Development of venlafaxine hydrochloride nasal thermosensitive in-situ gel with P407/P188: enhanced bioavailability and antidepressant effects in depressive rats

Objective To develop and optimise a VEN nasal thermosensitive in-situ gel for reducing the first-pass effect and enhancing bioavailability.Methods High performance liquid chromatography, central composite design-response surface methodology, the membrane-free erosion and the Franz vertical diffusion cell method were used to clarify the optimised formulation. Pharmacokinetic and pharmacodynamic studies evaluated sustained release and efficacy.Results The optimal formulation (32.87-33.17 °C gelation temp) comprised 12.5% w/v VEN, 20.44% w/v poloxamer 407, 0.74% w/v P188, 5% w/v 2-Hydroxypropyl-β-cyclodextrin, 0.5% w/v hydroxypropyl methyl cellulose, 0.12% w/v potassium sorbate, 10% v/v glycerol, and 90% v/v water; it had a good stability and sustained-release effect of VEN and increased bioavailability and reduced O-desmethylvenlafaxine production. It achieved 90% cumulative release at 15h in vitro, and its intranasal Cmax was higher than oral VEN (p < 0.05) without detectable O-desmethylvenlafaxine. Treatment with VEN thermosensitive in-situ gel in a depressive rat model improved the sucrose preference rate in the sucrose preference test and the total distance of movement in the open field test, also significantly increased the level of 5-hydroxytryptamine and norepinephrine in the hippocampus (p < 0.01).Conclusion This innovative P407/P188-based gel enhances VEN bioavailability and antidepressant efficacy via sustained release and brain targeting, providing critical data for nasal formulation development.