distilled water, only 38% of DG was released in 48 h with a sharp release of 16% in 10 min. In contrast, 91% of DG was released in PBS (pH=7, 150 mmol·L-1) in 48 h. Conclusion Liver-targeted diammonium glycyrrhizinate chitosan oligosaccharide nanoparticles could be prepared easily by using microemulsion-coacervation method. Diammonium glycyrrhizinate was released from nanoparticles mainly through exchange with anions in the release medium, accompanied by erosion of the nanoparticles.