Evaluation of a nanoemulsion formulation strategy for oral bioavailability enhancement of danazol in rats and dogs

Abstract

The objective of this study was to determine whether nanoemulsion formulations constitute a viable strategy to improve the oral bioavailability of danazol, a compound whose poor aqueous solubility limits its oral bioavailability. Danazol-containing oil-in-water nanoemulsions (NE) with and without cosurfactants stearylamine (SA) and deoxycholic acid (DCA) were prepared and characterized. Nanoemulsion droplets size ranging from 238 to 344 nm and with surface charges of -24.8 mV (NE), -26.5 mV (NE-DCA), and +27.8 mV (NE-SA) were reproducibly obtained. Oral bioavailability of danazol in nanoemulsions was compared with other vehicles such as PEG400, 1% methylcellulose (MC) in water (1% MC), Labrafil, and a Labrafil/Tween 80 (9:1) mixture, after intragastric administration to rats and after oral administration of NE-SA, a Labrafil solution, or a Danocrine® tablet to dogs. The absolute bioavailability of danazol was 0.6% (PEG400), 1.2% (1% MC), 6.0% (Labrafil), 7.5% (Labrafil/Tween80), 8.1% (NE-DCA), 14.8% (NE), and 17.4% (NE-SA) in rats, and 0.24% (Danocrine), 6.2% (Labrafil), and 58.7% (NE-SA) in dogs. Overall, danazol bioavailability in any nanoemulsion was higher than any other formulation. Danazol bioavailability from NE and NE-SA was 1.8- to 2.2-fold higher than NE-DCA nanoemulsion and could be due to significant difference in droplet size.

Keywords: absorption; bioavailability; danazol; hepatic clearance; nanoemulsion; particle size; stearylamine; surfactants.

Figure 1

Average Plasma Concentration (ng/mL) of Danazol vs Time Following Intravenous Administration to (•) Rats (0.65 mg/kg); and (▲) Dogs (1 mg/kg) in aqueous 10%HPßCD. The data are mean ± SD of the results from 3 animals.

Figure 2

Average Plasma Concentration (ng/mL) of Danazol vs Time Following Oral Administration to Rats A) 10 mg/kg from PEG400 (•), 1%MC (▲), Labrafil (◆), and Labrafil +Tween 80 (9:1) (▪); B) 12 mg/kg from NE (•), 11.3 mg/kg from NE-SA (▲) and 17.5 mg/kg from NE-DCA (◆). The data are mean ± SD of the results from 3 animals.

Figure 2

Average Plasma Concentration (ng/mL) of Danazol vs Time Following Oral Administration to Rats A) 10 mg/kg from PEG400 (•), 1%MC (▲), Labrafil (◆), and Labrafil +Tween 80 (9:1) (▪); B) 12 mg/kg from NE (•), 11.3 mg/kg from NE-SA (▲) and 17.5 mg/kg from NE-DCA (◆). The data are mean ± SD of the results from 3 animals.

Figure 3

Average Plasma Concentration (ng/mL) of Danazol vs Time Following Oral Administration to Dogs at 20 mg/kg in Danocrine Tablet (•), 5 mg/kg in Labrafil Solution (▲) and 7.16 mg/kg in NE-SA (◆). The data are mean ± SD of the results from 3 animals.