Different formulation approaches were evaluated to ensure that the formulation of a poorly water soluble compound chosen during early development achieves optimum bioavailability. The insoluble compound has an aqueous solubility of 0.17 micro g/mL at 25 +/- 1 degrees C, a relatively high permeability (Caco2 P(app) = 6.1 x 10(-4) cm/min), and poor bioavailability in dogs (dry blend formulation). Based on the prediction by GastroPlus, the oral absorption of this compound is sensitive to its apparent solubility and particle size. The oral bioavailability of three different formulations was compared in a dog model: a cosolvent-surfactant solution, a solid dispersion in a mixture of polyethylene glycol 3350 and polysorbate 80, and a dry blend of micronized drug with microcrystalline cellulose. In absence of a parenteral injection, the bioavailability of the solution was considered to be 100%, and the relative oral bioavailability of the three formulations was 100, 99.1, 9.8, respectively. Comparable bioavailability was obtained with the solid dispersion and the cosolvent-surfactant solution, both of which showed a 10-fold higher bioavailability than the dry blend. Thus, a 20 mg dose strength capsule containing the solid dispersion formulation was selected for clinical development. The selected solid dispersion system was physically and chemically stable for at least 16 months at 25 degrees C/60% RH. In conclusion, the bioavailability of a poorly water soluble drug was greatly enhanced using the solid dispersion formulation containing a water soluble polymer with a surface active agent.
Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1165-1175, 2004