Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation.
OBJECTIVE
To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug.


METHODS
Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified.


RESULTS
The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations.


CONCLUSIONS
Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.
Porter
Christopher J H
CJ
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia. Chris.Porter@vcp.monash.edu.au
Kaukonen
Ann Marie
AM
Boyd
Ben J
BJ
Edwards
Glenn A
GA
Charman
William N
WN
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003613:Danazol / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004063:Digestion; D004285:Dogs; D016503:Drug Delivery Systems; D004655:Emulsions / Q000008:administration & dosage*; D007408:Intestinal Absorption; D008049:Lipase / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D010316:Particle Size; D011208:Powders; D012995:Solubility
D004655:Emulsions; D011208:Powders; D008049:Lipase; D003613:Danazol