Ophthalmic drug delivery using a multi-layer contact lens design that enables targeting, constant-rate release and failure protection

项目摘要 父母奖-青光眼是全球范围内的一个主要问题，目前有6000万人受到影响，112 预计到2040年。目前，青光眼的主要治疗依赖于给药， 含有前列腺素类似物的局部滴眼液作为一线治疗，占处方总数的51%。 然而，滴眼液由于泪液引流而在生物利用度方面存在显著的限制，并且患者的不良反应可能会增加。 每日滴注方案的患者依从率为50%。二线下降需要更频繁 观察到每天的剂量增加，因此对治疗的依从性更差。我们建议开发一种药物输送系统， 接触透镜（DDCL），长期配戴，持续药物释放长达7天，用于治疗开放性 角型青光眼目标是取代局部滴眼液作为青光眼的标准护理。关键优势 的DDCL将是较低的给药频率，以恒定的速率直接递送到角膜表面，高- 精确的剂量和靶向，所有这些都是通过具有成本竞争力的透镜装置实现的。拟议的第二阶段工作计划将侧重于 改进DDCL的原型（包括药物释放，材料等），扩大生产规模， 证明了耐受性、药代动力学和药效学的动物模型研究的可行性。的 拟议的DDCL不仅将解决滴眼液管理的所有缺陷，而且还可以建立一个新的 与眼部绷带、可注射聚合物、外科植入物等其他竞争技术相比， （a）在一级至零级动力学之间精确控制药物释放速率 （B）生物可利用药物量的精确剂量基于以下的匹配速率： 药物释放、泪液周转和角膜吸附，（c）7天配戴所需的透镜材料创新 舒适性、安全性、易于操作（由老年人操作）以及具有竞争力的成本。在第二阶段结束时，最终生产- 具有动物可行性数据的规模原型（63只家兔，毒性/PK/PD）将准备用于后续IND- 如即将到来的IIb期项目中所提议的那样，为人类研究提供研究和IND申请。 行政补充-本行政补充提议增加预算费用168，192美元 完成先前计划与一所大学（坦普尔）合作的次级奖励动物研究，但由于时间安排， 人员和其他限制已转移到CRO（Ora Inc.）。研究设计保持不变， 唯一的变化是次级获奖者，设施和预算，将允许及时完成工作。 更新的IACUC批准和OLAW保证已经完成。

PROJECT SUMMARY Parent award – Glaucoma is a major problem worldwide, with 60 million people currently affected and 112 million expected by 2040. At present, the primary treatment of glaucoma relies on medication administered as topical eye drops, with prostaglandin analogues, as the first-line therapy, representing 51% of total prescriptions. However, eye drops present significant limitations in bioavailability due to tear drainage, and a poor patient adherence rate of 50% amongst those with a daily drop regimen. Second-line drops require even more frequent dosing per day and hence worse adherence to the therapy is observed. We propose to develop a drug-delivering contact lens (DDCL) with extended wear and sustained drug release of up to 7 days for the treatment of open- angle glaucoma. The goal is to replace topical eye drops as the standard of care for glaucoma. Key advantages of the DDCL will be lower dosing frequency, direct delivery to the corneal surface at a constant rate, high- precision dosing and targeting, all by a cost-competitive lens device. The proposed Phase II work plan will focus on refining prototypes of the DDCL (including drug release, materials, etc.), scaling up the production, and demonstrating feasibility in animal model studies of tolerability, pharmacokinetics and pharmacodynamics. The proposed DDCL will not only resolve all the deficiencies of eye drop administration, but also could set a new standard against other competing technologies of ocular bandages, injectable polymers, surgical implants, etc. in the following categories: (a) The accurate control of drug release rate between first to zero order kinetics throughout the delivery duration, (b) The precise dosing of bioavailable drug amount based on matching rates of drug discharge, tear turnover and corneal adsorption, (c) The lens material innovation required for 7-day wearing comfort, safety, easy of handling (by elderlies), and at a competitive cost. At the end of Phase II, final production- scale prototypes with animal feasibility data (63 rabbits, toxicity/PK/PD) will be ready for subsequent IND- enabling studies and IND filing for study in humans as proposed in an upcoming Phase IIb project. Administrative supplement – This administrative supplement proposes $168,192 of incremental budget costs to complete subaward animal research that was previously planned with a university (Temple), but due to timing, personnel and other constraints has been moved to a CRO (Ora Inc.). The study design remains the same, with the only changes being the subawardee, facility, and budget that will allow for timely completion of the work. Updated IACUC approval and OLAW assurance have already been completed.