Delineamento de biocompósitos baseados em paligorsquita e quitosana como carreadores de etambutol

Abstract

Tuberculosis, a transmissible disease that affects the lungs for infection by Mycobacterium tuberculosis, is still a serious public health problem, ranking ninth in the global cause of death, with millions of new cases each year. One problem associated with the treatment of tuberculosis refers to the requirement of administration of four drugs (ethambutol, rifampicin, isoniazid, and pyrazinamide) as a fixed dose combination product, which leads to interaction and stability problems. Considering the difficulty found in this treatment, this work proposed to develop composites to carry the tuberculostatic ethambutol based on palygorskite, a fibrous clay mineral, with a high specific area and moderately negative charge, and on the cationic biopolymer chitosan. In this sense it was intended to improve the stability of the formulation, using raw materials widely available in the Northeast region of Brazil. Initially composition and purity of chitosan and palygorskite were determined and the adsorption study of the drug to the phyllosilicate was carried out. Molecular modeling was performed in order to predict the possibility of interaction and to determine the potential sites involved in the adsorption of the drug to the phyllosilicate. Then, the product of this interaction (ETB / Paly) was characterized using spectroscopic (FTIR, XRD, EDS) and thermoanalytical (DSC and TG) techniques, microscopy, hygroscopicity, stability and in vitro release assays. The interaction between palygorskite and chitosan was performed by the solution intercalation method, obtaining a composite that was characterized by the evaluation of the surface charge, specific area, thermal analysis, FTIR and XRD. The biocomposites loaded with ethambutol were obtained by the spray drying technique and the main physicochemical properties of the microparticles were determined as well as their biocompatibility. In silico analysis indicated that drug adsorption to the clay mineral occurred spontaneously, the main groups involved were palygorskite Si-OH and ethambutol -OH and -NH2 groups. The results obtained corroborate with the computational analysis, demonstrating a high adsorption capacity of the tuberculostatic onto the inorganic carrier, predominantly on the surface, homogeneously distributed and promoting a reduction of drug hygroscopicity in the hybrid form (ETB / Paly), in relation to the free drug. Analysis of the biocomposites based on chitosan-palygorskite evidenced the involvement of electrostatic and hydrogen interactions between the raw materials, with superficial adsorption of the polymer to the phyllosilicate. In addition, the composites loaded with ethambutol presented as spherical microparticles, biocompatible and with a controlled release profile, influenced by the polymer: phyllosilicate rate. Therefore, the results obtained indicated the effectiveness of the system in modulating the pH-dependent release of ethambutol, reinforcing the involvement of electrostatic interactions between the components. Also, the use of biocompatible materials led to composites with reduced cytotoxicity in the 3T3 cell line, mainly in the systems based on palygorskite. This dataset allows us to envisage the possibility of applying these biocomposites in the treatment of tuberculosis as a simple and low-cost alternative for technological difficulties related to the current therapeutic regimen.