Dry powder inhalers of gentamicin and leucine: formulation parameters, aerosol performance and in vitro toxicity on CuFi1 cells.
The high hygroscopicity of gentamicin (G) as raw material hampers the production of respirable particles during aerosol generation and prevents its direct use as powder for inhalation in patients suffering from cystic fibrosis (CF). Therefore, this research aimed to design a new dry powder formulation of G studying dispersibility properties of an aminoacid, L-leucine (leu), and appropriate process conditions. Spray-dried powders were characterized as to water uptake, particle size distribution, morphology and stability, in correlation with process parameters. Aerodynamic properties were analyzed both by Single Stage Glass Impinger and Andersen Cascade Impactor. Moreover, the potential cytotoxicity on bronchial epithelial cells bearing a CFTR F508/F508 mutant genotype (CuFi1) were tested. Results indicated that leu may improve the aerosol performance of G-dried powders. The maximum fine particle fraction (FPF) of about 58.3% was obtained when water/isopropyl alcohol 7:3 system and 15-20% (w/w) of leu were used, compared to a FPF value of 13.4% for neat G-dried powders. The enhancement of aerosol efficiency was credited both to the improvement of the powder flowability, caused by the dispersibility enhancer (aminoacid), and to the modification of the particle surface due to the influence of the organic co-solvent on drying process. No significant degradation of the dry powder was observed up to 6 months of storage. Moreover, particle engineering did not affect either the cell viability or cell proliferation of CuFi1 over a 24 h period.
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy.
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Aquino
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy.
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Prota
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy.
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Auriemma
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy.
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Santoro
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy.
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Mencherini
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
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Colombo
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo Invariate 7, 84084 Fisciano (SA), Italy. Electronic address: paorusso@unisa.it.
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Russo
D019840:2-Propanol / Q000737:chemistry; D000280:Administration, Inhalation; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004355:Drug Stability; D058995:Dry Powder Inhalers; D005079:Excipients / Q000737:chemistry* / Q000633:toxicity*; D005839:Gentamicins / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D007930:Leucine / Q000737:chemistry* / Q000633:toxicity*; D009154:Mutation; D010316:Particle Size; D011208:Powders; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018570:Risk Assessment; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D014867:Water / Q000737:chemistry
D000336:Aerosols; D000900:Anti-Bacterial Agents; C505032:CFTR protein, human; D005079:Excipients; D005839:Gentamicins; D011208:Powders; D012997:Solvents; D014867:Water; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007930:Leucine; D019840:2-Propanol