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

描述（由申请人提供）：本小型企业创新项目旨在开发一种创新的眼药水配方，用于治疗青光眼和高眼压。Charlesson从多瑙河制药公司（Danube Pharmaceuticals）收购了一种新的小分子化合物MSH-1001（以前称为DNB-001或KR- 31378）。MSH-1001具有眼部低血压和神经保护作用。它是ATP敏感的K通道开启剂。该项目的目标是证明一种基于乳剂的滴眼液可以将治疗水平的MSH-100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ind支持研究，支持首次人体研究。本提案的目标是1)制造三种不同类型的乳液型滴眼液，可以加入MSH-1001。2)选择符合我们所有标准（即期望的渗透压、pH值、粘度和液滴大小）的三种最有希望的乳剂，在荷兰带兔体内测试它们的眼耐受性和组织学。将耐受性制剂的眼药代动力学特性与药理活性实验悬浮液进行比较。给荷兰兔滴眼液（40 5L/眼1滴）。在不同的时间点（0.25、0.5、1、2、4和8小时），将在安乐死后进行眼睛去核。然后仔细解剖房水并用LC-MS定量MSH- 1001。成功的眼用乳剂将显示出至少等于或优于实验悬浮液的眼部分布。

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,. .