期刊
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
卷 142, 期 -, 页码 543-552出版社
ELSEVIER
DOI: 10.1016/j.ejpb.2019.08.004
关键词
Ciprofloxacin; Bacteriophages; Pseudomonas aeruginosa; Respiratory infection; Spray drying; Cystic fibrosis; Inhalation; L-leucine; Powder formulation
资金
- National Institute of Allergy and Infectious Disease of the National Institutes of Health [R33 AI121627]
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(8) and 10(9) 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 (TM). 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.
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