Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues

Abstract

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-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-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 delivery.

Thermodynamic properties of hydroxypropyl-β-cyclodextrin/guest interaction: a survey of recent studies

“…In two very recent papers, the thermodynamic studies of HP-β-CD/drug or β-CD/drug interactions have been coupled to biological studies [21,22]. The first one by Amaro et al focuses on the synthetic antibiotic ofloxacin (OFLOX) [21].…”

“…The second paper, by Muniz Cuoto et al, describes the combined effect of a two-drugs, a local anaesthetic (mepivacaine hydrochloride) and the analgesic capsaicin (CAP), on an inflamed tissue [22]. The idea comes from the finding that the local anaesthetic in acidic environment is charged and reduces its penetration in the cell.…”

The Physical Chemistry and Chemical Physics (PCCP) Section of the International Journal of Molecular Sciences in Its Publications: The First 300 Thematic Articles in the First 3 Years

“…The last one seems to be the most detailed, and it is precisely this that we will try to implement in the course of our narrative. As it should be expected, a priori, most of the publications in this direction are devoted to organic compounds, and primarily organic molecules; these include, with varying degrees of correctness, publications [ 1 , 2 , 3 , 102 , 103 , 104 , 106 , 108 , 112 , 117 , 118 , 119 , 121 , 124 , 127 , 128 , 130 , 131 , 132 , 133 , 135 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 146 , 147 , 148 , 151 , 153 , 154 , 156 , 157 , 164 , 165 , 166 , 168 , 171 , 172 , 174 , 176 , 178 , 180 , 183 , 185 , 186 ]. Much less space is occupied by the works related to polymeric (in fact, to a high molecular weight) compounds [ 113 , …”

Membrane Interactivity of Capsaicin Antagonized by Capsazepine

“…Capsaicin is not only used for the perioperative pain management, but also clinically expected as an agent for multimodal analgesia in addition to application to various neuropathic chronic pain conditions [ 1 , 2 ]. Capsaicin has been also suggested to improve local anesthesia, especially in inflamed tissues, by combining with local anesthetics [ 3 ].…”