Particle size reduction and pharmacokinetic evaluation of a poorly soluble acid and a poorly soluble base during early development.

摘要

AIM: The aim of the present study was to find out if nanosuspensions were a better choice compared with microsuspensions, for the present substances with water solubility in the order of 2-3 muM (pH 6.8, small intestinal pH) and no permeability limitations. The ambition was also to understand what the higher solubility in the stomach for BA99 means in terms of absorption properties of the substance. METHOD: The pharmacokinetic parameters of a poorly soluble acid (AC88) and a poorly soluble base (BA99) administered orally as nanosuspensions have been compared with those from microsuspensions using rat as in vivo species. RESULTS: A significant difference was observed between the two suspensions for AC88 already at the lowest dose, 5 mumol/kg (the particle size of the nanosuspensions and the microsuspensions was about 200 nm and 14 mum, respectively). These results were further confirmed at a high dose (500 mumol/kg). However, for BA99, there were no significant differences between the two formulations at any dose investigated (the particle size of the nanosuspensions and the microsuspensions was about 280 nm and 12 mum, respectively). CONCLUSIONS: The study demonstrated a clear correlation between particle size and in vivo exposures for an acidic compound, the nanosuspensions providing the highest exposure. For a basic compound, on the other hand, with the present properties and doses, a microsuspension was sufficient. In the latter case, the higher solubility at gastric pH, because of the basic pK(a), limits the need for particle reduction.