Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation

Abstract

Ana Claudia Mendonça dos Santos,1 Alessandra Cristina Santos Akkari,1 Iasmin Rosanne Silva Ferreira,2 Cintia Rodrigues Maruyama,3 Monica Pascoli,3 Viviane Aparecida Guilherme,4 Eneida de Paula,4 Leonardo Fernandes Fraceto,5 Renata de Lima,3 Patrícia da Silva Melo,2 Daniele Ribeiro de Araujo1 1Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, 2Faculdades Integradas Metropolitanas de Campinas, Campinas, 3Departamento de Biotecnologia, Universidade de Sorocaba, Sorocaba, 4Departamento de Bioquímica, Universidade Estadual de Campinas, Campinas, 5Departamento de Engenharia Ambiental, Universidade Estadual ‘Júlio de Mesquita Filho’, Sorocaba, São Paulo, Brazil Abstract: In this work, poloxamer (PL)-based binary hydrogels, composed of PL 407 and PL 188, were studied with regard to the physicochemical aspects of sol-gel transition and pharmaceutical formulation issues such as dissolution-release profiles. In particular, we evaluated the cytotoxicity, genotoxicity, and in vivo pharmacological performance of PL 407 and PL 407–PL 188 hydrogels containing tramadol (TR) to analyze its potential treatment of acute pain. Drug–micelle interaction studies showed the formation of PL 407–PL 188 binary systems and the drug partitioning into the micelles. Characterization of the sol-gel transition phase showed an increase on enthalpy variation values that were induced by the presence of TR hydrochloride within the PL 407 or PL 407–PL 188 systems. Hydrogel dissolution occurred rapidly, with approximately 30%–45% of the gel dissolved, reaching ~80%–90% up to 24 hours. For in vitro release assays, formulations followed the diffusion Higuchi model and lower Krel values were observed for PL 407 (20%, Krel =112.9±10.6 µg·h-1/2) and its binary systems PL 407–PL 188 (25%–5% and 25%–10%, Krel =80.8±6.1 and 103.4±8.3 µg·h-1/2, respectively) in relation to TR solution (Krel =417.9±47.5 µg·h-1/2, P<0.001). In addition, the reduced cytotoxicity (V79 fibroblasts and hepatocytes) and genotoxicity (V79 fibroblasts), as well as the prolonged analgesic effects (>72 hours) pointed to PL-based hydrogels as a potential treatment, by subcutaneous injection, for acute pain. Keywords: micelle, cytotoxicity, genotoxicity, analgesia