Metronidazole nanosuspension loaded dissolving microarray patches: An engineered composite pharmaceutical system for the treatment of skin and soft tissue infection

Bacteroides fragilis is one of the most common causative group of microorganisms that is associated with skin and soft tissue infections (SSTI). Metronidazole (MTZ) is the drug of choice used in the treatment of SSTI caused by the bacterium. However, owing to its physiochemical properties, MTZ have limited skin permeation, which render the drug unsuitable for the treatment of deep-rooted SSTIs. One strategy to overcome this limitation is to reformulate MTZ into nanosuspension which will then be loaded into dissolving microarray patches (MAPs) for the treatment of SSTIs caused by B. fragilis. Herein, we report for the first time on the preparation and optimisation of MAP loaded with MTZ nanosuspension (MTZ-NS). After screening a range of polymeric surfactants, we identified that Soluplus® resulted in the formation of MTZ-NS with the smallest particle size (115 nm) and a narrow PDI of 0.27.

Highlights

• Metronidazole was formulated into nanosuspension and optimised using a design of experiments (DoE) approach

• The optimised formulation of metronidazole nanosuspension (MTZ-NS) was loaded into dissolving microarray patches (MAPs)

• The MTZ-NS loaded dissolving MAPs displayed minimal toxicity and acceptable biocompatibility

• MTZ-NS loaded MAPs were able to deliver MTZ across the skin with delivery efficiency of 95% after 24-hour permeation study

Next, the MTZ-NS was further optimised using a design of experiments (DoE) approach. The optimised MTZ-NS was then loaded into dissolving MAPs with varying MTZ-NS content. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell proliferation assays along with LIVE/DEAD™ staining on the 3T3L1 cell line showed that the MTZ-NS loaded dissolving MAPs displayed minimal toxicity and acceptable biocompatibility. In vitro dermatokinetic studies showed that the MTZ-NS loaded MAPs were able to deliver the nitroimidazole antibiotic across all strata of the skin resulting in a delivery efficiency of 95 % after a 24-hour permeation study. Lastly, agar plating assay using bacterial cultures of B. fragilis demonstrated that MTZ-NS loaded MAP resulted in complete bacterial inhibition in the entire plate relative to the control group. Should this formulation be translated into clinical practice, this pharmaceutical approach may provide a minimally invasive strategy to treat SSTIs caused by B. fragilis.

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Materials

2-Methyl-5-nitroimidazole-1-ethanol (purity, >99 %) was purchased from Alfa Aesar (Lancashire, UK). Tween® 80 was procured from Tokyo Chemical Industry (Oxford, UK). Soluplus®, Lutrol® F108 and Pluronic® F88 Pastille were kindly supplied by BASF (Ludwigshafen, Germany). PVP 90 kDa was supplied by Ashland (Kidderminster, UK). Ultrapure water used in the work was obtained from Elga PURELAB DV 25 purification system, (Veolia Water Systems, Dublin, Ireland). The remaining materials were of analytical grade and procured from Sigma-Aldrich (Dorset, UK) or Fisher Scientific (Loughborough, UK). Bacteroides fragilis NCTC 9343 (National Collection of Type Cultures, Salisbury, UK) was maintained in Brain Heart Infusion (BHI) broth with 15 % glycerol at −80 °C and cultivated in BHI broth at 37 °C for 48 h when required for the microbiological assessments. Full-thickness neonatal porcine skins were obtained from stillborn piglets within 24 h post-mortem and stored at −20 °C until use.

Qonita Kurnia Anjani, Akmal Hidayat Bin Sabri, Juan Domínguez-Robles, Natalia Moreno-Castellanos, Emilia Utomo, Luki Ahmadi Hari Wardoyo, Eneko Larrañeta, Ryan F. Donnelly, Metronidazole nanosuspension loaded dissolving microarray patches: An engineered composite pharmaceutical system for the treatment of skin and soft tissue infection, Biomaterials Advances, Volume 140, 2022, 213073, ISSN 2772-9508, https://doi.org/10.1016/j.bioadv.2022.213073