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）：这个小型企业创新项目旨在开发一种创新的眼滴剂，以治疗青光眼和眼高血压。 Charlesson已从多瑙河Pharmaceuticals MSH-1001（一种新的小分子化合物（以前称为DNB-001或KR-31378）获得。 MSH-1001具有眼部低血压和神经保护剂特性。它是一个ATP敏感的K通道开启器。该项目的目的是证明，基于乳液的眼睛下降可以将MSH-100的治疗水平传递给水性幽默，并具有长期目标（第2阶段）在适当的眼内高血压模型中降低了眼压的长期目标（2阶段），并进行了支持的研究研究，从而支持了一项支持第一对人的研究。该提案的目的是1）制造三种不同类型的基于乳液的眼滴，可以结合MSH-1001。 2）采用符合我们所有标准的三种最有前途的乳液（即所需的渗透压，pH，粘度和液滴尺寸），并在荷兰腰带兔子中对它们进行视眼耐受性和组织学测试。将耐受制剂的眼科药代动力学特性与药理活性实验悬浮液进行比较。眼睛（一滴40升/眼）将用于荷兰腰带兔子。在不同的时间点（0.25、0.5、1、2、4和8小时），安乐死后将摘除眼睛。然后，将仔细解剖水性幽默，并通过LC-MS定量MSH-1001。成功的眼科乳液将显示眼分布至少相等或优于实验悬浮液。 公共卫生相关性：青光眼主要通过给药以降低眼内压（IOP）来治疗。前列腺素通常通过增加葡萄球菌流出作为一线治疗来降低IOP。尽管具有强大的功效，但许多患者通常需要多种药物或青光眼手术，而在药物治疗的病例中，才能实现目标压力控制。非常需要开发新型的有效IOP降低药物，以便眼科医生可以更有效地更好地控制这些患者的目标压力。研究一直集中在识别新型分子靶标，以便将当前疗法改善为独立或前列腺素的辅助手段。该提案的目的是开发MSH-1001的临床眼科乳液，这是一种新型的小分子，通过通过一种新型的作用机理来增强小梁流出，从而有效地降低IOP。 。