Enhancement of dissolution and bioavailability of ezetimibe by amorphous solid dispersion nanoparticles fabricated using supercritical antisolvent process

Abstract

The purpose of the present study was to fabricate ezetimibe-hydroxypropyl cellulose (HPC) solid dispersion nanoparticles with enhanced dissolution and oral bioavailability using the supercritical antisolvent (SAS) process. We investigated the influence of SAS process parameters (pressure, temperature, and solute concentration) on the formation of ezetimibe-HPC solid dispersion particles. Physico-chemical properties of solid dispersion nanoparticles were characterized by scanning electron microscopy, differential scanning calorimeter, powder X-ray diffraction, a particle size analyzer, and measurements of the specific surface area. The mean particle size of ezetimibe-HPC solid dispersions could be controlled by the solute concentration. Physico-chemical analysis demonstrated that ezetimibe is amorphous in all solid dispersions. The dissolution rate of the solid dispersion nanoparticles was inversely proportional to the mean particle size. Ezetimibe administered in the form of 150.6-nm HPC solid dispersion nanoparticles demonstrated rapid dissolution of up to 95 % of the total amount within 10 min, as well as higher oral bioavailability than the drug introduced in the physical mixture. We also observed 3.2- and 2.0-fold increases in Cmax and AUC0→24 h values, respectively, for ezetimibe administered in the nanoparticle form compared to the drug within the physical mixture. Therefore, these results demonstrated that dissolution and oral absorption of ezetimibe can be enhanced by formulating it in the form of amorphous HPC solid dispersion nanoparticles manufactured using the SAS process.