Advanced Drug Delivery Group, Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Eur J Pharm Biopharm. 2022 Apr;173:132-140. doi: 10.1016/j.ejpb.2022.03.003. Epub 2022 Mar 18.
Although inhalation powder aerosols of antibiotics have been used to treat respiratory infections caused by Pseudomonas aeruginosa, biofilms are difficult to clear. Ciprofloxacin and D-amino acids (D-Met, D-Trp and D-Phe) were shown to facilitate P. aeruginosa biofilm removal. Spray dried powders for inhalation tend to be amorphous, hence unstable to moisture which causes deterioration in the aerosol performance. Hydrophobic L-amino acids such as leucine can impart moisture protection. In this study, we hypothesized that co-spray dried formulations of ciprofloxacin and hydrophobic D-amino acids will offer the combined benefits of both anti-biofilm and moisture protection properties. Of the three D-amino acids tested, D-Met and D-Trp (at 5 mM) but not D-Phe reduced clinical isolate P. aeruginosa biofilm loads and the extent of biofilm clearance was further enhanced in the presence of ciprofloxacin. Subsequently, ciprofloxacin was spray dried alone or in combination with 30% (w/w) D-Met or D-Trp. The biological and physicochemical properties of the powders were assessed, including the minimum inhibitory concentration, anti-biofilm activity, particle size distribution and morphology, solid-state properties, water sorption, and aerosol performance. The spray dried combination powders were physically stable and inhalable with fine particle fraction (<5 µm) values of 50-57% when aerosolized. The powders exhibited enhanced anti-biofilm activity compared with ciprofloxacin alone. The presence of D-amino acids provided moisture protection, with the recrystallization event shifting from 50% RH to 80% RH in powders containing D-Trp. In conclusion, the use of D-amino acids (D-Met or D-Trp) is an attractive formulation strategy which offers dual benefits of anti-biofilm effect and moisture protection.
虽然吸入式抗生素干粉气溶胶已被用于治疗铜绿假单胞菌引起的呼吸道感染，但生物膜很难清除。环丙沙星和 D-氨基酸（D-Met、D-Trp 和 D-Phe）被证明可以促进铜绿假单胞菌生物膜的去除。用于吸入的喷雾干燥粉末往往是无定形的，因此对水分不稳定，这会导致气溶胶性能恶化。疏水性 L-氨基酸，如亮氨酸，可以提供水分保护。在这项研究中，我们假设环丙沙星和疏水性 D-氨基酸的共喷雾干燥配方将提供抗生物膜和水分保护特性的双重益处。在测试的三种 D-氨基酸中，D-Met 和 D-Trp（5 mM）而不是 D-Phe 降低了临床分离株铜绿假单胞菌生物膜的负荷，并且在环丙沙星存在的情况下，生物膜的清除程度进一步增强。随后，环丙沙星单独或与 30%（w/w）D-Met 或 D-Trp 一起喷雾干燥。评估了粉末的生物学和物理化学性质，包括最小抑菌浓度、抗生物膜活性、粒度分布和形态、固态特性、水分吸附和气溶胶性能。喷雾干燥的组合粉末物理稳定，可吸入，当雾化时，细颗粒分数（<5 µm）值为 50-57%。与单独使用环丙沙星相比，这些粉末表现出增强的抗生物膜活性。D-氨基酸的存在提供了水分保护，在含有 D-Trp 的粉末中，再结晶事件从 50%RH 转移到 80%RH。总之，使用 D-氨基酸（D-Met 或 D-Trp）是一种有吸引力的配方策略，它提供了抗生物膜作用和水分保护的双重益处。
