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

详细信息    查看全文

• 作者：G. Costabile^a ; I. d'Angelo^b ; R. d'Emmanuele di Villa Bianca^c ; E. Mitidieri^c ; B. Pompili^d ; P. Del Porto^d ; L. Leoni^e ; P. Visca^e ; A. Miro^a ; F. Quaglia^a ; F. Imperi^d ; R. Sorrentino^c ; ¹ ; F. Ungaro^a ; ¹ ; ^{ungaro@unina.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Inhalable powder ; Hyaluronic acid ; Flucytosine ; Lung delivery ; Pseudomonas aeruginosa ; Candida albicans
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 September 2016
• 年：2016
• 卷：238
• 期：Complete
• 页码：80-91
• 全文大小：1018 K

文摘

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.