Silver oxynitrate gel formulation for enhanced stability and antibiofilm efficacy

Abstract

Topical semi-solid formulations are ubiquitous in personal care and pharmaceutical applications. For centuries, these topical formulations have facilitated delivery of active ingredients such as botanical oils, medicinal extracts and more recently antibiotics and biologics. Numerous strategies exist for the stabilization and release of these active ingredients from semi-solid formulations, namely, inclusion of anti-oxidants and surfactants to extend shelf life and facilitate delivery respectively. However, in the instance where the active ingredient itself is an oxidizing agent, traditional strategies for formulation have limited utility. Recent evidence has highlighted the exceptional efficacy and safety of highly oxidizing silver compounds, containing Ag²⁺ and Ag³⁺. These higher oxidation states of silver provide antimicrobial and antibiofilm activity without impairing healing. However, as strong oxidizing agents, their application in medical device and pharmaceutical formulations such as semi-solid formulations are limited. The present study reports on the development of a silicone-based gel formulation of silver oxynitrate (Ag₇NO₁₁), a higher oxidation state silver complex. In this study the chemical stability of silver oxynitrate was examined through solid state characterization with X-ray diffraction, formulation stability and microstructure of the semi-solid gel evaluated through various rheological techniques, therapeutic functionality of the semi-solid formulation investigated through in-vitro planktonic and biofilm antimicrobial studies, and biocompatibility assessed though in-vitro mammalian fibroblast and in-vivo porcine wound healing models. Enhanced stability of silver oxynitrate within the semi-solid formulation was observed over a four-month X-ray diffraction study. At the end of the study, silver oxynitrate was identified as the principal diffraction pattern in the semi-solid formulation where argentic oxide diffraction peaks were observed to be dominant in silver oxynitrate powders alone. Viscoelastic or gel-like behavior of the formulation was observed under dynamic rheological study where the storage modulus (G' = 1.77 ± 0.02 × 10⁴ Pa) significantly exceeded the loss modulus (G″ = 4.89 ± 3.72 × 10² Pa) (p < 0.0001). No significant (p = 0.84) change was observed in the apparent viscous response within the last three months of the study period indicative that the formulation approached a steady rheological state. The silver oxynitrate semi-solid formulation provided sustained in-vitro antimicrobial activity (>99.99% kill) over seven days with a significant reduction in biofilm within 6 h (p < 0.001). In-vitro mammalian fibroblast studies demonstrated the formulation to be non-cytotoxic and 100% epithelialization was observed within a six-day in-vivo porcine deep partial-thickness wound. The improved chemical stability, biocompatibility and efficacy results indicate that silicone gel semi-solid formulation may be a promising medicinal configuration to facilitate expansion of the clinical use of silver oxynitrate.

Keywords: Antibiofilm; Biocompatible; Formulation; Gel; Higher oxidation states; Silicone; Silver oxynitrate.