Sublingual delivery of peptide therapeutics is hindered by mucosal barriers and poor bioavailability. This study aimed to evaluate and optimize sublingual administration of TE-8105, a long-acting dual fatty acid-conjugated GLP-1 receptor agonist that has successfully completed a Phase 1/2a clinical trial. We hypothesized that fatty acid chains may enhance mucosal permeability, and optimizing formulation parameters may enable effective sublingual delivery. We systematically optimized drug concentration, pH, mucosal contact duration, and assessed excipient effects in diabetic db/db mice using blood glucose, body weight, food/water intake as efficacy readouts. A 3 mg/mL TE-8105 liquid formulation at pH 7.6 with a 5-minute mucosal contact yielded optimal glycemic control. The optimized parameters were adapted into prototype soft gel and tablet formulations for feasibility testing. Phenol (0.3-0.5%) and mannitol (4%) enhanced efficacy beyond either alone, with peppermint oil further enhancing tablet efficacy. Although sublingual TE-8105 and semaglutide achieved similar therapeutic potency (∼7%) relative to the subcutaneous route, TE-8105's prolonged plasma half-life enabled once-every-2-days dosing for sustained glycemic control, whereas semaglutide required daily administration. These findings establish a promising sublingual delivery system for fatty acid-conjugated peptides, and position sublingual TE-8105 as a potential needle-free alternative to injectable GLP-1 therapies.
