PARTICLE-SIZE REDUCTION FOR IMPROVEMENT OF ORAL BIOAVAILABILITY OF HYDROPHOBIC DRUGS .1. ABSOLUTE ORAL BIOAVAILABILITY OF NANOCRYSTALLINE DANAZOL IN BEAGLE DOGS
Gg. Liversidge et Kc. Cundy, PARTICLE-SIZE REDUCTION FOR IMPROVEMENT OF ORAL BIOAVAILABILITY OF HYDROPHOBIC DRUGS .1. ABSOLUTE ORAL BIOAVAILABILITY OF NANOCRYSTALLINE DANAZOL IN BEAGLE DOGS, International journal of pharmaceutics, 125(1), 1995, pp. 91-97
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.