Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs.
OBJECTIVE
To investigate the impact of a change in the proportions of lipid, surfactant and co-solvent on the solubilisation capacity of self-emulsifying formulations of danazol during in vitro dispersion and digestion studies and correlation with in vivo bioavailability in beagle dogs.


METHODS
Formulations from within the phase diagram of the pseudo-ternary system composed of soybean oil:maisine 35-1 (1:1 w/w), Cremophor EL and ethanol were assessed in vitro on dispersion and digestion. The relative bioavailability of danazol after administration of a series of these formulations was also determined.


RESULTS
All formulations formed microemulsions in the presence of water and no drug precipitation was observed on dispersion. In contrast, drug solubilisation was markedly affected by lipase-mediated digestion and a reduction in lipid (and increase in surfactant) content resulted in increased drug precipitation. Consistent with these data, the bioavailability of danazol decreased significantly when the lipid content in the formulations was reduced.


CONCLUSIONS
A rank-order correlation was observed between the patterns of solubilisation obtained during in vitro digestion and the in vivo performance of self-emulsifying formulations of danazol. In general a decrease in the lipid content and an increase in the proportions of surfactant and co-solvent resulted in reduced danazol bioavailability.
Cuiné
Jean F
JF
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, Australia.
Charman
William N
WN
Pouton
Colin W
CW
Edwards
Glenn A
GA
Porter
Christopher J H
CJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003613:Danazol / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding; D004655:Emulsions; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000431:Ethanol / Q000737:chemistry; D005989:Glycerides / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D007408:Intestinal Absorption; D008049:Lipase / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis; D008297:Male; D010316:Particle Size; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013024:Soybean Oil / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D004337:Drug Carriers; D004655:Emulsions; D004965:Estrogen Antagonists; D005989:Glycerides; D008055:Lipids; D012997:Solvents; D013501:Surface-Active Agents; D014867:Water; D000431:Ethanol; C000515:cremophor EL; D013024:Soybean Oil; D008049:Lipase; D003613:Danazol; D005990:Glycerol