Solvent-free in situ self-nanoemulsifying dissolving microneedles for rapid and safe transdermal treatment of acute pain with plant-derived eugenol

Abstract

Acute pain treatment is often limited by the delayed onset and gastrointestinal side effects of NSAIDs, as well as the addiction potential of opioids. Eugenol (EUG), a natural plant-derived compound with rapid analgesic and anti-inflammatory effects, offers a safer alternative but is restricted by its gastrointestinal irritation. Here, we developed a surfactant-free self-emulsifying dissolving microneedle (DMN) system based on an amorphous solid dispersion of EUG. Amphiphilic PVP VA64 mediates interfacial interactions at the oil–water interface, enabling in situ nanoemulsion formation upon contact with the interstitial fluid, promoting rapid transdermal drug release and efficient skin permeation. In vivo, the DMN achieved a T_max of ∼25 min, inhibited acetic acid-induced writhing by 72.5 ± 4.3%, and reduced formalin-induced pain in the second phase by 68.9 ± 5.1%, significantly outperforming oral NSAIDs (writhing inhibition: 45.3 ± 3.8%; formalin second phase: 42.6 ± 4.0%). This innovative DMN platform provides a safe, efficient, and clinically translatable strategy for the transdermal management of acute pain.