School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK; Fakultas Farmasi, Universitas Megarezky, Jl. Antang Raya No. 43, Makassar 90234, Indonesia.
School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
Biomater Adv. 2022 Sep;140:213073. doi: 10.1016/j.bioadv.2022.213073. Epub 2022 Aug 9.
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. 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.
脆弱拟杆菌是与皮肤和软组织感染（SSTI）相关的最常见微生物致病群之一。甲硝唑（MTZ）是治疗由该细菌引起的 SSTI 的首选药物。然而，由于其物理化学性质，MTZ 皮肤渗透有限，因此不适合治疗根深蒂固的 SSTI。克服这一限制的一种策略是将 MTZ 重新配方为纳米混悬剂，然后将其装载到溶解微阵列贴剂（MAP）中，用于治疗由脆弱拟杆菌引起的 SSTI。在此，我们首次报道了载有 MTZ 纳米混悬剂（MTZ-NS）的 MAP 的制备和优化。在筛选了一系列聚合物表面活性剂后，我们发现 Soluplus®可形成粒径最小（115nm）且 PDI 为 0.27 的 MTZ-NS。接下来，使用实验设计（DoE）方法进一步优化 MTZ-NS。然后将优化后的 MTZ-NS 加载到具有不同 MTZ-NS 含量的溶解 MAP 中。此外，3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴化物（MTT）和细胞增殖测定以及 3T3L1 细胞系上的 LIVE/DEAD™染色表明，载有 MTZ-NS 的溶解 MAP 显示出最小的毒性和可接受的生物相容性。体外皮肤药代动力学研究表明，MTZ-NS 负载的 MAP 能够将硝基咪唑抗生素递送到皮肤的所有层，在 24 小时渗透研究后递送效率达到 95%。最后，使用脆弱拟杆菌的细菌培养物进行琼脂平板测定，结果表明，与对照组相比，载有 MTZ-NS 的 MAP 导致整个平板完全抑制细菌。如果这种制剂转化为临床实践，这种药物方法可能为治疗由脆弱拟杆菌引起的 SSTI 提供一种微创策略。
