Temperature-sensitive hydrogels composed of chitosan and hyaluronic acid as injectable carriers for drug delivery

Temperature-sensitive hydrogels composed of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) and chitosan + hyaluronic acid (CPNHA) were grafted in order to examine their physicochemical characteristics, in vitro drug release, and in vivo pharmacodynamics. The sol–gel transition behavior was investigated by UV/visible spectrophotometry, differential scanning calorimetry, and viscometry. A slight difference in the transition temperatures was observed among these polymer systems, with CPN and CPNHA exhibiting higher temperatures compared with PNIPAAm. A zeta potential determination revealed a positive charge for the CPN hydrogel, whereas no or only a negligible charge was observed for PNIPAAm and CPNHA. The entanglement of CPN hydrogels observed using scanning electronic microscopy showed the densest cross-linkage structure, followed by CPNHA and PNIPAAm. Both hydrophilic and lipophilic drugs, including nalbuphine, indomethacin, and the nalbuphine prodrug, were used as model drugs in an in vitro drug release experiment. All 3 hydrogels significantly prolonged drug release. The release rate of hydrophilic nalbuphine increased in the order CPN < CPNHA < PNIPAAm. The drug release of these hydrogels exhibited a trend opposite to that of lipophilic drugs. A cold ethanol tail-flick study was utilized in order to examine the antinociceptive activity of intravenous nalbuphine. CPN and CPNHA prolonged the analgesic duration of nalbuphine with no influence on the onset time. The loading of nalbuphine in the CPNHA hydrogel exhibited the longest analgesic duration (4 h) among the 3 hydrogels tested.