A novel ODT or chewable dosage form for acetaminophen: an isoleucine prodrug approach

The physiochemical property of acetaminophen makes it difficult to be formulated as an orally disintegrating tablet (ODT) or chewable dosage form due to its unpleasantly bitter taste. Prodrug approach of acetaminophen may mask the bitterness of acetaminophen. Isoleucine ester prodrug of acetaminophen (Isoleucine-APAP) was synthesized and evaluated for its hydrolysis in PBS buffer at various pH values and in Caco-2 cell homogenate. Physicochemical characteristics such as melting point and stability of the Isoleucine-APAP prodrug were determined by MDSC technique. The results demonstrate that Isoleucine-APAP is more stable at lower pH than higher pH in PBS buffer. For example, the half-life (T 1/2 ) of Isoleucine-APAP is 200 min at pH 2.0, but 158 min at pH 5.0, and 4.34 min at pH 7.4, respectively. When Carboxypeptidase-A was added to the PBS buffer at pH 7.4, the T 1/2 of Isoleucine-APAP was reduced to 2.30 min. Furthermore, at pH 7.4, the T 1/2 of Isoleucine-APAP in a solution containing Caco-2 cell homogenate is only 0.682 min, much shorter than that in the PBS buffer. This demonstrates that enzymes in the cell homogenate accelerate the hydrolysis of the ester bond. These data indicate that Isoleucine prodrug of acetaminophen may be a good candidate to be developed as ODT or chewable formulations.