RESUMEN
The objective of this study was to develop a tablet formulation of ketoconazole incorporating drug nanoparticles to enhance saturation solubility and dissolution velocity for enhancing bioavailability and reducing variability in systemic exposure. The bioavailability of ketoconazole is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of ketoconazole was developed. Ketoconazole nanoparticles were prepared using a media-milling technique. The nanosuspension was layered onto water-soluble carriers using a fluid bed processor. The nanosuspensions were characterized for particle size before and after layering onto water-soluble carriers. The saturation solubility and dissolution characteristics were investigated and compared with commercial ketoconazole formulation to ascertain the impact of particle size on drug dissolution. The drug nanoparticles were evaluated for solid-state transitions before and after milling using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). This study demonstrated that tablet formulation incorporating ketoconazole nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared with commercially available tablet formulation. There was no affect on solid-state properties of ketoconazole following milling. The manufacturing process used is relatively simple and scalable indicating general applicability to enhance dissolution and bioavailability of many sparingly soluble compounds.