Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
J Control Release. 2014 Dec 10;195:120-9. doi: 10.1016/j.jconrel.2014.06.047. Epub 2014 Jun 30.
Thiolated polymers or designated thiomers are obtained by immobilization of sulhydryl bearing ligands on the polymeric backbone of well-established polymers such as poly(acrylates) or chitosans. This functionalization leads to significantly improved mucoadhesive properties compared to the corresponding unmodified polymers, as disulfide bonds between thiol groups of thiomers and cysteine-rich glycoproteins of the mucus gel layer are formed. Furthermore, enzyme- and efflux-pump inhibiting as well as improved permeation-enhancing properties are advantages of thiolization. By the covalent attachment of mercaptonicotinamide substructures via disulfide bonds to thiolated polymers these properties are even substantially further improved and stability towards oxidation even in aqueous media can be provided. Meanwhile, more than 50 research groups worldwide are working on thiolated polymers. For certain thiomers the scale up process for industrial production has already been done and GMP material is available. Furthermore, safety of thiolated poly(acrylic acid), thiolated chitosan and thiolated hyaluronic acid could be demonstrated via orientating studies in human volunteers and via various clinical trials. The first product (Lacrimera® eye drops, Croma-Pharma) containing a chitosan-N-acetylcysteine conjugate for treatment of dry eye syndrome will enter the European market this year. It is the only product providing a sustained protective effect on the ocular surface due to its comparatively much more prolonged residence time worldwide. Various further products utilizing, for instance, thiolated hyaluronic acid in ocular surgery are in the pipeline.
巯基化聚合物或指定的硫醚是通过将含巯基的配体固定在诸如聚丙烯酸酯或壳聚糖等已有聚合物的主链上来获得的。与相应的未修饰的聚合物相比，这种功能化导致显著改善的粘膜粘附性能，因为硫醚的巯基与粘液凝胶层中富含半胱氨酸的糖蛋白之间形成二硫键。此外，酶和外排泵抑制以及改善的渗透增强特性是硫醚化的优点。通过通过二硫键将巯基烟酸亚结构共价连接到巯基化聚合物上，这些性质甚至可以进一步大大改善，并且即使在水性介质中也可以提供对氧化的稳定性。同时，全球有 50 多个研究小组正在研究巯基化聚合物。对于某些硫醚，已经完成了用于工业生产的放大过程，并且可以提供 GMP 材料。此外，通过在人类志愿者中的定向研究以及各种临床试验，已经证明了巯基化聚（丙烯酸）、巯基化壳聚糖和巯基化透明质酸的安全性。含有壳聚糖-N-乙酰半胱氨酸缀合物的第一种产品（Lacrimera®滴眼液，Croma-Pharma）用于治疗干眼症综合征，今年将进入欧洲市场。由于其在全球范围内的滞留时间相对较长，它是唯一提供对眼表面持续保护作用的产品。各种其他产品正在利用例如眼科手术中的巯基化透明质酸。
