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

Author(s)

Couto, Veronica Muniz ^[1] ; de Oliveira-Nascimento, Laura ^[2] ; Cabeca, Luiz Fernando ^[3] ; Geraldes, Danilo Costa ^[2] ; Ribeiro Costa, Juliana Souza ^[2] ; Riske, Karin A. ^[4] ; Franz-Montan, Michelle ^[5] ; Yokaychiya, Fabiano ^{[6, 7]} ; Dias Franco, Margareth K. K. ^[6] ; de Paula, Eneida ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, BR-13083862 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Fac Pharmaceut Sci, BR-13083871 Campinas, SP - Brazil

^[3] Technol Fed Univ Parana, BR-80060000 Londrina, Parana - Brazil

^[4] Univ Fed Sao Paulo, Dept Biophys, BR-04023062 Sao Paulo, SP - Brazil

^[5] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Physiol Sci, BR-13414903 Piracicaba, SP - Brazil

^[6] IPEN CNEN SP, Nucl & Energy Res Inst, BR-05508000 Sao Paulo, SP - Brazil

^[7] Helmholtz Zentrum, Dept Quantum Phenomena Novel Mat, D-14109 Berlin - Germany

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 16 AUG 2020.
• Web of Science Citations: 0

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-beta-CD), as shown by the phase solubility study. The resulting complex (HP-beta-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(1)H-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. (AU)

• FAPESP's process: 14/20224-3 - Multiuser equipment approved in grant # 2014/14457-5: PILOT shelf freeze-dryer
• Grantee: Eneida de Paula
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 15/11804-9 - Local anesthetic combined with capsaicin:hydroxypropyl-beta-cyclodextrin inclusion complex to selective increase the anesthetic potency
• Grantee: Verônica Muniz Couto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/14457-5 - Lipid-based nanocarriers (SLN/NLC and remote-loading liposomes) used to improve the upload and potency of local anesthetics
• Grantee: Eneida de Paula
• Support Opportunities: Research Projects - Thematic Grants