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.

在美国，眼部炎症性疾病是导致失明的主要原因。 炎症可以是遗传性的，也可以是特发性的，病原体如感染眼睛的细菌、真菌和病毒 微生物感染是主要原因，首先用抗菌药物治疗，然后用抗炎药物治疗。 如地塞米松、泼尼松、环孢素等这些抗炎药物的治疗方案 作用时间较长，药物可持续数月甚至数年，但通常避免全身给药。 除非必要，局部给药方案可能由于反复用药而导致患者依从性较低。 每天的管理需求是影响全球数百万人的一种疾病。 原发性感染通常见于儿童或青少年，并与水疱有关。 皮炎、滤泡性眼睑结膜炎、浅表点状角膜炎 (SPK) 或伴有树突状溃疡 然而，疱疹病毒可以永远潜伏在宿主体内并引起。 所有年龄段患者的复发性眼部感染，而最常见的治疗方法是治疗活动性眼部感染。 疱疹感染包括每天服用阿昔洛韦 (ACV) 或 ACV 类似物，抑制病毒后炎症， 可导致眼部疼痛和角膜永久性混浊，通过局部糖皮质激素进行 避免使用泼尼松或地塞米松等局部糖皮质激素疗法。 在病毒活跃复制期间，只能与口服抗病毒药物联合使用，以避免感染的风险 虽然局部糖皮质激素治疗涉及更深的基质结构，对视力构成威胁。 在大多数情况下可有效减轻炎症，但需要重复给药（每天 6-10 次）并遭受痛苦 一种改善局部治疗眼部保留时间的简单而有效的方法。 我们最近已经证明，ACV 可以装载到高度多孔的药物中。 活性炭又称药物封装碳（DECON），能有效吸附到角膜上 我们表明，使用 DECON 来输送 ACV 可以减少表面和以持续方式输送药物。 在此，小鼠的给药频率从一天 3 次到每隔一天一次。 就此而言，我们建议展示 DECON 作为持续药物释放平台的新用途，以提供 病毒性炎症后时期的地塞米松 在本提案中，我们希望 (1) 了解 使用 DECON 进行体外、离体和体内载药、保留和释放地塞米松的功效 体内模型和（2）通过临床相关指标评估 DECON 减少传染性和 非感染性抑制病毒复制后的炎症。