Nifurtimox inclusion complexes. A promising strategy for Chagas disease

BEDOGNI, GR; SEREMETA, KP; OKULIK, NB; SALOMON, CJ

Rosario

Encuentro; 7ma Reunión Internacional de Ciencias Farmacéuticas (RICiFa); 2023

Chagas disease is a neglected tropical disease, potentially lethal, that affects around 6-10 million people worldwide. It is also known to be one of the deadliest parasitic diseases for children1. Nifurtimox (NFX), one of the two drugs approved for its treatment, exhibits limited water solubility2. This can pose challenges in terms of drug formulation and administration, as drugs that are poorly soluble in water can have reduced bioavailability. To overcome this limitation, complexation with cyclodextrins can be considered an interesting approach. Thus, this work aimed to develop inclusion complexes with sulfobutyl ether β cyclodextrin (SBEβCD) to solve such inconvenience. The phase solubility studies showed that NFX and SBEβCD interacted in a 1:1 molar ratio. Then, an inclusion complex (NFX-Ic) was prepared through the co-evaporation method at a 1:1 molar ratio. The corresponding physical mixture (NFX-Pm) was also prepared, for comparison. Bidimensional Nuclear Magnetic Resonance (1H- 1H ROESY) confirmed the formation of a 1:1 inclusion complex, showing strong interaction between external H of the broader side of SBEβCD and H close to the nitrogen from the thiazinam group, alongside a more moderate interaction with H from the methyl group. Interaction between H from sulfobutyl and H from nitrofuran indicated the incorporation of the methanimine inside the cyclodextrin cavity. These results agree with the induced chemical shifts calculated in 13C-RMN spectra. The inclusion of NFX inside the cavity introduced changes in the crystalline structure of NFX, increasing the amorphous phase. NFX presented a sharp endothermic event at 184,40 °C, while NFX-Ic y NFX-Pm presented it at 183,20 °C and 182,70 °C, with relative crystalline percentages of 43,17 and 47,89 %, respectively. These reductions in crystalline content were also observed in X-ray diffraction patterns. The dissolution assay showed a remarkable increase in the NFX dissolution rate from the NFX-Ic (90% in 30 min). In agreement, dissolution efficiencies (DE) were higher for NFX-Ic. While DE 15 was 39% for NFX-Ic, it was 26 y 19% for NFX-Pm and NFX, respectively. After 60 min, DE 60 was 76%, 54%, and 40% for NFX-Ic, NFX-Pm, and NFX respectively. In conclusion, SBEβCD is an effective carrier for solving solubility-related problems of NFX and enhancing its dissolution rate, leading to a fast-release system with improved biopharmaceutical properties.