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
Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Pharmaceutics. 2021 May 1;13(5):647. doi: 10.3390/pharmaceutics13050647.
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.
青光眼是全球不可逆性失明的主要原因。眼压升高是青光眼发病和进展的主要危险因素之一，现有的药物干预措施均专门针对降低眼压。然而，尽管眼压大幅降低，视网膜神经节细胞（RGC）的退化仍可能继续进展。降低眼压的一种补充策略是使用神经保护剂，通过独立于眼压的机制中断细胞死亡过程。在此，我们描述了一种离子络合方法，用于制备含有约50%蛋白激酶抑制剂舒尼替尼负载量的微晶，通过结膜下注射提高RGC的存活率。单次结膜下注射舒尼替尼-帕莫酸盐复合物（SPC）微晶可使视网膜药物水平持续20周，从而在视神经损伤大鼠模型中实现神经保护。此外，结膜下注射SPC微晶在角膜新生血管大鼠模型中也产生了治疗效果。重要的是，在猪身上通过结膜下注射SPC微晶达到了与治疗相关的视网膜药物浓度。对于青光眼等慢性疾病，一种能提供持续治疗效果以补充降低眼压疗法的制剂可以改善疾病管理并提高患者生活质量。
