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Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections

Costabile, G. ; d'Angelo, I. ; d'Emmanuele di Villa Bianca, R. ; Mitidieri, E. ; Pompili, B. ; Del Porto, P. ; Leoni, L. ; Visca, P. ; Miro, A. ; Quaglia, F. ; Imperi, F. ; Sorrentino, R. ; Ungaro, F.

Journal of controlled release, 2016-09, Vol.238, p.80-91 [Periódico revisado por pares]

Netherlands: Elsevier B.V

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Título:
Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections
Autor: Costabile, G. ; d'Angelo, I. ; d'Emmanuele di Villa Bianca, R. ; Mitidieri, E. ; Pompili, B. ; Del Porto, P. ; Leoni, L. ; Visca, P. ; Miro, A. ; Quaglia, F. ; Imperi, F. ; Sorrentino, R. ; Ungaro, F.
Assuntos: Administration, Inhalation ; Aerosols - chemistry ; Animals ; Anti-Bacterial Agents - administration & dosage ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Antifungal Agents - administration & dosage ; Antifungal Agents - pharmacokinetics ; Antifungal Agents - pharmacology ; Candida albicans ; Candida albicans - drug effects ; Candidiasis - drug therapy ; Drug Repositioning ; Dry Powder Inhalers ; Flucytosine ; Flucytosine - administration & dosage ; Flucytosine - pharmacokinetics ; Flucytosine - pharmacology ; Humans ; Hyaluronic acid ; Hyaluronic Acid - chemistry ; Inhalable powder ; Lung - microbiology ; Lung delivery ; Lung Diseases, Fungal - drug therapy ; Male ; Mannitol - chemistry ; Particle Size ; Powders ; Pseudomonas aeruginosa ; Pseudomonas aeruginosa - drug effects ; Pseudomonas Infections - drug therapy ; Rats, Wistar
É parte de: Journal of controlled release, 2016-09, Vol.238, p.80-91
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Flucytosine (5-fluorocytosine, 5-FC) is a fluorinated analogue of cytosine currently approved for the systemic treatment of fungal infections, which has recently demonstrated a very promising antivirulence activity against the bacterial pathogen Pseudomonas aeruginosa. In this work, we propose novel inhalable hyaluronic acid (HA)/mannitol composite dry powders for repositioning 5-FC in the local treatment of lung infections, including those affecting cystic fibrosis (CF) patients. Different dry powders were produced in one-step by spray-drying. Powder composition and process conditions were selected after in depth formulation studies aimed at selecting the 5-FC/HA/mannitol formulation with convenient aerosolization properties and drug release profile in simulated lung fluids. The optimized 5-FC/HA/mannitol powder for inhalation (HyaMan_FC#3) was effectively delivered from different breath-activated dry powder inhalers (DPI) already available to CF patients. Nevertheless, the aerodynamic assessment of fine particles suggested that the developed formulation well fit with a low-resistance DPI. HyaMan_FC#3 inhibited the growth of the fungus Candida albicans and the production of the virulence factor pyoverdine by P. aeruginosa at 5-FC concentrations that did not affect the viability of both wild type (16HBE14o-) and CF (CFBE41o-) human bronchial epithelial cells. Finally, pharmacokinetics of HyaMan_FC#3 inhalation powder and 5-FC solution after intratracheal administration in rats were compared. In vivo results clearly demonstrated that, when formulated as dry powder, 5-FC levels in both bronchoalveolar lavage fluid and lung tissue were significantly higher and sustained over time as compared to those obtained with the 5-FC solution. Of note, when the same 5-FC amount was administered intravenously, no significant drug amount was found in the lung at each time point from the injection. To realize a 5-FC lung concentration similar to that obtained by using HyaMan_FC#3, a 6-fold higher dose of 5-FC should be administered intravenously. Taken together, our data demonstrate the feasibility to deliver 5-FC by the pulmonary route likely avoiding/reducing the well-known side effects associated to the high systemic 5-FC doses currently used in humans. Furthermore, our results highlight that an appropriate formulation design can improve the persistence of the drug at lungs, where microorganisms causing severe infections are located. [Display omitted]
Editor: Netherlands: Elsevier B.V
Idioma: Inglês

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Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections

Costabile, G. ; d'Angelo, I. ; d'Emmanuele di Villa Bianca, R. ; Mitidieri, E. ; Pompili, B. ; Del Porto, P. ; Leoni, L. ; Visca, P. ; Miro, A. ; Quaglia, F. ; Imperi, F. ; Sorrentino, R. ; Ungaro, F.

Netherlands: Elsevier B.V

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