Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 52, Josef Möller Haus, 6020 Innsbruck, Austria.
Int J Pharm. 2011 Jun 15;411(1-2):10-7. doi: 10.1016/j.ijpharm.2011.02.063. Epub 2011 Mar 4.
The purpose of this study was to design and characterize a novel cationic thiolated polymer. In this regard a hydroxyethylcellulose-cysteamine conjugate (HEC-cysteamine) was synthesized. Oxidative ring opening with periodate and reductive amination with cysteamine were performed in order to immobilize free thiol groups to HEC. The resulting HEC-cysteamine displayed 2035 ± 162 μmol immobilized free thiol groups and 185 ± 64 μmol disulfide bonds per gram of polymer being soluble in both acidic and basic conditions. Unlike the unmodified HEC, in case of HEC-cysteamine, a three-fold increase in the viscosity was observed when equal volumes of the polymer were mixed with mucin solution. Tablets based on HEC-cysteamine remained attached on freshly excised porcine mucosa for 8 0h and displayed increased disintegration time of 2h. Swelling behavior of HEC-cysteamine tablets in 0.1M phosphate buffer pH 6.8 indicated swelling ratio of 19 within 8h. In contrast, tablets comprising unmodified HEC detached from the mucosa within few seconds and immediately disintegrated. In addition, they did not exhibit swelling behavior. The transport of rhodamine 123 across freshly excised rat intestine enhanced by a value of approximately 1.6-fold (p-value = 0.0024) in the presence of 0.5% (m/v) HEC-cysteamine as compared to buffer control. Result from cytotoxicity test of HEC-cysteamine applied to Caco-2 cells in concentration of 0.5% (m/v) revealed 82.4 ± 4.60% cell viability. According to these results, HEC-cysteamine seems to be a promising polymer for various pharmaceutical applications especially for intestinal drug delivery.
本研究旨在设计并表征一种新型阳离子型巯基聚合物。在这方面，合成了羟乙基纤维素-半胱胺缀合物（HEC-半胱胺）。通过高碘酸盐氧化开环和半胱胺还原胺化反应，将游离巯基固定到 HEC 上。所得 HEC-半胱胺每克聚合物显示 2035 ± 162 μmol 固定的游离巯基和 185 ± 64 μmol 二硫键，且在酸性和碱性条件下均具有良好的溶解性。与未修饰的 HEC 不同，在 HEC-半胱胺的情况下，当等体积的聚合物与粘蛋白溶液混合时，观察到粘度增加了三倍。基于 HEC-半胱胺的片剂在新鲜切除的猪黏膜上可附着 80h，且显示出 2h 的崩解时间增加。HEC-半胱胺片剂在 0.1M 磷酸盐缓冲液 pH 6.8 中的溶胀行为表明在 8h 内溶胀比为 19。相比之下，包含未修饰 HEC 的片剂在几秒钟内从黏膜上脱落，并立即崩解。此外，它们没有表现出溶胀行为。与缓冲对照相比，在存在 0.5%（m/v）HEC-半胱胺的情况下， rhodamine 123 经新鲜切除的大鼠肠的转运增加了约 1.6 倍（p 值=0.0024）。在 0.5%（m/v）浓度下应用于 Caco-2 细胞的 HEC-半胱胺的细胞毒性试验结果显示 82.4 ± 4.60%的细胞活力。根据这些结果，HEC-半胱胺似乎是一种有前途的聚合物，可用于各种制药应用，特别是用于肠道药物输送。
