b-Cyclodextrin-dextran polymers for the solubilization of poorly soluble drugs Massimiliano di Cagno a, *, Thorbjørn Terndrup Nielsen b , Kim Lambertsen Larsen b , Judith Kuntsche a , Annette Bauer-Brandl a a Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense M 5230, Denmark b Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, Sohngaardsholmsvej 57, Aalborg 9000, Denmark A R T I C L E I N F O Article history: Received 12 March 2014 Received in revised form 9 April 2014 Accepted 12 April 2014 Available online 16 April 2014 Keywords: Cyclodextrins Calorimetry (ITC) bCD-dextran polymers Solubilization Poorly soluble drugs A B S T R A C T The aim of this study was to assess the potential of novel b-cyclodextrin (bCD)-dextran polymers for drug delivery. The size distribution of bCD-dextrans (for eventual parenteral administration), the influence of the dextran backbones on the stability of the bCD/drug complex, the solubilization efficiency of poorly soluble drugs and drug release properties were investigated. Size analysis of different bCD- dextrans was measured by size exclusion chromatography (SEC) and asymmetrical flow field-flow fractionation (AF4). Stability of drug/bCD-dextrans was assessed by isothermal titration calorimetry (ITC) and molar enthalpies of complexation and equilibrium constants compared to some commercially available bCD derivatives. For evaluation of the solubilization efficiency, phase-solubility diagrams were made employing hydrocortisone (HC) as a model of poorly soluble drugs, whereas reverse dialysis was used to detect potential drug supersaturation (increased molecularly dissolved drug concentration) as well as controlled release effects. Results indicate that all investigated bCD-polymers are of appropriate sizes for parenteral administration. Thermodynamic results demonstrate that the presence of the dextran backbone structure does not affect the stability of the bCD/drug complex, compared to native bCD and commercially available derivatives. Solubility studies evidence higher solubilizing abilities of these new polymers in comparison to commercially available bCDs, but no supersaturation states were induced. Moreover, drug release studies evidenced that diffusion of HC was influenced by the solubilization induced by the bCD-derivatives. ã 2014 Elsevier B.V. All rights reserved. 1. Introduction Poor solubility of active pharmaceutical ingredients (API) is one of the biggest challenges in drug development: a large number of drugs on the market (approximately 40%), and even more those under development (approx. 70%), belong to class II, or respectively class IV of the Biopharmaceutics Classification System (BCS) and are therefore associated with solubility issues and as a conse- quence, poor oral bioavailability (Williams et al., 2013; Fahr and Liu, 2007; Amidon et al., 1995). In the last few years, a number of techniques have been suggested to increase bioavailability of such APIs (Williams et al., 2013; Fahr and Liu, 2007; Zhang et al., 2008). Amongst these, the use of cyclodextrins (CDs) has emerged as an efficient approach for solubilization. Cyclodextrins are cyclic oligosaccharides consisting of (a-1,4)-linked a-D-glucopyranose units. CD molecules are shaped like truncated cones, with a hydrophobic cavity inside and a hydrophilic surface outside. For many years CDs have been intensively investigated for pharma- ceutical use due to their ability to spontaneously complex poorly soluble drug molecules, inducing solubilization (enhancement in apparent solubility) (Loftsson et al., 2002, 2004; Connors, 1997). For pharmaceutical purposes, b-cyclodextrins (bCDs, 7 glucose units in the ring) are mostly studied. Although bCDs are hydrophilic (as well as their complexes), their aqueous solubility is comparably low. The reason for this fact is associated with the high crystal lattice energy (Loftsson and Brewster, 2010) as well as intramolecular hydrogen bond formation that compromise the interaction with water molecules (solvation). To overcome this limitation, derivatives of the bCDs with higher aqueous solubility have been developed by introducing substituents at specific positions of the glucose rings, breaking the intramolecular net of hydrogen bonds and thereby enhancing aqueous solubility. The * Corresponding author. Tel.: +45 65502504; fax: +45 66158780. E-mail addresses: mdc@sdu.dk (M. di Cagno), ttn@bio.aau.dk (T. Terndrup Nielsen), kll@bio.aau.dk (K. Lambertsen Larsen), kuntsche@sdu.dk (J. Kuntsche), annette.bauer@sdu.dk (A. Bauer-Brandl). http://dx.doi.org/10.1016/j.ijpharm.2014.04.029 0378-5173/ ã 2014 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 468 (2014) 258–263 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm