Bernkop-Schnürch A, Kast C E, Guggi D
Institute of Pharmaceutical Technology and Biopharmaceutics, Center of Pharmacy, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria.
J Control Release. 2003 Dec 5;93(2):95-103. doi: 10.1016/j.jconrel.2003.05.001.
Thiolated polymers (= thiomers) in combination with reduced glutathione (GSH) were shown to improve the uptake of hydrophilic macromolecules from the GI tract. The mechanism responsible for this permeation enhancing effect seems to be based on the thiol groups of the polymer. These groups inhibit protein tyrosine phosphatase, being involved in the closing process of tight junctions, via a GSH-mediated mechanism. The strong permeation enhancing effect of various thiomer/GSH systems such as poly(acrylic acid)-cysteine/GSH or chitosan-4-thio-butylamidine (chitosan-TBA)/GSH could be shown via permeation studies on freshly excised intestinal mucosa in Ussing-type chambers. Furthermore, the efficacy of the system was also shown in vivo. By utilizing poly(acrylic acid)-cysteine/GSH as carrier matrix, an absolute oral bioavailability for low molecular weight heparin of 19.9 +/- 9.3% and a pharmacological efficacy--calculated on the basis of the areas under the reduction in serum glucose levels of the oral formulation versus subcutaneous (s.c.) injection-for orally given insulin of 7% could be achieved. The incorporation of salmon calcitonin in chitosan-TBA/GSH led on the other hand to a pharmacological efficacy based on the areas under the reduction in plasma calcium levels of the oral thiomer formulation versus intravenous (i.v.) injection of 1.3%. Because of this high efficacy (i), the possibility to combine thiomer/GSH systems with additional low molecular weight permeation enhancers acting in other ways (ii) and minimal toxicological risks as these polymers are not absorbed from the GI tract (iii), thiolated polymers represent a promising novel tool for the oral administration of hydrophilic macromolecules.
巯基化聚合物（=硫醇聚合物）与还原型谷胱甘肽（GSH）联合使用可提高胃肠道对亲水性大分子的摄取。这种渗透增强作用的机制似乎基于聚合物的巯基。这些基团通过GSH介导的机制抑制参与紧密连接关闭过程的蛋白酪氨酸磷酸酶。通过在Ussing型小室中对新鲜切除的肠黏膜进行渗透研究，可以证明各种硫醇聚合物/GSH系统（如聚丙烯酸-半胱氨酸/GSH或壳聚糖-4-硫代丁脒（壳聚糖-TBA）/GSH）具有很强的渗透增强作用。此外，该系统在体内也显示出有效性。以聚丙烯酸-半胱氨酸/GSH作为载体基质，低分子量肝素的绝对口服生物利用度为19.9±9.3%，口服胰岛素的药理疗效（根据口服制剂与皮下注射相比血清葡萄糖水平降低的曲线下面积计算）为7%。另一方面，将鲑鱼降钙素掺入壳聚糖-TBA/GSH中，基于口服硫醇聚合物制剂与静脉注射相比血浆钙水平降低的曲线下面积，药理疗效为1.3%。由于这种高疗效（i）、将硫醇聚合物/GSH系统与其他作用方式的低分子量渗透促进剂联合使用的可能性（ii）以及由于这些聚合物不会从胃肠道吸收而具有最小的毒理学风险（iii），巯基化聚合物是口服亲水性大分子的一种有前途的新型工具。
