Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent...

The aim of this study was to improve the physicochemical properties and oral absorption of poorly water-soluble everolimus via preparation of a solid dispersion (SD) system using a solvent wetting (SW) technique. The physicochemical properties, drug release profile, and bioavailability of SD prepared by SW process were also compared to SD prepared by the conventional co-precipitation method. Solid state characterizations using scanning electron microscopy, particle size analysis and X-ray powder diffraction indicated that drug homogeneously dispersed and existed in an amorphous state within the intact polymeric carrier. Whereas, a film-like mass was obtained by a co-precipitation method and further pulverization step was needed for tabletization. The drug release from the SD tablet prepared by SW process at a ratio of drug to hydroxypropyl methylcellulose of 1:15 was markedly higher than the drug alone and equivalent to the marketed product (Afinitor(®), Novartis Pharmaceuticals), a SD tablet prepared by co-precipitation method, archiving over 75% the drug release after 30 min. At the accelerated (40°C/75% R.H.) and stress (80°C) stability tests, the novel formula was more stable than drug powder and provided comparable drug stability with the commercially available product, which contains a potentially risky antioxidant, butylated hydroxyl toluene. The pharmacokinetic parameters after single oral administration in beagles showed no significant difference (P>0.01) between the novel SD-based tablet and the marketed product. The results of this study, therefore, suggest that the novel SD system prepared by the solvent wetting process may be a promising approach for improving the physicochemical stability and oral absorption of the sirolimus derivatives.