Exploring the Potent Combination of Quercetin-Boronic Acid, Epalrestat, and Urea Containing Nanoethosomal Keratolytic Gel for the Treatment of Diabetic Neuropathic Pain: In Vitro and In Vivo Studies

Transdermalpenetration of therapeutic moieties from topical dosageforms always remains a challenge due to the presence of permeationimpeding keratin which should be addressed. The purpose of the studywas to formulate quercetin and 4-formyl phenyl boronic acid (QB complex)used for the preparation of nanoethosomal keratolytic gel (EF3-G).The QB complex was confirmed by Fourier transform infrared spectroscopywhile skin permeation, viscosity, and epalrestat entrapment efficiencywere used for the optimization of nanoethosomal gel. The keratolyticeffect of the proposed nanoethosomal gel with urea (QB + EPL + U)was calculated in rat and snake skin. The spherical shape of nanoethosomeswas confirmed by scanning electron microscopy. According to the findingsof stability studies, viscosity decreases as temperature increases,proving their thermal stability. The negative charge of optimizedEF3 with 0.7 PDI proved narrow particle size distribution with homogeneity.Optimized EF3 showed two folds increase of epalrestat permeation inhighly keratinized snake skin as compared to rats' skin after24 h. Antioxidant behaviors of EF3 (QB) > QB complex > quercetin>ascorbic acid proved reduction of oxidative stress in DPPH reductionanalysis. Interestingly, the hot plate and cold allodynia test inthe diabetic neuropathic rat model reduced 3-fold pain as comparedto the diabetic control group which was further confirmed by in vivobiochemical studies even after the eight week. Conclusively, urealkeratolysis, primary dermal irritation index reduction, and improvedloading of epalrestat render the nanoethosomal gel (EF3-G) ideal forthe treatment of diabetic neuropathic pain.