Valenta C, Kast C E, Harich I, Bernkop-Schnürch A
Institute of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria.
J Control Release. 2001 Dec 13;77(3):323-32. doi: 10.1016/s0168-3659(01)00520-x.
The purpose of the present study was to design a novel carrier system based on a mucoadhesive polymer exhibiting improved properties concerning drug delivery to the vaginal mucosa. This was reached by the covalent attachment of L-cysteine to commercially available polyacrylic acid (Carbopol 974P). Mediated by a carbodiimide, increasing amounts of L-cysteine were covalently linked to the polymer. The resulting thiolated polyacrylic acid conjugates (NaC974P-Cys) displayed between 24.8 and 45.8 micromol thiol groups per gram of polymer. Because of the formation of intra- and/or intermolecular disulfide bonds, the viscosity of an aqueous thiolated polymer gel (3%) increased about 50% at pH 7.0 within 1 h. In oscillatory rheological measurements, it was shown that this increase in viscosity is mainly due to the increase in elasticity. Tensile studies carried out on freshly excised cow vagina demonstrated a significant (P<0.05) increase in the total work of adhesion (TWA) compared to the unmodified polymer. An amount of 24.8 micromol thiol groups per gram of polymer resulted in a 1.45-fold increase in the TWA, whereas an amount of 45.8 micromol showed an even 2.28-fold increase. These improved mucoadhesive properties can be explained by the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The release rate of the model drug progesterone from tablets based on microcrystalline cellulose serving as the reference was approximately 1% per hour, whereas it was 0.58% per hour for the unmodified polymer (NaC974P) and 0.12% per hour for the thiolated polymer (NaC974P-Cys). Therefore, this thiolated polymer is a promising carrier for progesterone providing a prolonged residence time and a controlled drug release.
本研究的目的是设计一种基于粘膜粘附聚合物的新型载体系统，该系统在向阴道粘膜给药方面具有改进的性能。这是通过将L-半胱氨酸共价连接到市售聚丙烯酸（卡波姆974P）上实现的。在碳二亚胺的介导下，越来越多的L-半胱氨酸与聚合物共价连接。所得的硫醇化聚丙烯酸共轭物（NaC974P-Cys）每克聚合物显示出24.8至45.8微摩尔的硫醇基团。由于分子内和/或分子间二硫键的形成，硫醇化聚合物水凝胶（3%）在pH 7.0时1小时内粘度增加约50%。在振荡流变学测量中，表明粘度的增加主要是由于弹性的增加。对新鲜切除的母牛阴道进行的拉伸研究表明，与未改性的聚合物相比，粘附总功（TWA）显著增加（P<0.05）。每克聚合物含24.8微摩尔硫醇基团导致TWA增加1.45倍，而45.8微摩尔的量则显示出2.28倍的增加。这些改善的粘膜粘附性能可以通过硫醇化聚合物与粘液层富含半胱氨酸的亚结构域之间形成二硫键来解释。以微晶纤维素为参比的片剂中模型药物黄体酮的释放速率约为每小时1%，而未改性聚合物（NaC974P）为每小时0.58%，硫醇化聚合物（NaC974P-Cys）为每小时0.12%。因此，这种硫醇化聚合物是黄体酮的一种有前景的载体，可提供延长的停留时间和可控的药物释放。
