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Antinociceptive effects of bupivacaine and its sulfobutylether-β-cyclodextrin inclusion complex in orofacial pain

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Abstract

Bupivacaine hydrochloride (BVC) represents an option to produce long-lasting analgesia, and complexation in cyclodextrins has shown improvements in biopharmaceutical properties. This study aimed to characterize and test the cytotoxicity and antinociceptive effects of BVC complexed in sulfobutylether-β-cyclodextrin (SBEβCD). The kinetics and stoichiometry of complexation and BVC-SBEβCD association constant were evaluated by phase solubility study and Job’s plot. Evidence of the BVC-SBEβCD complex formation was obtained from scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The cytotoxicity was evaluated in keratinocyte (HaCaT) and neuroblastoma (SH-SY5Y). Antinociceptive effects were registered via orofacial pain models: the formalin test, carrageenan-induced hyperalgesia, and postoperative pain (intraoral incision). The complex formation occurred at a 1:1 BVC-SBEβCD molar ratio, with a low association constant (13.2 M−1). SEM, DSC, and FTIR results demonstrated the host–guest interaction. The IC50% values determined in SH-SY5Y were 216 µM and 149 µM for BVC and BVC-SBEβCD, respectively (p < 0.05). There was no difference in HaCaT IC50%. In orofacial pain model, BVC-SBEβCD significantly prolonged antinociceptive effect, in about 2 h, compared to plain BVC. SBEβCD can be used as a drug delivery system for bupivacaine, whereas the complex showed long-lasting analgesic effects.

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Acknowledgements

The authors thank Cristália Chemical and Pharmaceutical Products (Itapira, SP, Brazil) and CycloLab Cyclodextrin Research and Development Laboratory (Budapest, Hungary) for donation of bupivacaine hydrochloride and sulfobutylether-β-cyclodextrin (DexvolveTM), respectively. The authors thank CAPES (Coordination for the Improvement of Higher Education Personnel) for the fellowship support for E. I. Araya, and CNPq (National Council for Scientific and Technological Development) for the fellowship support for D. F. Baggio. J. G. Chichorro is recipient of CNPq research productivity fellowship.

Funding

This work was supported by FAPESP (Fundação Amparo à Pesquisa do Estado de São Paulo, grant: FAPESP #2018/14206–3).

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Contributions

JSFD collaborated with the investigation, formal analysis, writing, and original draft preparation. SMDS collaborated with the conceptualization, investigation, formal analysis, writing, and original draft preparation. JNRF worked in the investigation and formal analysis. BMM collaborated with the investigation and formal analysis. DFB was involved in the investigation, formal analysis, writing, and original draft preparation. WH collaborated with the investigation, methodology, and formal analysis. EIA was involved in the investigation, formal analysis, writing, and original draft preparation. EP collaborated with the funding acquisition, supervision, writing, reviewing, and editing the manuscript. JGC was involved in the funding acquisition, data curation, supervision, writing, reviewing, and editing the manuscript. LENF collaborated with the funding acquisition, project administration, data curation, writing, and original draft preparation. The authors declare that all data were generated in-house and that no paper mill (criminal science publishing gangs) was used. The complete data (raw data, original data, individual data points) are available as related files.

Corresponding author

Correspondence to Luiz Eduardo Nunes Ferreira.

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Ethics approval

The animal studies were approved by the Ethics Committee for Animal Use from Biological Sciences Section of the Federal University of Paraná (CEUA/BIO UFPR #1057, April 11, 2019), in accordance with the Brazilian regulations on animal welfare.

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Not applicable. The study did not involve the participation of human volunteers.

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All authors and the institutions consent to publish this research article.

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Not applicable. The study did not use any material from living or dead patients.

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Not applicable. The study did not use biological materials donated or acquired from biobank/biorepository.

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The authors declare no competing interests.

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de Freitas Domingues, J.S., dos Santos, S.M.D., das Neves Rodrigues Ferreira, J. et al. Antinociceptive effects of bupivacaine and its sulfobutylether-β-cyclodextrin inclusion complex in orofacial pain. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1405–1417 (2022). https://doi.org/10.1007/s00210-022-02278-4

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