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目的合成2类两亲性壳聚糖(chitosan,CS)衍生物,自组装成聚合物胶束作为难溶性药物的新型递药载体。方法先将CS与碘甲烷反应生成N-三甲基壳聚糖(trimethyl chitosan,TMC),然后在TMC的氨基上引入长链脂肪酸(软脂酸和癸酸),合成了两亲性的N-脂肪酰-N-三甲基壳聚糖(N-fatty acyl-N-Trimethyl chitosan,FA-TMC)衍生物。通过FT-IR、1H-NMR和元素分析法,对衍生物的分子结构和N-位取代度进行表征,同时以疏水性药物蛇床子素(osthole,OST)为模型,探讨其胶束增溶特性。结果实验合成了2类6种不同的新型CS衍生物,分析显示季胺化程度和脂肪酰基接枝率对FA-TMC的胶束性质有较大的影响;对于超声法制备的OST载药胶束,季胺化程度为62.00%、软脂酰基接枝率为13.37%的N-软脂酰-N-三甲基壳聚糖(N-palmitoyl-N-trimethyl chitosan,PA-TMC)和季胺化程度为43.06%、癸酰基接枝率为22.00%的N-癸酰-N-三甲基壳聚糖(N-caprinoyl-N-trimethyl chitosan,CA-TMC)的包封率分别为76.67%、79.11%,载药量分别为19.01%、19.08%,可使OST在水中的溶解度提高两个数量级。结论 FA-TMC是一种具有潜在应用价值的增溶载体,其在水中能自组装形成胶束,并对OST有明显的增溶作用,为OST制剂深入研究与应用奠定了基础。
OBJECTIVE: To synthesize two types of chitosan (CS) derivatives and self-assemble into polymer micelles as novel drug delivery carriers. The method first reacts CS with methyl iodide to form trimethyl chitosan (TMC), then introduces long chain fatty acids (palmitic acid and capric acid) into the amino group of TMC to synthesize amphiphilic N - N-fatty acyl-N-Trimethyl chitosan (FA-TMC) derivatives. The molecular structure and N-substituted degree of the derivatives were characterized by FT-IR, 1H-NMR and elemental analysis. The hydrophobic drug osthole (OST) was used as a model to study the solubilization of micelles characteristic. Results Two classes of six novel CS derivatives were synthesized. The results showed that the degree of quaternization and the degree of fatty acyl group grafting had a significant effect on the micellar properties of FA-TMC. For the OST-loaded gels prepared by ultrasound, Bundle, N-palmitoyl-N-trimethyl chitosan (PA-TMC) with a degree of quaternization of 62.00% and a palmitoyl group grafting ratio of 13.37% The entrapment efficiencies of N-caproyl-N-trimethyl chitosan (CA-TMC) with a degree of amination of 43.06% and a decanoyl group grafting ratio of 22.00% were 76.67 % And 79.11%, respectively. The drug loadings were 19.01% and 19.08% respectively, which could increase the solubility of OST in water by two orders of magnitude. Conclusion FA-TMC is a potentially useful solubilizing carrier. It can self-assemble into micelles in water and has obvious solubilization effect on OST, which lays the foundation for the further research and application of OST preparations.