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

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

doi:10.3390/pharmaceutics13050647

Pharmaceutics (May 2021)

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

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

Affiliations

Henry T. Hsueh: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Yoo-Chun Kim: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Ian Pitha: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Matthew D. Shin: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Cynthia A. Berlinicke: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Renee Ti Chou: Department of Computational Biology, Bioinformatics, and Genomics, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA
Elizabeth Kimball: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Julie Schaub: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Sarah Quillen: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Kirby T. Leo: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Hyounkoo Han: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Amy Xiao: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Youngwook Kim: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Matthew Appell: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Usha Rai: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
HyeYoung Kwon: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Patricia Kolodziejski: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Laolu Ogunnaike: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Nicole M. Anders: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
Avelina Hemingway: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
Joan L. Jefferys: Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Abhijit A. Date: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Charles Eberhart: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Thomas V. Johnson: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Harry A. Quigley: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Donald J. Zack: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Justin Hanes: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Laura M. Ensign: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA

DOI: https://doi.org/10.3390/pharmaceutics13050647
Journal volume & issue: Vol. 13, no. 5
p. 647

Abstract

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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.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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