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

Abstract

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.

• Authors: G Costabile, I d'Angelo, R d'Emmanuele di Villa Bianca, E Mitidieri, B Pompili, P Del Porto, L Leoni, P Visca, A Miro, F Quaglia, F Imperi, R Sorrentino, F Ungaro
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 238 Pg. 80-91 (09 28 2016) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 27449745 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Aerosols
• Anti-Bacterial Agents
• Antifungal Agents
• Powders
• Mannitol
• Hyaluronic Acid
• Flucytosine

Topics

• Administration, Inhalation
• Aerosols (chemistry)
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics, pharmacology)
• Antifungal Agents (administration & dosage, pharmacokinetics, pharmacology)
• Candida albicans (drug effects)
• Candidiasis (drug therapy)
• Drug Repositioning
• Dry Powder Inhalers
• Flucytosine (administration & dosage, pharmacokinetics, pharmacology)
• Humans
• Hyaluronic Acid (chemistry)
• Lung (microbiology)
• Lung Diseases, Fungal (drug therapy)
• Male
• Mannitol (chemistry)
• Particle Size
• Powders
• Pseudomonas Infections (drug therapy)
• Pseudomonas aeruginosa (drug effects)
• Rats, Wistar