Abstract

Background: Uncomplicated skin and soft tissue infections account for approximately 200 million visits to ambulatory care settings annually. Linezolid (LNZ) is an oxazolidinone that has proven its effectiveness in combating skin and soft tissue infections caused by gram-positive pathogens. LNZ is administered via oral suspension, tablets, or an intravenous route in most instances. However, its extended therapy leads to undesirable side effects like diarrhoea, thrombocytopenia, myelosuppression, lactic acidosis, etc. and even life-threatening complications. The dermal administration of LNZ offers an alternative route, ensuring localized and sustained release at the site of infection. This approach may reduce systemic exposure and allow for lower doses compared to oral ingestion, which can decrease the risk of adverse effects.

Objectives: This research aimed to develop a nanostructured lipid carrier (NLC)-based gel for delivering LNZ via the dermal route to treat uncomplicated skin and soft tissue infections.

Methods: NLC were developed by high-shear homogenisation and sonication method using glyceryl trimyristate as a solid lipid and neem oil as a liquid lipid. The Taguchi design was employed to optimize NLCs using surfactant concentration (mg), drug-to-lipid ratio, and sonication time (sec) as independent variables. Their effect on particle size, zeta potential, and entrapment efficiency was studied. The optimized nanocarriers were developed into a gel product and evaluated for drug release, permeation, and antibacterial activity.

Results: The optimised process parameters to attain outcomes were 2% surfactant, 1:1 drug-tolipid ratio and 300 seconds of sonication. The resulting NLC had an average size of 191.2 ± 2.76 nm, a zeta potential of -30.7 ± 4.50 mV, and 84.89 ± 2.76% drug entrapment. NLC-based gel displayed anomalous transport with a 90.16 % drug release. The gel showed a strong antibacterial effect against Staphylococcus aureus with a 7.57 ± 0.12 cm mean zone of inhibition. Ex-vivo skin permeation studies revealed 24.19 ± 0.19 % drug permeation and 64.46 ± 0.58% cutaneous deposition. NLC-based gel demonstrated a significant decrease in colony-forming units in infected animal models.

Conclusion: The ex-vivo investigations demonstrated the presence of LNZ at the infection site, enhancing therapeutic effectiveness. In vitro and in-vivo findings illustrated the substantial antibacterial efficacy of LNZ NLC-based gel. The adoption of NLC-based gel exhibits promising potential as a carrier for dermal delivery of LNZ.

Keywords: Nanostructured lipid carrier, linezolid, skin and soft tissue infection, dermal delivery, Taguchi design, tape-stripped skin infection model.

Graphical Abstract