Liposomal Formulations Containing Amino Acid Menthol Ester Naproxenate: Physicochemical Characterization and Transdermal Delivery Potential

Non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, are widely used for the treatment of pain and inflammation; however, their therapeutic application is limited by poor aqueous solubility and low bioavailability. This study aimed to synthesize and characterize a novel amino acid-based naproxen derivative, L-phenylalanine menthol ester naproxenate ([PheOMent][NAP]), develop liposomal formulations containing the obtained compound, and evaluate their physicochemical properties and transdermal delivery potential. The derivative was synthesized via a three-step procedure and characterized using NMR, FT-IR, TG, DSC, and XRD analyses. Compared with naproxen, [PheOMent][NAP] exhibited lower lipophilicity (log P = 1.36 vs. 1.70). Liposomal formulations containing the modified derivative showed high encapsulation efficiency (89.6–90.7%), higher than that observed for naproxen-loaded liposomes (51.7–54.7%). The prepared systems exhibited bimodal particle size distributions, comprising both submicrometre and micrometre vesicle populations depending on the preparation method, as well as negative zeta potential values (−18.17 to −23.72 mV) and pH values ranging from 6.18 to 7.07, demonstrating physicochemical characteristics suitable for topical formulations. In vitro permeation studies using porcine skin demonstrated markedly enhanced transdermal delivery of [PheOMent][NAP]. After 24 h, cumulative permeation exceeded that of naproxen formulations by more than 1.5-fold (416.7 vs. 281.6 μg cm−2). These findings indicate that liposomal formulations containing amino acid-modified naproxen derivatives represent a promising strategy for improving transdermal NSAID delivery.