Optimized intranasal delivery of segesterone acetate progestin to the brain using nanoemulsions and microemulsions.

Segesterone acetate (SA) is a selective and potent progesterone receptor agonist with potential application in the treatment of neurological diseases, such as multiple sclerosis and stroke. In this study, a microemulsion (ME) and three nanoemulsions (NEs) with a target SA concentration of 0.48 mg/g were developed for intranasal administration and extensively characterized regarding their physicochemical properties, stability, antimicrobial activity, and safety (in primary cortical cells, Hen’s Egg Test, MucilAir™ model and in rats). Plasma and brain SA levels were measured 30 and 60 min after intranasal administration in male rats.The ME and the different NEs exhibited a droplet mean diameter of approximately 20 nm and 100 nm, respectively, with a low polydispersity index (≤ 0.1). Depending on their composition, they had neutral, positive, or negative zeta potentials and varying viscosities. The NEs exhibited good chemical and physical stability for 150–180 days at 4 °C, while the ME required a reduction in initial SA concentration to avoid drug precipitation. The NEs also demonstrated antimicrobial activity, although not ensuring effective antimicrobial preservation. The ME was the least cytotoxic of the formulations in vitro. No significant impairment of olfactory function or histopathological evidence of toxicity was observed in rats following single or repeated administrations of the ME and neutral NE at doses up to 40 µg/kg of SA. After a single intranasal administration of 40 µg/kg, SA brain concentrations exceeded 4 ng/g at 30 min, with no significant differences observed among the different formulation strategies. Notably, the ME led to a higher brain-to-plasma ratio (~ 7) at 30 min and thereby is a promising strategy to increase brain targeting.