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，眼部炎症性疾病是致盲的主要原因。而眼球的出现 炎症可以是遗传性的或特发性的，感染眼睛的细菌、真菌和病毒等病原体 是主要原因。微生物感染先用抗菌药治疗，然后再用抗炎药治疗。 如地塞米松、泼尼松、环孢素等。这些抗炎的治疗方案 毒品会持续很长时间，可以持续几个月甚至几年。虽然通常避免全身给药 除非有必要，否则局部给药方案会因为重复给药而降低患者的依从性。 每天的管理要求。其中一种影响全球数百万人的疾病是 眼部疱疹。原发感染通常见于儿童或青少年，并与水泡有关。 皮炎、滤泡性眼睑结膜炎、浅表性点状角膜炎(SPK)或树突状溃疡 耳前淋巴结病。然而，疱疹病毒可以永远潜伏在宿主中，并导致 各年龄段患者复发性眼部感染。虽然治疗活动性眼部最常见的治疗方法 疱疹感染包括每天服用阿昔洛韦(ACV)或阿昔洛韦类似物，抑制病毒后炎症， 可导致眼痛和永久性角膜混浊，是通过外用糖皮质激素进行的。 强的松或地塞米松等治疗。避免使用这些局部糖皮质激素疗法 在活跃的病毒复制期间，仅与口服抗病毒药物联合使用，以避免发生 涉及较深的间质结构，对视力构成威胁。而外用糖皮质激素治疗是 在大多数情况下，它们在消炎方面有效，需要重复服药(每天6-10次)，并遭受 因为眼球保持不好。一种简单而有效的方法来提高局部治疗的眼滞留时间 就是使用药物缓释平台。我们最近发现，ACV被装载到高度渗透性的 被称为药物包埋炭(DECON)的活性碳可以有效地吸附在角膜上 以持续的方式浮出水面并输送药物。我们展示了使用迪康来交付ACV，减少了 给药频率由单日3次改为隔日1次。在这 在这方面，我们建议展示Decon作为一种持续药物释放平台的新用途 病毒后炎症期地塞米松。在这项建议中，我们希望(1)了解 地塞米松体外、体外和体内载药、滞留和释药的研究 活体模型和(2)通过临床相关指标评估DECON降低感染性和 在病毒复制后阶段，非感染性抑制炎症。