Department of Drug Delivery Research, Hoshi University, Tokyo, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Int J Pharm. 2011 May 30;410(1-2):17-22. doi: 10.1016/j.ijpharm.2011.03.004. Epub 2011 Mar 22.
Recently, many people have developed rheumatoid arthritis (RA), and prednisolone (PD) is often used for treatment; however, long use and a large dose of PD can cause toxic side effects. In this study, in order to enhance the therapeutic effects and to suppress the toxic side effects, the conjugate (GC-SP) was prepared by coupling between glycol-chitosan (GC) and succinyl-prednisolone (SP). The drug-release properties of GC-SP were examined and analyzed kinetically. The plasma concentration-time profiles of GC-SP and released PD were investigated after i.v. injection to normal rats, and their pharmacokinetic profiles were analyzed. PD was stable and released gradually (ca. 1%/h) from GC-SP at physiological pH, while PD was unstable at basic pH and the release from GC-SP was accelerated at basic pH. GC-SP showed good systemic retention (more than 16-fold area under the plasma concentration-time curve (AUC) as compared to PD alone), and released PD gradually in vivo. The in vivo release rate was calculated to be much faster than the in vitro rate. From these results, it is expected that GC-SP will be accumulated at inflammatory sites based on enhanced permeability and retention (EPR) effects, and release PD there effectively.
最近，许多人患有类风湿性关节炎（RA），常使用泼尼松龙（PD）进行治疗；然而，长期大剂量使用 PD 会引起毒副作用。在这项研究中，为了提高治疗效果，抑制毒副作用，通过将乙二醇壳聚糖（GC）和琥珀酰泼尼松龙（SP）偶联，制备了轭合物（GC-SP）。考察了 GC-SP 的释药特性，并进行了动力学分析。将 GC-SP 静脉注射给正常大鼠后，考察了其血浆浓度-时间曲线和释放的 PD，并对其药代动力学特征进行了分析。GC-SP 在生理 pH 下，PD 稳定且逐渐释放（约 1%/h），而在碱性 pH 下 PD 不稳定，GC-SP 中的 PD 释放加速。GC-SP 在体内具有良好的系统保留性（与单独使用 PD 相比，AUC 增加了 16 倍以上），并在体内逐渐释放 PD。体内释放速率比体外释放速率快得多。从这些结果可以预期，GC-SP 将基于增强的通透性和保留效应（EPR）在炎症部位蓄积，并在该处有效释放 PD。
