Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis

Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10–20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200 nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8 °C for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45 mg/kg in rats. A single dose inhalation at a predicted dose of 22.5 mg/kg resulted in maximum lung tissue concentration of 21.4 μg/g tissue with a terminal half-life of 25.4 h. Serum concentrations were lower, with a maximum concentration of 104 ng/ml at 4 h after dosing and a terminal half-life of 10.5 h.The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.

Graphical abstractItraconazole is insoluble in aqueous media. Using wet-milling with organic grinding media and polysorbate 80 in water, a stable nanosuspension was generated with up to 20% itraconazole, which can be nebulized with standard inhaler technology. An inhaled dose of 45 mg/kg administered once daily for 7 days was well tolerated in rats. Inhalation resulted in high lung exposure with >24 h tissue half-life in rats.Figure optionsDownload full-size imageDownload high-quality image (243 K)Download as PowerPoint slide