Dapagliflozin embedded polymeric nanomicelles for enhanced ocular drug delivery: A promising strategy for glaucoma therapy.

Glaucoma, a progressive neurodegenerative disorder, accentuates the need for a neuroprotective therapy to overcome the risk of blindness. Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 3 (NLRP3) inhibitors like dapagliflozin (DAPA) may exert neuroprotective effects in the glaucoma therapy. As DAPA suffers from poor permeability and solubility challenges, it cannot be administered in the eyes. Also, invasive methods as well as retinal drug delivery suffers from compliance and safety issues. Thus, the aim was to develop and assess DAPA loaded mixed polymeric, nanomicellar (DAPA MPN) formulation using non-ionic polymers, Poloxamer 188 and Soluplus. In-silico studies involving DAPA and brinzolamide (BRZ) revealed the key targets of glaucoma for comparative analysis. Ensuing CMC determination and drug-polymer ratio optimization, stable, DAPA MPN batch was formulated with particle size of 144.57 nm, spherical morphology with 90.18 % entrapment efficiency. Topical DAPA MPN formulation showed effective encapsulation, drug-excipient compatibility and sustained drug release with 1.45 folds enhancement. As per the OECD TG 405 studies, DAPA MPN was found to be safe for ocular application. During in-vivo screening in ɑ-chymotrypsin induced glaucoma model of New Zealand white rabbits, DAPA MPN demonstrated significant anti-inflammatory, anti-oxidative and anti-apoptotic benefits on the retina. Also, DAPA MPN showed IOP lowering effects as confirmed from the TGF-β1 levels in the aqueous humor. In conclusion, polymeric nanomicelles proved to be promising platform for successful retinal delivery of DAPA, thereby exerting neuroprotective benefits during glaucoma therapy.