Nanopartículas de diacetato de celulose contendo um derivado espiro acridínico para o tratamento da leishmaniose visceral

Abstract

Visceral leishmaniasis is a neglected tropical disease that if left untreated can lead to the death of the individual, current treatments are ineffective and have wide toxicity. In this way, the emergence of spiro-acridine derivatives such as AMTAC-06, are an alternative for a more efficient therapy, however, due to their high lipophilicity they cannot be administered intravenously using aqueous solvents, requiring a high concentration of surfactants that could cause various side effects. As an alternative, the encapsulation of this molecule in polymeric nanoparticles can direct it to the specific biological target that are macrophages using safe concentrations of surfactants in the formulation. The objective of this work was to develop and characterize cellulose diacetate nanoparticles containing AMTAC-06 for the treatment of leishmaniasis. Analytical validation was performed for the quantification of AMTAC-06. The methods of nanoprecipitation and emulsification/solvent evaporation were studied, and the samples obtained were lyophilized. The systems were characterized in terms of their physicochemical and morphological aspects using the following techniques: macroscopic appearance, particle size, zeta potential (PZ), polydispersion index (PDI), encapsulation efficiency (EE%), thermogravimetry ( TG/DTG), differential thermal analysis (DTA), scanning electron microscopy (SEM), X-ray diffraction and Fourier transform infrared spectroscopy (FTIR). Analytical validation proved to be a specific, exact, precise and robust method. The emulsification/solvent evaporation method proved to be more suitable for the development of the formulation. Choosing the formulation containing 0.2% cellulose diacetate polymer, 1.25% Kolliphor® HS 15 and 0.25% polysorbate 80, with a bimodal particle size distribution of 11.08 ± 0, 58 nm and 178 ± 31.00 nm, PDI of 0.341 ± 0.02 and PZ of -15.4 ± 1.10 mV, when adding the drug, the nanoparticles presented size, PZ and PDI of 7.324 ± 0.05, 96.52 ± 29.36 and 396.4 ± 130.23 nm, a PDI of 0.41 ± 0.086, a PZ of -28.13 ± 2.75, respectively, with an encapsulation efficiency of 86.09 ± 1.8% with 10% drug (20 µg/mL) in the formulation. The lyophilization process altered the size profile of the nanoparticles, causing instability in the system. For macroscopic analysis, liquid, transparent, clear and homogeneous formulations were observed. By SEM it was found that the results corroborate the particle size data and, by the morphological analysis, it is observed that they have a spherical shape and smooth surface. Through TG/DTG, DTA and FTIR it is possible to verify possible drug interactions with other components, as well as disappearance of bands and peaks referring to the drug, indicating its encapsulation. In X-ray diffraction, the binary drug:polymer mixture (1:1) indicates an amorphization of the drug. The in vitro release study revealed a delayed release, in which the drug began to release within 1 h after the start of release and reached 100% within 12 h, in addition to being hemocompatible. Therefore, the proposed nanoencapsulated system was able to incorporate AMTAC-06, demonstrating that this could be a promising alternative to improve the bioavailability of AMTAC-06.