title: Reduced Food-Effect on Intestinal Absorption of Dronedarone by Self-microemulsifying Drug Delivery System (SMEDDS).
abstract: The oral absorption of dronedarone (DRN), a benzofuran derivative with anti-arrhythmic activity, is significantly affected by food intake. The absolute bioavailability of the marketed product (Multaq, Sanofi, U.S.) was about 4% without food, but increased to 15% when administered with a high fat meal. Therefore, to reduce the food-effect on the intestinal absorption of DRN, a novel self-microemulsifying drug delivery system (SMEDDS) was formulated and the comparative in vivo absorption studies with the marketed product were carried out using male beagle dogs either in the fasted or fed state. The SMEDDS consisted of the drug, Labrafil M 1944CS, and Kolliphor EL in a weight ratio of 1 : 1 : 2, rapidly formed a fine oil-in-water emulsion with a droplet size less than 50 nm. An in vivo absorption study revealed that the area-under-curve (AUC0-24 h) and maximal plasma concentration (Cmax) were 10.4-fold (p<0.05) and 8.6-fold (p<0.05) higher, respectively, after the marketed product was orally administered to beagles in the fed state when compared to those in the fasted state. This food-effect were remarkably alleviated by SMEDDS formulation, with AUC0-24 h and Cmax 2.9-fold (p<0.05) and 2.6-fold (p<0.05) higher in the fed state when compared to the fasted state, by facilitating intestinal absorption of DRN in the fasted state. The results of this study suggest that SMEDDS may decrease the differences in oral absorption of DRN between the prandial states, improving therapeutic efficacy as well as patient compliance.
authors.affiliation: Dong-A Pharmaceutical Co., Ltd.
authors.forename: Sang Duk
authors.initials: SD
authors.lastname: Han
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Jung
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Jang
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.forename: Byoung Moon
authors.initials: BM
authors.lastname: Kim
authors.forename: Myung Joo
authors.initials: MJ
authors.lastname: Kang
mesh_terms: D000284:Administration, Oral; D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002368:Castor Oil / Q000031:analogs & derivatives / Q000737:chemistry; D004285:Dogs; D000077764:Dronedarone; D016503:Drug Delivery Systems; D004655:Emulsions; D018565:Food-Drug Interactions; D005989:Glycerides / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D007408:Intestinal Absorption; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000889:Anti-Arrhythmia Agents; D004655:Emulsions; D005989:Glycerides; C514708:Labrafil M 1944 CS; D011136:Polysorbates; D013501:Surface-Active Agents; C440220:Labrasol; C022131:cremophor; D011092:Polyethylene Glycols; C000515:cremophor EL; D002368:Castor Oil; D000077764:Dronedarone; D000638:Amiodarone; D005990:Glycerol