DECON: A sustained topical delivery platform to treat ocular inflammation

DECON：治疗眼部炎症的持续局部给药平台

• 批准号: 10735478
• 负责人: Tejabhiram Yadavalli
• 金额: $ 41.33万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735478
• 关键词: Acyclovir; Adolescent; Adrenal Cortex Hormones; Adsorption; Affect; Age; Anti-Inflammatory Agents; Antiinflammatory Effect; Antiviral Agents; Area; Bacteria; Benzalkonium Chloride; Blindness; Carbon; Cells; Characteristics; Child; Cornea; Cyclosporine; Data; Dermatitis; Dexamethasone; Dialysis procedure; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug usage; Encapsulated; Eye; Eye Development; Eye Infections; Eyedrops; Formulation; Frequencies; Genetic; Glucocorticoids; Goals; Herpes Simplex Infections; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Herpetic Keratitis; Hour; Human; Implant; In Vitro; Individual; Infection; Inflammation; Inflammatory; Intellectual Property; Interleukin-1 beta; Keratitis; Knowledge; Legal patent; Light; Mechanics; Modality; Modeling; Mus; National Eye Institute; Oral; Paper; Particle Size; Patients; Persons; Pharmaceutical Preparations; Physiological; Porosity; Prednisone; Primary Infection; Publishing; Recurrence; Regimen; Reporting; Research; Risk; Sampling; Science; Severities; Simplexvirus; Site; Standardization; Structure; Surface; System; Techniques; Testing; Therapeutic; Time; Tissues; Topical Corticosteroids; Topical application; Treatment Protocols; Tube; Ulcer; Universities; Viral; Virus; Virus Replication; Vision; analog; antimicrobial; clinical efficacy; clinically relevant; common treatment; compliance behavior; design; dosage; drug efficacy; drug release profile; efficacy evaluation; fungus; improved; in vivo; in vivo Model; lymphadenopathy; microbial; mouse model; next generation; novel; novel therapeutics; ocular pain; particle; pathogen; standard of care; treatment duration

Ocular inflammatory diseases are the primary cause of blindness in the USA. While emergence of ocular inflammation can be genetic or idiopathic, pathogens such as bacteria, fungi and viruses that infect the eye are primary causes. Microbial infections are treated with antimicrobials followed by anti-inflammatory drugs such as dexamethasone, prednisone, cyclosporine etc. The treatment regimen for these anti-inflammatory drugs is prolonged and can last up to many months or even years. While systemic dosing is often avoided unless necessary, topical dosage regimens can have low patient compliance due to repeated administration requirements per day. One such ailment that affects millions of people around the globe is ocular herpes. Primary infections are usually seen in children or adolescents and associated with vesicular dermatitis, follicular blepharo-conjunctivitis, superficial punctate keratitis (SPKs) or dendritic ulcer with preauricular lymphadenopathy. However, herpesviruses can reside forever in the host latently and cause recurrent ocular infection in patients of all ages. While the most common treatment for treating active ocular herpes infection includes daily dosing of Acyclovir (ACV) or ACV analogs, curbing post viral inflammation, which can cause ocular pain and permanent clouding of the cornea, is performed by topical glucocorticoid treatments such as prednisone or dexamethasone. These topical glucocorticoid therapies are avoided during active viral replication and only prescribed in conjunction with oral antivirals to avoid the risk of involving deeper stromal structures with threats to vision. While topical glucocorticoid treatments are effective in reducing inflammation in most cases, they require repeated dosing (6-10 times daily) and suffer from poor ocular retention. A simple yet effective way to improve ocular retention time for topical therapies is to use sustained drug release platforms. We have recently shown that ACV loaded into highly porous activated carbon termed as drug encapsulated carbon (DECON), can effectively adsorb to the corneal surface and deliver drug in a sustained fashion. We showed that use of DECON to deliver ACV, reduced the dosage frequency from 3 in a single day to a single dose once every alternate day in mice. In this regard, we propose to demonstrate a new use for DECON as a sustained drug release platform to deliver dexamethasone during post viral inflammation period. In this proposal, we would like to (1) understand the efficacy of drug loading, retention and release of dexamethasone from DECON using in vitro, ex vivo and in vivo models and (2) through clinically relevant metrics assess DECON’s ability to reduce infectious and non-infectious suppress inflammation during post viral replication period.

眼部炎症性疾病是美国失明的主要原因。而眼的出现 炎症可能是遗传性或特发性，病原体，例如细菌，真菌和感染眼睛的病毒 是主要原因。用抗菌药物处理微生物感染，然后用抗炎药处理 例如地塞米松，泼尼松，环孢菌素等。这些抗炎的治疗方案 毒品延长了，可以持续数月甚至几年。虽然通常避免使用全身剂量 除非有必要，局部剂量方案由于重复而具有较低的患者依从性 每天管理要求。一种影响全球数百万人的疾病是 眼疱疹。原发性感染通常在儿童或青少年中看到，并与水泡相关 皮炎，卵泡性孔珠连通炎，表面点状角膜炎（SPK）或树突状溃疡，带有树突状溃疡 前淋巴结肿大。但是，疱疹病毒可以永远存在于宿主中，并导致 所有年龄段患者的复发性眼感染。而治疗活性眼的最常见治疗方法 疱疹感染包括每天给Acyclovir（ACV）或ACV类似物的剂量，病毒后注射后遏制， 会导致眼部疼痛和角膜永久蒙阴影，由局部糖皮质激素进行 泼尼松或地塞米松等治疗方法。避免了这些局部糖皮质激素疗法 在主动病毒复制期间，仅与口服抗病毒药一起开处方，以避免 涉及对视力威胁的更深的基质结构。局部糖皮质激素治疗是 在大多数情况下，有效减少炎症，需要重复给药（每天6-10次），并受苦 来自较差的眼部保留。改善局部疗法的眼部保留时间的简单但有效的方法 是使用持续的药物释放平台。我们最近表明，ACV加载到高度多孔 被称为药物封装的碳（Decon）的活性碳可以有效地吸附到角膜 表面并以持续的方式输送药物。我们表明使用Decon提供ACV，减少 在小鼠中，每天的剂量频率从一天中的3次到单剂量。在这个 考虑到，我们建议展示DeCon的新用途，作为持续的药物释放平台，以交付 病毒后炎症期间地塞米松。在此提案中，我们想（1）了解 使用体外，Ex Vivo和In中的DECON的药物加载，保留和释放的药物加载和释放的功效 体内模型和（2）通过临床相关的指标评估Decon减少感染性和 在病毒后复制期间非感染抑制注射。