Skip to main content

Advertisement

SpringerLink
Log in

A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

The use of dental varnish for therapeutic purposes has been reported for fluoride or antibacterial drugs. Our objectives were to develop a sustained-release varnish containing an antifungal drug (clotrimazole) for topical application and to evaluate the release rate of the drug in human saliva in comparison with an available commercial troche and their acceptance by healthy volunteers. Following in vitro optimization of the release rate from the varnish, we have embarked on a crossover comparative study assessing the oral sensations and pharmacokinetics of a 10-mg clotrimazole oral troche versus a 10-mg sustained-release clotrimazole varnish in 14 human volunteers over a period of 5 h. Saliva samples were assessed for clotrimazole concentration by high performance liquid chromatography analysis. The volunteers’ evaluation of the varnish and troche (taste, other sensory changes, convenience, and oral suitability) were recorded. At all time points, salivary clotrimazole concentrations were higher, and the terminal half-life was significantly prolonged in the varnish group in comparison to the control group. This can be attributed to continuous release of clotrimazole from the varnish formulation. The duration of the drug over the minimal inhibitory concentration, following application of the varnish, was more than threefold longer than following administration of the troche. The developed sustained-release varnish can be applied in patients at a lower frequency than troches, thus, achieving higher patient compliance and efficacy. This novel varnish application can serve as the basis for a new treatment approach to oral candidiasis, a very common chronic opportunistic infection with improved clinical outcome.

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

Similar content being viewed by others

References

  1. Zhang Q, Van’t Hof MA, Truin GJ et al (2006) Caries-inhibiting effect of chlorhexidine varnish in pits and fissures. J Dent Res 85:469–472

    Article  PubMed  Google Scholar 

  2. Azarpazhooh A, Main PA (2008) Fluoride varnish in the prevention of dental caries in children and adolescents: a systematic review. J Can Dent Assoc 74:73–79

    PubMed  Google Scholar 

  3. Steinberg D, Tal T, Friedman M (2006) Sustained-release delivery systems of triclosan for treatment of Streptococcus mutans biofilm. J Biomed Mater Res B Appl Biomater 77:282–286

    PubMed  Google Scholar 

  4. Friedman M, Steinberg D (1990) Sustained-release delivery systems for treatment of dental diseases. Pharm Res 7:313–317

    Article  PubMed  Google Scholar 

  5. Rex JH, Walsh TJ, Sobel JD et al (2000) Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis 30:662–678

    Article  PubMed  Google Scholar 

  6. Ellepola AN, Samaranayake LP (2000) Oral candidal infections and antimycotics. Crit Rev Oral Biol Med 11:172–198

    Article  PubMed  Google Scholar 

  7. Zegarelli DJ (1993) Fungal infections of the oral cavity. Otolaryngol Clin North Am 26:1069–1089

    PubMed  Google Scholar 

  8. Cunha-Cruz J (2006) One in 3 removable denture users in the United States has denture stomatitis. J Evid Based Dent Pract 6:197–198

    Article  PubMed  Google Scholar 

  9. Figueiral MH, Azul A, Pinto E et al (2007) Denture-related stomatitis: identification of aetiological and predisposing factors—a large cohort. J Oral Rehabil 34:448–455

    Article  PubMed  Google Scholar 

  10. Haveman CW (2004) Xerostomia management in the head and neck radiation patient. Tex Dent J 121:483–497

    PubMed  Google Scholar 

  11. Holmberg K, Meyer RD (1986) Fungal infections in patients with AIDS and AIDS-related complex. Scand J Infect Dis 18:179–192

    Article  PubMed  Google Scholar 

  12. Kostler WJ, Hejna M, Wenzel C et al (2001) Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 51:290–315

    Article  PubMed  Google Scholar 

  13. Samaranayake LP, Cheung KL, Samaranayake YH (2002) Candidiasis and other fungal diseases of the mouth. Dermatol Ther 15:251–269

    Article  Google Scholar 

  14. Torres SR, Peixoto CB, Caldas DM et al (2002) Relationship between salivary flow rates and Candida counts in subjects with xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 93:149–154

    Article  Google Scholar 

  15. Jainkittivong A, Kuvatanasuchati J, Pipattanagovit P et al (2007) Candida in oral lichen planus patients undergoing topical steroid therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:61–66

    Article  PubMed  Google Scholar 

  16. Akpan A, Morgan R (2002) Oral candidiasis. Postgrad Med J 78:455–459

    Article  PubMed  Google Scholar 

  17. Torres-Rodriguez JM, Mendez R, Lopez-Jodra O et al (1999) In vitro susceptibilities of clinical yeast isolates to the new antifungal eberconazole compared with their susceptibilities to clotrimazole and ketoconazole. Antimicrob Agents Chemother 43:1258–1259

    PubMed  Google Scholar 

  18. Ruskin JD, Wood RP, Bailey MR et al (1992) Comparative trial of oral clotrimazole and nystatin for oropharyngeal candidiasis prophylaxis in orthotopic liver transplant patients. Oral Surg Oral Med Oral Pathol 74:567–571

    Article  PubMed  Google Scholar 

  19. Redding SW (2005) Cancer therapy-related oral mucositis. J Dent Educ 69:919–929

    PubMed  Google Scholar 

  20. Worthington HV, Clarkson JE (2002) Prevention of oral mucositis and oral candidiasis for patients with cancer treated with chemotherapy: Cochrane systematic review. J Dent Educ 66:903–911

    PubMed  Google Scholar 

  21. Steinberg D, Moldovan M, Molukandov D (2001) Testing a degradable topical varnish of cetylpyridinium chloride in an experimental dental biofilm model. J Antimicrob Chemother 48:241–243

    Article  PubMed  Google Scholar 

  22. Steinberg D, Rozen R, Klausner EA et al (2002) Formulation, development and characterization of sustained release varnishes containing amine and stannous fluorides. Caries Res 36:411–416

    Article  PubMed  Google Scholar 

  23. Chang JY, Oh YK, Kong HS et al (2002) Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis. J Control Release 82:39–50

    Article  PubMed  Google Scholar 

  24. Steinberg D, Hirschfeld Z, Tayeb I et al (1999) The effect of parabens in a mouthwash and incorporated into a sustained release varnish on salivary bacteria. J Dent 27:101–106

    Article  PubMed  Google Scholar 

  25. Balanyk TE, Sandham HJ (1985) Development of sustained-release antimicrobial dental varnishes effective against Streptococcus mutans in vitro. J Dent Res 64:1356–1360

    PubMed  Google Scholar 

  26. Bouckaert S, Schautteet H, Lefebvre RA et al (1992) Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel. Eur J Clin Pharmacol 43:137–140

    Article  PubMed  Google Scholar 

  27. Steinberg D, Tal T, Friedman M (2005) Sustained-release delivery systems of triclosan for treatment of Streptococcus mutans biofilm. J Biomed Mater Res B Appl Biomater 77B(2):282–286

    Google Scholar 

  28. de Bruijn P, Kehrer DF, Verweij J et al (2001) Liquid chromatographic determination of ketoconazole, a potent inhibitor of CYP3A4-mediated metabolism. J Chromatogr B Biomed Sci Appl 753:395–400

    Article  PubMed  Google Scholar 

  29. Yang W, Wiederhold N, Williams R (2008) Drug delivery strategies for improved azole antifungal action. Expert Opin Drug Deliv 5:1199–1216

    Article  PubMed  Google Scholar 

  30. Dar-Odeh NS, Shehabi AA (2003) Oral candidosis in patients with removable dentures. Mycoses 46:187–191

    Article  PubMed  Google Scholar 

  31. Webb BC, Thomas CJ, Willcox MD et al (1998) Candida-associated denture stomatitis. Aetiology and management: a review. Part 1. Factors influencing distribution of Candida species in the oral cavity. Aust Dent J 43:45–50

    Article  PubMed  Google Scholar 

  32. Compagnoni MA, Souza RF, Marra J et al (2007) Relationship between Candida and nocturnal denture wear: quantitative study. J Oral Rehabil 34:600–605

    Article  PubMed  Google Scholar 

  33. Webb BC, Thomas CJ, Willcox MD et al (1998) Candida-associated denture stomatitis. Aetiology and management: a review. Part 3. Treatment of oral candidosis. Aust Dent J 43:244–249

    Article  PubMed  Google Scholar 

  34. Yu DT, Peterson JF, Seger DL, Gerth WC, Bates DW (2005) Frequency of potential azole drug–drug interactions and consequences of potential fluconazole drug interactions. Pharmacoepidemiol Drug Saf 14:755–767

    Article  PubMed  Google Scholar 

  35. Zhang A, Camp W, Elewski B (2007) Advances in topical and systemic antifungals. Dermatol Cli 25:165–183

    Article  Google Scholar 

  36. Kripalani S, Yao X, Haynes RB (2007) Interventions to enhance medication adherence in chronic medical conditions: a systematic review. Arch Intern Med 167:540–550

    Article  PubMed  Google Scholar 

  37. van Eijken M, Tsang S, Wensing M et al (2003) Interventions to improve medication compliance in older patients living in the community: a systematic review of the literature. Drugs Aging 20:229–240

    Article  PubMed  Google Scholar 

  38. Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497

    Article  PubMed  Google Scholar 

  39. Bloom BS (2001) Daily regimen and compliance with treatment. BMJ 323:647

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. The Department of Oral Medicine, Hebrew University-Hadassah Medical Center, P.O. Box 12272, Jerusalem, 91120, Israel

    Rakefet Czerninski & Sagi Sivan

  2. Institute of Dental Sciences, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

    Sagi Sivan & Doron Steinberg

  3. Department of Pharmaceutics, Hebrew University-School of Pharmacy, Jerusalem, Israel

    Irith Gati, Leonid Kagan & Michael Friedman

Authors
  1. Rakefet Czerninski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sagi Sivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Doron Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Irith Gati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leonid Kagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rakefet Czerninski.

Additional information

Rakefet Czerninski, Doron Steinberg, and Michael Friedman have equal contribution as PIs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Czerninski, R., Sivan, S., Steinberg, D. et al. A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis. Clin Oral Invest 14, 71–78 (2010). https://doi.org/10.1007/s00784-009-0275-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-009-0275-3

Keywords

Search

Navigation