Combined Hydrogel/Microparticle Eye Drops for Sustained Delivery of Glaucoma Medication

描述(申请人提供)：用于持续输送青光眼药物的联合水凝胶/微粒滴眼液青光眼是全球第二大致盲原因，仅在美国每年的治疗费用就高达25亿美元。局部滴眼液是目前治疗青光眼和许多其他眼部疾病的临床标准。然而，频繁而困难的滴眼液使它们的效率非常低，在某些情况下，患者的依从性低至50%。依从性差会使患者面临视力恶化和失明的风险，治疗成本大幅增加。患者和临床医生都将受益于一种更有效的治疗方法，这种方法将提高患者的依从性，并更有效地将药物输送到房水，以避免全身毒性。隐形眼镜和包括纳米颗粒在内的新型眼药水是传统眼药水的一种舒适和熟悉的替代品，但最多只能将递送窗口延长到几个小时或几天。相比之下，可以提供数周至数月药物释放的配方目前需要临床医生在眼睛内注射或植入。如果一种眼部递送策略能够将滴眼液的舒适性和简单性与长期给药结合起来，它不仅可以彻底改变青光眼药物的递送方式，而且还可以彻底改变其他眼科药物的递送方式。该项目的目标是开发一种新的、易于管理的非侵入性治疗方法，能够长期将青光眼药物释放到眼睛。这种配方将极大地减少与患者依从性相关的并发症，因为这种简单的患者给药形式和剂量频率的显著减少。滴眼液所固有的全身毒性和眼吸收不足的后果将通过更直接地提供100倍以上的药物而得到缓解。使用高度可定制的聚合物微粒(MP)控制的原位形成凝胶滴眼液中所含的酒石酸溴莫尼定(BT)的联合给药方法，将为青光眼的治疗提供一种舒适和更有效的给药形式。这种凝胶滴眼液用于穹隆下部，在那里它舒适地符合结膜死胡同，并释放药物长达30天。该项目的主要目标是优化定制设计的MPS，以释放Bt的治疗水平，并设计一种温度响应性、水凝胶基质来保留MPS。在计算机模拟中，将使用建模方法来开发药物输送系统，然后进行必要的体外药物释放动力学验证。该凝胶/MP系统将在兔高眼压模型上进行测试，以展示临床相关的结果和持续的BT传递。最后，通过无创磁共振成像(MRI)监测药物在体内的释放和分布，将评估这种新的药物输送系统作为治疗其他眼部疾病的平台。最终，这项工作代表了一种模块化策略的临床前有效性和安全性测试的启动，该策略使用新的体内药物输送和可视化技术来输送各种眼部治疗药物。

DESCRIPTION (provided by applicant): Combined Hydrogel/Microparticle Eye Drops for Sustained Delivery of Glaucoma Medication Glaucoma is the second leading cause of blindness worldwide and costs $2.5B to treat every year in the US alone. Topical eye drops are the current clinical standard in treating glaucoma and numerous other ocular pathologies. However, the frequent and difficult administration of eye drops makes them highly inefficient, with patient compliance in some cases as low as 50%. Poor compliance puts patients at risk for worsening vision and blindness, with a significant increase in treatment costs. Both patients and clinicians would benefit greatly from a more efficient treatment method that would increase patient compliance and deliver drug more efficiently to the aqueous humor to avoid systemic toxicity. Contact lenses and novel eye drops including nanoparticles are a comfortable and familiar alternative to traditional eye drops, but have only extended delivery windows to several hours or days at most. In contrast, formulations that can provide weeks to months of drug release currently require injection or implantation into the eye by a clinician. If an ocular deliery strategy could combine the comfort and simplicity of an eye drop with long-term drug delivery, it could revolutionize the delivery of not only glaucoma medication, but other ocular medications as well. The goal of this project is to develop a new, easy-to-administer, and noninvasive treatment capable of long- term release of glaucoma medication to the eye. Such a formulation would dramatically reduce patient compliance-related complications due to the simple, patient-administered format and the marked decrease in dosing frequency. The consequences of systemic toxicity and insufficient ocular absorption inherent to eye drops would be mitigated with a more direct delivery of over 100x less drug. Using a combined approach of highly customizable, polymer microparticle (MP)-controlled delivery of brimonidine tartrate (BT) contained in an in situ forming gel eye drop will provide a comfortable and vastly more efficient delivery format for the treatment of glaucoma. The gel eye drop is intended for administration to the lower fornix, where it comfortably conforms to the conjunctival cul-de-sac and releases drug for up to 30 days. The project's primary objective is to optimize custom-designed MPs to release therapeutic levels of BT and engineer a thermoresponsive, hydrogel matrix for retaining the MPs. In silico modeling methods will be used to develop the drug delivery system, followed by requisite in vitro validation of drug release kinetics. The gel/MP system will be tested in a rabbit model of ocular hypertension to demonstrate clinically relevant results and sustained BT delivery. Finally, this new drug delivery system will be evaluated as a platform for treating othe ocular diseases by using noninvasive magnetic resonance imaging (MRI) to monitor drug release and distribution in vivo. Ultimately, this work represents the initiation of preclinical efficacy and safety testing of a modular strategy for delivering of a variety of ocular therapeutic using novel in vivo drug delivery and visualization techniques.