Amino-functionalized poloxamer-hyaluronate in situ gels for sustained delivery of timolol maleate in glaucoma therapy

Poloxamer-based in situ gels face limitations in ocular drug delivery due to weak mucoadhesion and low mechanical strength. Herein, we developed an amino-functionalized poloxamer-hyaluronate graft copolymer (Am-P407-HA) to overcome these challenges. Comprehensive characterizations confirmed successful synthesis of copolymer, which interacted with mucin to enhance the mucoadhesion of poloxamer. Using timolol maleate (TM) as a model drug, an ophthalmic in situ gel (TM@Am-P407-HA) was developed. The thermosensitive gel demonstrated sustained release properties (93.07 % cumulative release over 10 h) following Fickian diffusion kinetics. In vivo fluorescence tracking indicated that the TM@Am-P407-HA prolonged the TM residence time on the ocular surface. Pharmacokinetic study of TM@Am-P407-HA revealed 4.46-fold and 2.29-fold increases in AUC 0-t for tear fluid and aqueous humor, respectively, along with 3.30-fold and 2.34-fold prolongations in residence times compared to conventional eye drops. Ocular hypertension models showed TM@Am-P407-HA provided smoother pressure reduction curve with a prolonged duration of efficacy. Moreover, biosafety evaluations confirmed excellent biocompatibility of TM@Am-P407-HA through cytotoxicity, Draize irritation, and histopathological studies. This novel graft copolymer system represents a significant advancement in ocular drug delivery, offering enhanced bioavailability and reduced dosing frequency for glaucoma therapy