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Acute postoperative pain is commonly treated with flurbiprofen (FBP), but conventional delivery methods are suboptimal. This study prepared a new non-burst release microneedles (MNs) using genipin cross-linked gelatin (cGel). By adding varying amounts of genipin to modulate the crosslinking degree of cGel, the drug release behavior of the drug-loaded MNs in the skin can be altered. The crosslinking parameters that meet therapeutic requirements are selected, thus providing rapid and long-lasting analgesic effects. cGel solutions were successfully cross-linked, altering matrix material microstructure, confirmed by scanning electron microscope imaging and fourier transform infrared spectroscopy. MNs demonstrated increasing mechanical strength with higher crosslinking. Drug release rates were rapid initially, then slowed, exhibiting a characteristic of decreased release rates with increasing degrees of crosslinking. In vivo, FBP/cGel MNs significantly reduced allodynia and hyperalgesia post-surgery, with the greatest effect observed at 2–3 h post-surgery, and can maintain analgesia for up to 6 h. Biosafety tests confirmed good biocompatibility. FBP/cGel MNs effectively penetrate the stratum corneum, safely delivering drugs with significant analgesic effects, excellent mechanical properties, and good biocompatibility, representing a promising strategy for managing acute postoperative pain.
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