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), 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.