Onychomycosis is a prevailing disease caused by fungal infection of nails that mostly affects athletes and the elderly. Ciclopirox is approved by the US Food and Drug Administration for the topical treatment of onychomycosis. However, the desired penetration of ciclopirox into the nail bed has not been achieved via topical application for efficient treatment. Therefore, the main aim of this study was to enhance ciclopirox permeation and retention in nail by the development of a new nail lacquer formulation. We screened the effects of different solvents, alkalizing agents, and permeation enhancers on the permeation of bovine hooves by ciclopirox and its retention in human nail clippings. The results suggest that isopropyl alcohol, potassium hydroxide, and urea as the solvent, alkalizing agent, and permeation enhancer, respectively, improved the permeation of the ciclopirox nail lacquer formulation the most with high flux rates. Comparison of the final formulation and marketed product revealed enhanced retention of ciclopirox from our developed formulation in human nail clippings. Therefore, our newly developed nail lacquer may be a potentially effective formulation for the treatment of onychomycosis in humans.

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...

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In order to enhance the dissolution rate of dronedarone hydrochloride (DRN), a novel soluplus ® (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer)-based solid dispersion (SD) was formulated using a hot melt extrusion technique. The physical characteristics determined using scanning electron microscopy and X-ray powder diffraction, revealed that the active compound was molecularly dispersed in the amphiphilic polymer in a stable amorphous form. The dissolution rate of DRN from the tablet dosage form of SD extrudate consisted of the drug and Soluplus ® in a weight ratio of 1 : 1, and was obviously more rapid and higher than that of the intact drug and marketed product (Multaq ® , Sanofi, U.S.A.) at pH 1.2, 4.0 and 6.8. This suggests that Soluplus ® -based SD formula can be a promising approach for enhancing the dissolution and oral absorption of DRN with a simple preparation process.Key words dronedarone hydrochloride; Soluplus ® ; hot melt extrusion; dissolution Dronedarone hydrochloride (Fig. 1, DRN), an antiarrhythmic agent, has been recently prescribed to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter.1,2) In a clinical study, DRN effectively reduced hospitalization due to cardiovascular events or death due to any cause by 24.2% when compared to the placebo group.2) However, the oral absorption of DRN is quite challenging owing to its pH-dependent aqueous solubility; solubility in a weak acidic environment (pH 3 to 5) is about 1 to 2 mg/mL, but the solubility is remarkably decreased to one hundredth of a point in gastric fluid (pH 1.2) and/or intestinal fluid (pH 6.8).3) To improve oral absorption of the antiarrhythmic agent, the originator (Sanofi, U.S.A.) formulated an oral dosage form (Multaq ® tablet, 400 mg as base) based on the solid dispersion (SD) system using conventional solvent method, with a triblock copolymer of polypropylene glycol and polyethylene glycol.3) In the SD formula, the drug may be dispersed within the hydrophilic carrier at a molecular level in the amorphous state, and the formula provides a large surface, which enhances the dissolution rate of the poorly water-soluble molecule. [4][5][6] However, the oral absorption of the marketed product is still unsatisfactory. The absolute bioavailability (BA) of DRN was about 4% without food, while the BA was approximately 15% when administered with a high fat meal. 7)Hot melt extrusion (HME) is a promising preparation tool to prepare SD formulations for improved drug dissolution and oral BA.8) The mixture of active pharmaceutical ingredients (APIs) and hydrophilic carriers was melted at an elevated temperature and mixed homogeneously at a molecular level, resulting in an amorphous state of API dispersed in the carrier.9,10) The process to prepare extrudates by HME is relatively economic and does not require complicated processes used in the preparation of conventional solvents. Polyethyleneglycol (PEG)-polyvinyl caprolactam-polyvinyl a...