Development of wound care formulations for PVP/NO: A novel nitric oxide releasing platform with potent antimicrobial and anti-biofilm properties

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The central goal of this SBIR research effort is to advance and commercialize a novel biomaterial with a nitric oxide (NO)-based delivery system for the wound care market. This Phase I proposal will build on iFyber’s strong preliminary data for this biomaterial as a potent antimicrobial and anti-biofilm platform. Specifically, through past in vitro studies, iFyber has shown this system to exhibit excellent antibacterial and anti-biofilm properties as evidenced by both in vitro and ex vivo biofilm models where it significantly outperforms commercially available wound care dressings for Gram positive/negative bacteria, yeast, and mold. Results form pilot animal studies have shown activity of this system, in vivo, but have highlighted formulation development as a key focus area prior to advancing the technology further. If funded, iFyber aims to use this Phase I project to advance effective and wound-relevant topical formulations that provide stable and sustained NO-release. These formulations will be further advanced in a full battery of animal studies planned for Phase II. Nitric oxide-releasing technologies offer a compelling alternative to standard antimicrobial treatments and antibiotics currently used to combat infection in wounds. Our current data set clearly demonstrate the potential clinical utility of PVP/NO in addressing microbial infection in general, and more importantly, prevention and treatment of microbial biofilms that plague chronic skin wounds. An important milestone for this Phase I project will be to expand on the PVP/NO technology by developing candidate PVP/NO-based topical formulations that will serve as a non-antibiotic prophylactic treatment against microbial infection and as a treatment for chronically infected wounds – two unmet needs within the wound care field. Completion of Phase I efforts will result in a compelling data set that outlines the efficacy and defines the minimal requirements for product formulation in terms of topical application. Together, these studies will help in the transition to broader Phase II studies aimed to support entry of a PVP/NO-based product into the FDA's regulatory process. iFyber will address the efficacy of the newly developed formulations of the NO-releasing biomaterial through the Phase I aims and tasks outlined below: AIM 1. Identify lead and contingency topical formulations through a screening campaign Task 1. Screen PVP/NO-based topical formulations for adherence to target product profile (TPP) requirements. Past R&D efforts have established that NO release from the PVP/NO is rapid if not protected from simultaneous exposure to H+/water. This can be difficult to control, in vivo, where sustained release is desired. This can be done by controlling the exposure of PVP/NO to H+/water as we have recently shown through a balanced hydrophilicity-lipophilicity organic acid “BHLOA” approach to controlling pH change in these systems. In Phase I we will build on these preliminary findings by further advancing the BHLOA formulation approach to provide lead and back up PVP/NO formulations that will be selected based on test results from the NO-release and ex vivo model studies (Task 2) followed by pilot in vivo studies (Tasks 3 and 4). Task 2. Verify anti-biofilm efficacy and select lead and contingency formulations. The goal of this task is to evaluate the efficacy of the candidate formulations from Task 1 in an ex vivo porcine dermal model of biofilm to define suitable antimicrobial and anti-biofilm semi-solid dressings for wounds. A main goal in this task will be to down-select formulations for pilot animal studies (Tasks 3 and 4). AIM 2. Guide PVP/NO prototype development through pre-clinical pilot studies Task 3. Conduct in vivo testing on selected formulations. Promising formulations identified through Tasks 1-2 will be evaluated in two pilot in vivo studies conducted in the laboratory of Prof. Steven Davis at the University of Miami. These studies will establish efficacy in biofilm prevention (study 1) and reduction in an existing biofilm-associated infection (study 2), and results of these studies will help to further down-select PVP/NO formulations for future Phase II development. Task 4. Determine the baseline in vivo biocompatibility profile of PVP/NO. In addition to assessing infection prevention and anti-biofilm efficacy, the effects of the candidate PVP/NO formulations on non- infected wounds will also be assessed with respect to the wound healing process (study 3); specifically, inflammatory response, erythema, re-epithelialization, granulation tissue formation, and initial molecular screens for healing and inflammatory processes.