Capsaicin cyclodextrin complex enhances mepivacaine targeting and improves local anesthesia in inflamed tissues

Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics LA . Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin CAP triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two drug combination LA and CAP on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl beta cyclodextrin HP amp; 946; CD , as shown by the phase solubility study. The resulting complex HP amp; 946; CD CAP showed 1 1 stoichiometry and high association constant, according to phase solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry DSC , X ray diffraction, and 1H NMR. The freeze dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2 mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug deliver