title: 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.
authors.affiliation: Absorption Systems LP, Exton, Pennsylvania, 19341.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Devalapally
authors.forename: Svitlana
authors.initials: S
authors.lastname: Silchenko
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Jessica
authors.initials: J
authors.lastname: McDade
authors.forename: Galina
authors.initials: G
authors.lastname: Goloverda
authors.forename: Albert
authors.initials: A
authors.lastname: Owen
authors.forename: Ismael J
authors.initials: IJ
authors.lastname: Hidalgo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003613:Danazol / Q000737:chemistry* / Q000493:pharmacokinetics*; D004285:Dogs; D004655:Emulsions / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004655:Emulsions; D013501:Surface-Active Agents; D014867:Water; D003613:Danazol
keywords: absorption; bioavailability; danazol; hepatic clearance; nanoemulsion; particle size; stearylamine; surfactants