Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells
| Autor: | Matthew B. Appell, Ian Pitha, Renee Ti Chou, Abhijit A. Date, Laura M. Ensign, Charles G. Eberhart, Matthew D. Shin, Cynthia A. Berlinicke, Nicole M. Anders, Usha Rai, Hyounkoo Han, Joan L. Jefferys, Henry T. Hsueh, Avelina Hemingway, Elizabeth C. Kimball, Sarah Quillen, Thomas V. Johnson, Justin Hanes, Amy Xiao, Harry A. Quigley, Donald J. Zack, Yoo Chun Kim, Kirby T. Leo, Laolu Ogunnaike, Patricia Kolodziejski, Julie Schaub, Youngwook Kim, Hye Young Kwon |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
genetic structures medicine.drug_class sunitinib Pharmaceutical Science Glaucoma 02 engineering and technology pamoic acid 030226 pharmacology & pharmacy Retinal ganglion Neuroprotection ocular drug delivery Tyrosine-kinase inhibitor Article 03 medical and health sciences 0302 clinical medicine tyrosine kinase inhibitor Pharmacy and materia medica Ophthalmology medicine Retina business.industry Sunitinib Therapeutic effect 021001 nanoscience & nanotechnology medicine.disease eye diseases RS1-441 medicine.anatomical_structure glaucoma Corneal neovascularization neuroprotection sense organs 0210 nano-technology business medicine.drug |
| Zdroj: | Pharmaceutics, Vol 13, Iss 647, p 647 (2021) Pharmaceutics Volume 13 Issue 5 |
| ISSN: | 1999-4923 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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