It is increasingly recognized that erectile dysfunction (ED) not only affects a man's sex life but also impacts hisrelationships and overall psychological well-being. An indication of the importance of erectile function to men isthat, in the first 6 years after FDA approval of Viagra® (sildenafil, an oral treatment for ED), 23 million menworldwide filled Viagra® prescriptions, with average annual sales of about $1.7 billion, making it one of the morecommercially 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 sideeffects, use restrictions (dietary, contraindications), and long time-to-response, a significant percentage of menwith 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 overcomeby a local, topical delivery vehicle. However, an aqueous sildenafil citrate solution has not been shown totransdermally penetrate with any significance, as the physicochemical characteristics of these amphoteric drugsmake formulation and permeation challenging. With this in mind, our group initiated studies to determine if aproprietary silica particle delivery system developed at Albert Einstein College of Medicine and licensed to ZylöTherapeutics 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 inanimal models of aging. Since then, a second-generation delivery system has been developed by Zylö for topicaldelivery of other payloads such as lidocaine and cannabidiol (CBD). The goal of this proposal is to adapt thissecond-generation technology to sildenafil and optimize it for clinical and commercial translation with the overallhypothesis that topical delivery of sildenafil through the use of a nanoparticle delivery system (sildenafil-NP) canimprove erectile function.The proposal will be conducted over the course of one year and will incorporate two specific aims. In SpecificAim 1, Zylö will generate an optimized prototype formulation of sildenafil-NP. This will include modulations to thechemical formulation of the nanoparticles such that a significant increase in the carrying capacity for PDE5i willbe realized. In Specific Aim 2, proof-of-principle experiments will be conducted to assess the efficacy of topicalapplication of these second-generation sildenafil-NP in eliciting an erectile response in an animal model of EDresulting from aging.At the conclusion of these proposed Phase I studies, we will have identified a lead sildenafil-NP formulation thatis optimized for clinical translation as a topical treatment of ED.
Public Health Relevance Statement: Narrative
Sildenafil is a member of the phosphodiesterase-type-5 inhibitors (PDE5i) drug class, which is by far the most
commonly prescribed treatment for erectile dysfunction (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. In these proposed Phase
I studies, Zylö Therapeutics will optimize for clinical translation a nanoparticle delivery system that would facilitate
local topical application of the leading PDE5i (sildenafil), which has the potential to overcome several of the
drawbacks associated with an oral/systemic route of PDE5i administration.
Project Terms:
