Development of sprayable thermoreversible hydrogels as a topical treatment for skin wounds

Riannon Jade Smith

doi:10.25820/etd.007299

Severe burns and chronic, non-healing wounds are critical health care concerns due to the cost of care, the time to heal, and the increased risk of infection these wounds present. Burns and chronic wounds are typically very painful due to the damaged and sensitized tissue in or surrounding the wound, and current topical treatments can exacerbate patient discomfort. Due to the increased risk of infection, topical antimicrobial treatments are typically applied as creams or ointments and manually spread into the wound bed. The manual pressure required to manipulate these treatments increases patient pain. Furthermore, infection rates are still high in both burns and chronic wounds despite decades of wound care improvement.We hypothesize that a sprayable hydrogel will reduce application pain for topical treatments. Additionally, loading the hydrogel with a pain medication or an antimicrobial will provide targeted pain relief and improve infection treatment. A thermoreversible hydrogel, Pluronic F127, was used to investigate these hypotheses. Pluronic F127 is liquid at cold temperatures, allowing it to be sprayed as a cold liquid, and a gel at physiologic temperatures, causing it to gel when in contact with the skin. Both the spray application and the cold formulation on the skin could alleviate application pain, thus making dressing changes more comfortable for those suffering from these wounds. Using a hydrogel as a wound dressing has additional advantages over creams and ointments, as prolonged drug release achieved with a gel could reduce the number of dressing changes and their ability to keep the wound bed moist could promote healing. The goal of this work was to develop a sprayable, antimicrobial formulation from Pluronic F127 that formed a gel below skin temperature, released an antimicrobial agent in concentrations above critical concentrations for pathogens common in wound infections, and that had appropriate spray pattern characteristics for clinical use. Topical sprays from hand-held sprayers can exhibit widely different spray patterns from very concentrated in one location or dispersed over a wider area. Thus, quantifying the area covered by cold, thermoreversible hydrogel formulations was important to determine how far a dose would spread over a surface. To characterize the sprayability of Pluronic F127 formulations and identify parameters that can tune the spray patterns to match desired characteristics, the sprayability of F127 15%, 17%, and 20% w/w hydrogels with and without 0.4% - 1.7% w/v diclofenac sodium, a non-steroidal anti-inflammatory drug, or 0.5% - 1% w/v hyaluronic acid from handheld sprayers was evaluated. Diclofenac sodium was added to determine how a model pain-relieving drug for wound dressings would alter the spray patterns, while hyaluronic acid was added as a viscosity modifier that has accelerated wound healing. A MATLAB code was developed to aid in spray pattern quantification, and the full spray pattern and concentrated core regions of the spray pattern were analyzed. Traditional spray metrics including major axis, minor axis, and ovality were calculated to understand the spread and shape of the spray pattern. The area covered by each region and the percent of the spray pattern that was included in the core analysis were included to determine how dispersed the pattern was and where the majority of the therapeutic dose would land. As distance to target increased, the full spray pattern increased while also becoming more dispersed. As the viscosity increased, the area of the spray pattern and the pattern became more concentrated. The addition of diclofenac sodium did not significantly change the patterns much from the bare gel formulations. However, the addition of hyaluronic acid increased the formulation viscosity and significantly decreased the size of the spray patterns. This work was important to better quantify the deposition of the topical sprays generated and can be used to guide future sprays. While the ability to tune spray patterns is useful for topical application, countering the high rates of infection in severe wounds is also a priority. To further improve current treatments, we developed antimicrobial, thermoreversible hydrogels and evaluated their rheological properties, drug release, and antimicrobial activity. Because F127 hydrogels are not inherently antimicrobial, formulations were loaded with 0.3% or 0.5% w/v ciprofloxacin hydrochloride, a broad-spectrum antimicrobial agent. The addition of 5% w/w Pluronic F68 was also evaluated to tune the rheological and drug release characteristics. No changes were observed in viscosity, gelation temperature, or final gel storage modulus with the addition of ciprofloxacin hydrochloride, likely because of the small concentration. However, the addition of F68 increased the viscosity and gelation temperatures. The cumulative percent of drug released, determined using in-line diffusion cells, was similar for both concentrations of drug, but the 17% F127 formulations released more drug over the 24-hour study. Permeation studies using impaired, excised pig skin showed that small drug concentrations permeated through the impaired skin over time, with most of the drug retained in the skin. This result was desired because the antimicrobial agent is needed at the site of bacterial colonization, in this case the wounded skin. The antimicrobial activity of the formulations was tested against four bacterial pathogens commonly isolated from infected wounds in a well-diffusion study. The antimicrobial F127 formulations exhibited significantly greater zones of inhibited bacterial growth than commercially available controls for all four bacteria tested. This could improve current topical infection treatments through comparable or greater inhibitory action than available products. This work demonstrated the ability to develop sprayable, antimicrobial hydrogels with excellent drug retention in the skin and bacterial inhibition against common wound pathogens. Because Pluronic F127 has been widely researched for drug delivery purposes, multiple methods of drug-loading have been described. However, little work has been done to determine if the drug-loading method impacts Pluronic F127 properties. This is important because physical properties impact the gelation process and release of drugs from the hydrogels. Three different methods of loading 0% - 2% w/v diclofenac sodium into 15%, 17%, and 20% F127 Pluronic formulations were used, and the gelation temperature, dissolution over time, and micelle structure were determined. Storage modulus and gelation temperature were determined using rheology, and dissolution was measured as mass dissolved over time using two physiological buffers. Small-angle X-ray scattering was used to examine the structure of the formulations. Significant differences in storage moduli, gelation temperature, and dissolution after 4 hours were observed between methods. The small-angle X-ray scattering data also indicated differences in the micellar structure based on loading method. This improved understanding of how drug-loading method impacts the physical properties of F127 formulations is necessary for standardizing formulation processing and can be used to tune key properties including dissolution, gelation temperature, and gel stiffness. Overall in this work, antimicrobial and analgesic sprayable hydrogel formulations were developed for easy sprayability, gelation at skin temperature, controlled drug release, and good drug retention in the skin. As part of this work, new metrics and scripts were developed to better quantify the spray characteristics of topical sprays. This analysis can help guide formulation and spray device characteristics that result in desired spray patterns for appropriate skin coverage.

Development of sprayable thermoreversible hydrogels as a topical treatment for skin wounds

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