Solid-state effects of Brinzolamide on sustained intravitreal release from hot-melt extruded PLGA implants

Intravitreal (IVT) injections treat diseases of the posterior eye segment, but frequent dosing limits patient compliance and increases costs. Some long-acting IVT implants are available but further understanding of polymer behavior and solid-state properties is required to expand this space for more drug molecules and generic formulations. We evaluated four poly(D,L-lactide-co-glycolide) (PLGA) polymers varying in lactide content and molecular weight, and one poly(D,L-lactide) (PLA), as rod-shaped IVT implants. Brinzolamide (BRZ) was used as a model drug because its melting point (130°C) enables production of hot-melt extruded implants containing amorphous (T_extrusion > T_m) or crystalline (T_extrusion < T_m) drug. Implants (0.2 × 20 mm) were characterized for impurities, endotoxin levels, solid-state properties, and microstructure. Drug release was assessed using in vitro model with artificial vitreous and saline compartments. IVT elimination of BRZ solution in rabbits (n = 12) occurred mostly via posterior route (aqueous humor (AH)/ vitreous humor (VH) AUC ratio 0.0053). In vitro release data, combined with in silico simulations, guided implant selection and dosing for the in vivo study. Two selected amorphous implants were administered intravitreally via trocar into rabbits (n = 8/implant). BRZ release was sustained over 42 days in vitro and in vivo, with AH levels < 1 % of VH. The in vitro model produced good in vitro-in vivo correlation. Crystalline implants exhibited faster, dissolution-driven release from a porous, non-uniform structure. Amorphous implants showed slower, PLGA degradation-limited release from a homogeneous matrix. These findings demonstrate that drug solid-state critically determines implant microstructure and release mechanisms in PLGA-based IVT systems.