ENGINEERING A NANO‑OLEOGEL SYSTEM TO ENHANCE ORAL ADMINISTRATION OF PEA FOR ANTI‑INFLAMMATORY APPLICATIONS

Palmitoylethanolamide (PEA) is a well-established nutraceutical product with anti-inflammatory and analgesic activity, particularly in neuropathic pain. However, its poor aqueous solubility and lipophilicity limit oral bioavailability. This work describes the development of an innovative nano-oleogel emulsion aiming to enhance oral dispersion and promote PEA efficacy toward neuronal cells. A structured oleogel matrix was produced by inducing gelation within two different lipid environments: vegetal linseed oil and mineral vaseline oil. Gelation occurred through the incorporation of stearic acid and glyceryl monostearate as low‑molecular‑weight organogelators. These excipients promoted the self‑assembly of a three‑dimensional lipid network capable of immobilizing the oil phase, thereby gen-erating a semi‑solid oleogel suitable for subsequent emulsification and nanoparticle formation. Multiple surfactants were screened to identify a stable nano emulsion system compatible with PEA and the li-pid matrix. Process parameters (sonication, high shear homogenization) and formulation variables were systematically optimized to reduce particle size and improve homogeneity. The optimized formu-lations were characterized by DLS, and PEA solubility was assessed in the presence of 2% (w/v) sodi-um taurocholate in which PEA demonstrate a solubility easily measurable by HPLC. Additional explor-atory studies included cytotoxicity assays by CCK-8 test on HMC3 microglial cells. The addition of Tween 80 (1%, w/v) resulted in the formation of a stable nano-oleogel emulsion, with stability monitored over time at two storage temperatures, room temperature and 5 °C. Progressive re-duction of the total lipid phase, maintaining a constant final volume, significantly decreased particle size, reaching ~238 nm with low polydispersity (PDI 0.20) in the optimized formulation. However, an increase in PEA loading did not affect particle size. Solubility studies showed comparable PEA con-centrations between native PEA and nano oleogel formulations in taurocholate media, indicating that the system primarily improves colloidal dispersion rather than intrinsic solubility. Preliminary results on HMC3 cells aimed to determinate IC50 are ongoing. The developed nano oleogel emulsions represent a promising oral delivery platform for PEA, combin-ing a biocompatible lipid gel matrix with nanoscale dispersion to improve handling and potential intes-tinal absorption. The system offers a versatile basis for future functionalization and could support en-hanced nutraceutical strategies for managing chronic inflammation and neuropathic pain.