Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation

• Published in: International journal of pharmaceutics Vol. 548; no. 1; pp. 443 - 453
• Main Authors: Mangal, Sharad, Park, Heejun, Zeng, Lingfei, Yu, Heidi H., Lin, Yu-wei, Velkov, Tony, Denman, John A., Zemlyanov, Dmitry, Li, Jian, Zhou, Qi (Tony)
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05-09-2018
• Subjects: Acinetobacter baumannii - drug effects; Acinetobacter baumannii - growth & development; Administration, Inhalation; Aerosol performance; Aerosols; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - chemistry; Antimicrobial synergy; Colistin; Colistin - administration & dosage; Colistin - chemistry; Drug Synergism; Dry powder inhaler; Meropenem; Particle Size; Porosity; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - growth & development; Spray drying; Surface Properties; Thienamycins - administration & dosage; Thienamycins - chemistry; Dry powder inhaler; Antimicrobial synergy; Spray drying; Aerosol performance; Meropenem; Colistin
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2018.07.010

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Antibiotic combination therapy is promising for the treatment of lower respiratory tract infections caused by multi-drug resistant Gram-negative pathogens. Inhaled antibiotic therapy offers the advantage of direct delivery of the drugs to the site of infection, as compared to the parenteral administrations. In this study, we developed composite particle formulations of colistin and meropenem. The formulations were characterized for particle size, morphology, specific surface area, surface chemical composition, in-vitro aerosolization performance and in-vitro antibacterial activity. The combinations demonstrated enhanced antibacterial activity against clinical isolates of Acinetobacter baumannii N16870 and Pseudomonas aeruginosa 19147, when compared with antibiotic monotherapy. Spray-dried meropenem alone showed a poor aerosolization performance as indicated by a low fine particle fraction (FPF) of 32.5 ± 3.3%. Co-spraying with colistin improved the aerosolization of meropenem with up to a two-fold increase in the FPF. Such improvements in aerosolization can be attributed to the enrichment of colistin on the surface of composite particles as indicated by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), and the increases in particle porosity. Intermolecular interactions between colistin and meropenem were observed for the combination formulations as measured by FT-IR. In conclusion, our results show that co-spray drying with colistin improves the antibacterial activity and aerosol performance of meropenem and produces a formulation with synergistic bacterial killing.