Synthesis and assessment of a novel peptide conjugate to deliver phenytoin for wound repair

Crude preparations containing phenytoin, a medication used clinically as an anti-convulsant for epilepsy, have been shown to accelerate wound healing in both animals and humans. We hypothesized that a phenytoin-octa(l-arginine) conjugate, lysed in wound exudate would release phenytoin to produce improved healing while the arginine moiety would form nitric oxide inducing angiogenesis and cell proliferation. In addition, the expected increase in solubility of this new chemical entity would facilitate formulation and increase phenytoin availability at the receptor targets. Following synthesis of the conjugate molecule, its effect on Keratinocyte Growth Factor secretion by cultured human gingival fibroblasts was examined. Gel preparations containing phenytoin and the phenytoin-octa(l-arginine) conjugate were then applied to a diabetic wound model and wound healing parameters were measured. Results indicate that this novel compound demonstrates equivalent efficacy to phenytoin alone at a considerably lower phenytoin dose. The improved wound repair apparent here as well as the increased solubility give the phenytoin-octa(l-arginine) conjugate an advantage over previously examined phenytoin preparations.