Investigation of the complexation of albendazole with cyclodextrins for the design of new antiparasitic formulations Bénédicte Pradines a,b , Jean-François Gallard c , Bogdan I. Iorga c , Claire Gueutin a , Philippe M. Loiseau b , Gilles Ponchel a , Kawthar Bouchemal a,⇑ a Institut Galien Paris Sud, UMR CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296 Châtenay-Malabry cedex, France b BioCis, Biomolécules: conception, isolement, synthèse-Chimiothérapie Antiparasitaire, UMR CNRS 8076, Université Paris-Sud, Faculté de Pharmacie, 5, rue J.B. Clément, 92296 Châtenay-Malabry cedex, France c Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif-sur-Yvette, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France article info Article history: Received 28 March 2014 Received in revised form 2 June 2014 Accepted 6 June 2014 Available online 17 June 2014 Keywords: Albendazole Cyclodextrins Solubilization studies Bidimensional 1 H RMN Molecular docking abstract Albendazole (ABZ) exhibits a potent antiparasitic activity against a broad spectrum of parasites. Unfortu- nately, the very low water solubility of ABZ (0.2 lg mL 1 , 0.7 lM) impairs considerably its formulation. Phase solubility diagrams showed that a-cyclodextrin (10% w/w), hydroxypropyl-b-cyclodextrin (40% w/w) and sulfobutylether-b-cyclodextrin (40% w/w) allowed an increase of apparent solubility with enhancement factors of 570, 3970, and 5880, respectively. The apparent aqueous solubility of ABZ was markedly increased from 0.2 lg mL 1 (0.7 lM) without cyclodextrins to 1.52 mg mL 1 (5.69 mM) with random methyl-b-cyclodextrin (Me-b-CD) (40% w/w). This corresponds to an apparent solubility enhancement factor of 7600 which is the maximal enhancement factor of ABZ apparent aqueous solubil- ity ever reported in the literature using conventional cyclodextrins. The complexation mechanism between ABZ and cyclodextrins has been investigated using phase solubility diagrams, nuclear magnetic resonance ( 1 H NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations. The results showed that the central bicyclic fragment from ABZ interacts with Me-b-CD according to 1:1 stoichiometry. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Albendazole (ABZ), (methyl[5-(propylthio)-1H-benzimidazol-2- yl]carbamate, Fig. 1), belongs to the group of benzimidazole deriv- atives. This molecule has a broad spectrum of activity against human and animal helminthic parasites such as nematodes, and metacestodes. It was approved for human use since 1982. ABZ showed antiprotozoal activity against Trichomonas vaginalis 1 in vitro. The IC 50 of ABZ against T. vaginalis was estimated in a range of 3–4 lM. 2 ABZ was also used to boost the trichomonacidal activity of metronidazole. 3 However, like other benzimidazole car- bamates, ABZ belongs to biopharmaceutical classification system type II (BCS class II) with low aqueous solubility (0.2 lg mL 1 at 25 °C) and high permeability through the biological membranes. Low water solubility of drugs results very generally in low sol- ubility in biological fluids and is likely to considerably impair either attainable local drug concentrations (when local delivery is foreseen) or pharmacokinetic profiles (after systemic administration). Different approaches have been previously investigated to solve the aqueous solubility limitation of ABZ, including the use of surfactants such as polysorbates, 4 bile salts 5 or co-solvent like molecules (diethylene glycol monoethyl ether: Transcutol Ò ). 6 High ABZ apparent solubility (up to 2.226 mg mL 1 ) was obtained using Transcutol Ò (40% w/w) at a pH of 1.2. 4 However, the use of many of these agents should be restricted whenever possible because they can be irritants to mucosa membranes. There is some evidence in the literature that the addition of cyclodextrins (CDs) into ABZ formulations could enhance ABZ oral bioavailability, particularly hydroxypropyl-b-cyclodextrin (HP-b- CD) which significantly increased ABZ absorption in comparison with a surfactant-based formulation. 7 This study conducted on healthy volunteers showed that the relative bioavailability of ABZ formulated in arachid oil-polysorbate 80 or HP-b-CD containing formulations was enhanced by 4.3- and 9.7-folds, respectively, compared to commercial tablets. The interest of combining ABZ to HP-b-CD was further confirmed by Evrard et al. 8 who showed an improvement of the oral and the effectiveness of ABZ/HP-b- CD inclusion complex against encapsulated larvae of Trichinella spiralis in a murine model. 9 ABZ complexed to HP-b-CD resulted http://dx.doi.org/10.1016/j.carres.2014.06.008 0008-6215/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +33 (0)1 46 83 55 81; fax: +33 (0)1 46 61 93 34. E-mail address: kawthar.bouchemal@u-psud.fr (K. Bouchemal). Carbohydrate Research 398 (2014) 50–55 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres