Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1783697592508481536
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
work_keys_str_mv AT hsuehhenryt ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT kimyoochun ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT pithaian ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT shinmatthewd ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT berlinickecynthiaa ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT choureneeti ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT kimballelizabeth ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT schaubjulie ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT quillensarah ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT leokirbyt ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT hanhyounkoo ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT xiaoamy ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT kimyoungwook ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT appellmatthew ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT raiusha ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT kwonhyeyoung ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT kolodziejskipatricia ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT ogunnaikelaolu ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT andersnicolem ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT hemingwayavelina ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT jefferysjoanl ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT dateabhijita ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT eberhartcharles ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT johnsonthomasv ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT quigleyharrya ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT zackdonaldj ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT hanesjustin ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells
AT ensignlauram ioncomplexmicrocrystalformulationprovidessustaineddeliveryofamultimodalkinaseinhibitorfromthesubconjunctivalspaceforprotectionofretinalganglioncells