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

Authors :
Henry T. Hsueh
Yoo-Chun Kim
Ian Pitha
Matthew D. Shin
Cynthia A. Berlinicke
Renee Ti Chou
Elizabeth Kimball
Julie Schaub
Sarah Quillen
Kirby T. Leo
Hyounkoo Han
Amy Xiao
Youngwook Kim
Matthew Appell
Usha Rai
HyeYoung Kwon
Patricia Kolodziejski
Laolu Ogunnaike
Nicole M. Anders
Avelina Hemingway
Joan L. Jefferys
Abhijit A. Date
Charles Eberhart
Thomas V. Johnson
Harry A. Quigley
Donald J. Zack
Justin Hanes
Laura M. Ensign
Source :
Pharmaceutics, Vol 13, Iss 5, p 647 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

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.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.3232c89326b24142bbf27c0ff670b9ea
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13050647