PARTICLE-SIZE REDUCTION FOR IMPROVEMENT OF ORAL BIOAVAILABILITY OF HYDROPHOBIC DRUGS .1. ABSOLUTE ORAL BIOAVAILABILITY OF NANOCRYSTALLINE DANAZOL IN BEAGLE DOGS

Danazol is a poorly water soluble compound (10 mu g/ml) that demonstra tes poor bioavailability. The impact on bioavailability of increasing the area for dissolution by decreasing drug crystal particle size to l ess than 200 nm and stabilizing the particles to prevent agglomeration in the GI tract has been evaluated. A randomized three-way crossover study was conducted in fasted male beagle dogs to compare absolute ora l bioavailability of danazol from three formulations. The three formul ations examined were: A, an aqueous dispersion of nanoparticulate dana zol (mean particle size 169 nm); B, danazol-hydroxypropyl-beta-cyclode xtrin (HPB) complex; C, an aqueous suspension of conventional danazol particles (mean particle size 10 mu m). The three formulations were ad ministered (200 mg) at 1 week intervals, and a fourth leg was conducte d using intravenous danazol-HPB at a dose of 3 mg/kg. Plasma samples w ere obtained over the course of 24 h and analyzed by SPE-HPLC. Absolut e oral bioavailability of each formulation was determined by compariso n of oral AUC values to intravenous AUC values in the same dog, normal ized to a 20 mg/kg dose. Absolute bioavailabilities of the three formu lations were: nanoparticulate danazol, 82.3 +/- 10.1%; cyclodextrin co mplex, 106.7 +/- 12.3%; conventional danazol suspension, 5.1 +/- 1.9%. The bioavailabilities of nanoparticle dispersion and cyclodextrin com plex are not significantly different (P = 0.05) suggesting that the na noparticle dispersion had overcome the dissolution rate limited bioava ilabilty observed with conventional suspensions of danazol. This appro ach should have general applicability to many poorly soluble drugs wit h dissolution rate-limited absorption.