Thermosensitive Mucoadhesive Intranasal In Situ Gel of Risperidone for Nose-to-Brain Targeting: Physiochemical and Pharmacokinetics Study

<b>Background/Objectives:</b> Non-invasive central nervous system (CNS) therapies are limited by complex mechanisms and the blood-brain barrier, but nasal delivery offers a promising alternative. The study planned to develop a non-invasive in situ intranasal mucoadhesive thermosensitive gel to deliver CNS-active risperidone via nose-to-brain targeting. Risperidone, a second-generation antipsychotic, has shown efficacy in managing both psychotic and mood-related symptoms. The mucoadhesive gel formulations help to prolong the residence time at the nasal absorption site, thereby facilitating the uptake of the drug. <b>Methods:</b> The poloxamer 407 (18.0% <i>w</i>/<i>v</i>), HPMC K100M and K15M (0.3-0.5% <i>w</i>/<i>v</i>), and benzalkonium chloride (0.1% <i>v</i>/<i>v</i>) were used as thermosensitive polymers, a mucoadhesive agent, and a preservative, respectively, for the development of in situ thermosensitive gel. The developed formulations were evaluated for various parameters. <b>Results:</b> The pH, gelation temperature, gelation time, and drug content were found to be 6.20 ± 0.026-6.37 ± 0.015, 34.25 ± 1.10-37.50 ± 1.05 °C, 1.65 ± 0.30-2.50 ± 0.55 min, and 95.58 ± 2.37-98.03 ± 1.68%, respectively. Furthermore, the optimized F3 formulation showed satisfactory gelling capacity (9.52 ± 0.513 h) and an acceptable mucoadhesive strength (1110.65 ± 6.87 dyne/cm²). Diffusion of the drug through the egg membrane depended on the formulation's viscosity, and the F3 formulation explained the first-order release kinetics, indicating concentration-dependent drug diffusion with <i>n</i> < 0.45 (0.398) value, indicating the Fickian-diffusion (diffusional case I). The pharmacokinetic study was performed with male Wistar albino rats, and the F3 in situ thermosensitive risperidone gel confirmed significantly (<i>p</i> < 0.05) ~5.4 times higher brain AUC_0-∞ when administered intranasally compared to the oral solution. <b>Conclusions:</b> Based on physicochemical, in vitro, and in vivo parameters, it can be concluded that in situ thermosensitive gel is suitable for administration of risperidone through the nasal route and can enhance patient compliance through ease of application and with less repeated administration.