基于多糖球形链构象的黄芩自分散结肠靶向释药系统研究

The chain conformations of polysaccharides are closely related to their functions. Studies have shown that it′s better for Scutellaria to treat ulcerative colitis (UC), whose components are flavonoids and polysaccharides. However, the poor solubility of flavonoid limites the efficacy, while polysaccharide had dispersion function based on the sphere-like conformation. Thus, this project proposes hypothesis: Scutellaria flavonoid component-polysaccharide self-dispersion system can be formed using active polysaccharide owing sphere-like conformation as carrier to accelerate the dissolution of insoluble components. The concentration of drug reached colon is lower. However, the colon targeted drug delivery system of Scutellaria self-dispersion system could achieve the objective of colon-specific delivery and rapid drug release, and helps increase the concentration of drug in colon. This project will use laser light scattering, size exclusion chromatography combined with laser light scattering, transmission electron microscopy, atomic force microscopy and other instruments to research the chain conformation of polysaccharide, and use plasma concentration method and pharmacological effects to study the action of promoting dissolution and mechanism of improving bioavailability of sphere-like conformation of polysaccharide. Then, the synergistic mechanism of colon targeted drug delivery system of Scutellaria self-dispersion was considered. The effect of macromolecular polysaccharide on dispersion function of self-dispersion carrier was deeply clarified from microscopic structure to macroscopic efficacy.

多糖链构象与其功能密切相关。研究表明，黄芩治疗溃疡性结肠炎（UC）效果较好，活性组分为黄酮和多糖。但是黄酮组分溶解性差，限制了药效的发挥，而黄芩多糖基于球形链构象特点具备分散功能。因此提出假说：具有球形链构象的活性组分黄芩多糖可作为载体形成黄芩黄酮组分-多糖组分自分散体系，从而促进难溶性组分溶出。药物到达结肠时浓度较低，构建黄芩自分散结肠靶向释药系统可达到结肠定位和快速释药的目的，并提高结肠部位药物浓度。本项目利用激光光散射、尺寸排除色谱—光散射联用仪、原子力显微镜、透射电子显微镜等探讨黄芩多糖的链构象，采用药动学血药浓度法和药理效应法研究球形链构象多糖促进自分散体中难溶性组分溶出及提高其生物利用度的作用机制，并研究黄芩自分散结肠靶向释药系统增强黄芩抗UC的药效机制。从微观结构到宏观药效，深层次阐明中药大分子黄芩多糖球形链构象对自分散体载体分散功能的影响。

黄芩黄酮组分具备抗溃疡性结肠炎药效，但是溶解性差限制了其广泛应用。溃疡性结肠炎病变部位低，药物到达病变部位浓度低。针对黄芩黄酮组分溶解性差的特点，利用具有球形链构象的黄芩多糖分散功能，制备黄芩黄酮组分-多糖组分自分散体，提高其溶出速率；针对药物到达结肠病变部位浓度低的问题，构建黄芩黄酮组分-多糖组分自分散结肠靶向释药系统，提高结肠部位药物浓度的同时，促进难溶性药物的溶出，从而最大程度发挥黄芩抗溃疡性结肠炎药效。实验发现，黄芩苷通过抑制TLR4/NF-κB通路发挥抗溃疡性结肠炎作用。为提高其药效，制备黄芩苷-介孔碳纳米粉固体分散体。采用正交试验设计优选黄芩多糖提取工艺，考察了提取温度、提取时间、液料比、提取次数对多糖得率的影响，得到最佳提取工艺：100℃下液料比为10:1时提取3次。黄芩多糖具有抗溃疡性结肠炎活性。黄芩粗多糖经分离纯化后，得到5个多糖组分，我们测定其相对分子质量分别为4.94*106Da、3.72*106Da、1.64*106Da、4.46*106Da、2.18*106Da。HPLC法分析5个黄芩多糖组分组成，SP1主要由Man、Rib、GlcUA、Glc、Xyl和Ara六种单糖组成；SP2主要由Man、Rib、Rha、GlcUA、Glc、Xyl、Ara、Fuc八种单糖组成；SP3主要由Man、Rib、Rha、GlcUA、GalN、Glc、Xyl、Ara、Fuc九种单糖组成；SP4主要由Man、Rib、Rha、GlcUA、Glc、Xyl、Ara、Fuc八种单糖组成；SP5主要由Man、Rib、GlcUA、GalN、Glc、Xyl、Ara、Fuc八种单糖组成。扫描电镜观察各多糖组分的形态，红外光谱法、紫外光谱法、核磁共振光谱法对其进行光谱解析。以药用丙烯酸树脂中的Eudragit S100 为辅料，制备pH依赖型黄芩自分散结肠靶向片，能达到结肠定位释药的目的，且具有较好的治疗溃疡性结肠炎药效。