Optimization of a nanoparticle-based topical PDE5i formulation for treatment of erectile dysfunction

用于治疗勃起功能障碍的基于纳米颗粒的局部 PDE5i 制剂的优化

• 批准号: 10601895
• 负责人: Andrew R Draganski
• 金额: $ 26.34万
• 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: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601895
• 关键词: Affect; Aging; Animal Model; Area; Cannabidiol; Carrying Capacities; Characteristics; Chemicals; Clinical; Data; Dose; Enzymes; Erectile dysfunction; Formulation; Future; Generations; Goals; Hour; Human; Ingestion; Lead; Lidocaine; Life; Medicine; Mind; Modeling; Oral; Penetration; Pharmaceutical Preparations; Publishing; Rattus; Route; Sales; Sildenafil citrate; Silicates; Silicon Dioxide; Skin; Surface; Suspensions; System; Technology; Therapeutic; Time; Tissues; Topical application; Translating; Translations; Viagra; Well in self; Work; aqueous; base; clinical translation; college; commercialization; comparative efficacy; delivery vehicle; dietary; efficacy testing; experimental study; improved; inhibitor; inhibitor therapy; man; member; men; nanoparticle; nanoparticle delivery; nanosized; particle; penis; phase 1 study; phosphoric diester hydrolase; prototype; response; sex; side effect; sildenafil

Abstract It is increasingly recognized that erectile dysfunction (ED) not only affects a man’s sex life but also impacts his relationships and overall psychological well-being. An indication of the importance of erectile function to men is that, in the first 6 years after FDA approval of Viagra® (sildenafil, an oral treatment for ED), 23 million men worldwide filled Viagra® prescriptions, with average annual sales of about $1.7 billion, making it one of the more commercially successful drugs of all time. Sildenafil is a member of the phosphodiesterase-type-5 inhibitors (PDE5i) drug class, which is by far the most commonly prescribed treatment for ED. However, because of side effects, use restrictions (dietary, contraindications), and long time-to-response, a significant percentage of men with ED either discontinue use of PDE5i within the first year or never begin treatment in the first place. Several of the drawbacks associated with an oral/systemic route of administration could potentially be overcome by a local, topical delivery vehicle. However, an aqueous sildenafil citrate solution has not been shown to transdermally penetrate with any significance, as the physicochemical characteristics of these amphoteric drugs make formulation and permeation challenging. With this in mind, our group initiated studies to determine if a proprietary silica particle delivery system developed at Albert Einstein College of Medicine and licensed to Zylö Therapeutics Inc. could act as an effective topical delivery system for PDE5i. Initial studies utilizing first- generation technology demonstrated the feasibility of this approach using nano-sized particles in treating ED in animal models of aging. Since then, a second-generation delivery system has been developed by Zylö for topical delivery of other payloads such as lidocaine and cannabidiol (CBD). The goal of this proposal is to adapt this second-generation technology to sildenafil and optimize it for clinical and commercial translation with the overall hypothesis that topical delivery of sildenafil through the use of a nanoparticle delivery system (sildenafil-NP) can improve erectile function. The proposal will be conducted over the course of one year and will incorporate two specific aims. In Specific Aim 1, Zylö will generate an optimized prototype formulation of sildenafil-NP. This will include modulations to the chemical formulation of the nanoparticles such that a significant increase in the carrying capacity for PDE5i will be realized. In Specific Aim 2, proof-of-principle experiments will be conducted to assess the efficacy of topical application of these second-generation sildenafil-NP in eliciting an erectile response in an animal model of ED resulting from aging. At the conclusion of these proposed Phase I studies, we will have identified a lead sildenafil-NP formulation that is optimized for clinical translation as a topical treatment of ED.

抽象的 人们越来越认识到勃起功能障碍（ED）不仅会影响男人的性生活，而且会影响他的性生活 关系和整体心理健康。表明勃起功能对男性重要性的指示是 在FDA批准伟哥®（Sildenafil，ED口服治疗）后的头六年中，2300万人 全球填补了伟哥处方，平均年销售额约为17亿美元，使其成为更多 有史以来商业上成功的药物。西地那非是磷酸二酯酶型-5抑制剂的成员 （PDE5I）药物类，这是迄今为止ED最常见的治疗方法。但是，由于一边 效果，使用限制（饮食，禁忌症）和长时间的响应，很大一部分男性 ED在第一年内停止使用PDE5I，或者首先从未开始治疗。 可能会克服与口头/系统的管理途径相关的一些缺点 由本地局部送货车使用。但是，尚未证明西地那非柠檬酸盐水溶液 由于这些两性药物的物理特性 提出公式和渗透挑战。考虑到这一点，我们的小组开始了研究，以确定是否是 专有二氧化硅粒子递送系统在阿尔伯特·爱因斯坦医学院开发，并获得了Zylö的许可 Therapeutics Inc.可以充当PDE5i的有效局部交付系统。使用首先研究的初步研究 一代技术证明了使用纳米大小的粒子在处理中的可行性 衰老的动物模型。从那以后，Zylö开发了第二代输送系统 提供其他有效载荷，例如利多卡因和大麻二酚（CBD）。该提议的目的是适应 西地那非的第二代技术，并优化它用于临床和商业翻译 假设通过使用纳米颗粒输送系统（Sildenafil-np）的西地那非局部传递可以 提高勃起功能。 该提案将在一年的时间内进行，并将结合两个具体的目标。具体 AIM 1，Zylö将生成Sildenafil-NP的优化原型公式。这将包括调制 纳米颗粒的化学公式使PDE5I的承载能力显着增加 实现。在特定的目标2中，将进行原理证明实验以评估局部的效率 这些第二代西地那非-NP在ED动物模型中引发勃起反应中的应用 衰老导致。 在这些拟议的I期研究的结论时，我们将确定Sildenafil-NP铅公式 优化用于临床翻译作为ED的局部处理。