ADAMS, Gregg Patrick,YAPURA, Maria Jimena,PIERSON, Roger A.,BADEA, Ildiko
申请号：
CACA2014/050390
公开号：
WO2014/169395A1
申请日:
2014.04.17
申请国别(地区):
CA
年份:
2014
代理人:
摘要：
Described herein is an intravaginal device that provides biologically active circulating concentrations of an aromatase inhibitor for at least about of 4 days. Three compounds with estradiol inhibitory capability (letrozole, anastrozole and fenbendazole) were tested in vitro using bovine granulosa cell culture. Letrozole was found to be the most efficient and potent inhibitor. Liposome-based and a wax-based formulations were used to assess letrozole diffusion through bovine vaginal mucosa in a diffusion chamber study. Samples were collected over a 24 h period. The wax-based vehicle was selected for further development of a letrozole intravaginal device based on its steady release rate. In an in vivo study in cattle, 3 different intravaginal devices containing 3 g of letrozole were tested: Wax (with 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine, DOPE) + gel coat (n=2), Wax + gel coat (n=4) and Wax (n=4). Blood samples were collected serially from time 0 to 120 h, and daily thereafter to measure circulating concentrations of letrozole by LC/MS/MS. The addition of a letrozole-containing gel coating improved initial absorption and hastened the increase on plasma concentrations of the active ingredient, while the letrozole-containing wax-based vehicle maintained prolonged delivery from the intravaginal device.La présente invention porte sur un dispositif intravaginal qui assure des concentrations biologiquement actives en circulation d'un inhibiteur de l'aromatase pendant au moins environ 4 jours. Trois composés doués d'un pouvoir inhibiteur d'estradiol (le létrozole, l'anastrozole et le fenbendazole) ont été testés in vitro à l'aide d'une culture de cellules de la granulosa bovine. Il a été trouvé que le létrozole était l'inhibiteur le plus efficace et puissant. Des formulations à base de liposomes et à base de cire ont été utilisées pour évaluer la diffusion de létrozole à travers la muqueuse vaginale bovine dans une étude en chambre de diffusion. Des échantillons ont
