Phosphosulindac for dry eye

摘要 干眼病(DED)的治疗一直受到药物薄弱、显著副作用的阻碍。 效果好，成本高。DED的不同病因统一的病理生理标志 眼表发炎是其临床表现的原因。最优的 DED的治疗必须提供强大的疗效；局部止痛；安全；方便的剂量；以及 低成本。DED的现有治疗方法都不符合这些标准。 硫代磷酸(PS)是一种专利化合物。我们培育了一种新的健壮的兔子 DED模型包括其主要病理生理亚群(蒸发型、水型 不足和混合)。PS对DED有显著疗效；极佳的安全性；实用 即刻局部止痛；在疗效方面优于环孢素和利非格司特， 目前可用于治疗DED的两种药物；并预计将以较低的成本 初步数据包括支持IND的PS放大合成的开发；以及 开发和验证所有必需的分析方法。我们还确认了 PS的分子靶点；并开发了几种PS的剂型，包括主要 物理化学分类。 我们的目标是开发PS作为治疗DED的有效药物。在此Fast Track应用程序中， 我们建议进行以下研究： 第一阶段研究：目标1：研究PS在DED蒸发模型中的作用， 用缺水模型和混合模型补充了我们的结果。目标2：发展 主导PS配方。 第二阶段研究：目标#3：从目标#2优化铅配方。目标#4：研究 多糖组分的体外代谢稳定性和血浆蛋白结合。目标5：进行毒性研究 PS.目标6：为FDA准备IND方案和方案。 拟议的工作，如果成功，将极大地有助于成功地治疗 DED，一种流行的人类疾病，代表着一种未得到满足的医疗需求。

ABSTRACT The treatment of dry eye disease (DED) has been hampered by weak agents, significant side effects and high cost. The pathophysiological hallmark of DED that unifies its diverse etiologies is inflammation of the ocular surface that accounts for its clinical manifestations. The optimal treatment of DED must provide strong efficacy; topical analgesia; safety; convenient dosing; and low cost. None of the available treatments for DED meets these criteria. Phosphosulindac (PS) is a proprietary compound. We developed novel robust rabbit models of DED encompassing its main pathophysiological subgroups (evaporative, aqueous deficient and mixed). PS showed remarkable efficacy against DED; excellent safety; practically instantaneous topical analgesia; superiority in terms of efficacy over cyclosporine and lifitegrast, the two currently available drugs for the treatment of DED; and has projected low cost Additional preliminary data include the IND-enabling development of a scaled-up synthesis of PS; and development and validation of all the required analytical methods. We have also identified molecular targets of PS; and developed several formulations for PS encompassing the main physicochemical categories. Our goal is to develop PS as an efficacious drug for DED. In this Fast Track application, we propose the following studies: Phase I studies: Aim#1: Study the effect of PS in an evaporative model of DED, complementing our results with the aqueous deficient and mixed models. Aim #2: Develop the lead formulation of PS. Phase II studies: Aim #3: Optimize the lead formulation from aim #2. Aim #4: Study the in vitro metabolic stability and plasma protein binding of PS. Aim #5: Perform toxicity studies of PS. And Aim # 6: Prepare the IND protocol and package for the FDA. The proposed work, if successful, will contribute greatly towards a successful treatment of DED, a prevalent human disease, which represents an unmet medical need.