Antifungal drugs combinations: a patent review 2000-2015.

INTRODUCTION: Combination therapy has emerged as an approach to improve the efficacy of antifungal drugs. Its main objective is to achieve synergistic interaction with higher antifungal properties and lower toxic effects than each substance alone. AREAS COVERED: Twenty-four patents disclosed in the period of 2000-2015 were covered in this review. Twenty of them were devoted to pharmacodynamic potentiation, while four were dedicated to pharmacokinetic actions. EXPERT OPINION: The common characteristic of most patents published in this area is that the main partner is a commercial antifungal drug. In the most innovative combinations the second component was either a modifier of proton homeostasis, an antibody, an inhibitor of the adhesion of epithelial or endothelial cells or a keratinolytic agent that improves the skin penetration. The evaluation of synergism is always made with simple in vitro methods, which constitutes a weakness of the disclosed patents, due to the lack of in vivo studies, since the in vitro tests cannot predict the in vivo behavior. Also, it is surprising that none of the patents analyze the toxicity of the new combinations, taking into account that one of the main objectives of the combinations is to reduce the toxicity of the existing antifungal drugs.