Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs.
Lipid-based formulations of danazol with varying quantities of included surfactant have been examined in vitro and in vivo. Formulations comprising fatty acid ester surfactants were readily hydrolysed during in vitro digestion, although Cremophor RH40 (CrRH) was less effectively hydrolysed than Cremophor EL (CrEL). Formulations comprising high quantities of digestible surfactant also appeared to less effectively prevent danazol precipitation during in vitro evaluation. These trends were replicated in vivo where danazol bioavailability in beagle dogs was higher after oral administration of self-emulsifying formulations employing 55% (w/w) CrRH when compared with CrEL. The oral bioavailability of danazol after administration of drug formulated in surfactant alone, however, was poor. Studies using predispersed and encapsulated formulations of CrRH subsequently suggested that the low bioavailability of the single surfactant formulations reflected poor dispersion. Mixtures of surfactants, improved dispersion and good oral bioavailability of danazol was evident after administration of formulations comprising CrRH and either Pluronic L121 or Gelucire 44-14, in spite of evidence of danazol precipitation during in vitro digestion of the Gelucire formulation. These data suggest that effective dispersion and resistance to precipitation during both dispersion and digestion are key design parameters for lipid-based formulations comprising high proportions of surfactant.
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia. chris.porter@vcp.monash.edu.au
Jean F
JF
Cuiné
Claire L
CL
McEvoy
William N
WN
Charman
Colin W
CW
Pouton
Glenn A
GA
Edwards
Hassan
H
Benameur
Christopher J H
CJ
Porter
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D016503:Drug Delivery Systems; D004655:Emulsions; D008297:Male; D012995:Solubility; D013501:Surface-Active Agents / Q000494:pharmacology*
D004655:Emulsions; D013501:Surface-Active Agents; D003613:Danazol