A generic technology for long-acting intravitreal therapy

Intravitreal (IVT) injection is a crucial drug delivery method for ocular diseases, but it requires frequent administration due to short drug half-lives. This study presents a novel approach to long-acting IVT therapy using biodegradable tetra-PEG hydrogel microspheres (MSs) as drug carriers. These MSs, approximately 50 μm in diameter, are designed with β-eliminative cleavable linkers that allow for controlled drug release and programmed carrier degradation. The study demonstrates that MSs can persist in the vitreous without clearing for very long periods – perhaps years – controlled by the rate of degradation programmed into the microspheres. Drug surrogates tethered to MSs via releasable linkers exhibited release half-lives of up to 60 days, consistent with the employed linkers. By incorporating cleavable linkers in MS crosslinks with different degradation rates, the time to reverse gelation (tRG) into clearable tetra-PEG monomers was successfully programmed, with one gel studied showing degradation within 8 weeks, and another within 12 months post-injection. Tolerability studies conducted in rabbits over 14 months, encompassing MS biodegradation, showed stable intraocular pressure, maintained lens transparency, and no significant changes in retinal structures or signs of inflammation. The MS technology offers several additional advantageous features, including excellent injectability through a 29G needle, autoclave sterilization capability, and applicability to various drug types. Importantly, proof-of-concept studies demonstrated sustained release of the clinically important anti-VEGF antibody bevacizumab in rabbits over extended periods, and maintenance of therapeutic concentrations significantly longer than conventional bolus injection. This "plug-and-play" technology allows for easy assembly of IVT delivery systems with predictable and tunable drug half-lives and dosing frequencies, addressing the need for extended dosing intervals in ocular drug delivery.