Abstract

Purpose: The aim of the present study was to find out if nanosuspensions (and microsuspensions) are as good (in terms of exposure and safety) as a solution at different doses. Methods:BX211 used as a model compound of insoluble drugs, was ground in a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was monitored. The pharmacokinetic parameters of BX211 administered as a nanosuspension were compared with those from a solution and/or a microsuspension using the rat as an in vivo species. All formulations were administered orally. Results:The particle size of the nanosuspensions was about 200 nm and about 4 μm for the microsuspensions. The crystallinity and the crystalline form of the ground samples were conserved. The physical and chemical stability of the two kinds of suspensions were unchanged during the investigation time period (six months for the nanosuspensions). The in vivo results of this study show that the pharmacokinetic parameters investigated were comparable at a low dose (3 μmol/kg) for all formulations. However, at a high dose (300 μmol/kg), where the solubility was too low to allow preparation and administration of the substance as a solution, a significant difference was observed between the two suspensions. Conclusion:This study demonstrated a clear correlation between the particle size and in vivo exposure at the high dose. The nanosuspensions provide higher exposure at a high dose (300 μmol/kg) compared with microsuspensions. The nanoparticles have a larger surface, resulting in a higher in vivo dissolution rate, faster absorption and increased bioavailability, compared with microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, is due to a combination of a low dissolution rate and low solubility in the small intestine, followed by the overall low absorption from the colon.


Keywords:  Nanosuspension   Pharmacokinetics   Poorly soluble   Rats