Assessment of Dose Proportionality of Rivaroxaban Nanocrystals.

Abstract

Rivaroxaban (RXB) is a class II drug, according to the Biopharmaceutics Classification System. Since its bioavailability is low at high doses, dose proportionality is not achieved for pharmacokinetic parameters. However, when taken with food, its bioavailability increases at high doses. In this study, nanocrystal technology was used to increase the solubility and, hence, the bioavailability of RXB. Pluronic F127, pharmacoat 603, and PVP K-30 were used as stabilizers to prepare RXB nanosuspension, combining ball mill and high pressure homogenization methods. Particle sizes of RXB in nanosuspension (formulation A:348nm; formulation B:403nm) and nanocrystal formulations (formulation A:1167nm; formulation B:606nm) were significantly reduced (p < 0.05) compared to those of bulk RXB. In both formulations, 80% of the drug dissolved in 30min. For dose proportionality evaluation, 3, 10, and 15mg/kg of RXB nanosuspensions (formulation B) were administered to rabbits. The dose proportionality for AUC and Cmax of RXB nanocrystals was assessed by the power model, variance analysis of pharmacokinetic parameters, linear regression, and equivalence criterion methods. Dose proportionality for AUC was achieved at doses between 10-15 and 3-15mg/kg. In conclusion, the preparation of a nanocrystal formulation of RXB improved its dissolution rate and pharmacokinetic profile.