Extended release formulation of a new IOP lowering drug for improved treatment of glaucoma

青光眼是世界上导致不可逆性失明的主要原因。眼压升高是 初次开放时视网膜神经元死亡和导致视野丧失的最重要危险因素 房角型青光眼，青光眼最常见的形式。目前青光眼的治疗标准包括眼压- 降低局部用药，如滴眼液，可减少房水体积 通过抑制其生产或加强其排水。目前没有一种治疗方法会影响这两种生产 和排水系统。由于它们的半衰期短，在角膜上的停留时间有限，因此需要给药。 从每天一到三次，这大大限制了患者的依从性，并增加了 眼眶和全身副作用。利用系统遗传学的方法，我们已经：1)鉴定CACNA2D1是一种 新的降眼压靶点；2)证明普瑞巴林具有很强的降眼压作用；3) 结果表明，普瑞巴林的摄取特性限制了全身暴露，而不影响眼睛扩散； 开发了普瑞巴林微乳制剂，可在缓释制剂中提供，以 减少目前治疗所需的剂量。在眼科治疗中，我们将讨论 目前眼压治疗的主要局限性在于推进了缓释剂的开发 协调多个靶点的降眼压配方，包括睫状体和 小梁网状结构使眼压正常化。这种治疗策略将减轻患者的负担， 提高青光眼患者的依从性并导致更好的视觉结果。我们的中心假设是 普瑞巴林--在具有缓释、生物黏附特性的局部微乳中配制时， 和角膜穿透增强-将引起等于或更大的眼压降低反应 与目前市场上的其他青光眼药物相比，该药的作用幅度更大，持续时间更长。在……里面 本第一阶段SBIR建议书将提供概念证明，并通过以下方式解决关键的可行性问题 建立我们的普瑞巴林微乳的功效、药效学、生物相容性和生物分布。 我们将根据不同浓度的单一- 剂量，局部应用普瑞巴林微乳，以实现最大限度的降低眼压。我们还将建立 普瑞巴林微乳每日重复给药21天维持眼压水平的疗效观察 24小时内单次给药最大限度减少。我们还将建立眼内(以及全眼- 全身)局部应用微乳21天后普瑞巴林的分布。我们的最低性能 终点将包括普瑞巴林靶向睫状体和小梁网的演示。 根据我们的初步数据，我们预计我们的SBIR第一阶段工作将验证概念验证 孕激素微乳治疗高眼压这些研究将使我们能够继续进行 直接用于第二阶段示范项目，为第二阶段B和/或第三阶段商业化做准备。

Glaucoma is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is the most significant risk factor contributing to death of retinal neurons and resulting visual field loss in primary open angle glaucoma, the most common form of glaucoma. The current standard of care for glaucoma includes IOP- lowering medications delivered topically as eye drops, which decrease the volume of aqueous humor either through inhibition of its production or enhancement of its drainage. No current therapies affect both production and drainage. Because of their short half-lives and limited residence time on the cornea, dosing is required from one-to-three times daily, which significantly limits patient compliance and also increases the incidence of orbital and systemic side effects. Using a systems genetics approach, we have: 1) identified CACNA2D1 as a new ocular target for lowering IOP; 2) demonstrated that pregabalin exhibits potent IOP-lowering activity; 3) shown that uptake properties of pregabalin limit systemic exposure without affecting ocular diffusion; and 4) developed a pregabalin microemulsion formulation that can be delivered in an extended release formulation to decrease the number of doses required by current treatments. At OculoTherapy, we will address the major limitations of current IOP therapy by advancing our development of a sustained-release IOP-lowering formulation that coordinates multiple targets including the ciliary body and trabecular meshwork to normalize IOP. This treatment strategy will reduce the burden to the patient, increase compliance and lead to better visual outcomes for glaucoma patients. Our central hypothesis is that pregabalin—when formulated in a topical microemulsion with characteristics of sustained release, bioadhesion, and corneal penetration enhancement—will elicit an IOP-lowering response that is equal to or greater in amplitude, and significantly greater in duration, than other glaucoma medications currently on the market. In this Phase I SBIR proposal we will provide proof of concept and address key feasibility questions by establishing efficacy, pharmacodynamics, biocompatibility and biodistribution of our pregabalin microemulsion. We will establish minimum performance endpoints based on the efficacy of various concentrations of single- dose, topically applied pregabalin microemulsion to achieve maximal IOP reduction. We will also establish efficacy of repeated daily dosing of pregabalin microemulsion for 21 days to sustain IOP at a level equal to the maximal reduction achieved by a single dose within 24 hrs. We will also establish intraocular (as well as whole- body) distribution of pregabalin after 21 days of topically applied microemulsion. Our minimum performance end point will include the demonstration that pregabalin targets the ciliary body and trabecular meshwork. Based on our preliminary data, we anticipate that our SBIR Phase I work will validate the proof of concept for pregablin microemulsion therapy for treatment of elevated IOP. These studies will position us to proceed directly to a Phase II demonstration project in preparation for Phase IIB and/or Phase III commercialization.