Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, 66123 Saarbrücken, Germany.
Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus C4 1, 66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Campus E8 1, 66123 Saarbrücken, Germany.
Eur J Pharm Biopharm. 2020 Dec;157:200-210. doi: 10.1016/j.ejpb.2020.10.010. Epub 2020 Oct 24.
Nowadays, the resistance of bacterial biofilms towards the available antibiotics is a severe problem. Therefore, many efforts were devoted to develop new formulations using nanotechnology. We have developed an inhalable microparticle formulation using spray-drying combining multiple drugs: an antibiotic (tobramycin, ciprofloxacin or azithromycin), N-acetylcysteine (NAC), and curcumin (Cur). The use of PLGA nanoparticles (NP) also allowed incorporating curcumin to facilitate spray drying and modify the release of some compounds. The aerosolizable microparticles formulations were characterized in terms of size, morphology, and aerodynamic properties. Biocompatibility when tested on macrophage-like cells was acceptable after 20 h exposure for concentrations up to at least 32 µg/mL. Antibacterial activity of free drugs versus drugs in the multiple drug formulations was evaluated on P. aeruginosa in the same range. When co-delivered the efficacy of tobramycin was enhanced compared to the free drug for the 1 µg/mL concentration. The combinations of azithromycin and ciprofloxacin with NAC and Cur did not show an improved antibacterial activity. Bacteria-triggered cytokine release was not inhibited by free antibiotics, except for TNF-α. In contrast, the application of NAC and the addition of curcumin-loaded PLGA NPs showed a higher potential to inhibit TNF-α, IL-8, and IL-1β release. Overall, the approach described here allows simultaneous delivery of antibacterial, mucolytic, and anti-inflammatory compounds in a single inhalable formulation and may therefore pave the way for a more efficient therapy of pulmonary infections.
如今，细菌生物膜对现有抗生素的耐药性是一个严重的问题。因此，人们投入了大量的努力来开发使用纳米技术的新配方。我们开发了一种使用喷雾干燥法制备的可吸入微颗粒制剂，该方法结合了多种药物：抗生素（妥布霉素、环丙沙星或阿奇霉素）、N-乙酰半胱氨酸（NAC）和姜黄素（Cur）。PLGA 纳米颗粒（NP）的使用还允许姜黄素的掺入，以促进喷雾干燥并改变某些化合物的释放。可吸入微颗粒制剂的特性包括粒径、形态和空气动力学特性。在巨噬细胞样细胞中进行的生物相容性测试表明，在 20 小时内，浓度高达至少 32μg/ml 时，其具有可接受的生物相容性。在相同范围内，评估了游离药物与多药物制剂中的药物对铜绿假单胞菌的抗菌活性。当联合给药时，与游离药物相比，1μg/ml 浓度下妥布霉素的疗效增强。与 NAC 和 Cur 联合使用的阿奇霉素和环丙沙星并没有显示出增强的抗菌活性。游离抗生素除 TNF-α 外，不能抑制细菌触发的细胞因子释放。相比之下，NAC 的应用和载有姜黄素的 PLGA NP 的添加显示出更高的抑制 TNF-α、IL-8 和 IL-1β 释放的潜力。总的来说，这里描述的方法允许在单一可吸入制剂中同时递送抗菌、黏液溶解和抗炎化合物，因此可能为肺部感染的更有效治疗铺平道路。
