Journal
JOURNAL OF CONTROLLED RELEASE
Volume 352, Issue -, Pages 472-484Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2022.10.036
Keywords
Anti-VEGF; In-situ forming hydrogel; Microneedles; Posterior ocular disease; Suprachoroidal injection
Funding
- National Institutes of Health [R01EY022097, R01EY025286]
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We developed an in-situ forming hydrogel for slow release of Bev, which can provide long-acting treatment for AMD. The hydrogel released Bev for over 6 months in the eye and showed good tolerance.
Patients with wet age-related macular degeneration (AMD) require intravitreal injections of bevacizumab (Bev) or other drugs, often on a monthly basis, which is a burden on the healthcare system. Here, we developed an in -situ forming hydrogel comprised of Bev and hyaluronic acid (HA) crosslinked with poly(ethylene glycol) dia-crylate for slow release of Bev after injection into the suprachoroidal space (SCS) of the eye using a microneedle. Liquid Bev formulations were cleared from SCS within 5 days, even when formulated with high viscosity, unless Bev was conjugated to a high molecular-weight HA (2.6 MDa), which delayed clearance until 1 month. To extend release to 6 months, we synthesized in-situ forming Bev-HA hydrogel initially as a low-viscosity mixture suitable for injection and flow in the SCS to cover a large area extending to the posterior pole of the eye where the macula is located in humans. Within 1 h after injection, Bev and HA were crosslinked, which retained Bev for slow release as the hydrogel biodegraded. In vivo studies in the rabbit eye reported Bev release for >6 months, depending on gel formulation and Bev assay. The in-situ forming Bev-HA hydrogel was well tolerated, as assessed by clinical exam, fundus imaging, histological analysis, and intraocular pressure measurement. We conclude that Bev released from an in-situ forming hydrogel may enable long-acting treatments of AMD and other posterior ocular indications.
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