Advanced Drug Delivery Group, School of Pharmacy, University of Sydney, Sydney, NSW, Australia.
Centenary Institute and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Eur J Pharm Biopharm. 2019 Sep;142:543-552. doi: 10.1016/j.ejpb.2019.08.004. Epub 2019 Aug 6.
Recently we showed that nebulized ciprofloxacin and phage PEV20 in combination had a synergistic bactericidal effect against antibiotic-resistant Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Compared to nebulization, dry powders for inhalation may improve patient handling characteristics and compliance. In the present study, we co-spray dried ciprofloxacin and phage PEV20 using L-leucine with or without lactose as excipients. Two formulations were identified for testing in this study. The mass ratios were set at 1:1:1 for ciprofloxacin, lactose and L-leucine (Formulation A) or 2:1 for ciprofloxacin and L-leucine without lactose (Formulation B). Concentrations of PEV20 were set at 10 and 10 PFU/mL for two clinical P. aeruginosa strains FADD1-PA001 and JIP865, respectively. Formulations A and B were characterized as partially crystalline and the powders recrystallized at >40% relative humidity (RH). Both formulations exhibited strong synergistic antimicrobial killing effect on the two strains. Formulations A and B maintained bactericidal synergy after dispersion using both low and high resistance Osmohaler™. Powder aerosol performance was examined by next generation impactor (NGI) in low resistance inhaler at 100 L/min and by multi-stage liquid impinger (MSLI) in high resistance inhaler at 60 L/min. Fine particle fractions (FPF) obtained by NGI were 59.7 ± 2.1% and 64.3 ± 2.9% for A and B, respectively. FPF obtained by MSLI were 71.0 ± 3.4% and 73.3 ± 5.0%, respectively. In conclusion, it is feasible to prepare stable and inhalable combination powder formulations of phage PEV20 and ciprofloxacin for potential treatment of respiratory infections caused by multi-drug resistant (MDR) P. aeruginosa.
最近，我们发现雾化环丙沙星和噬菌体 PEV20 联合使用对来自囊性纤维化患者的耐抗生素铜绿假单胞菌分离株具有协同杀菌作用。与雾化相比，干粉吸入剂可能会改善患者的处理特性和顺应性。在本研究中，我们使用 L-亮氨酸将喷雾干燥的环丙沙星和噬菌体 PEV20 共喷雾干燥，同时使用或不使用乳糖作为赋形剂。确定了两种配方进行本研究测试。环丙沙星、乳糖和 L-亮氨酸的质量比设定为 1:1:1（配方 A）或 2:1 且不含乳糖（配方 B）。噬菌体 PEV20 的浓度设定为两种临床铜绿假单胞菌菌株 FADD1-PA001 和 JIP865 的 10 和 10 PFU/mL。配方 A 和 B 被鉴定为部分结晶，粉末在 >40%相对湿度 (RH) 下再结晶。两种配方对两种菌株均表现出强烈的协同抗菌杀菌作用。在使用低和高阻力 Osmohaler™ 分散后，配方 A 和 B 均保持杀菌协同作用。通过下一代撞击器 (NGI) 在低阻力吸入器中以 100 L/min 以及通过多阶段液体撞击器 (MSLI) 在高阻力吸入器中以 60 L/min 检查粉末气溶胶性能。NGI 获得的细颗粒分数 (FPF) 分别为 59.7±2.1%和 64.3±2.9%，配方 A 和 B。MSLI 获得的 FPF 分别为 71.0±3.4%和 73.3±5.0%。总之，制备稳定且可吸入的噬菌体 PEV20 和环丙沙星联合干粉制剂用于治疗多药耐药 (MDR) 铜绿假单胞菌引起的呼吸道感染是可行的。
