Skip to main content

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

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.

Graphical abstract

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

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.

Consent to participate

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

Consent for publication

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

Consent and already available data and/or biologic material

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

Data protection, confidentiality, and privacy

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

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 147 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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 (2022). https://doi.org/10.1007/s00210-022-02278-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00210-022-02278-4

Keywords

  • Bupivacaine
  • Sulfobutylether-β-cyclodextrin
  • Drug delivery
  • Cytotoxicity
  • Orofacial pain
  • Hyperalgesia