Benznidazole-loaded multiparticulate drug delivery systems based on interpolyelectrolyte complexes for improving Chagas disease treatment

GARCÍA, MÓNICA C; MANZO, RUBEN ; AOKI, MARÍA DEL PILAR; JIMENEZ-KAIRUZ, ALVARO

Congreso; 4º Reunión Internacional de Ciencias Farmacéuticas-RICiFa.; 2016

Chagas disease (CD) is caused by Trypanosoma cruzi infection and represents one of the most significant public health problems in Latin America1,2. Benznidazole (BZ) is the selected drug for treatment and it presents 60-80% parasitological cure rate3,4. Nevertheless, it shows very low solubility, several side effects and toxicity (e.g. hepatotoxicity, hypersensitivity, bone narrow suppression, peripheral neuropathy) conditioning the efficacy and safety of pharmacotherapy. Multiparticulate drug delivery systems (MDDS) based on polymeric carriers are interesting alternatives to improve the performance of BZ for CD treatment. The goal of this work was to development BZ-loaded MDDS based on interpolyelectrolyte complexes, and to characterize their physicochemical, pharmacotechnical and in-vitro biopharmaceutical properties. The MDDS were obtained by casting solvent (water and hydroalcoholic medium) and wet granulation. The polyelectrolytes selected were natural (chitosan-alginic acid) and synthetic (cationic/anionic Eudragit´s). The MDDS were typified using analytical sieving and were characterized by rheological studies, fluid up-take measurements, confocal microscopy, powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), and in-vitro release studies. In addition, hard-gelatin capsules containing different MDDS combinations were prepared and its in-vitro release properties were evaluated. The MDDS were obtained by a simple methodology with yields >90% of total solid-material processed. From sieved, particle sizes in range of 450-600, 600-850 and 850-1000µm were obtained. Physicochemical properties of MDDS showed adequate rheology properties for hard gelatin-capsule formulation. The FTIR exhibited ionic interaction between polyelectrolytes. Microscopy and PXRD revealed free BZ on the surface of multiparticles, uniformly distributed in the MDDS. The dissolution profiles showed modulation in BZ release, from slow and controlled (Q120min≤40%) to very fast (Q15min>85%), dependent on composition of the MDDS. Capsules containing MDDS with different BZ release rate presented multikinetic release profiles. Erosion-relaxation and swollen-diffusion were identified as main mechanisms for BZ release, in accordance with the fluid up-take exhibited. The MDDS had good performance and their composition presented a high potential for designing multikinetic release systems, whose properties could improve pharmacokinetic parameters and safety of BZ for CD pharmacotherapy. Keywords: Benznidazole, interpolyelectrolyte complexes, multiparticulate systems, Chagas diseaseReferences:[1] World Health Organization (2015). Chagas disease. Available at: http://www.who.int/tdr/research/ntd/chagas/en/. Accessed July 22nd.[2] Campi-Azevedo AC, Gomes JA, Teixeira-Carvalho A, Silveira-Lemos D, Vitelli-Avelar DM, Sathler-Avelar R, Peruhype-Magalhaes V, Bela SR, Silvestre KF, Batista MA, Schachnik NC, Correa-Oliveira R, Eloi-Santos SM, Martins-Filho OA. 2015. Etiological treatment of Chagas disease patients with benznidazole lead to a sustained pro-inflammatory profile counterbalanced by modulatory events. Immunobiology 220:564-574.[3] Coura JR, de Castro SL. 2002. A Critical Review on Chagas Disease Chemotherapy. Memórias do Instituto Oswaldo Cruz 97:3-24.[4] Urbina JA. 2010. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. Acta Trop 115:55-68.