Poster de conférence
Résumé : Introduction: Efficient Itraconazole (ITZ) oral administration shows numerous limitations because of (i) the poor aqueous ITZ solubility inducing low and unpredictable bioavailability, (ii) the hepatic metabolism to an active metabolite and (iii) the large cytochrome inhibition increasing risks of drug-drug interactions. In case of pulmonary fungal infections, these issues increase the variability of plasmatic concentration in lungs to combat or prevent infection. ITZ pulmonary delivery would be an alternative by increasing ITZ concentration in the lungs while decreasing systemic exposure. Industrial production requires high solids/solutes concentration, using easily evaporable and non-flammable solvents (water, ethanol, isopropanol, ethyl acetate, etc...) while keeping dry powder properties obtained (particles size, residual moisture) at the laboratory scale to reach lungs but at a higher production scale.Materials and method: A screening of ITZ and mannitol solubility is performed on different organic solvent mixtures. Solid dispersions containing ITZ in mannitol matrix were obtained from solutions (So1, So2, and So3) or suspension (Su1) at 3.0% (So1, So3), 4.5% (So2) or 8% (Su1) (w/v) in the preferential organic solvent mixture. In the solutions, mannitol and 35% (So1, So2) or 60% (So3) of ITZ were dissolved. In the suspension, 10% of ITZ were dissolved and some particles of mannitol were suspended. The production method was the spray-drying using a B-290 Mini Spray Dryer (Büchi, Switzerland). The powders were characterized on their physico-chemical and aerodynamic properties (fine particle fraction - FPF), and on their dissolution profiles. Results: All the solid dispersion-based dry powders obtained after spray-drying showed no presence of crystalline ITZ (i.e. complete amorphous state). Because of drying of dissolved particles in the presence of undissolved mannitol particles, solid dispersion from the suspension presented median size (d(0.5)) bigger than solid dispersions from the solutions. Nevertheless, solid dispersion Su 1 (FPF of 59 ± 3 %) presented a better aerodynamic behaviour than solid dispersions So1 (FPF = 33 ± 2 %), So2 (FPF = 31.3 ± 0.7 %) and So3 (FPF = 39 ± 8 %). In vitro dissolution tests showed that all the solid dispersions present a significantly higher dissolution rate than crystalline ITZ bulk.Conclusion: Solid dispersions with amorphous ITZ in mannitol matrix as dry powders, which were prepared using an easily scalable production method, present an improved dissolution rate, good aerodynamic behaviour and interesting properties to combat or prevent pulmonary aspergillosis.