Narisawa S, Nagata M, Hirakawa Y, Kobayashi M, Yoshino H
Pharmaceutics Research Laboratory, Tanabe Seiyaku Co. Ltd., Osaka, Japan.
J Pharm Sci. 1996 Feb;85(2):184-8. doi: 10.1021/js950180o.
The drug release mechanism of the sigmoidal release system (SRS), which is a newly developed multiple-unit type time-controlled release system, was investigated. The drug release rate from the Eudragit RS-coated theophylline beads was considerably enhanced in succinic acid aqueous solution compared with the release rate in water. However, the drug release rate from the beads coated with Eudragit NE 30D, which has no quaternary ammonium groups in the polymer chain, was not affected by succinic acid, suggesting that the quaternary ammonium groups of Eudragit RS are essential to produce the unique drug release profile of the SRS. Ion-exchange experiments revealed that organic acids could interact with Eudragit RS by an ion exchanging mode to various extents depending on the acid species. To examine the individual effect of dissociated and undissociated forms of succinic acid on the drug release behavior of the Eudragit RS-coated theophylline beads, dissolution studies were performed in succinic acid or monosodium succinate aqueous solutions with various concentrations. The drug release rate was found to change depending on the concentration of either the dissociated or the undissociated form of succinic acid with different concentration dependency. From the glass transition temperature measurement using Eudragit RS cast film, it was assumed that the undissociated succinic acid was distributed to the hydrophobic segment of the polymer, resulting in the increase in mechanical flexibility of the film; whereas the dissociated succinic acid electrostatically interacted with the quaternary ammonium groups of the polymer to promote the distribution and to create new ionic circumstances: both effects of the organic acid can accelerate the hydration of Eudragit RS film. All these results suggest that the unique S-shaped drug release profile of SRS can be brought about by a drastic increase in the permeability through the hydration of Eudragit RS-based coating during the drug release process.
对一种新开发的多单元型定时控释系统——S形释放系统（SRS）的药物释放机制进行了研究。与在水中的释放速率相比，在琥珀酸水溶液中，乙基纤维素RS包衣的茶碱微丸的药物释放速率显著提高。然而，用在聚合物链中没有季铵基团的乙基纤维素NE 30D包衣的微丸的药物释放速率不受琥珀酸的影响，这表明乙基纤维素RS的季铵基团对于产生SRS独特的药物释放曲线至关重要。离子交换实验表明，有机酸可通过离子交换方式与乙基纤维素RS发生不同程度的相互作用，这取决于酸的种类。为了研究琥珀酸的离解形式和未解离形式对乙基纤维素RS包衣的茶碱微丸药物释放行为的单独影响，在不同浓度的琥珀酸或琥珀酸钠水溶液中进行了溶出研究。发现药物释放速率会根据琥珀酸离解形式或未解离形式的浓度而变化，且具有不同的浓度依赖性。通过对乙基纤维素RS流延膜的玻璃化转变温度测量，推测未解离的琥珀酸分布到聚合物的疏水链段，导致膜的机械柔韧性增加；而离解的琥珀酸与聚合物的季铵基团发生静电相互作用，促进分布并创造新的离子环境：有机酸的这两种作用均可加速乙基纤维素RS膜的水化。所有这些结果表明，SRS独特的S形药物释放曲线可通过药物释放过程中基于乙基纤维素RS的包衣水化导致的渗透性急剧增加而实现。
