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:
- 金额:$ 48.14万
- 依托单位:
- 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:
- 关键词:Adrenal Cortex HormonesAge related macular degenerationAnimal ModelAnteriorAntibodiesAreaAttentionBackBiocompatible MaterialsBiologicalBiological AvailabilityBiological ProductsChoroidClinicalContact LensesConvectionCorneaDataDevicesDexamethasoneDiameterDiffuseDiffusionDiseaseDropsDrug ControlsDrug Delivery SystemsDrug DesignDrug ExposureDrug KineticsDrug TransportEndophthalmitisEngineeringEyeEye diseasesEyedropsFormulationFrequenciesHourHydrogelsHydrophilic Contact LensesHydrophobicityIn VitroInjectionsLateralLengthMeasuresMediatingModelingNew ZealandOcular PhysiologyOryctolagus cuniculusPathway interactionsPharmaceutical PreparationsPharmacologyPilocarpinePolymersPorosityPosterior UveitisPosterior eyeball segment structurePrazosinPropertyRecommendationResearchResearch PersonnelRetinaRetinal DetachmentRetinal DiseasesRoleRotationSchemeScleraSeriesSideSiliconesSteroidsTestingTherapeuticTimeTissuesTopical applicationTreatment outcomeVitamin Eanterior chamberbevacizumabbulbar conjunctivaconjunctivadesigndiabeticdrug release kineticsexperienceexperimental studyin silicoin vivoin vivo monitoringinsightintravitreal injectionlenslipophilicitymacular edemamanufacturemathematical modelnovelnovel strategiesophthalmic drugpolymerizationpredictive modelingpressureresidencesmall moleculetool
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方法都是基于频繁的玻璃体内注射,这是侵入性的,
导致严重并发症如眼内炎和视网膜脱离。频繁的注射是必要的,因为
通过注射递送的药物通过多种途径从玻璃体中清除。的注射频率
在现实世界的经验中,可能低于推荐的,导致比预期差的治疗结果。它是理想
作为滴眼剂局部施用眼科药物,但由于生物利用度低,它们不适合实现
在眼睛后面的治疗效果。隐形眼镜已经被广泛研究用于递送药物以治疗
前节疾病,因为晶状体中约50%的药物渗透到角膜中,
用眼药水将药物递送到眼睛后部,包括通过接触镜持续递送,
相当少的关注。在这里,我们建议通过确定角膜接触镜的厚度,
潜在的递送机制,评价相对于滴眼剂,镜片的增强和持续递送,
开发预测基于接触镜的药物递送的模型,以及开发用于递送生物制剂的新型透镜。
我们有初步的数据显示接触透镜介导的药物递送到眼睛后部的可行性。该提案
将研究有助于从接触透镜向眼睛后部递送的两个主要途径:a)扩散
穿过角膜进入前房,随后葡萄膜巩膜流出进入巩膜-脉络膜,和B)非角膜运输
包括扩散到泪液中,随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、体内和计算机模拟研究,以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,并使用基于透镜工程的方法来评估葡萄膜巩膜流出途径。
在目标2中需要背驮式镜片的方法,以了解非角膜途径并通过其中一个
两条路。此外,在目标2中,我们将开发和验证一种新的、机械的、计算机模拟的模型,
组织特性。该模型将允许设计隐形眼镜,用于在治疗时将药物输送到眼睛后部。
浓度的在目标3中,我们将开发新的多孔环形晶状体,以提供抗VEGF抗体,
用于治疗湿性老年性黄斑变性。所有体内和离体实验将在New
通常用于测量眼部药代动力学的新西兰白色兔。在目标1和3中,地塞米松,
其用于治疗糖尿病性黄斑水肿,并且在目标2中,一系列皮质类固醇具有Log(P)
范围从0.53到3.2,用于探索疏水性的影响。在每一个目标中,我们都使用了一种新的方法,
将维生素E纳米载体整合到隐形眼镜(NB-CL)中以控制药物释放动力学。该办法将
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,
NB-CL的持续给药将成为一种非侵入性的方法,用于眼后给药,以取代侵入性给药
玻璃体内注射
项目成果
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