AN ORGANIC ACID-INDUCED SIGMOIDAL RELEASE SYSTEM FOR ORAL CONTROLLED-RELEASE PREPARATIONS .2. PERMEABILITY ENHANCEMENT OF EUDRAGIT RS COATING LED BY THE PHYSICOCHEMICAL INTERACTIONS WITH ORGANIC-ACID

The drug release mechanism of the sigmoidal release system (SRS), whic h is a newly developed multiple-unit type time-controlled release syst em, was investigated. The drug release rate from the Eudragit RS-coate d theophylline beads was considerably enhanced in succinic acid aqueou s 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 s uccinic acid, suggesting that the quaternary ammonium groups of Eudrag it RS are essential to produce the unique drug release profile of the SRS. ion-exchange experiments revealed that organic acids could intera ct with Eudragit RS by an ion exchanging mode to various extents depen ding on the acid species. To examine the individual effect of dissocia ted and undissociated forms of succinic acid on the drug release behav ior of the Eudragit RS-coated theophylline beads, dissolution studies were performed in succinic acid or monosodium succinate aqueous soluti ons with various concentrations. The drug release rate was found to ch ange depending on the concentration of either the dissociated or, the undissociated form of succinic acid with different concentration depen dency. From the glass transition temperature measurement using Eudragi t RS cast film, it was assumed that the undissociated succinic acid wa s distributed to the hydrophobic segment of the polymer, resulting in the increase in mechanical flexibility of the film; whereas the dissoc iated succinic acid electrostatically interacted with the quaternary a mmonium groups of the polymer to promote the distribution and to creat e new ionic circumstances: both effects of the organic acid can accele rate 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 Eud ragit RS-based coating during the drug release process.