Development and optimization of a nitric oxide releasing microparticle-basedtopical treatment for onychomycosis

基于一氧化氮释放微粒的甲癣局部治疗方法的开发和优化

• 批准号: 10547384
• 负责人: Andrew R Draganski
• 金额: $ 30万
• 依托单位: ZYLO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547384
• 关键词: Address; Adverse effects; Affect; Aging; Anti-Bacterial Agents; Antifungal Agents; Arthrodermataceae; Aspergillus flavus; Bacterial Antibiotic Resistance; Biological Assay; Blood Vessels; Cadaver; Candida; Candida albicans; Clinical; Cream; Dermal; Development; Diabetes Mellitus; Diatoms; Disease; Dose; Drug resistance; Fibroblasts; Formulation; Gases; Generations; Goals; Growth; Hepatotoxicity; Human; Human body; Immunomodulators; Immunosuppression; In Vitro; Industrial fungicide; Infection; Lead; Measures; Medicine; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Molds; Morphology; Mutation; Nail plate; Nitric Oxide; Obesity; Onychomycosis; Organism; Pain; Particle Size; Penetration; Pharmaceutical Preparations; Phase; Prevalence; Quality of life; Recording of previous events; Risk Factors; Safety; Scientist; Silicon Dioxide; Site; System; Testing; Therapeutic; Tinea Pedis; Tissues; Topical application; Trauma; Treatment/Psychosocial Effects; Trichophyton; Yeasts; base; chronic rhinosinusitis; clinical translation; college; comorbidity; cost; cytotoxicity; efficacy study; efflux pump; improved; keratinization; keratinocyte; manufacturability; novel; novel therapeutics; pathogenic fungus; phase 1 study; prototype; safety study; scale up

Onychomycosis is an extremely common and difficult-to-treat fungal nail infection that causes nail disfigurement, pain, associated infections, and psychosocial effects that negatively impact quality of life. It is caused predominantly by dermatophytes such as Trichophyton rubrum (T. rubrum) but may also involve yeasts such as Candida albicans or non-dermatophyte molds. Typical risk factors include trauma, aging, and history of tinea pedis, but additional comorbidities such as diabetes, obesity, and immune suppression are also significant risk factors, which are increasing in prevalence. Onychomycosis is typically treated by antifungal drugs administered topically or systemically, but each approach has significant shortcomings leading to low complete cure rates of less than 30% and 60%, respectively5,6. Topical antifungals are limited by difficulties in delivering the drug through the nail plate, which is a highly keratinized, difficult-to-penetrate protective barrier3,4. Systemic antifungals are generally high cost, may be restricted by limited vascular access to the site of infection, and are associated with potentially severe adverse effects, including hepatotoxicity. In addition, drug resistance in onychomycosis may manifest through the development of biofilm growth or through induction of efflux pumps and mutations. Therefore, the development of an improved treatment for onychomycosis would fill a significant unmet need and improve the quality of life for those affected by the disease. The goal of this proposal will be achieved through two interconnected specific aims. In Specific Aim 1, zMPNO for clinical translation will be synthesized and characterized prior to being evaluated for in vitro antifungal activity against T. rubrum and other fungal strains relevant to onychomycosis as well as for preliminary cytotoxicity. In Specific Aim 2, the concentrations of zMPNO in a representative cream vehicle required to deliver sufficient NO through the nail plate to achieve fungicidal activity will be established. This formulation will then be used to assess zMPNO efficacy in treating T. rubrum and C. albicans in a RoMar™ ex vivo infected nail model (MedPharm). At the conclusion of this Phase I study, an Optimized Formulation will be established with defined concentration of zMPNO suitable for further formulation development, scale-up, safety studies, and ex vivo efficacy studies in Phase II.

甲真菌病是一种极其常见且难以治疗的指甲真菌感染，会导致指甲畸形， 疼痛、相关感染和心理社会影响对生活质量产生负面影响。 主要由皮肤癣菌如红色毛癣菌 (T. rubrum) 引起，但也可能涉及酵母菌，如 白色念珠菌或非皮肤癣菌霉菌的典型危险因素包括外伤、衰老和癣病史。 足病，但糖尿病、肥胖和免疫抑制等其他合并症也是重大风险 甲真菌病的患病率正在增加，通常通过服用抗真菌药物来治疗。 局部或全身治疗，但每种方法都有明显的缺点，导致完全治愈率较低 分别低于 30% 和 60%5,6。 穿过指甲板，这是一种高度角质化、难以穿透的全身性保护屏障3,4。 抗真菌药物通常成本较高，可能会受到感染部位血管通路有限的限制，并且 与潜在的严重不良反应有关，包括肝毒性。 甲真菌病可能通过生物膜生长或外排泵的诱导而表现出来 因此，开发一种改进的甲癣治疗方法将填补这一空白。 显着未满足的需求并改善受该疾病影响的人们的生活质量。 该提案的目标将通过两个相互关联的具体目标来实现，即具体目标 1：zMPNO。 用于临床转化的药物将在评估体外抗真菌活性之前进行合成和表征 针对红色毛癣菌和其他与甲真菌病相关的真菌菌株以及初步的细胞毒性。 具体目标 2，代表性霜媒介物中提供足够 NO 所需的 zMPNO 浓度 通过指甲板达到杀菌活性的方法将被用来建立。 评估 zMPNO 在 RoMar™ 离体感染指甲模型中治疗红色毛癣菌和白色念珠菌的功效 （医学制药）。 在第一阶段研究结束时，将建立一个优化的配方，其定义如下： zMPNO 的浓度适合进一步的制剂开发、放大、安全性研究和实验 II 期体内功效研究。