Novel emulsion-based formulation of the anti-glaucoma MSH-1001 for improved topic

抗青光眼 MSH-1001 的新型乳剂配方可改善治疗主题

• 批准号: 8123992
• 负责人: Ronald A Wassel
• 金额: $ 28.79万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123992
• 关键词: Accounting; Adrenergic beta-Antagonists; Affect; Animal Model; Anterior; Aqueous Humor; Axon; Biological Availability; Blindness; Businesses; Characteristics; Chemicals; Clinical; Data; Development; Disease; Dose; Drainage procedure; Drops; Drug Formulations; Drug Kinetics; Emulsions; Enzymes; Euthanasia; Exhibits; Eye; Eyedrops; Glaucoma; Goals; Histology; Histopathology; Homeostasis; Human; Latanoprost; Lead; Liquid substance; Liver; Minor; Modeling; Molecular Target; Movement; Neuroprotective Agents; North America; Ocular Hypertension; Oils; Ophthalmologist; Oral; Oryctolagus cuniculus; Osmolalities; Osmolar Concentration; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Phase; Phase II Clinical Trials; Physiologic Intraocular Pressure; Pigments; Plasma; Potassium Channel; Primary Open Angle Glaucoma; Production; Property; Prostaglandins; Refractory; Regimen; Research; Retinal Ganglion Cells; Rights; Risk; Risk Factors; Suspension substance; Suspensions; Testing; Therapeutic; Time; Topical application; Trabecular meshwork structure; Translating; Uvea; Viscosity; Vision; alpha 2 agonist; antiglaucoma drug; aqueous; base; dosage; drug distribution; glaucoma surgery; improved; in vivo; inhibitor/antagonist; innovation; man; meetings; nanoemulsion; nanoscale; novel; ocular hypotensive; optic nerve disorder; pressure; small molecule

DESCRIPTION (provided by applicant): This Small Business Innovation project aims to develop an innovative eye drop formulation for the treatment of glaucoma and ocular hypertension. Charlesson has acquired from Danube Pharmaceuticals MSH-1001, a new small molecule compound (previously known as DNB-001 or KR- 31378). MSH-1001 is has both ocular hypotensive and neuroprotectant properties. It is an ATP- sensitive K channel opener. The goal of this project is to demonstrate that an emulsion based eye drop can deliver therapeutic levels of MSH-100, to the aqueous humor with the long term goal (Phase 2) of reducing intraocular pressure in an appropriate animal model of ocular hypertension and conducting the IND-enabling studies supporting a first-on-man study. The goal of this proposal is to 1) Make three different types of emulsion based eye drops that can incorporate MSH-1001. 2) Take the three most promising emulsions that meet all of our criteria (i.e. the desired osmolality, pH, viscosity and droplet size) and test them in-vivo for ocular tolerance and histology in Dutch Belted rabbits. Ocular pharmacokinetic properties of the tolerated formulations will be compared to the pharmacologically active experimental suspension. Eyedrops (one drop of 40 5L/eye) will be administered to Dutch Belted rabbits. At different time points (0.25, 0.5, 1, 2, 4, and 8hrs), eyes will be enucleated following euthanasia. Aqueous humor will then carefully be dissected and The MSH- 1001 quantified by LC-MS. The successful ophthalmic emulsion will show ocular distribution at least equal or superior to the experimental suspension. PUBLIC HEALTH RELEVANCE: Glaucoma is primarily treated by administering drugs to decrease intraocular pressure (IOP). Prostaglandins are commonly used to lower IOP by increasing the uveoscleral outflow as first-line therapy. Despite their robust efficacy, many patients often require multiple medications, or glaucoma surgery in the cases refractory to pharmacological treatments, to achieve target pressure control. There is a highly need to develop novel potent IOP lowering drugs so that ophthalmologists can more effectively achieve a better control of the target pressure in those patients. Research has been focused on identifying novel molecular targets with the potential to better the current therapies as a stand-alone or an adjunct to the first-line prostaglandin. The goal of this proposal is to develop a clinical ophthalmic emulsion of MSH-1001, a novel small molecule that effectively lowers IOP by enhancing the trabecular outflow through a novel mechanism of action,. .

描述（由申请人提供）：该小型企业创新项目旨在开发一种用于治疗青光眼和高眼压症的创新滴眼液配方。Charlesson从Danube Pharmaceuticals获得了一种新的小分子化合物MSH-1001（以前称为DNB-001或KR- 31378）。MSH-1001具有眼水肿和神经保护剂的特性。它是ATP敏感性钾通道开放剂。本项目的目的是证明基于乳剂的滴眼液可以向房水递送治疗水平的MSH-100，长期目标（II期）是在适当的高眼压动物模型中降低眼内压，并进行支持首次人体研究的IND使能研究。本提案的目标是：1）制备三种不同类型的可掺入MSH-1001的乳液型滴眼液。2)取符合我们所有标准（即所需的渗透压摩尔浓度、pH值、粘度和液滴大小）的三种最有前途的乳剂，并在荷兰带兔中进行体内眼耐受性和组织学测试。将耐受制剂的眼部药代动力学性质与具有抗炎活性的实验混悬液进行比较。将对Dutch Belted兔滴眼液（一滴40 5 L/眼）。在不同时间点（0.25、0.5、1、2、4和8小时），将在人道处死后摘除眼睛。然后仔细解剖眼房水，并通过LC-MS定量MSH- 1001。成功的眼用乳剂将显示出至少等于或上级于实验悬浮液的眼部分布。 公众健康相关性：青光眼主要通过给药降低眼内压（IOP）来治疗。前列腺素通常用于通过增加葡萄膜巩膜流出来降低IOP，作为一线治疗。尽管它们具有强大的疗效，但许多患者通常需要多种药物，或在药物治疗难治的情况下进行青光眼手术，以实现目标压力控制。非常需要开发新的有效的IOP降低药物，使得眼科医生可以更有效地实现对这些患者的目标压力的更好控制。研究的重点是确定新的分子靶点，这些靶点有可能作为一线前列腺素的独立或辅助治疗来改善目前的治疗。本提案的目的是开发MSH-1001的临床眼用乳剂，MSH-1001是一种新型小分子，通过一种新的作用机制增强小梁外流，有效降低IOP。.