Colloid‐Forming Prodrug‐Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection

Colloidal drug aggregates (CDAs) are challenging in drug discovery due to their unpredictable formation and interference with screening assays. These limitations are turned into a strategic advantage by leveraging CDAs as a drug delivery platform. This study explores the deliberate formation and stabilization of CDAs for local ocular drug delivery, using a modified smallmolecule glaucoma drug. A series of timolol prodrugs are synthesized and self-assembled into CDAs. Of four prodrugs, timolol palmitate CDAs have a critical aggregate concentration of 2.72 µM and sustained in vitro release over 28 d. Timolol palmitate CDAs are dispersed throughout in situ gelling hyaluronan-oxime hydrogel and injected into the subconjunctival space of rat eyes. The intraocular pressure is significantly reduced for at least 49 d with a single subconjunctival injection of timolol-palmitate CDAs compared to 6 h for conventional timolol maleate. The systemic blood concentrations of timolol are significantly lower, even after 6 h, for timolol palmitate CDA-loaded hydrogel versus free timolol maleate, thereby potentially reducing the risk of systemic side effects. This innovative approach redefines the role of CDAs and provides a framework for long-acting ocular therapeutics, shifting their perception from a drug screening challenge to a powerful tool for sustained local drug delivery.