The pharmacokinetic profile of NCEs administered by the inhalation route depends on multiple factors, including the physico-chemical properties of the formulation, especially when the NCE is delivered as a powder. In this case, solubility of the compound may influence its bioavailability, efficacy and safety. Compound A reported in this study is a NCE designed for inhalation for the treatment of respiratory diseases. Good in vitro pharmacological and ADME profile supported the progression of the compound to in vivo evaluation. Intratracheal administration to rodents as a blend of crystalline micronized API resulted in a lung half-life longer than 120 hours and limited systemic exposure, suggesting that the lack of reproducibility observed during the in vivo PD tests was mainly due to the low solubility of the powder. In light of these data, two different formulations were investigated in order to increase the solubility of Compound A: 1) conversion of the crystalline API in amorphous powder by a lyophilization process, and 2) formulation of composite particles including Compound A with mannitol and DPPC by spray-drying of a solution. The crystalline micronized material, the amorphous powder and the spray-dried formulation were administered intratracheally to rats using the innovative PreciseInhale system.
The formulation of Compound A with mannitol and DPPC showed shorter lung t1/2 (19 hours), compared to amorphous (t1/2 = 44 hours) and crystalline API (t1/2 > 120 hours). Systemic exposure was comparable between the amorphous-based formulations and 10-fold lower for the crystalline powder. Moreover, a good correlation was found between lung PK parameters (lung t1/2, lung MRT) of the administered powders and their dissolution profile determined in simulated lung fluid.
The results obtained suggested that the spray-dried formulation with DPPC and mannitol represents a useful platform to overcome solubility issues of poorly water-soluble compounds during in vivo PD experiments and it could be extended to other poorly water-soluble molecules, in order to investigate their real efficacy in vivo and avoid discarding promising compounds due to sub-optimal powder characteristics.