Ex Vivo Permeation Study of Levodopa Using In Situ Gelling Systems for Nasal Drug Delivery

Abstract

The intranasal drug administration route offers reduced peripheral toxicity, targeted drug delivery, and improved bioavailability, especially for therapeutics intended for the treatment of neurological disorders. The most common therapy for Parkinson's disease includes the use of the aromatic amino acid levodopa, whose chronic oral application precedes the onset of on/off phenomena, dyskinesia, and other adverse drug reactions. Additionally, levodopa has low oral bioavailability, and therapeutic challenges remain unresolved even after combining it with enzyme inhibitors. The aim of the present study is to investigate the ex vivo effects of in situ gelling systems with levodopa and the sesquiterpene alpha-bisabolol, included due to its known permeation-enhancing properties. The studied nasal formulations were designed to deliver the active pharmaceutical ingredient directly to the brain through the olfactory region of the nasal cavity, bypassing first-pass metabolism and the blood-brain barrier. Two in situ thermogelling systems were prepared, each loaded with 0.1% levodopa in Poloxamer 407 15% hydrosol, with alpha-bisabolol solubilized at 1% in the second system. The test formulations underwent an ex vivo permeation study using nasal mucosa as a membrane on a Franz diffusion cell. The results of the conducted analysis showed that the in situ gelling system containing alpha-bisabolol ensured a higher drug permeation rate (Jss) of levodopa through the mucosa (2.00 µg·cm⁻²·min⁻¹) compared to the reference formulation without alpha-bisabolol (1.35 µg·cm⁻²·min⁻¹). The well-known permeation-enhancing mechanism of alpha-bisabolol, which increases the fluidity of membrane lipids, along with the obtained results, suggests that the primary transport mechanism for levodopa is intracellular, passing through the lipid membranes of epithelial cells.