Hyaluronic acid-mediated nanocomplexation enhances ocular retention and therapeutic efficacy of dorzolamide in a biodegradable gelatin insert.

Conventional dorzolamide (DZ) eye drops for glaucoma therapy suffer from rapid precorneal clearance, low ocular bioavailability, and frequent dosing requirements. Herein, we developed a sustained-release ocular delivery platform by rationally engineering DZ into hyaluronic acid (HA)-based polyelectrolyte nanocomplexes and integrating them into a biodegradable crosslinked gelatin ocular insert (GelOI-HA/DZ). HA/DZ nanocomplexes were formed via mild aqueous complexation and optimized using a Box-Behnken design, yielding nanosystems of ~67 nm with high complexation efficiency (~91%) and a stable negative surface charge. Embedding the optimized nanocomplexes into gelatin inserts significantly reduced porosity, enhanced mucoadhesion, improved tensile strength, and controlled swelling behavior, establishing a hierarchical nano-in-micro architecture. GelOI-HA/DZ achieved a dual-barrier sustained release profile, extending dorzolamide delivery for one full week, in contrast to rapid release from nanocomplexes alone. In vivo pharmacokinetic evaluation in rabbits demonstrated that a single GelOI-HA/DZ insert produced a ~ 50-fold increase in ocular bioavailability, an ~18-fold prolongation in mean residence time, and a ~ 6-fold higher peak aqueous humor concentration compared with conventional eye drops. A strong Level-A in vitro-in vivo correlation (r2 = 0.9922) validated the predictability of the release platform. Importantly, GelOI-HA/DZ provided stable intraocular pressure reduction for one week, minimizing the peak-trough fluctuations associated with drop therapy. Collectively, this work introduces a rationally engineered hierarchical nano-in-micro ocular system that converts molecular polyelectrolyte complexation into a predictable, zero-order, once-weekly therapeutic platform advancing the design paradigm of long-acting biodegradable ophthalmic drug delivery.