Thyroid hormone (levothyroxine) replacement via the respiratory route by inhalation: in vitro exploratory studies.

Objectives: To conduct proof of principle studies that will enable development of noninvasive (respiratory) delivery systems for levothyroxine (T4).

Methods: Preformulation (solubility, stability), formulation and biopharmaceutical (in vitro absorption, transport, gene expression) studies were conducted. Calu-3 cell line was used for permeation studies.

Results: Solubility profiles of T4 were established in aqueous (PBS, HBSS, isotonic saline) and non-aqueous solvents (PEG 400, PEG 600, propylene glycol, glycerine). Transport of the compound across Calu-3 cells suggested involvement of active transport systems. This correlated with expression of thyroxine transporters (MCT8, MCT10, OATP1A2, LAT1 and LAT2) in the cell line. Diffusion characteristics showed significant absorption with no detection of T4 metabolite (triiodothyronine). Formulation studies revealed that stable formulations could be prepared using a combination of aqueous and non-aqueous solvents.

Conclusions: Results of the studies indicated that T4 can be absorbed effectively from the respiratory mucosa. Factors affecting stability such as pH and temperature should be taken into account during formulation development of this compound for the respiratory route.