Promising nanoparticulate system for topical delivery of diphenhydramine hydrochloride: In-vitro and in-vivo evaluation

Abstract

Diphenhydramine hydrochloride is a potent antihistaminic drug; its oral administration often leads to attention disturbance, CNS or anticholinergic adverse effects as dry mouth resulting in a less patient compliance with the therapy. The aim of the current study was to prepare diphenhydramine hydrochloride loaded nanoparticulate system, using chitosan as a natural polymer for topical application. Eight formulae were prepared adopting 23 factorial design. Diphenhydramine hydrochloride loaded nanoparticles were prepared by ionic gelation technique using chitosan and sodium tripolyphosphate (TPP). The formulae were evaluated regarding TEM, entrapment efficiency, particle size, zeta potential, in-vitro release, DSC, XRD, kinetics study, and in-vivo study regarding skin irritation test and histopathological examination using rats. The results revealed that the entrapment efficiency was significantly increased when increasing the chitosan concentration, the drug to polymer ratio and the chitosan to TPP (w/w) ratio. The particle size was significantly increased when increasing the chitosan concentration, the drug to polymer ratio but significantly decreased when increasing the chitosan to TPP (w/w) ratio. The zeta potential was significantly increased by increasing the chitosan concentration, the drug to polymer ratio and the chitosan to TPP (w/w) ratio. The in-vitro release study showed prolongation of drug release up to 6hrs. A comparison was made between the candidate formula (F8) (0.375% of diphenhydramine hydrochloride, drug to polymer 1:2, chitosan concentration 0.75% and chitosan to TPP (w/w) 5:1) and the marketed gel. The skin irritation test of F8 revealed its dermal safety and the statistical analysis revealed significant increase in its antihistaminic activity with reduction in the wheal area (from 150 mm2 ± 7.8 to 43.6 mm2 ± 4.9) when compared to the marketed gel (from 155 mm2 ± 6.1 to 82.1 mm2 ± 8.54). A value of r = 0.97704 suggested a good correlation between the in vitro-in vivo data of the candidate formula. The results revealed that the developed nanoparticles could have a potential for topical delivery of diphenhydramine hydrochloride.