Optimization, characterization and in vivo evaluation of mupirocin nanocrystals for topical administration

Abstract

Treatment of infectious skin conditions resulting from wounds and burns with topical antibiotics is challenging, particularly those caused by methicillin-resistant Staphylococcus aureus bacteria (MRSA). This is due to the formation of bacterial biofilms characterized by antimicrobial resistance. Mupirocin (MP), a widely used topical antibiotic, is active against gram-positive bacteria including MRSA. However, MP suffers from sub-optimal therapeutic efficacy due to its poor water-solubility and the significant rise in MP-resistant S. aureus. In this study, the physico-chemical characteristics of MP were modified through nanocrystallization to improve its therapeutic efficacy for the treatment of skin infections. Mupirocin-nanocrystals (MP-NC) were prepared using a nanoprecipitation technique and optimized using a D-optimal response surface design. The optimization of MP-NC produced ultra-small monodisperse spherical particles with a mean diameter of 70 nm and a polydispersity index of 0.2. The design resulted in two optimal MP-NC formulations that were evaluated by performing series of in vitro, ex vivo, microbiological, and in vivo studies. In-vitro results showed a 10-fold increase in the saturation solubility and a 9-fold increase in the dissolution rate of MP-NC. Ex vivo permeation studies, using pig ears skin, showed a 2-fold increase in the dermal deposition of MP-NC with the highest drug deposition occurring at 500-µm skin depth. Moreover, the optimal MP-NC formulations were lyophilized and incorporated into a 2% w/w cream. Microbiological studies revealed a 16-fold decrease in the minimum inhibitory concentration and the minimum bactericidal concentration of MP-NC. In vivo studies, using a rat excision burn wound model, demonstrated rapid and complete healing of infected burn wounds in rats treated with MP-NC cream in comparison to marketed Avoban ointment. Our results suggest that nanocrystallization of MP may provide an avenue through which higher levels of a topically applied MP can be permeated into the skin to reach relevant infectious areas and exert potential local antibacterial effects.