A Novel Liposomal Palmitoylethanolamide (PEA) with Enhanced Gastrointestinal Permeating Properties

Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide and an endocannabinoid-related lipid that has been extensively studied for its analgesic, immunomodulatory, antimicrobial, and anti-inflammatory properties. It has demonstrated efficacy in various applications and is currently utilized as a nutraceutical for its antinociceptive, neuroprotective, and immunomodulatory effects, particularly in supporting brain and joint health and in mitigating inflammatory processes. Background/Objectives: Despite its significant therapeutic potential, the clinical effectiveness of PEA is limited by its poor water solubility and, consequently, low oral bioavailability. Additionally, degradation in the acidic gastrointestinal environment further compromises its absorption. To address these challenges, several technological strategies have been explored to improve its pharmacokinetic profile, including conventional micronization and ultra-micronization techniques. The objective of this study was to characterize a novel liposomal formulation based on PEA and evaluate its intestinal permeation and absorption. Methods: Comparative permeation studies of PEA were conducted using ex vivo models to evaluate its absorption characteristics across gastrointestinal mucosae. The experiments were performed in a Franz diffusion cell system using a porcine colon mucosa in two physiologically relevant media: Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF). Results: Liposomal PEA showed a more efficient and continuous release over time, reaching higher concentrations of PEA permeated through the membrane. Conclusions: Our findings demonstrate a significant improvement in PEA’s permeability and absorption in an ex vivo simulated gastrointestinal environment. Liposomal PEA appears to be more affine to biological membranes. These results suggest that liposomal PEA may represent a promising therapeutic strategy for managing chronic pain and inflammatory conditions such as chronic pelvic pain.