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 (AUC 0-24 h ) and maximal plasma concentration (C max ) 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 AUC 0-24 h and C max 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.Key words dronedarone; self-microemulsifying drug delivery system (SMEDDS); food-effect; oral absorption; solubilization Dronedarone (N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methane sulfonamide; DRN) is a benzofuran derivative with anti-arrhythmic properties belonging to all four Vaughan-Williams classes.1,2) This drug, commercialized under the trade name Multaq ® (Sanofi, U.S.), has been approved by the Food and Drug Administration (FDA) since 2009 in the tablet dosage form containing the hydrochloride salt of DRN (400 mg as base).3) In a clinical study, the antiarrhythmic agent effectively reduced cardiovascular hospitalization or death from any cause by 24.2% compared to the placebo group. 1) However, the oral administration of DRN has some problems such as extensive first-pass metabolism and food-effect on oral absorption.3) Although the original manufacturer (Sanofi, U.S.) formulated an oral dosage form (Multaq ® ) based on the solid dispersion (SD) system with a triblock copolymer of polypropylene glycol and polyethylene glycol to increase drug dissolution in the gastrointestinal (GI) tract, 4) the oral absorption of this biopharmaceutics classification system (BCS) ΙΙ compound is significantly affected by food intake. The absolute bioavailability (BA) of DRN is approximately 4% without food, which increased to approximately 15% when administered with a high fat meal.3) In this regard, Multaq ® tablets should be taken shortly after a meal to increase its intestinal abs...

Synthesis and Physicochemical Evaluation of Entecavir-Fatty Acid Conjugates in Reducing Food Effect on Intestinal Absorption

“…The equilibrium solubilities of lipidic prodrugs in biorelevant media such as FaSSGF, FeSSGF, FaSSIF, and FeSSIF [ 32 , 33 ] were assessed. FaSSGF was prepared with 0.08 mM of sodium taurocholate, 0.02 mM of lecithin, and 34.2 mM of NaCl in 1000 mL of distilled water (pH 1.6).…”

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Clove Oil Endorsed Transdermal Flux of Dronedarone Hydrochloride Loaded Bilosomal Nanogel: Factorial Design, In vitro Evaluation and Ex vivo Permeation

“…Dronedarone hydrochloride (DRN) is a new agent in class III antiarrhythmic drug that has been officially approved by FDA in 2009 for the treatment of atrial fibrillation (type of heart arrhythmia) analogous to amiodarone but with less side effects [1][2][3]. DRN suffers from poor oral bioavailability which is an outcome of extensive first-pass metabolism, low solubility, and reduced absorption in the gastrointestinal tract [3,4]. The reported absolute bioavailability of the tablet dosage form of DRN (Multaq®, Sanofi) in fasted state is only about 4%, while it reaches about 15% when it is administered with a high-fat meal in healthy volunteers [3,4].…”

“…DRN suffers from poor oral bioavailability which is an outcome of extensive first-pass metabolism, low solubility, and reduced absorption in the gastrointestinal tract [3,4]. The reported absolute bioavailability of the tablet dosage form of DRN (Multaq®, Sanofi) in fasted state is only about 4%, while it reaches about 15% when it is administered with a high-fat meal in healthy volunteers [3,4]. The solubility of DRN is pH dependent which reach about 1-2 mg/mL, at pH 3-5, while it significantly decreases in both gastric fluid (pH 1.2) and intestinal fluid (pH 6.8) [3,4].…”

“…Additionally and most importantly, transdermal route is ideal for drugs suffer from first-pass metabolism when administered orally which is the main hurdle that limits DRN oral bioavailability [7]. Several previous formulation approaches to enhance DRN solubility, oral absorption, and oral bioavailability have been reported such as preparation of DRN complexes [8,9], DRN entrapment into proliposomes [10], formulation of solid dispersions [3], entrapment into solid lipid nanoparticles [2], and formulation of self micro-emulsifying drug delivery systems [4]. The previous studies focused mainly on improvement of oral bioavailability.…”