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.

青光眼是世界上不可逆性失明的主要原因。因为眼内压升高 (IOP)和IOP波动是视野丧失的主要危险因素， 成人型青光眼的治疗包括使用降低IOP的药物进行治疗，这些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，委员会认为， 使用的药物种类有限。在解决限制的一个重要步骤中， 目前市售的降眼压滴剂，我们设计了一种新的无刺激性微乳液（ME）制剂， 提供普瑞巴林（PRG）的延长释放，这是一种重新利用的FDA批准的药物，具有以下新机制： 降低IOP的措施。虽然我们的ME具有许多功能，可以填补IOP管理的主要空白， 需要每天自我给药为了直接解决这一未满足的临床需求，我们将优化和评估 结膜下可生物降解的静电纺丝贮库的降IOP特性和安全性， PRG。OculoTherapy的长期研究目标是开发保护青光眼患者视力的疗法。 在目前的SBIR I期应用中，我们测试了结膜下贮库由缓慢的 生物可降解和生物相容性的纳米纺聚合物可以被工程化以提供 PRG，其将IOP维持在生理范围内，直到储药耗尽。我们的目标是最终 实现从单次结膜下注射中释放4个月。我们的假设得到了支持 我们的初步数据表明，由聚合物共混物组成的载有PRG的纳米纤维提供释放， 的PRG，仅13%的负载药物在4周后释放，表明从PRG释放4个月， 只有一个仓库在射程内本项目的整体优势包括：1）实力雄厚，经验丰富 跨学科眼科治疗团队; 2）使用聚合物 预期提供延长的药物释放的生物相容性贮库; 3）使用非常有前途的FDA- 被批准的药物被重新用作青光眼治疗;和4）潜在的高度显着的 患者依从性的增加，因为消除了对来自患者的每日输入的需要。在本阶段I SBIR中， 建议，我们提供概念验证数据，并通过建立安全性和 生物工程结膜下放置的聚合物贮库的功效。目的1：我们测试假设， 由生物可降解和生物相容性聚合物组成的结膜下静电纺丝贮库可以提供高达4 几个月的零订单释放PRG。几种聚合物和聚合物共混物将单独或在 组合.目的2：我们检验我们的结膜下PRG贮库具有生物相容性和有效性的假设。 将评价IOP和安全性。还将进行眼部生物分布研究。最低性能 指标包括：1）单次储药后IOP持续降低约4个月; 2）无显著变化 耐受性;和3）与其对IOP降低的作用相关的药物的眼内分布。