Discovery of novel long-acting co-prodrugs NSAIDs-PEA: Synthesis, nanocrystals preparation, characterizations and antinociceptive effects

Chronic pain affects more than 30% of people worldwide and represents a highly prevalent clinical problem. However, current analgesics are often limited by inadequate efficacy, serious adverse effects, and the need for frequent administration. Therefore, developing novel long-acting analgesics is crucial for the effective treatment of chronic pain. In this study, we synthesized four new co-prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) with the endogenous lipid palmitoylethanolamide (PEA), which were further prepared as nanocrystal (NC) formulations to achieve long-acting and enhanced antinociceptive effects. The chemical structures of co-prodrugs NSAIDs-PEA were characterized through HR-MS, and NMR spectroscopy. In mouse liver microsomal stability assays, these co-prodrugs were metabolized into two individual drugs. The NCs of co-prodrugs NSAIDs-PEA were prepared using the wet milling method and tween 80 as the only excipient. All prepared NCs were spherical and had a size between 100 and 200 nm, polydispersity index (PDI) ≤ 0.3 and Zeta potential values from −20 to −30 mV. In a rat model of chronic pain elicited by complete Freund's adjuvant (CFA), intramuscular administration of naproxen-palmitoylethanolamide (NAP-PEA) NCs produced a rapid onset of analgesia and sustained pain relief lasting up to 72 h. Moreover, NAP-PEA NCs had good biocompatibility and induced only a minor local inflammatory reaction, which gradually returned to normal within 5 days. These results indicated that NAP-PEA NCs provided a promising strategy for chronic pain treatment.