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.

摘要 越来越多的人认识到，勃起功能障碍（艾德）不仅影响男性的性生活，而且还影响他的生活质量。 关系和整体心理健康。勃起功能对男性的重要性的一个迹象是 在FDA批准伟哥®（西地那非，一种治疗艾德的口服药物）后的前6年， 全球范围内填充伟哥®处方，平均年销售额约为17亿美元，使其成为世界上 商业上最成功的药物西地那非是5型磷酸二酯酶抑制剂的一员 （PDE 5i）药物类，这是迄今为止最常见的ED处方治疗。 效果，使用限制（饮食，禁忌症）和反应时间长，男性的显着比例 患有艾德的患者在第一年内停止使用PDE 5 i或从未开始治疗。 与口服/全身给药途径相关的几个缺点有可能被克服 通过局部的局部递送载体。然而，尚未显示西地那非柠檬酸盐水溶液 由于这些两性药物的物理化学特性， 使得配制和渗透具有挑战性。考虑到这一点，我们的小组开始研究，以确定 由阿尔伯特·爱因斯坦医学院开发并授权给Zylö的专有二氧化硅颗粒输送系统 Therapeutics Inc.可以作为PDE 5i的有效局部递送系统。初步研究利用第一- 发电技术证明了这种方法的可行性，使用纳米尺寸的颗粒在治疗艾德， 衰老的动物模型从那时起，Zylö开发了第二代递送系统，用于局部给药。 递送其他有效载荷，例如利多卡因和大麻二酚（CBD）。该提案的目标是适应这一点， 西地那非的第二代技术，并优化其临床和商业转化， 假设通过使用纳米颗粒递送系统（西地那非-NP）局部递送西地那非可以 改善勃起功能。 该提案将在一年内进行，并将包括两个具体目标。在特定 目标1，Zylö将生成西地那非-NP的优化原型制剂。这将包括对 纳米颗粒的化学配方使得对PDE 5i的承载能力的显著增加将 实现。在具体目标2中，将进行原理验证实验以评估局部给药的疗效。 这些第二代西地那非-NP在艾德动物模型中引发勃起反应的应用 因老化而导致。 在这些拟定的I期研究结束时，我们将确定一种先导西地那非-NP制剂， 作为ED的局部治疗进行了优化的临床翻译。