Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan; School of Traditional Chinese Medicine, China Pharmaceutical University, 24, Tongjiaxiang, Nanjing, 210009, China.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Int J Pharm. 2014 Apr 25;465(1-2):255-61. doi: 10.1016/j.ijpharm.2014.01.035. Epub 2014 Feb 4.
We investigated the drug solubilization mechanism of α-glucosyl stevia (Stevia-G) which was synthesized from stevia (rebaudioside-A) by transglycosylation. (1)H and (13)C NMR peaks of Stevia-G in water were assigned by two-dimensional (2D) NMR experiments including (1)H-(1)H correlation, (1)H-(13)C heteronuclear multiple bond correlation, and (1)H-(13)C heteronuclear multiple quantum coherence spectroscopies. The (1)H and (13)C peaks clearly showed the incorporation of two glucose units into rebaudioside-A to produce Stevia-G, supported by steviol glycoside and glucosyl residue assays. The concentration-dependent chemical shifts of Stevia-G protons correlated well with a mass-action law model, indicating the self-association of Stevia-G molecules in water. The critical micelle concentration (CMC) was 12.0 mg/mL at 37°C. The aggregation number was 2 below the CMC and 12 above the CMC. Dynamic light scattering and 2D (1)H-(1)H nuclear Overhauser effect spectroscopy (NOESY) NMR experiments demonstrated that Stevia-G self-associated into micelles of a few nanometers in size with a core-shell structure, containing a kaurane diterpenoid-based hydrophobic core and a glucose-based shell. 2D (1)H-(1)H NOESY NMR measurements also revealed that a poorly water-soluble drug, naringenin, was incorporated into the hydrophobic core of the Stevia-G micelle. The Stevia-G self-assembly behavior and micellar drug inclusion capacity can achieve significant enhancement in drug solubility.
我们研究了α-葡萄糖基甜菊糖苷（Stevia-G）的药物增溶机制，它是通过转糖苷作用从甜菊糖（Rebaudioside-A）合成的。通过二维（2D）NMR 实验（包括（1）H-（1）H 相关、（1）H-（13）C 异核多键相关和（1）H-（13）C 异核多量子相干光谱学），对水中 Stevia-G 的（1）H 和（13）C 峰进行了归属。Steviol glycoside 和 glucosyl residue 分析支持 Stevia-G 的形成，即 Rebaudioside-A 中掺入了两个葡萄糖单元生成 Stevia-G。（1）H 和（13）C 峰清楚地表明，Stevia-G 质子的浓度依赖性化学位移与质量作用定律模型很好地相关，表明 Stevia-G 分子在水中的自缔合。在 37°C 时，临界胶束浓度（CMC）为 12.0mg/mL。CMC 以下的聚集数为 2，CMC 以上的聚集数为 12。动态光散射和 2D（1）H-（1）H 核 Overhauser 效应光谱（NOESY）NMR 实验表明，Stevia-G 自组装成几纳米大小的胶束，具有核壳结构，包含基于贝壳烯二萜的疏水性核心和基于葡萄糖的壳。2D（1）H-（1）H NOESY NMR 测量还表明，一种难溶于水的药物柚皮素被纳入 Stevia-G 胶束的疏水性核心。Stevia-G 的自组装行为和胶束药物包封能力可以显著提高药物溶解度。
