Repurposing glibenclamide for retinal protection: TUDCA-modified liposomes for ocular delivery

: Glibenclamide, widely used as an oral treatment for type 2 diabetes, represents a promising example of drug repurposing. This second-generation sulfonylurea has demonstrated neuroprotective effects on ocular tissues following oral administration, showing potential benefits in the prevention and management of diabetic retinopathy and age-related macular degeneration (AMD). These findings suggest that local administration could be particularly advantageous for patients not receiving systemic glibenclamide therapy. However, to enhance ocular bioavailability and achieve sustained drug release, an appropriate delivery system is required. This study aimed to develop a topical liposomal formulation for the ocular delivery of glibenclamide. To improve penetration across biological barriers, liposome properties were optimized by incorporating tauroursodeoxycholic acid (TUDCA), a bile salt derivative that also demonstrated neuroprotective activity. The inclusion of this molecule within the lipid bilayer impacted phospholipid organization, increasing vesicle deformability, as confirmed by small-angle X-ray scattering (SAXS) analysis. Glibenclamide loading did not affect vesicle deformability and was higher in TUDCA-modified liposomes compared to conventional liposomes. Ex vivo permeation studies using isolated porcine ocular tissues (cornea, conjunctiva, and sclera) further supported TUDCA's role as an edge activator, enhancing drug penetration. Notably, glibenclamide liposomes were also able to accumulate in the sclera, forming a reservoir for sustained release over time. Finally, the liposomal formulation demonstrated good tolerability in ARPE-19 cell lines, highlighting its potential as a safe and effective system for ocular delivery of glibenclamide.