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首页> 外文学位 >Preformulation and mechanistic studies on inclusion complexes of selected flavonoids with beta-cyclodextrin and its water-soluble derivatives.
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Preformulation and mechanistic studies on inclusion complexes of selected flavonoids with beta-cyclodextrin and its water-soluble derivatives.

机译：所选黄酮类化合物与β-环糊精及其水溶性衍生物的包合物的预配制和机理研究。

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摘要

The present project aimed to investigate the feasibility of utilizing unsubstituted beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) to enhance the stability and aqueous solubilities of quercetin and other selected bioactive flavonoids (as a possible means of improving their bioavailability) and to elucidate the modes of complexation between the beta-CDs and flavonoids. Being important determinants in subsequent formulation development work, the antioxidant activity of the flavonoids and the impact of the beta-CDs on intestinal membrane permeability were also studied. Antioxidant activity was determined using an in vitro Cu2+-mediated low-density lipoprotein (LDL) oxidation assay. Phase solubility analysis, stability assessment and solution nuclear magnetic resonance (NMR) spectroscopy were employed in conjunction with molecular modeling to establish a flavonoid/beta-CD inclusion complex model. Spray-dried complexes of quercetin with HP-beta-CD/SBE-beta-CD were prepared and characterized by laser-diffraction particle sizing, scanning electron microscopy, BET nitrogen adsorption, thermal analysis, powder X-ray diffractometry, and dissolution testing. Effects of beta-CDs on transport of selected markers through rat intestinal epithelium were determined using an Ussing Chamber. Antioxidative activity determination demonstrated that the presence of two adjacent hydroxyl groups in the B-ring of the flavonoid structure is essential for antioxidative activity while other potential reactive sites e.g. the keto group at C4, and the double bond between C2 and C3, are least important. Phase solubility and stability studies revealed that the solubility- and stability-enhancing effects of beta-CDs on quercetin follow the rank order: SBE-beta-CD > HP-beta-CD > beta-CD. Replacement of the proton in the OH group by a sugar moiety and loss of the planar structure in flavonoids tends to reduce their binding to beta-CDs. An inclusion complex model deduced from stability, NMR and molecular modeling data suggested that the B-ring, C-ring and at least part of the A-ring of the flavonoids (except C6) are enclosed within the beta-CD hydrophobic cavity. Physical characterization studies indicated that the spray-dried complexes are amorphous and hygroscopic, consistent in particulate properties between batches and highly water-soluble. Intestinal permeability measurements showed no significant impact on both transcellular and paracellular absorption routes with all three beta-CDs, attesting to their role as carriers rather than penetration enhancers for the substrates.
机译：本项目旨在研究利用未取代的β-环糊精（β-CD），羟丙基-β-环糊精（HP-β-CD）和磺丁基醚β-环糊精（SBE-β-CD）增强稳定性和可行性的可行性槲皮素和其他选定的生物活性类黄酮的水溶性（作为提高其生物利用度的可能方法），并阐明β-CD和类黄酮之间的络合方式。作为后续制剂开发工作的重要决定因素，还研究了类黄酮的抗氧化活性以及β-CD对肠膜通透性的影响。使用体外Cu2 +介导的低密度脂蛋白（LDL）氧化测定法确定抗氧化活性。相溶解度分析，稳定性评估和解决方案核磁共振（NMR）光谱与分子建模相结合，以建立类黄酮/β-CD包合物的复杂模型。制备了槲皮素与HP-β-CD/SBE-β-CD的喷雾干燥复合物，并通过激光衍射粒度分析，扫描电子显微镜，BET氮吸附，热分析，粉末X射线衍射和溶出度测试对其进行了表征。使用Ussing Chamber确定β-CD对选定标记通过大鼠肠上皮运输的影响。抗氧化活性的测定表明，在类黄酮结构的B环中存在两个相邻的羟基对于抗氧化活性是必不可少的，而其他潜在的反应性位点例如是C。最不重要的是C4的酮基以及C2和C3之间的双键。相溶解度和稳定性研究表明，β-CD对槲皮素的溶解度和稳定性增强作用遵循以下顺序：SBE-β-CD>HP-β-CD>β-CD。 OH基中的质子被糖部分取代以及类黄酮中平面结构的损失往往会降低它们与β-CD的结合。从稳定性，NMR和分子建模数据推导的包合物模型表明，类黄酮的B环，C环和至少一部分A环（除C6外）被包围在β-CD疏水腔内。物理特征研究表明，喷雾干燥的复合物是无定形的和吸湿性的，批次之间的颗粒性质一致且高度水溶性。肠道通透性测量结果显示，所有三种β-CD对跨细胞和旁细胞吸收途径均无显着影响，证明了其作为载体的作用，而不是底物的渗透促进剂。

著录项

  • 作者

    Zheng, Ying.;

  • 作者单位

    The Chinese University of Hong Kong (People's Republic of China).;

  • 授予单位 The Chinese University of Hong Kong (People's Republic of China).;
  • 学科 Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 233 p.
  • 总页数 233
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药物化学;
  • 关键词

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