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(申请人提供)：这个小企业创新项目旨在开发一种治疗青光眼和高眼压的创新眼药水配方。CharLesson从多瑙河制药公司获得了一种新的小分子化合物(以前称为DNB001或KR-31378)。MSH-1001具有降眼压和神经保护作用。它是一种对ATP敏感的K通道开放剂。该项目的目标是证明一种基于乳剂的滴眼液可以将MSH-100的治疗水平输送到房水中，长期目标(第二阶段)是在适当的高眼压动物模型中降低眼压，并进行支持IND的研究，以支持首个人的研究。这项提议的目标是1)制造三种不同类型的乳剂眼药水，可以加入MSH-1001。2)选择符合我们所有标准(即所需渗透压、pH、粘度和液滴大小)的三种最有希望的乳剂，并在荷兰皮带兔体内测试它们的眼耐受性和组织学。耐受性制剂的眼部药代动力学特性将与药理活性的实验混悬剂进行比较。荷兰带兔滴眼液(40 5L/只眼1滴)。在安乐死后的不同时间点(0.25、0.5、1、2、4、8小时)摘除眼球。然后仔细解剖房水，并用LC-MS对MSH-1001进行定量。成功的眼用乳剂将显示至少等于或优于实验悬浮液的眼部分布。 公共卫生相关性：青光眼的主要治疗方法是使用药物降低眼压(IOP)。前列腺素通常用于通过增加葡萄膜巩膜流出量来降低眼压，作为一线治疗。尽管疗效显著，但许多患者经常需要多种药物治疗，或者在药物治疗无效的情况下进行青光眼手术，以实现目标压力控制。迫切需要开发新的有效的降眼压药物，以便眼科医生能够更有效地实现对这些患者的目标压力的控制。研究一直集中在寻找新的分子靶点，作为一线前列腺素的独立或辅助治疗，有可能改善目前的治疗方法。这项建议的目标是开发一种临床用MSH-1001眼用乳剂，这种新型小分子通过一种新的作用机制促进小梁流出，有效地降低眼压。。