Levothyroxine dry powder for inhalation: spray drying or micronization?

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic and progressive fibrosis of the lung parenchyma of unknown origin. It is characterized by active tissue remodelling, excessive extracellular matrix deposition, and phenotypic changes in fibroblasts and epithelial cell leading to loss of lung function and premature death. The link between mitochondrial dysfunction and fibrosis progression has been extensively investigated, suggesting that such dysfunction could represent a therapeutic target. In this context, thyroid hormones have been proposed as potential agents to reverse the fibrotic state in IPF. In our previous work, the efficient delivery of levothyroxine to the deep lung using nano-embedded spray-dried powders was demonstrated. However, the production of inhalable powders by spray drying is still less standardized than the preparation of adhesive binary and ternary mixtures of micronized drugs. In this work, aerodynamic properties and cell tolerability of micronized levothyroxine formulated as binary or ternary mixtures with mannitol or lactose were compared to those of spray dried powders. The ternary mixtures, prepared with either lactose or mannitol, showed the highest in vitro respirable fraction >75%. However, they produced a greater reduction in A549 cell metabolic activity under the conditions evaluated (<60%) compared with the spray-dried nano-embedded formulations (>80%). The latter afforded significantly lower, in vitro macrophage clearance (10%) compared to micronized formulations (around 50%); therefore, they present a better balance between technological and toxicological/biological properties. These findings confirm that the spray-dried nano-embedded powders are a promising candidate for an innovative treatment of idiopathic pulmonary fibrosis with great translational potential.