Supercritical CO₂ Antisolvent-Micronised Naringin and Naringenin Alleviate Paclitaxel-Induced Pain Syndrome

Background/Objectives: Paclitaxel is a chemotherapy drug used to treat various tumours, but its use is often limited by an acute and chronic pain syndrome that is poorly managed. Naringin and its aglycone, naringenin, exhibit antioxidant, antitumour, anti-inflammatory, and antinociceptive effects, making them potential alternative treatments. However, their low water solubility limits their oral bioavailability in humans. Micronisation in a supercritical medium reduces particle size and enhances the dissolution of compounds, offering a possible solution. In this study, we investigated whether micronising naringin and naringenin via supercritical technology could improve their dissolution and oral efficacy against paclitaxel-induced pain syndrome. Methods: Micronisation was performed using supercritical CO₂. Molecular docking was used to analyse the binding of naringin and naringenin to TRPV1, a key target for pain relief. Swiss mice were used in capsaicin (TRPV1 agonist)-induced nociception and paclitaxel-caused acute and chronic pain models. We assessed mechanical, cold, and heat sensitivity, potential adverse effects, and TRPV1 mRNA expression. Results: Micronisation improved the apparent dissolution profile of molecules. Docking results showed that naringin and naringenin bind to TRPV1. Both micronised compounds reduced capsaicin-induced nociception without affecting locomotion or body temperature. Micronised naringin and naringenin alleviated mechanical and cold allodynia, as well as thermal hyperalgesia in both acute and chronic paclitaxel-induced pain, outperforming their conventional forms. They also downregulated TRPV1 mRNA expression in the mice's sciatic nerve. Conclusions: Taken together, these results show that supercritical micronisation improved the apparent dissolution and oral antinociceptive efficacy of naringin and naringenin, emphasising their potential as promising alternatives for managing paclitaxel-induced pain, with TRPV1 being a probable contributor to the observed antinociceptive effects.