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失明的主要原因。因为眼内压 （IOP）和IOP波动是视野丧失的主要风险因素，这是当前的护理标准 对于成人发作的青光眼包括使用降低IOP的药物的治疗 当眼睛下降。不幸的是，自我管理的需求会对患者的依从性产生负面影响。而且， 有限的毒品家庭正在使用。在解决局限性的重大步骤中 目前，我们销售了降低IOP的滴剂，我们设计了一种新型的非辐射微乳液（ME）配方 提供了pregabalin（PRG）¾a的扩展释放，并以新的机制为 降低IOP的动作。虽然我们的我有许多功能可以填补IOP管理的重大空白，但 需要每天的自我剂量。为了直接满足这种未满足的临床需求，我们将优化和评估 含有IOP的降低特性和安全性生物降解的电纺矿床的安全性 prg。 Ocultherapy的长期研究目标是开发可保护青光眼患者视力的疗法。 在当前的SBIR I期应用程序中，我们测试了一个慢慢完成的亚junjunctivalival矿床的假设 可以设计可生物降解和生物相容性的纳米弹种聚合物，以提供零订单的释放 PRG，它将将IOP保持在物理范围内，直到支出为止。我们的目标是最终 从单个亚象征注射中释放4个月。我们的假设得到了支持 我们的初步数据表明，由聚合物混合物组成的PRG负载的纳米纤维提供了释放 4周后仅释放了13％的已加载药物的PRG的PRG，这表明从 一个仓库在范围内很好。该项目的总体优势包括：1）强大而有经验的 跨学科的动眼疗法团队； 2）使用聚合物的创新交付策略的工程 有望提供扩展药物释放的生物相容性仓库； 3）使用高度承诺的FDA- 被批准为青光眼治疗的药物； 4）具有高度意义的潜力 由于消除了患者每日输入的需求，因此患者依从性的增加。在这个阶段我 提案，我们通过建立安全性和 AIM 1：我们检验了一个假设，即生物工程的亚结合了聚合物沉积物。目标1：我们检验了一个假设 可生物降解和生物相容性聚合物的近结式电纺仓库可提供多达4 PRG的零订单释放月。几种聚合物和聚合物混合物将单独或在 组合。 AIM 2：我们检验了我们的亚象征PRG仓库具有生物相容性和有效效率的假设。 IOP和安全将评估。还将进行眼部生物分布研究。最低性能 指标包括：1）IOP持续下降约4个月； 2）没有重大发展 容忍； 3）药物的眼内分布与其对IOP还原的影响相关。