Injectable biodegradable temperature-responsive PLGA–PEG–PLGA copolymers: Synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels

Abstract

Injectable biodegradable temperature-responsive poly( dl-lactide-co-glycolide-b–ethylene glycol-b- dl-lactide-co-glycolide) (PLGA–PEG–PLGA) triblock copolymers with dl-lactide/glycolide molar ratio ranging from 6/1 to 15/l were synthesized from monomers of dl-lactide, glycolide and polyethylene glycol and characterized by 1H NMR. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The hydrophobicity of the copolymer increased with the increasing of dl-lactide/glycolide molar ratio. In vitro dissolution studies with two different hydrophobic drugs (5-fluorouracil and indomethacin) were performed to study the effect of dl-lactide/glycolide molar ratio on drug release and to elucidate drug release mechanism. The release mechanism for hydrophilic 5-fluorouracil was diffusion-controlled, while hydrophobic indomethacin showed an biphasic profile comprising of an initial diffusion-controlled stage followed by the hydrogel erosion-dominated stage. The effect of dl-lactide/glycolide molar ratio on drug release seemed to be dependent on the drug release mechanism. It has less effect on the drug release during the diffusion-controlled stage, but significantly affected drug release during the hydrogel erosion-controlled stage. Compared with ReGel system, the synthesized copolymers showed a higher gelation temperature and longer period of drug release. The copolymers can solubilize the hydrophobic indomethacin and the solubility (13.7 mg/ml) was increased 3425-fold compared to that in water (4 μg/ml, 25 °C). Two methods of physical mixing method and solvent evaporation method were used for drug solubilization and the latter method showed higher solubilization efficiency.