Investigating the effect of leucine and dipalmitoylphosphatidylcholine on aerosolization properties of high-dose dry powder inhaler formulations of itraconazole nanoparticles

This study aims to develop a high-dose dry powder inhaler (DPI) formulation of itraconazole (ITZ) nanoparticles with leucine and/or dipalmitoylphosphatidylcholine (DPPC) as excipients to increase drug solubility and aerosolization performance. To do this, we co-spray-dried leucine and DPPC with an optimized ITZ nanosuspension and measured the physical properties, dissolution and aerosolization characteristics of the formulations. Among the formulations, those containing 50% (w/wITZ) leucine (N3) or 30% (w/wITZ) leucine with 20% (w/wITZ) DPPC (N5), which had the highest FPF (68.88 ± 1.90% for N3 and 78.81 ± 1.17% for N5) and dissolved percentage of the drug (cumulative release percentage in 180 min, 69.10 ± 1.46% for N3 and 94.34 ± 1.30% for N5), were selected for in vivo pharmacokinetic studies and insufflated intratracheally to rats. An ITZ suspension was administered as a control by gavage. Among the selected formulations, N3 produced the highest AUC in lung tissue, approximately two-fold higher than N5. Furthermore, the AUCLung-to-AUCPlasma ratio for N3 was approximately 24-fold and 800-fold higher than those of N5 and the oral formulations, respectively, indicating enhanced pulmonary retention and potentially reduced systemic exposure. Overall, N3 represents a promising high-dose DPI formulation for further preclinical development of inhaled ITZ.