Phosphosulindac for dry eye

磷舒林治疗干眼症

• 批准号: 9907964
• 负责人: Basil Rigas
• 金额: $ 37.71万
• 依托单位: APIS THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907964
• 关键词: Absence of pain sensation; Address; Affect; Analgesics; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Artificial Tears; Binding Proteins; Biodistribution; Blindness; Blood Circulation; CD4 Positive T Lymphocytes; Categories; Cauterize; Characteristics; Chronic; Clinical; Complement; Concanavalin A; Cornea; Cyclosporine; Data; Development; Diagnosis; Diagnostic; Dose; Drug Kinetics; Etiology; Excision; Eye diseases; Eyedrops; Film; Formulation; Functional disorder; Gelatinase B; Goals; Goblet Cells; Gold; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Injections; Innate Immune Response; Interferon Type II; Interleukin-1 beta; Interleukin-17; Investigational Drugs; Lacrimal gland structure; Lactoferrin; Lead; Lectin; Medical; Metabolic; Modeling; Molecular Target; Mucins; Narcotics; Nerve Endings; Neuropathy; New Agents; Operative Surgical Procedures; Oryctolagus cuniculus; Osmolar Concentration; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma Proteins; Prevalence; Price; Production; Protocols documentation; Rose Bengal; Safety; Signs and Symptoms; Stains; Stress; Subgroup; Sulindac; Symptoms; T-Lymphocyte; Testing; Time; Toxic effect; Toxicology; Validation; Work; adaptive immune response; analytical method; aqueous; base; conjunctiva; corneal epithelium; cost; cytokine; evaporation; eye dryness; human disease; improved; lead optimization; meibomian gland; melting; novel; ocular pain; ocular surface; optimal treatments; phase 1 study; phase 2 study; posterior eyeball chamber; preclinical development; preclinical evaluation; scale up; side effect; small molecule; sulfated glycoprotein 2

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.

抽象的 干眼症（DED）的治疗受到弱药物的阻碍，重要的一面 效果和高成本。 DED的病理生理标志统一了其多样化的病因 是解释其临床表现的眼表的炎症。最佳 DED的治疗必须提供强大的功效；局部镇痛；安全;方便的给药；和 低成本。 DED的可用治疗方法都不符合这些标准。 Phosphoslindac（PS）是专有化合物。我们开发了新颖的健壮兔子 DED涵盖其主要病理生理亚组的模型（蒸发，水性 不足和混合）。 PS对DED显示出了显着的功效；出色的安全；几乎 瞬时局部镇痛；在疗效方面优于环孢菌素和LifiteGrast， 目前两种用于治疗DED的药物；并预计低成本额外 初步数据包括PS的扩大合成的辅助发展；和 开发和验证所有所需的分析方法。我们还确定了 PS的分子靶标；并开发了几种用于包含主要的PS的配方 物理化学类别。 我们的目标是开发PS作为DED的有效药物。在这个快速轨道应用中， 我们提出以下研究： 第一阶段研究：目标＃1：研究PS在DED的蒸发模型中的效果， 通过水性不足和混合模型来补充我们的结果。目标＃2：开发 PS的铅公式。 第二阶段研究：目标＃3：优化目标＃2的铅配方。目标＃4：研究 PS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。 AIM＃6：为FDA准备IND协议和软件包。 拟议的工作，如果成功的话，将为成功的待遇做出很大贡献 DED是一种普遍的人类疾病，代表了未满足的医疗需求。