Preparation, Characterization and in vitro/vivo Evaluation of Long-Acting Rivaroxaban-Loaded Microspheres

Background: Rivaroxaban is widely used for long-term prevention and maintenance therapy of thromboembolic disorders. The existing oral dosage forms of rivaroxaban lead to poor patient adherence because of repeated daily administration. The aim of this study is to design long-acting rivaroxaban- loaded microspheres to reduce dosing frequency and improve patient compliance. Methods: Rivaroxaban-loaded microspheres were prepared using the emulsion-solvent evaporation method. The microspheres were evaluated in terms of morphology, particle size, drug loading and encapsulation efficiency, the physical state of the drug in the matrix, in vitro release/release mechanism, and in vivo pharmacokinetics in Sprague Dawley rats. Results & Discussion: Rivaroxaban-loaded microspheres presented spherical-shaped particles displaying a mean particle size of 89.3 μm, drug loading of 16.5% and encapsulation efficiency of 97.8%. The X-ray diffraction indicated that rivaroxaban existed in crystal form in the microspheres. In vitro release lasting approximately 50 days was characterized as a tri-phasic pattern: (1) an initial burst release, mainly due to the dissolution of drug particles with direct access to the microparticles’ surface, (2) a “plateau” phase with a slow-release rate controlled by the diffusion and (3) a final, rapid drug release phase controlled by polymer erosion. Pharmacokinetic studies showed that rivaroxaban microspheres maintained a sustained release for more than 42 days. Conclusion: Rivaroxaban-loaded microspheres have great potential clinical advantages in reducing dosing frequency and improving patient compliance. The data obtained from this study could be used as scientific evidence for decision-making in future formulation development.