Discovery of a long-acting nanocrystal formulation of INND-2201, a new co-drug of pregabalin and palmitoylethanolamide with synergistic analgesic effects

Chronic pain is a global health problem affecting approximately 30% of the adult population worldwide. Currently available painkillers often showed limited efficacy or serious adverse effects and require frequent administration to maintain therapeutic effects. To develop new long-acting analgesics with synergistic antinociceptive effects, a new co-drug INND-2201 of pregabalin and palmitoylethanolamide (PEA) was synthesized, characterized and prepared as a nanocrystal formulation. INND-2201 was slowly metabolized into pregabalin and PEA in microsomal stability test, and oral INND-2201 exhibited significant and synergistic antinociceptive effects for inflammatory and neuropathic pain with ED 50 values of 4.43 and 5.54 mg/kg, respectively. Nanocrystals (NCs) of INND-2201 were then prepared by the ball milling method with the particle size of 107.1 ± 2.7 nm. Intramuscular administration of INND-2201 NCs demonstrated prolonged pain relief lasting up to 5 days for chronic inflammatory pain in mice. Acute toxicity test, muscular irritation evaluation, rotarod test and open field test indicated that INND-2201 had a good safety profile. Taken together, INND-2201 NCs exerted long-acting analgesic effects and provided a promising strategy for the management of chronic pain. • A new co-drug INND-2201 was obtained by esterification of pregabalin with palmitoylethanolamide; • Oral INND-2201 exerted synergistic antinociceptive effects for inflammatory pain and neuropathic pain; • INND-2201 nanocrystals demonstrated prolonged pain relief lasting up to 5 days for chronic inflammatory pain in mice; • INND-2201 and INND-2201 nanocrystals hold good safety profiles in acute toxicity test or muscular irritation evaluation.