Development of a novel depot delivery system for a glaucoma therapeutic

开发用于青光眼治疗的新型储库递送系统

• 批准号: 10699791
• 负责人: Dianna Ammons Johnson
• 金额: $ 33.6万
• 依托单位: OCULO THERAPY, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699791
• 关键词: Address; Adult; Back; Biodistribution; Biomedical Engineering; Blindness; Caring; Clinic; Clinical; Cornea; Data; Development; Dosage Forms; Dose; Drops; Emulsions; Engineering; Eye; Eyedrops; FDA approved; Family; Formulation; Generations; Glaucoma; Goals; Home; Hour; Injections; Legal patent; Marketing; Mechanics; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Physiological; Polymers; Positioning Attribute; Preparation; Prevalence; Property; Research; Risk Factors; Safety; Schedule; Self Administration; Small Business Innovation Research Grant; Specialist; System; Technology; Testing; Therapeutic; Time; Topical application; Vision; Visual Fields; biocompatible polymer; biodegradable polymer; biomaterial compatibility; commercialization; compliance behavior; design; drug distribution; experience; innovation; irritation; nanofiber; negative affect; novel; phase 1 study; pre-Investigational New Drug meeting; pregabalin; preservation; pressure; residence; side effect; standard of care; therapy development

Glaucoma is the leading cause of irreversible blindness in the world. Because elevated intraocular pressure (IOP) and IOP fluctuations are the primary risk factors for loss of visual field, the current standard of care for adult-onset glaucoma includes treatment with IOP-lowering medications, which are typically delivered topically as eye drops. Unfortunately, the need for self-administration negatively affects patient compliance. Moreover, there are a limited number of drug families that are in use. In a major step toward addressing the limitations of currently marketed IOP-lowering drops, we engineered a novel non-irritative microemulsion (ME) formulation that provides extended release of pregabalin (PRG)¾a repurposed FDA-approved drug with a new mechanism of action for IOP-lowering. While our ME has many features that position it to fill major gap in IOP management, it requires daily self-dosing. To directly address this unmet clinical need, we will optimize and evaluate the IOP-lowering properties and safety of a subconjunctival biodegradable electrospun depot containing PRG. OculoTherapy’s long-term research goal is to develop therapies that preserve vision in glaucoma patients. In this current SBIR Phase I application, we test the hypothesis that a subconjunctival depot comprised of slowly biodegradable and biocompatible nanospun polymers can be engineered to provide zero order release of PRG, which will maintain IOP in the physiological range until the depot is spent. Our objective is to ultimately achieve 4 months of release from a single subconjunctival injection. Our hypothesis is supported our preliminary data demonstrating that PRG-loaded nanofibers comprised of a polymeric blend provide release of PRG with only 13% of loaded drug being released after 4 weeks, demonstrating that 4 months of release from a single depot is well within range. Overall strengths of this project include: 1) a strong and experienced interdisciplinary OculoTherapy team; 2) engineering of an innovative delivery strategy using a polymeric biocompatible depot that is expected to provide extended drug release; 3) the use of a highly promising FDA- approved drug that is being repurposed as a glaucoma therapeutic; and 4) the potential for a highly significant increase in patient adherence because the need for daily input from the patient is eliminated. In this Phase I SBIR proposal, we provide proof-of-concept data and address key feasibility questions by establishing the safety and efficacy of a bioengineered subconjunctivally placed polymer depot. Aim 1: We test the hypothesis that a subconjunctival electrospun depot comprised of biodegradable and biocompatible polymers can provide up to 4 months of zero order release of PRG. Several polymers and polymer blends will be evaluated either alone or in combination. Aim 2: We test the hypothesis that our subconjunctival PRG depot is biocompatible and efficacious. IOP and safety will be evaluated. Ocular biodistribution studies will also be performed. Minimum performance metrics include: 1) a sustained decrease in IOP for ~4 months from a single depot; 2) no significant development of tolerance; and 3) an intraocular distribution of the drug that correlates with its effect on IOP reduction.

青光眼是世界上导致不可逆性失明的主要原因。因为眼压升高 眼压和眼压波动是视野丧失的主要危险因素，这是目前的护理标准 成人青光眼的治疗包括用降眼压药物治疗，这种药物通常是局部给药 作为眼药水。不幸的是，自我给药的需要对患者的依从性产生了负面影响。此外， 目前正在使用的毒品家族数量有限。在朝着解决以下限制迈出的重要一步 目前上市的降眼压滴剂，我们设计了一种新的无刺激性微乳(ME)配方， 提供普瑞巴林(PRG)的延长释放，这是FDA批准的一种用途改变的药物，具有新的机制 降眼压行动。虽然我们的ME具有许多功能，使其能够填补眼压管理方面的主要空白，但它 需要每天自服。为了直接满足这一未得到满足的临床需求，我们将优化和评估 生物可降解结膜下电纺库的降眼压性能和安全性 PRG。眼科疗法的长期研究目标是开发保存青光眼患者视力的疗法。 在目前的SBIR第一阶段应用中，我们测试了一种假设，即结膜下储点由缓慢的 可生物降解和生物兼容的纳米聚合体可以被设计成提供零级释放 PRG，它将把眼压维持在生理范围内，直到仓库用完。我们的目标是最终 一次结膜下注射可释放4个月。我们的假设得到了支持 我们的初步数据表明，由聚合物混合物组成的负载PRG的纳米纤维提供了释放 在4周后只有13%的加载药物释放，表明4个月的释放 一个仓库都在射程之内。本项目的总体优势包括：1)较强且经验丰富 跨学科的眼科治疗团队；2)使用聚合物设计创新的交付策略 生物兼容库，预计将提供延长药物释放；3)使用前景看好的FDA- 正被重新用于青光眼治疗的批准药物；以及4)高度显著的潜在 患者依从性增加，因为不再需要患者的日常投入。在此阶段I SBIR中 建议，我们提供概念验证数据，并通过建立安全和 生物工程结膜下放置聚合物库的功效。目标1：我们检验假设 由可生物降解和生物相容的聚合物组成的结膜下电纺库可以提供多达4 PRG连续几个月零订单放行。几种聚合物和聚合物混合物将单独或在 组合。目的2：我们验证了我们的结膜下PRG是生物相容和有效的假说。 将评估眼压和安全性。还将进行眼部生物分布研究。最低性能 衡量指标包括：1)单个仓库的眼压持续下降约4个月；2)没有显著进展 耐受性；以及3)药物在眼内的分布与其降低眼压的效果相关。