N-脂肪酰-N-三甲基壳聚糖的合成及其对蛇床子素的增溶作用

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。

Synthesis of N-fatty acyl-N-trimethyl chitosan and its solubilization on osthole

Objective To synthesize two kinds of amphipathic chitosan (CS) derivatives, self-assembling to polymeric micelles as novel drug delivery system. Methods N-Trimethyl chitosan (TMC) was synthesized by the reaction between CS and CH₃I, and long-chain fatty acid was combined to amino group of TMC so as to synthesize the derivative of N-fatty acyl-N-TMC (FA-TMC). The polymer structure was confirmed by FT-IR, ¹H-NMR spectra, and element analysis. Then the hydrophobicity drug of osthole (OST) was used as model drug to evaluate the solubilizing ability on those polymeric micelles. Results Two kinds of six novel CS derivatives were synthesized, the results indicated that the different degrees of quaternisation (DQ) and degrees of substitution (DS) were important parameters to the micelles properties of FA-TMC. To the OST loaded micelles prepared by ultrasonic method, the best candidate materials of the N-palmitoyl-N-TMC (PA-TMC) was the polyer with DQ of 62.00% and DS of 13.37%, while the N-caprinoyl-N-TMC (CA-TMC) was the polyer with DQ of 43.06% and DS of 22.00%. The entrapment efficiency of PA-TMC and CA-TMC were 76.67% and 79.11%, and the drug-loading rates of PA-TMC and CA-TMC were 19.01% and 19.08%, respectively. The solubility of OST increased up to two orders of magnitude in the OST-loaded micelles. Conclusion FA-TMC is a potential solubilization carrier, self-assembling to polymeric micelles in water, with obvious solubilization on OST, and lays the foundation for the further research and application of OST preparation.