Skip to main content

Advertisement

SpringerLink
Log in

Physicochemical characterization and cytotoxicity of articaine-2-hydroxypropyl-β-cyclodextrin inclusion complex

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Articaine (ATC) is one of the most widely used local anesthetics in dentistry. Despite its safety, local toxicity has been reported. This study aimed to develop an ATC-2- hydroxypropyl-β-cyclodextrin inclusion complex (ATC HPβCD) and to assess its toxicity in vitro. The inclusion complex was performed by solubilization, followed by a fluorimetric and job plot assay to determine the complex stoichiometry. Scanning electron microscopy, DOSY- 1 H-NMR, differential scanning calorimetry (DSC), and sustained release kinetics were used to confirm the inclusion complex formation. In vitro cytotoxicity was analyzed by MTT assay and immunofluorescence in HGF cells. Fluorimetric and job plot assay determined the inclusion complex stoichiometry (ATC:HPβCD = 1:1) and complex formation time (400 min), as indicated by a strong host/guest interaction (Ka = 117.8 M − 1), complexed fraction (f = 41.4%), and different ATC and ATC HPβCD melting points (172 °C e 235 °C, respectively). The mean of cell viability was 31.87% and 63.17% for 20-mM ATC and 20-mM ATC HPβCD, respectively. Moreover, remarkable cell toxicity was observed with free ATC by immunofluorescence. These results indicate the ATC HPβCD complex could be used to improve the safety of ATC. Further research are needed to establish the anesthetic safety and effectiveness in vivo .

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Arantes LM, Scarelli C, Marsaioli AJ, de Paula E, Fernandes SA (2009) Proparacaine complexation with β-cyclodextrin and p-sulfonic acidcalix[6]arene, as evaluated by varied 1H-NMR approaches. Mag Res Chem 47:757–763. https://doi.org/10.1002/mrc.2460

    Article  CAS  Google Scholar 

  • Araújo DR, Fraceto LF, Braga AFA, de Paula E (2005) Drug-delivery systems for racemic BPV (S50-R50) and BPV enantiomeric mixture (S75-R25): cyclodextrins complexation effects on sciatic nerve blockade in mice. Rev Bras Anestesiol 55:316–328

    Article  Google Scholar 

  • Araújo DR, Tsuneda SS, Cereda CM, Carvalho FGF, Preté PSC, Fernandes SA, Yokaichiya F, Franco MK, Mazzaro I, Fraceto LF, de F A Braga A, de Paula E (2008) Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex. Eur J Pharm Sci 33:60–71. https://doi.org/10.1016/j.ejps.2007.09.010

    Article  CAS  PubMed  Google Scholar 

  • Braga MA, Martini MF, Pickholz M, Yokaichiya F, Franco MKD, Cabeça LF, Guilherme VA, Silva CM, Limia CE, de Paula E (2016) Clonidine complexation with hydroxypropyl-beta-cyclodextrin: from physico-chemical characterization to in vivo adjuvant effect in local anesthesia. J Pharm Biomed Anal 119:27–36. https://doi.org/10.1016/j.jpba.2015.11.015

    Article  CAS  PubMed  Google Scholar 

  • Bratu I, Gavira-Vallejo JM, Hernanz A (2005) 1H-NMR study of the inclusion processes for alpha- and gamma-cyclodextrin with fenbufen. Biopolymers 77:361–367. https://doi.org/10.1002/bip.20245

    Article  CAS  PubMed  Google Scholar 

  • Cabeça LF, Figueiredo IM, de Paula E, Marsaioli AJ (2011) Prilocaine–cyclodextrin–liposome: effect of pH variations on the encapsulation and topology of a ternary complex using 1H-NMR. Magn Reson Chem 49:295–300. https://doi.org/10.1002/mrc.2740

    Article  CAS  PubMed  Google Scholar 

  • Cereda CM, Tofoli GR, Maturana LG, Pierucci A, Nunes LA, Franz-Montan M, de Oliveira AL, Arana S, de Araujo DR, de Paula E (2012) Local neurotoxicity and myotoxicity evaluation of cyclodextrin complexes of bupivacaine and ropivacaine. Anesth Analg 115:1234–1241. https://doi.org/10.1213/ANE.0b013e318266f3d9

    Article  CAS  PubMed  Google Scholar 

  • Cs N, Fodor M, Pokol G, Izvekov V, Sztatisz J, Arias MJ, Ginés JM (1998) Investigation of cyclodextrin complexes of mandelic acid. J Therm Anal Calorim 51:1039–1048

    Article  Google Scholar 

  • Davis ME, Brewster ME (2004) Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov 3:1023–1035. https://doi.org/10.1038/nrd1576

    Article  CAS  PubMed  Google Scholar 

  • de Paula E, Cereda CM, Tofoli GR, Franz-Montan M, Fraceto LF, Araújo DR (2010a) Drug delivery systems for local anesthetics. Recent Pat Drug Deliv Formul 4:23–34

    Article  Google Scholar 

  • de Paula E, Araujo DR, Fraceto LF (2010b) Nuclear magnetic resonance spectroscopy tools for physicochemical characterization of cyclodextrin inclusion. In: Hu J (ed) Cyclodextrins chemistry physics. Transworld Research Network, Kerala, pp 1–21

    Google Scholar 

  • Ferreira LE, Muniz BV, Dos Santos CP, Volpato MC, de Paula E, Groppo FC (2016) Comparison of liposomal and 2-hydroxypropyl-β-cyclodextrin-lidocaine on cell viability and inflammatory response in human keratinocytes and gingival fibroblasts. J Pharm Pharmacol 68:791–802. https://doi.org/10.1111/jphp.12552

    Article  CAS  PubMed  Google Scholar 

  • Ferreira LE, Muniz BV, Burga-Sánchez J, Volpato MC, de Paula E, Rosa EA, Groppo FC (2017) The effect of two drug delivery systems in ropivacaine cytotoxicity and cytokine release by human keratinocytes and fibroblasts. J Pharm Pharmacol 69:161–171. https://doi.org/10.1111/jphp.12680

    Article  CAS  PubMed  Google Scholar 

  • Franco de Lima RA, de Jesus MB, Cereda CM, Tofoli GR, Cabeça LF, Mazzaro I, Fraceto LF, de Paula E (2012) Improvement of tetracaine antinociceptive effect by inclusion in cyclodextrins. J Drug Target 20:85–96. https://doi.org/10.3109/1061186X.2011.622400

    Article  CAS  PubMed  Google Scholar 

  • Franz-Montan M, Baroni D, Brunetto G, Sobral VR, da Silva CM, Venâncio P, Zago PW, Cereda CM, Volpato MC, de Araújo DR, de Paula E, Groppo FC (2015) Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans. J Liposome Res 25(1):11–19. https://doi.org/10.3109/08982104.2014.911315

    Article  CAS  PubMed  Google Scholar 

  • Fréville JC, Dollo G, Le Corre P, Chevanne F, Le Verge R (1996) Controlled systemic absorption and increased anesthetic effect of bupivacaine following epidural administration of bupivacaine-hydroxypropyl-beta-cyclodextrin complex. Pharm Res 13:1576–1580

    Article  Google Scholar 

  • Garisto GA, Gaffen AS, Lawrence HP, Tenenbaum HC, Haas DA (2010) Occurrence of paresthesia after dental local anesthetic administration in the United States. J Am Dent Assoc 141:836–844

    Article  Google Scholar 

  • Giannakopoulos H, Levin LM, Secreto S, Moore PA, Peterson C, Hutcheson M, Bouhajib M, Mosenkis A, Townsend RR (2006) The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100.000 and 1:200.000 epinephrine. JADA 137:1562–1571

    PubMed  Google Scholar 

  • Giordano F, Novak C, Moyano JR (2001) Thermal analysis of cyclodextrins and their inclusion compounds. Thermochim Acta 380:123–151

    Article  CAS  Google Scholar 

  • Gouda R, Baishya H, Qing Z (2017) Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets. J Dev Drugs 6:1–8

    Google Scholar 

  • Haas DA (2006) Articaine and paresthesia: epidemiological studies. J Am Coll Dent 73:5–10

    PubMed  Google Scholar 

  • Haas DA, Lennon D (1995) A 21-year retrospective study of reports of paresthesias following local anesthetic administration. J Can Dent Assoc 61:319–330

    CAS  PubMed  Google Scholar 

  • Kambalimath DH, Dolas RS, Kambalimath HV, Agrawal SM (2013) Efficacy of 4% articaine and 2% lidocaine: a clinical study. J Maxillofac Oral Surg 12:3–10. https://doi.org/10.1007/s12663-012-0368-4

    Article  PubMed  Google Scholar 

  • Kämmerer PW, Seeling J, Alshihri A, Daubländer M (2013) Comparative clinical evaluation of different epinephrine concentrations in 4% articaine for dental local infiltration anesthesia. Clin Oral Investig 6:1010–1017. https://doi.org/10.1007/s00784-013-1010-7

    Article  Google Scholar 

  • Kopecký F, Vojteková M, Kaclík P, Demko M, Bieliková Z (2004) Bupivacaine hydrochloride complexation with some alpha- and beta-cyclodextrins studied by potentiometry with membrane electrodes. J Pharm Pharmacol 56:581–587. https://doi.org/10.1211/0022357023295

    Article  CAS  PubMed  Google Scholar 

  • Laverde A Jr, Conceiçao GJA, Queiroz SCN, Fujiwara FY, Marsaioli AJ (2002) An NMR tool for cyclodextrin selection in enantiomeric resolution by high-performance liquid chromatography. Magn Reson Chem 40:433–442. https://doi.org/10.1002/mrc.1043

    Article  CAS  Google Scholar 

  • Loftsson T, Duchêne D (2007) Cyclodextrins and their pharmaceutical applications. Int J Pharm 329:1–11

    Article  CAS  Google Scholar 

  • Loukas YL, Vraka V, Gregoriadis G (1998) Drugs in cyclodextrins in liposomes: a novel approach to the chemical stability of drugs sensitive to hydrolysis. Int J Pharm 162:137–142

    Article  CAS  Google Scholar 

  • Malamed SF, Gagnon S, Leblanc D (2001) Articaine hydrochloride: a study of the safety of a new amide local anesthetic. J Am Dent Assoc 132:177–185

    Article  CAS  Google Scholar 

  • Meier MM, Luiz MTB, Szpoganicz B, Soldi V (2001) Thermal analysis behavior of β and γ-cyclodextrin inclusion complexes with capric and caprilic acid. Thermochim Acta 375:153–160

    Article  CAS  Google Scholar 

  • Misiuk W, Zalewska M (2011) Spectroscopic investigations on the inclusion interaction between hydroxypropyl-β-cyclodextrin and bupropion. J Mol Liq 159:220–225

    Article  CAS  Google Scholar 

  • Moore PA, Haas DA (2010) Paresthesias in dentistry. Dent Clin N Am 54:715–730. https://doi.org/10.1016/j.cden.2010.06.016

    Article  PubMed  Google Scholar 

  • Moraes CM, Abrami P, Araújo DR, Braga AFA, Issa MG, Ferraz HG, de Paula E, Fraceto LF (2007a) Characterization of lidocaine: hydroxypropyl-b-cyclodextrin inclusion complex. J Incl Phenom Macrocycl Chem 57:313–316

    Article  CAS  Google Scholar 

  • Moraes CM, Abrami P, de Paula E, Braga AFA, Fraceto LF (2007b) Study of the interaction between S(−) bupivacaine and 2-hydroxypropyl-beta-cyclodextrin. Int J Pharm 331:99–106. https://doi.org/10.1016/j.ijpharm.2006.09.054.b

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  Google Scholar 

  • Mura P (2015) Analytical techniques for characterization of cyclodextrin complexes in the solid state: a review. J Pharm Biomed Anal 113:226–238. https://doi.org/10.1016/j.jpba.2015.01.058

    Article  CAS  PubMed  Google Scholar 

  • Mura P, Maestrelli F, Cirri M, Furlanetto S, Pinzauti S (2003) Differential scanning calorimetry as an analytical tool in the study of drug-cyclodextrin interactions. J Therm Anal Calorim 73:635–646

    Article  CAS  Google Scholar 

  • Pellicer-Chover H, Cervera-Ballester J, Sanchis-Bielsa JM, Peñarrocha-Diago MA, Peñarrocha-Diago M, García-Mira B (2013) Comparative split-mouth study of the anesthetic efficacy of 4% articaine versus 0.5% bupivacaine in impacted mandibular third molar extraction. J Clin Exp Dent 5:66–71. https://doi.org/10.4317/jced.50869

    Article  Google Scholar 

  • Piccinni C, Gissi DB, Gabusi A, Montebugnoli L, Poluzzi E (2015) Paraesthesia after local anaesthetics: an analysis of reports to the FDA adverse event reporting system. Basic Clin Pharmacol Toxicol 117(1):52–56. https://doi.org/10.1111/bcpt.12357

    Article  CAS  PubMed  Google Scholar 

  • Pinto LM, Fraceto LF, Santana MH, Pertinhez TA, Junior SO, de Paula E (2005) Physico-chemical characterization of benzocaine-beta-cyclodextrin inclusion complexes. J Pharm Biomed Anal 39:956–963. https://doi.org/10.1016/j.jpba.2005.06.010

    Article  CAS  PubMed  Google Scholar 

  • Pogrel MA (2012) Permanent nerve damage from inferior alveolar nerve blocks: a current update. J Calif Dent Assoc 40:795–797

    PubMed  Google Scholar 

  • Prado AR, Yokaichiya F, Franco MKKD, Silva CMGD, Oliveira-Nascimento L, Franz-Montan M, Volpato MC, Cabeça LF, de Paula E (2017) Complexation of oxethazaine with 2-hydroxypropyl-β-cyclodextrin: increased drug solubility, decreased cytotoxicity and analgesia at inflamed tissues. J Pharm Pharmacol 69:652–662. https://doi.org/10.1111/jphp.12703

    Article  CAS  PubMed  Google Scholar 

  • Ramteke KH, Dighe PA, Kharat AR, Patil SV (2014) Mathematical models of drug dissolution: a review. Sch Acad J Pharm 3(5):388–396

    Google Scholar 

  • Serpe L, Franz-Montan M, Santos CP, Silva CB, Nolasco FP, Caldas CS, Volpato MC, Paula E, Groppo FC (2014) Anaesthetic efficacy of bupivacaine 2-hydroxypropyl-β-cyclodextrin for dental anaesthesia after inferior alveolar nerve block in rats. Br J Oral Maxillofac Surg 52:452–457. https://doi.org/10.1016/j.bjoms.2014.02.018

    Article  CAS  PubMed  Google Scholar 

  • Shafi AAA, Shihry SS (2009) Fluorescence enhancement of 1-napthol-5-sulfonate by forming inclusion complex with β-cyclodextrin in aqueous solution. Spectrochim Acta 72:533–537. https://doi.org/10.1016/j.saa.2008.10.052

    Article  CAS  Google Scholar 

  • Shen J, Burgess DJ (2012) Accelerated in vitro release testing methods for extended release parenteral dosage forms. J Pharm Pharmacol 64:986–996. https://doi.org/10.1111/j.2042-7158.2012.01482.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sosnowska NS (1997) Fluorometric determination of association constants of three estrogens with cyclodextrins. J Fluoresc 7:195–200

    Article  Google Scholar 

  • Tortamano IP, Siviero M, Lee S, Sampaio RM, Simone JL, Rocha RG (2013) Onset and duration period of pulpal anesthesia of articaine and lidocaine in inferior alveolar nerve block. Braz Dent J 24:371–374. https://doi.org/10.1590/0103-6440201302072

    Article  PubMed  Google Scholar 

  • Vermet G, Degoutin S, Chai F, Maton M, Bria M, Danel C, Hildebrand HF, Blanchemain N, Martel B (2014) Visceral mesh modified with cyclodextrin for the local sustained delivery of ropivacaine. Int J Pharm 476:149–159. https://doi.org/10.1016/j.ijpharm.2014.09.042

    Article  CAS  PubMed  Google Scholar 

  • Xiliang G, Yu Y, Guoyan Z, Guomei Z, Jianbin C, Shaomin S (2003) Study on inclusion interaction of piroxicam with beta-cyclodextrin derivatives. Spectrochim Acta A Mol Biomol Spectrosc 59:3379–3386

    Article  Google Scholar 

  • Yilmaz VT, Karadag A, Icebudak H (1995) Thermal decomposition of β-cyclodextrin inclusion complexes of ferrocene and their derivatives. Thermochim Acta 261:107–118

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank PhD. Estefânia Campos and PhD. Jhones Luis Oliveira for the orientation during the DSC and the sustained release kinetics experiments. Also, we thank PhD. Débora Campanella Bastos for the support on immunofluorescence assay.

Funding

This work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), FAPESP #2015/20942-6.

Author information

Authors and Affiliations

  1. Department of Physiological Sciences, Piracicaba Dental School, University of Campinas – UNICAMP, Avenida Limeira, 901, Piracicaba, SP, 13414-903, Brazil

    Jonny Burga-Sánchez, Maria Cristina Volpato & Francisco Carlos Groppo

  2. Laboratory of Inflammation and Immunology, Guarulhos University, Praça Teresa Cristina, 229 - Centro, Guarulhos, SP, 07023-070, Brazil

    Luiz Eduardo Nunes Ferreira

  3. Parana Federal Technological University – Londrina City, Avenida dos Pioneiros 3131, Jd Morumbi, Londrina, PR, 86036-370, Brazil

    Luis Fernando Cabeça

  4. Department of Biochemistry, Biology Institute, University of Campinas – UNICAMP, Rua Monteiro Lobato, 255, Campinas, SP, 13083-862, Brazil

    Mario Braga & Eneida de Paula

  5. Laboratory of Environmental Nanotechnology, Institute of Science and Technology of Sorocaba, São Paulo State University (UNESP), Av. Três de Março, 511 - Aparecidinha, Sorocaba, SP, 18087-180, Brazil

    Leonardo Fernandes Fraceto

Authors
  1. Jonny Burga-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luiz Eduardo Nunes Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Cristina Volpato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis Fernando Cabeça
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mario Braga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leonardo Fernandes Fraceto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eneida de Paula
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francisco Carlos Groppo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JBS, LENF, and MB contributed with the design the study, literature research, data collection, figure art, and manuscript preparation. LFC, LFF, and EP contributed with drug delivery systems preparation, conducted experiments and manuscript review. FCG and MCV contributed with the design the study, funding acquisition and manuscript review.

Corresponding author

Correspondence to Jonny Burga-Sánchez.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burga-Sánchez, J., Ferreira, L.E.N., Volpato, M.C. et al. Physicochemical characterization and cytotoxicity of articaine-2-hydroxypropyl-β-cyclodextrin inclusion complex. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1313–1323 (2020). https://doi.org/10.1007/s00210-020-01879-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-020-01879-1

Keywords

Search

Navigation