Mitigation of dose-dependent cilostazol absorption from cocrystals: A coformer regulates gastric dissolution and...

The present study investigated dose-dependent effects on the oral absorption of cilostazol (CIL) from cocrystals with 4-hydroxybenzoic acid (4HBA) and attempted to mitigate these effects by adding an excess amount of intact 4HBA. With increasing CIL-4HBA doses in rats, the relative maximum plasma concentration (C_max) decreased and the time to C_max (T_max) was prolonged. Although the supersaturation and precipitation of CIL were noted in fasted-state simulated gastric fluid, their extent was not dependent on its dose. However, the dissolved fraction of 4HBA, an indicator of cocrystal dissolution, significantly decreased with increasing doses. An analysis of solubility products indicated that at high doses, both components rapidly reached the equilibrium solubility of CIL-4HBA, markedly reducing the dissolution rate. These in vitro results support the reduced absorption rate of CIL. To mitigate dose-dependent effects, a physical mixture of CIL-4HBA with excess 4HBA was evaluated. Cocrystal dissolution in the stomach was strongly suppressed, which led to the disappearance of differences in relative C_max and T_max. These results suggest that solubility products in the stomach govern CIL absorption from cocrystals and also that the addition of an excess amount of an intact coformer effectively mitigates dose-dependent absorption behavior.