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

使用多层隐形眼镜设计的眼科药物输送，可实现靶向、恒定速率释放和故障保护

• 批准号: 9140584
• 负责人: Arthur Yang
• 金额: $ 22.5万
• 依托单位: LYNTHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140584
• 关键词: Address; Affect; American; Animal Model; Area; Biological Availability; Blindness; Caliber; Caring; Clinical Trials; Collaborations; Contact Lenses; Cornea; Devices; Diagnostic; Disease; Dose; Drainage procedure; Drops; Drug Controls; Drug Delivery Systems; Extended-Wear Contact Lenses; Eyedrops; Failure; Film; Future; Glaucoma; Goals; Healthcare; Hour; Human; Hydrogels; Kinetics; Lead; Location; Manufacturer Name; Marketing; Methods; Modeling; Monitor; Open-Angle Glaucoma; Optics; Oxygen; Pathway interactions; Patients; Performance; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Phase; Polymers; Regimen; Sales; Schedule; Self-Administered; Silicones; Specificity; Structure; Structure of sinus venosus of sclera; Surface; Taiwan; Techniques; Technology; Time; Toxic effect; Trabecular meshwork structure; Vision; Work; absorption; antiglaucoma drug; biomaterial compatibility; commercialization; compliance behavior; controlled release; cost; design; dosage; drug market; imprint; improved; innovation; lens; non-compliance; novel; ophthalmic drug; prototype; public health relevance; research and development; residence; standard care; transmission process

 DESCRIPTION (provided by applicant): This project intends to create a contact lens for ocular drug delivery that resolves key barriers to commercial feasibility. Contact lens drug delivery has been studied for many years, but technical challenges such as constant-rate release and controlled triggering have inhibited progress. Current prototypes release drugs at a decreasing rate, and undesirably begin releasing in storage solution (needed to keep the lens soft/wearable). A successful alternative would quickly replace topical eye drops as the treatment standard for open-angle glaucoma, which affects 2.8M Americans ($5B market) and can eventually lead to blindness. Drops have limited bioavailability (5-10% drug absorption due to burst dosage and ocular drainage) and patient compliance (20- 60% non-compliance due to tedious dosing schedule). We propose to create a silicone hydrogel contact lens with a dual-layer coating on the post-lens surface to give zero order release kinetics and protection against burst dosage failure. Also, zonal loading of drug ingredient (i.e., ring configuration) will allow targeting of specific areas active in disease. The specific aims of the Phase I proposal are: Aim 1: Novel dual-layer structure on post-lens surface to achieve near zero order drug release - We will synthesize a nanoporous polymer matrix ("1st Layer"), embed it with model drug (bimatoprost), and imprint it on the post-lens surface. We will cover this drug-loaded layer with a hydrophilic barrier coating ("2nd Layer") that provides zero-order delivery, biocompatibility and burst failure protection. Milestones: Constant-rate drug release of bimatoprost over 24-hours. Phase II goal: Extending release time to 7 days, 30 days. Animal model to evaluate release kinetics, toxicity and efficacy. Aim 2: Hydrophilic barrier coating ("2nd Layer") to control turnovr rate of post-lens tear film - Compared to ocular tear film, PLTF turnover is significantly slower, and thus advantageous to drug residence time. We will modify the post-lens surface to further stabilize the PLTF and maximize drug residence. Milestones: Produce a barrier coating on SiHy lens to reduce contact angle with simulated tear film to <15º. Phase II goal: Animal model to compare PLTF turnover rate in animal model. Aim 3: Location-specific drug loading and delivery - We will zonally load the bimatoprost into the 1st Layer using a ring configuration with inner diameter 10mm (not residing in the optical pathway) and outer diameter up to 14mm (edge of the contact lens). We hypothesize location specificity to be clinically beneficial in concentrating drug on the ocular components that are active in disease or drug treatment (e.g. trabecular meshwork/Schlemm's canal in glaucoma), and understand this aspect of zonal drug loading on the contact lens to be novel. Milestones: Majority of drug (80%) lands within well-defined area of a model cornea, minimal unwanted outflow. Phase II goal: Animal model to demonstrate efficacy correlation to specific loading locations.

 描述（由申请方提供）：本项目旨在创建一种用于眼部药物递送的接触透镜，以解决商业可行性的关键障碍。接触透镜药物递送已经研究了多年，但是诸如恒定速率释放和受控触发的技术挑战阻碍了进展。目前的原型以降低的速率释放药物，并且不期望地开始在储存溶液中释放（需要保持透镜柔软/可佩戴）。一个成功的替代方案将迅速取代局部滴眼液作为开角型青光眼的治疗标准，这影响了280万美国人（50亿美元的市场），并最终导致失明。滴剂具有有限的生物利用度（由于突释剂量和眼部引流，5-10%的药物吸收）和患者依从性（由于繁琐的给药方案，20- 60%的不依从性）。我们建议创建一种硅水凝胶接触透镜，在后透镜表面上具有双层涂层，以提供零级释放动力学和防止突释剂量失效。此外，药物成分的区域加载（即，环构型）将允许靶向疾病中活跃的特定区域。第一阶段提案的具体目标是：目标1：在透镜后表面上的新型双层结构以实现近零级药物释放-我们将合成纳米多孔聚合物基质（“第一层”），将其与模型药物（比马前列素）包埋，并将其压印在透镜后表面上。我们将在这个载药层上覆盖 亲水屏障涂层（“第2层”），提供零级输送、生物相容性和爆破失效保护。Mild：比马前列素在24小时内的恒速药物释放。第二阶段目标：将发布时间延长至7天、30天。评价释放动力学、毒性和功效的动物模型。目标二：亲水性屏障涂层（“第二层”）以控制镜片后泪液膜的周转率-与眼部泪液膜相比，PLTF周转显著较慢，因此有利于药物停留时间。我们将修改晶状体后表面，以进一步稳定PLTF并最大化药物驻留。Milestone：在SiHy透镜上制备一层屏障涂层，以将与模拟泪膜的接触角降低至<15º。II期目标：动物模型，以比较动物模型中的PLTF转换率。目标3：位置特异性药物装载和递送-我们将使用内径为10 mm（不位于光路中）和外径高达14 mm（接触透镜边缘）的环形配置将比马前列素分区装载到第一层中。我们假设位置特异性在临床上有利于集中注意力， 在疾病或药物治疗中具有活性的眼部成分（例如青光眼中的小梁网/施累姆氏管）上的药物，并且理解接触透镜上的带状药物负载的这一方面是新颖的。Mild：大多数药物（80%）落在模型角膜的明确区域内，最小的不必要流出。II期目标：动物模型，以证明有效性与特定负载位置的相关性。