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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
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 c...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147274/ https://www.ncbi.nlm.nih.gov/pubmed/34062883 http://dx.doi.org/10.3390/pharmaceutics13050647 |
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author | Hsueh, Henry T. Kim, Yoo-Chun Pitha, Ian Shin, Matthew D. Berlinicke, Cynthia A. Chou, Renee Ti Kimball, Elizabeth Schaub, Julie Quillen, Sarah Leo, Kirby T. Han, Hyounkoo Xiao, Amy Kim, Youngwook Appell, Matthew Rai, Usha Kwon, HyeYoung Kolodziejski, Patricia Ogunnaike, Laolu Anders, Nicole M. Hemingway, Avelina Jefferys, Joan L. Date, Abhijit A. Eberhart, Charles Johnson, Thomas V. Quigley, Harry A. Zack, Donald J. Hanes, Justin Ensign, Laura M. |
author_facet | Hsueh, Henry T. Kim, Yoo-Chun Pitha, Ian Shin, Matthew D. Berlinicke, Cynthia A. Chou, Renee Ti Kimball, Elizabeth Schaub, Julie Quillen, Sarah Leo, Kirby T. Han, Hyounkoo Xiao, Amy Kim, Youngwook Appell, Matthew Rai, Usha Kwon, HyeYoung Kolodziejski, Patricia Ogunnaike, Laolu Anders, Nicole M. Hemingway, Avelina Jefferys, Joan L. Date, Abhijit A. Eberhart, Charles Johnson, Thomas V. Quigley, Harry A. Zack, Donald J. Hanes, Justin Ensign, Laura M. |
author_sort | Hsueh, Henry T. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8147274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81472742021-05-26 Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells Hsueh, Henry T. Kim, Yoo-Chun Pitha, Ian Shin, Matthew D. Berlinicke, Cynthia A. Chou, Renee Ti Kimball, Elizabeth Schaub, Julie Quillen, Sarah Leo, Kirby T. Han, Hyounkoo Xiao, Amy Kim, Youngwook Appell, Matthew Rai, Usha Kwon, HyeYoung Kolodziejski, Patricia Ogunnaike, Laolu Anders, Nicole M. Hemingway, Avelina Jefferys, Joan L. Date, Abhijit A. Eberhart, Charles Johnson, Thomas V. Quigley, Harry A. Zack, Donald J. Hanes, Justin Ensign, Laura M. Pharmaceutics Article 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. MDPI 2021-05-01 /pmc/articles/PMC8147274/ /pubmed/34062883 http://dx.doi.org/10.3390/pharmaceutics13050647 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hsueh, Henry T. Kim, Yoo-Chun Pitha, Ian Shin, Matthew D. Berlinicke, Cynthia A. Chou, Renee Ti Kimball, Elizabeth Schaub, Julie Quillen, Sarah Leo, Kirby T. Han, Hyounkoo Xiao, Amy Kim, Youngwook Appell, Matthew Rai, Usha Kwon, HyeYoung Kolodziejski, Patricia Ogunnaike, Laolu Anders, Nicole M. Hemingway, Avelina Jefferys, Joan L. Date, Abhijit A. Eberhart, Charles Johnson, Thomas V. Quigley, Harry A. Zack, Donald J. Hanes, Justin Ensign, Laura M. Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title | Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title_full | Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title_fullStr | Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title_full_unstemmed | Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title_short | Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells |
title_sort | ion-complex microcrystal formulation provides sustained delivery of a multimodal kinase inhibitor from the subconjunctival space for protection of retinal ganglion cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147274/ https://www.ncbi.nlm.nih.gov/pubmed/34062883 http://dx.doi.org/10.3390/pharmaceutics13050647 |
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