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Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections

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Abstract

Purpose

The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy.

Methods

Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus.

Results

Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 μm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 μg/cm2 of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria.

Conclusions

The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.

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Abbreviations

Blank-MP:

Blank microparticles

CLARI:

Clarithromycin

CLARI-MP:

Clarithromycin microparticles

DPI:

Dry powder inhalers

DSC:

Differential scanning calorimetry

ED:

Emitted dose

FPF:

Fine particle fraction

IS:

Internal standard

LC-MS/MS:

Liquid chromatography - tandem mass spectrometry

MIC:

Minimal inhibitory concentration

MMAD:

Mass median aerodynamic diameter

NGI:

Next-generation pharmaceutical impactor

PADDOCC:

Pharmaceutical aerosol deposition device on cell cultures

PM:

Physical mixture

RI:

Respiratory infection

SEM:

Scanning electron microscopy

TEER:

Transepithelial electrical resistance

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ACKNOWLEDGMENTS AND DISCLOSURES

Frantiescoli Dimer is thankful to the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) program “Ciência sem Fronteiras” project number BEX 18215/12-2. The authors kindly thank Simone Amann for bacteria experiments, Marius Hittinger for NGI and PADDOCC experiments and Dr. Chiara Rossi for technical support of LC-MS/MS and SEM analysis.

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Authors and Affiliations

  1. Department of Drug Delivery (DDEL), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, 66123, Saarbrücken, Germany

    Frantiescoli Dimer, Cristiane de Souza Carvalho-Wodarz & Claus-Michael Lehr

  2. Department of Drug Development and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, 66123, Saarbrücken, Germany

    Jörg Haupenthal & Rolf Hartmann

  3. Biopharmacy and Pharmaceutical Technology, Department of Pharmacy, Saarland University, Saarbrücken, 66123, Germany

    Claus-Michael Lehr

  4. Pharmaceutical and Medical Chemistry, Campus C2.3, Saarland University, 66123, Saarbrücken, Germany

    Rolf Hartmann

Authors
  1. Frantiescoli Dimer
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  2. Cristiane de Souza Carvalho-Wodarz
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  3. Jörg Haupenthal
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  5. Claus-Michael Lehr
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Corresponding author

Correspondence to Claus-Michael Lehr.

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Fig S1

Scanning electron micrograph of Clarithromycin raw material. (JPEG 416 kb)

High Resolution Image (TIFF 793 kb)

Fig S2

Bacteria growth after 18 h of treatment with microparticles without clarithromycin (BLANK-MP), clarithromycin solution (CLARI) and clarithromycin microparticles (CLARI-MP) compared to CONTROL against P. aeruginosa (A), E. coli (B) and S. aureus (C). The percentage was calculated from final experiment optical density subtracted from initial optical density compared to CONTROL. The data show 3 independent experiments (means ± SD). * Different from CONTROL: p < 0.05; ** Different from CONTROL: p < 0.01; *** Different from CONTROL: p < 0.001; ### Different from CLARI: p < 0.001. (JPEG 325 kb)

High Resolution Image (TIFF 1.60 mb)

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Dimer, F., de Souza Carvalho-Wodarz, C., Haupenthal, J. et al. Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections. Pharm Res 32, 3850–3861 (2015). https://doi.org/10.1007/s11095-015-1745-8

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  • DOI: https://doi.org/10.1007/s11095-015-1745-8

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