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）不仅影响男性的性生活，还影响他的性生活。 人际关系和整体心理健康。勃起功能对男性的重要性的一个指标是 在 FDA 批准 Viagra®（西地那非，一种治疗 ED 的口服药物）后的头 6 年里，2300 万男性 全球处方伟哥®，平均年销售额约 17 亿美元，使其成为全球销量最大的伟哥之一 有史以来商业上成功的药物。西地那非是 5 型磷酸二酯酶抑制剂的成员 (PDE5i) 药物类别，这是迄今为止治疗 ED 最常用的处方药物。然而，由于侧面 影响、使用限制（饮食、禁忌症）和较长的反应时间，很大一部分是男性 患有 ED 的患者要么在第一年内停止使用 PDE5i，要么从一开始就不开始治疗。 与口服/全身给药途径相关的几个缺点有可能被克服 通过本地局部给药工具。然而，柠檬酸西地那非水溶液尚未被证明可以 透皮渗透具有任何意义，因为这些两性药物的理化特性 使配方和渗透具有挑战性。考虑到这一点，我们的小组发起了研究，以确定是否 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 PDE5i 的有效局部给药系统。初步研究利用第一 生成技术证明了这种使用纳米颗粒治疗 ED 的方法的可行性 衰老动物模型。从那时起，Zylö 开发了第二代局部给药系统 其他有效负载的输送，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对其进行优化以用于临床和商业转化 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，并将包含两个具体目标。具体来说 目标 1，Zylö 将生成优化的西地那非-NP 原型配方。这将包括对 纳米颗粒的化学配方使得 PDE5i 的承载能力显着增加 被实现。在具体目标 2 中，将进行原理验证实验来评估局部治疗的功效 第二代西地那非纳米粒子在 ED 动物模型中引发勃起反应的应用 因老化而产生的。 在这些拟议的第一阶段研究结束时，我们将确定一种西地那非-NP先导制剂，该制剂 已针对 ED 局部治疗的临床转化进行了优化。