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

Sharad Mangal, Heejun Park, Lingfei Zeng, Heidi H. Yu, Yu-wei Lin, Tony Velkov, John A. Denman, Dmitry Zemlyanov, Jian Li, Qi (Tony) Zhou

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)443-453
Number of pages11
JournalInternational Journal of Pharmaceutics
Volume548
Issue number1
DOIs
Publication statusPublished - 5 Sep 2018

Keywords

  • Aerosol performance
  • Antimicrobial synergy
  • Colistin
  • Dry powder inhaler
  • Meropenem
  • Spray drying

Cite this

Mangal, Sharad ; Park, Heejun ; Zeng, Lingfei ; Yu, Heidi H. ; Lin, Yu-wei ; Velkov, Tony ; Denman, John A. ; Zemlyanov, Dmitry ; Li, Jian ; Zhou, Qi (Tony). / Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation. In: International Journal of Pharmaceutics. 2018 ; Vol. 548, No. 1. pp. 443-453.
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abstract = "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.",
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author = "Sharad Mangal and Heejun Park and Lingfei Zeng and Yu, {Heidi H.} and Yu-wei Lin and Tony Velkov and Denman, {John A.} and Dmitry Zemlyanov and Jian Li and Zhou, {Qi (Tony)}",
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Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation. / Mangal, Sharad; Park, Heejun; Zeng, Lingfei; Yu, Heidi H.; Lin, Yu-wei; Velkov, Tony; Denman, John A.; Zemlyanov, Dmitry; Li, Jian; Zhou, Qi (Tony).

In: International Journal of Pharmaceutics, Vol. 548, No. 1, 05.09.2018, p. 443-453.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Mangal, Sharad

AU - Park, Heejun

AU - Zeng, Lingfei

AU - Yu, Heidi H.

AU - Lin, Yu-wei

AU - Velkov, Tony

AU - Denman, John A.

AU - Zemlyanov, Dmitry

AU - Li, Jian

AU - Zhou, Qi (Tony)

PY - 2018/9/5

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N2 - 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.

AB - 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.

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KW - Dry powder inhaler

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