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

摘要 越来越多的人认识到勃起功能障碍(ED)不仅影响男性的性生活，而且还影响男性的 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迹象是 在FDA批准伟哥®(西地那非，一种治疗勃起功能障碍的口服药物)后的头6年里，2300万男性 全球各地都有伟哥®处方，年平均销售额约为17亿美元，使其成为 有史以来商业上最成功的药物。西地那非是磷酸二酯酶-5抑制剂的一员 (PDE5i)药物类别，这是迄今为止最常见的ED处方药。然而，由于侧面的原因 效果、使用限制(饮食、禁忌症)和长时间反应，相当大比例的男性 对于ED，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 由当地的局部递送工具运送。然而，柠檬酸西地那非水溶液还没有显示出 具有任何意义的经皮渗透，如这些两性药物的物理化学特性 使配方和渗透性具有挑战性。考虑到这一点，我们团队启动了一项研究，以确定 阿尔伯特·爱因斯坦医学院开发的专有二氧化硅颗粒输送系统，并授权给Zylö Treateutics Inc.可以作为PDE5i的有效局部给药系统。初步研究利用第一个- 发电技术证明了利用纳米颗粒治疗ED的可行性 衰老的动物模型。从那时起，Zylö为topical开发了第二代递送系统 运送利多卡因和大麻二酚(CBD)等其他有效载荷。这项提议的目标是适应这一点 第二代技术用于西地那非，并对其进行优化，以用于临床和商业翻译 假设通过使用纳米粒递送系统(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。具体而言 目标1，Zylö将产生西地那非-NP的优化原型配方。这将包括对 纳米颗粒的化学配方，使PDE5i的载量显著增加 被实现了。在具体目标2中，将进行原则验证实验以评估外用药物的疗效。 这些第二代西地那非-NP在诱发ED动物模型勃起反应中的应用 由于年龄增长而导致的。 在这些拟议的第一阶段研究结束时，我们将确定一种含铅的西地那非-NP配方 作为ED的一种局部治疗方法，已针对临床翻译进行了优化。

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.