摘要
A long-acting Taphalgin-loaded thermoresponsive chitosan hydrogel (TAP-CS/β-GP) depot was developed. • TAP-CS/β-GP rapidly undergoes sol-gel transition within 3 min at 37 °C. • TAP-CS/β-GP showed a first-order release profile with 72 h cumulative release ratio of 93.96%. • TAP-CS/β-GP extended the analgesic duration by 36-fold compared to free TAP. • Subcutaneous TAP-CS/β-GP depot showed a degradation ratio of > 85% within 14 days. The clinical application of Taphalgin (TAP), a tetrapeptide analgesic targeting μ 1 -opioid receptor, was greatly limited owing to fast systemic clearance. In this study, a TAP-loaded in situ injectable thermoresponsive chitosan (CS) hydrogel via β-glycerophosphate (β-GP) crosslinking (TAP-CS/β-GP) was prepared for long-term postoperative analgesia management. The porous microstructure of TAP-CS/β-GP was characterized by scanning electron microscopy (SEM). Rheological analysis further revealed that TAP-CS/β-GP precursor solution showed favorable injectability and shear-thinning behavior, which rapidly approached the solution to gel (sol-gel) transition within 3 min at 37 °C. Furthermore, TAP-CS/β-GP showed a first-order drug release profile with 72 h cumulative TAP release ratio of 93.96 ± 3.18%. The analgesic efficacy of TAP-CS/β-GP was thoroughly evaluated using the rat incisional pain model, mouse acetic acid-induced writhing test and mouse hot-plate test. TAP-CS/β-GP demonstrated fast, potent and sustained analgesia with paw withdrawal threshold (PWT) increase by 3.49-fold at 1 h and effectively prolonged the analgesic efficacy to 144 h for incisional pain. In addition, CS/β-GP demonstrated a degradation ratio of > 85% within 14 days. This TAP-CS/β-GP system provides a prolonged TAP release profile with potent analgesia and favorable safety profile, presenting an alternative strategy for postoperative analgesia. Download: Download high-res image (359KB) Download: Download full-size image
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