Bilayered dissolving microneedles for microemulsion-mediated ocular delivery of brimonidine tartrate in glaucoma therapy

Glaucoma remains a leading cause of irreversible blindness worldwide, primarily driven by progressive optic nerve degeneration associated with elevated intraocular pressure (IOP). Conventional brimonidine tartrate (BRT) eye drops suffer from rapid precorneal clearance and limited corneal permeability, necessitating frequent administration and resulting in poor patient compliance. To address these limitations, a microemulsion (ME)-based bilayer dissolving microneedles (BDMNs) system was developed for sustained ocular delivery of BRT. The BRT-ME formulation was optimized <i>via</i> D-optimal design, achieving a droplet size of 34.40 ± 2.80 nm, viscosity of 60.76 ± 3.99 mPa·s, high clarity (>96% transmittance), and good thermodynamic stability. This optimized ME was then incorporated into a bi-layer microneedle matrix composed of polyvinyl alcohol (PVA), chitosan, and Poloxamer 407, yielding a structurally robust system exhibiting high mechanical integrity and >95% insertion efficiency across triple-layered Parafilm^® M. <i>In vitro</i> studies demonstrated sustained BRT release from the BDMN system over 24 h (96% cumulative release), significantly outperforming ME alone. <i>Ex vivo</i> corneal permeation showed enhanced BRT flux, while ocular irritation assessments confirmed excellent biocompatibility. Importantly, <i>in vivo</i> studies in rabbit models revealed a peak IOP reduction of ∼47% at 6 h post-application, superior to the ∼31% reduction observed with BRT-ME alone at 4 h. Overall, these results highlight the BRT-ME-BDMNs system as a minimally invasive and stable platform that markedly improves drug retention and therapeutic efficacy, offering a next-generation solution for effective glaucoma management.