We wish to extend our appreciation to Pia Pedersen for technical assistance, Birgit Guldhammer Skov for consulting in pathological examination of tissues from in vivo experiments and Anncatrine Luisa Pedersen for providing weight data of organs of nude mice. This work was supported in part by a grant from the Danish Cancer Society and the Novo Nordisk Foundation. The authors state that no potential financial or personal conflicts exist concerning this manuscript. “
“The number of DAPT price poorly water-soluble drug candidates, encountered in drug discovery and development, causes increasing

problems with poor and variable bioavailability. In the early phases of drug discovery and drug development a potential way of overcoming these biopharmaceutical problems is by the use of cyclodextrins (CDs) [7]. CDs

are cyclic oligosaccharides consisting of several glycopyranose units with an outer hydrophilic surface and an inner hydrophobic cavity. The capability of CDs to form inclusion complexes with drug compounds, thereby improving their physico chemical properties, such as solubility and stability, has been studied extensively (review by e.g. [1], [2] and [13]). A number Selleck Hydroxychloroquine of chemically modified CDs have been prepared to improve the inclusion capacity and the physico chemical properties of the native CDs. Of the CD derivatives, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether β-cyclodextrin (SBE7βCD) are the most frequently 17-DMAG (Alvespimycin) HCl used within the pharmaceutical field on account of their fast dissolution rate, high solubility in water and low toxicity [4], [12] and [10]. From a drug development point of view, the relative large molecular weight of HPβCD and SBE7βCD can be a limitation for their use in solid oral dosage forms. The drug:CD mole ratio required for the inclusion complexes are frequently above one to one. For this reason a significant amount of CDs needs to be incorporated into the formulation,

meaning that solid formulations as tablets or capsules containing CD would become relatively large and thereby difficult to swallow for the patient and expensive to produce for the company. Native βCDs and βCD derivatives are hardly absorbed from the gastrointestinal tract [11] nor hydrolysed by α-amylases in the small intestine [5]. Besides the endogenous solubilising components in the gastrointestinal tract, i.e. bile salts and phosphorlipids, CDs should, hence, be capable of dissolving more drug then stoichiometric amounts as the equilibrium is dynamic and changes when the drug is absorbed. In partly support of this hypothesis, Savolainen et al. [10] reported similar bioavailability of phenytoin when dosed to dogs as either a physical mixture with HPβCD or a preformed lyophilised complex containing the same amount of CD.