Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

An ion‐paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection

“… 43 Pamoic acid did not negatively impact retinal ganglion cell survival in vitro at concentrations as high as 10 mg/ml. 43 While encouraging, the safety of pamoic acid dosed topically would need to be demonstrated before use in an eye drop. Furthermore, while the short‐term stability data are encouraging, longer‐term characterization and, if required, additional optimization to ensure long‐term shelf stability would be an important next step in development.…”

Targeted Microglial Attenuation through Dendrimer–Drug Conjugates Improves Glaucoma Neuroprotection

“…Peak IOP was not significantly different between treatment groups (Figure ) nor was the positive integral of IOP exposure, which represents the cumulative IOP elevation during the experiment in laser-treated eyes compared to fellow eye controls: 318 ± 128 mmHg·days for vehicle, 367 ± 100 for NAC, and 341 ± 83 for D-NAC. IOP elevation after treatment followed a course in which IOP peaks approximately 3 days after laser treatment, decreases over several weeks, and normalizes by post-laser day 31. , …”

“…IOP elevation after treatment followed a course in which IOP peaks approximately 3 days after laser treatment, decreases over several weeks, and normalizes by post-laser day 31. 37,56 RGC body counts from retinal whole mounts labeled with DAPI and RPBMS demonstrated significant protection from RGC loss in D-NAC compared to control eyes. When RGC counts in each animal were compared to the counts in the fellow eye, which did not undergo laser or drug treatment, D-NAC significantly increased RGC survival compared to control eyes (39 ± 12% survival for D-NAC versus 20 ± 15% survival for control, p = 0.02) but not NAC-treated eyes (26 ± 14% survival for NAC, p = 0.15).…”

New strategies for neuro protection in glaucoma

“…It was found to enhance survival of RGCs for neuroprotection. Recently, a hypotonic, thermosensitive gel-forming eye drop ( Kim et al, 2022 ) and a sunitinib-pamoate complex (SPC) microcrystals for subconjunctival injection ( Hsueh et al, 2021 ) were devised to continuously release for 1 and 20 weeks.…”