Pharmaceutical Research

, Volume 32, Issue 12, pp 3850–3861 | Cite as

Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections

  • Frantiescoli Dimer
  • Cristiane de Souza Carvalho-Wodarz
  • Jörg Haupenthal
  • Rolf Hartmann
  • Claus-Michael Lehr
Research Paper



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.


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.


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.


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.


aerosol dry powder inhaler lung infection safety 



Blank microparticles




Clarithromycin microparticles


Dry powder inhalers


Differential scanning calorimetry


Emitted dose


Fine particle fraction


Internal standard


Liquid chromatography - tandem mass spectrometry


Minimal inhibitory concentration


Mass median aerodynamic diameter


Next-generation pharmaceutical impactor


Pharmaceutical aerosol deposition device on cell cultures


Physical mixture


Respiratory infection


Scanning electron microscopy


Transepithelial electrical resistance



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.

Supplementary material

11095_2015_1745_Fig7_ESM.jpg (417 kb)
Fig S1

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

11095_2015_1745_MOESM1_ESM.tif (793 kb)
High Resolution Image (TIFF 793 kb)
11095_2015_1745_Fig8_ESM.jpg (325 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)

11095_2015_1745_MOESM2_ESM.tiff (1.6 mb)
High Resolution Image (TIFF 1.60 mb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Frantiescoli Dimer
    • 1
  • Cristiane de Souza Carvalho-Wodarz
    • 1
  • Jörg Haupenthal
    • 2
  • Rolf Hartmann
    • 2
    • 4
  • Claus-Michael Lehr
    • 1
    • 3
  1. 1.Department of Drug Delivery (DDEL), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI)Saarland UniversitySaarbrückenGermany
  2. 2.Department of Drug Development and Optimization (DDOP), Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI)Saarland UniversitySaarbrückenGermany
  3. 3.Biopharmacy and Pharmaceutical Technology, Department of PharmacySaarland UniversitySaarbrückenGermany
  4. 4.Pharmaceutical and Medical Chemistry, Campus C2.3Saarland UniversitySaarbrückenGermany

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