Back of the eye drug delivery: Novel contact lenses, pathways, and in-silico modeling

眼后药物输送：新型隐形眼镜、通路和计算机建模

基本信息

批准号：
10735642
负责人：
ANUJ CHAUHAN
金额：
$ 48.14万
依托单位：
COLORADO SCHOOL OF MINES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735642
关键词：
Adrenal Cortex Hormones Age related macular degeneration Animal Model Anterior Antibodies Area Attention Back Biocompatible Materials Biological Biological Availability Biological Products Choroid Clinical Contact Lenses Convection Cornea Data Devices Dexamethasone Diameter Diffuse Diffusion Disease Drops Drug Controls Drug Delivery Systems Drug Design Drug Exposure Drug Kinetics Drug Transport Endophthalmitis Engineering Eye Eye diseases Eyedrops Formulation Frequencies Hour Hydrogels Hydrophilic Contact Lenses Hydrophobicity In Vitro Injections Lateral Length Measures Mediating Modeling New Zealand Ocular Physiology Oryctolagus cuniculus Pathway interactions Pharmaceutical Preparations Pharmacology Pilocarpine Polymers Porosity Posterior Uveitis Posterior eyeball segment structure Prazosin Property Recommendation Research Research Personnel Retina Retinal Detachment Retinal Diseases Role Rotation Scheme Sclera Series Side Silicones Steroids Testing Therapeutic Time Tissues Topical application Treatment outcome Vitamin E anterior chamber bevacizumab bulbar conjunctiva conjunctiva design diabetic drug release kinetics experience experimental study in silico in vivo in vivo monitoring insight intravitreal injection lens lipophilicity macular edema manufacture mathematical model novel novel strategies ophthalmic drug polymerization predictive modeling pressure residence small molecule tool

项目摘要

Currently most treatments for retinal diseases are based on frequent intravitreal injections, which are invasive, and could lead to serious complications such as endophthalmitis and retinal detachment. The frequent injections are necessary because the drugs delivered through the injection are cleared from the vitreous by multiple pathways. The frequency of injections in real-world experience may be lower than recommended resulting in poorer-than-expected treatment outcomes. It is ideal to administer ophthalmic drugs topically as eye drops but due to low bioavailability, they are not suitable to achieve therapeutic benefits in the back of the eye. Contact lenses have been extensively investigated for delivering drugs to treat anterior segment diseases because about 50% of the drug in the lenses permeates into the cornea compared to about 1-5% with eye drops. Delivery of drugs to the back of the eye including sustained delivery by contact lenses has received considerably less attention. Here we propose to advance contact lenses for back of the eye delivery, by determining the underlying mechanisms of delivery, evaluating enhanced and sustained delivery with the lenses relative to eye drops, developing models predictive of contact lens-based drug delivery, and developing novel lenses for delivery of biologics. We have preliminary data showing feasibility of contact lens mediated delivery of drugs to the back of the eye. The proposal will investigate two major pathways that can contribute to the back of the eye delivery from a contact lens: a) diffusion across cornea into anterior chamber followed by uveoscleral outflow into sclera-choroid and b) non-corneal transport involving diffusion into the tears followed by transverse diffusion across sclera and choroid into retina and vitreous. This proposal combines in vitro, ex vivo, in vivo and in silico studies to determine the relative importance of these pathways. We use a pharmacology-based approach in Aim 1 to evaluate the uveoscleral outflow pathway and a lens engineering-based approach entailing piggyback lenses in Aim 2 to understand the non-corneal pathway and to deliver drugs via one of the two pathways. Further, in Aim 2, we will develop and validate a novel, mechanistic, in-silico model incorporating drug and tissue properties. The model will allow design of contact lenses for delivering drugs to the back of the eye at therapeutic concentrations. In Aim 3, we will develop novel porous annulus lenses to deliver anti VEGF antibodies that are commonly used for treating wet age-related macular degeneration. All in vivo and ex vivo experiments will be conducted in New Zealand white rabbits that are commonly used for measuring ocular pharmacokinetics. In Aims 1 and 3, dexamethasone, which is used for treating diabetic macular edema is investigated, and in Aim 2, a series of corticosteroids with Log(P) ranging from 0.53 to 3.2 are used to explore the effect of hydrophobicity. In each of the Aims we use a novel approach of integrating vitamin E nanobarriers into contact lenses (NB-CL) to control the drug release kinetics. The approach will provide new fundamental insights into sustained drug delivery to the back of the eye using contact lenses. If successful, NB-CL for sustained drug delivery will become a noninvasive approach for back of the eye drug delivery to replace invasive intravitreal injections.

目前，大多数视网膜疾病的治疗都是基于频繁的玻璃体内注射，这是侵入性的，并且可能导致眼内炎、视网膜脱离等严重并发症。频繁注射是必要的，因为通过注射输送的药物通过多种途径从玻璃体中清除。注射频率在现实世界中，治疗效果可能低于推荐值，导致治疗结果差于预期。这是理想的眼科药物以滴眼剂形式局部给药，但由于生物利用度低，不适合实现对眼后部的治疗效果。隐形眼镜已被广泛研究用于输送药物进行治疗眼前节疾病，因为镜片中大约 50% 的药物渗透到角膜，而这一比例约为 1-5% 用眼药水。将药物输送到眼后部，包括通过隐形眼镜持续输送，已收到关注度大大降低。在这里，我们建议通过确定传递的基本机制，评估镜片相对于滴眼剂的增强和持续传递，开发预测基于隐形眼镜的药物输送的模型，并开发用于输送生物制剂的新型镜片。我们有初步数据显示隐形眼镜介导的药物输送到眼睛后部的可行性。提案将研究有助于隐形眼镜传输到眼睛后部的两个主要途径：a) 扩散穿过角膜进入前房，然后葡萄膜巩膜流出进入巩膜脉络膜和 b) 非角膜运输涉及扩散到泪液中，然后横向扩散穿过巩膜和脉络膜进入视网膜和玻璃体。这该提案结合了体外、离体、体内和计算机研究来确定这些途径的相对重要性。我们在目标 1 中使用基于药理学的方法来评估葡萄膜巩膜流出途径和基于晶状体工程的方法目标 2 中需要背负式镜片的方法，以了解非角膜通路并通过其中之一输送药物两条途径。此外，在目标 2 中，我们将开发并验证一种新颖的机械计算机模型，该模型结合了药物和组织特性。该模型将允许设计隐形眼镜，以便在治疗时将药物输送到眼睛后部。浓度。在目标 3 中，我们将开发新型多孔环形镜片以提供常见的抗 VEGF 抗体。用于治疗湿性年龄相关性黄斑变性。所有体内和离体实验都将在新进行常用于测量眼部药代动力学的新西兰白兔。在目标 1 和 3 中，地塞米松，研究了用于治疗糖尿病性黄斑水肿的药物，在目标 2 中，使用了一系列具有 Log(P) 的皮质类固醇使用0.53至3.2范围内的值来探讨疏水性的影响。在每个目标中，我们都使用一种新颖的方法将维生素 E 纳米屏障集成到隐形眼镜 (NB-CL) 中以控制药物释放动力学。该方法将为使用隐形眼镜将药物持续输送到眼睛后部提供了新的基本见解。如果成功的话，用于持续给药的 NB-CL 将成为眼后给药的无创方法，以取代侵入式玻璃体内注射。