Estudo das interações intermoleculares de ciclodextrinas com fármacos antidiabéticos

Abstract

Metformin hydrochloride (MET) and phenformin hydrochloride (FEN) are antihyperglycemic drugs belonging to the biguanide class, with MET being a first-line therapy for the treatment of type II diabetes mellitus (DMII). MET is limited by its low bioavailability, whereas FEN was withdrawn from the market due to adverse side effects associated with its use. Cyclodextrins (CDs) are of great interest to industry, particularly the pharmaceutical sector, because of their ability to modify intrinsic drug properties such as solubility, stability, and bioavailability. The aim of this study was to investigate the thermodynamic parameters involved in the interactions between the drugs FEN and MET and natural cyclodextrins (α-CD, β-CD, and γ-CD), as well as modified cyclodextrins (CM-β-CD, HP-β-CD, and M-β-CD), and to structurally characterize the compounds formed. Thermodynamic parameters were determined using isothermal titration calorimetry (ITC); additionally, the effect of temperature variation was evaluated for the FEN:CM-β-CD system. Solid-state inclusion compounds were obtained by freeze drying. The inclusion compounds were characterized by vibrational spectroscopy in the infrared region (FTIR-ATR), and inclusion was confirmed by one- and two-dimensional 1H NMR experiments. By comparing the systems formed by MET and FEN using calorimetric titration, it was possible to verify that the presence of an aromatic ring in the FEN structure favored the formation of inclusion compounds with α-CD, β-CD, and CM-β-CD. Based on the 1H NMR results, the formation of inclusion compounds was confirmed for the FEN:β-CD and FEN:CM-β-CD systems, and possible structures for the complexes formed were proposed.