Pharmaceutical Research

, Volume 28, Issue 9, pp 2165–2175 | Cite as

Assessment of Topical Bioequivalence Using Dermal Microdialysis and Tape Stripping Methods

  • Tuba Incecayir
  • Ilbeyi Agabeyoglu
  • Ulver Derici
  • Sukru Sindel
Research Paper



To assess the bioequivalence of two commercial topical formulations of oxytetracycline HCl by tape stripping and microdialysis in healthy volunteers.


Tape stripping study was conducted on 12 healthy volunteers. After a 30-minute application of the formulations, adhesive tapes were used to sample stratum corneum at 0.25, 0.5, 1, 1.5, 2, 3, 4 hr. Ten of these volunteers were included in the microdialysis study with a period of 4 weeks between the experiments. Microdialysis probes were inserted into the dermis of the forearm. Following the application of the test and reference simultaneously, dialysates were collected in 30-minute sampling intervals up to 4 hr.


Pharmacokinetic evaluation by microdialysis yielded that the test could not be said to be bioequivalent to the reference at 90% CI. The intersubject variability of oxytetracycline content in stratum corneum was moderate when it was compared to the dermal levels. The test was found to be bioequivalent to reference according to the dermatopharmacokinetic evaluation by tape stripping.


No significant correlations were found between microdialysis and tape stripping methods as regarding the topical bioequivalence of oxytetracycline HCl formulations.


bioequivalence microdialysis oxytetracycline tape stripping topical 



area under the OTC content-time profile or area under the OTC concentration-time profile






amount of OTC at SC


confidence intervals




maximum observed OTC content of the DPK profile or maximum observed OTC concentration in dermis


coefficient of variation




dermal microdialysis




high performance liquid chromatography


absorption rate constant


elimination rate constant


limit of detection


limit of quantification




oxytetracycline HCl




relative recovery


stratum corneum


standard deviation


half life


time point at which Cmax was observed


lag time


tape stripping


ultra performance liquid chromatography tandem mass spectroscopy


area of distribution


volume of distribution



This study was supported by the research grant (107S177) from TUBITAK (The Turkish Scientific and Technological Research Council), which is gratefully acknowledged. The authors would like to thank Düzen-Norwest Laboratory, Ankara, Turkey, for the technical assistance in providing UPLC-MS-MS analysis.


  1. 1.
    Shah VP. Topical drug products-microdialysis: regulatory perspectives. Int J Clin Pharmacol Ther. 2004;42:379–81.Google Scholar
  2. 2.
    McCleverty D, Lyons R, Henry B. Microdialysis sampling and the clinical determination of topical dermal bioequivalence. Int J Pharm. 2006;308:1–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Narkar Y. Bioequivalence for topical products-an update. Pharm Res. 2010;27(12):2590–601.PubMedCrossRefGoogle Scholar
  4. 4.
    Wiedersberg S, Leopold CS, Guy RH. Dermatopharmacokinetics of betamethasone 17-valerate: influence of formulation viscosity and skin surface cleaning procedure. Eur J Pharm Biopharm. 2009;71:362–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Alberti I, Kalia YN, Naik A, Bonny J-D, Guy RH. In vivo assessment of enhanced topical delivery of terbinafine to human stratum corneum. J Control Release. 2001;71:319–27.PubMedCrossRefGoogle Scholar
  6. 6.
    Pershing LK, Nelson JL, Corlett JL, Shrivastava SP, Hare DB, Shah VP. Assessment of dermatopharmacokinetic approach in the bioequivalence determination of topical tretinoin gel products. J Am Acad Dermatol. 2003;48:740–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Plock N, Kloft C. Microdialysis-theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci. 2005;25:1–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Langer O, Müller M. Methods to assess tissue-specific distribution and metabolism of drugs. Curr Drug Metab. 2004;5:463–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Schnetz E, Fartasch M. Microdialysis for the evaluation of penetration through the human skin barrier-a promising tool for future research? Eur J Pharm Sci. 2001;12:165–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Kreilgaard M. Assessment of cutaneous drug delivery using microdialysis. Adv Drug Deliv Rev. 2002;54:S99–S121.PubMedCrossRefGoogle Scholar
  11. 11.
    Holmgaard R, Nielsen JB, Benfeldt E. Microdialysis sampling for investigations of bioavailability and bioequivalence of topically administered drugs: current state and future perspectives. Skin Pharmacol Physiol. 2010;23(5):225–43.PubMedCrossRefGoogle Scholar
  12. 12.
    Seagrave RC. Biomedical applications of heat and mass transfer. Ames: The Iowa State University Press; 1971.Google Scholar
  13. 13.
    Lange ECM, Boer AG, Breimer DD. Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev. 2000;45:125–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Ståhle L, Arner P, Ungerstedt U. Drug distribution studies with microdialysis III: extracellular concentration of caffeine in adipose tissue in man. Life Sci. 1991;49:1853–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Papadoyannis IN, Samanidou VF, Kovatsi LA. A rapid high performance liquid chromatographic (HPLC) assay for the determination of oxytetracycline in commercial pharmaceuticals. J Pharm Biomed Anal. 2000;23:275–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Sanderson H, Ingerslev F, Brain RA, Halling-Sǿrensen B, Bestari JK, Wilson CJ, et al. Dissipation of oxytetracycline, chlortetracycline, tetracycline and doxycycline using HPLC-UV and LC/MS/MS under aquatic semi-field microcosm conditions. Chemosphere. 2005;60:619–29.PubMedCrossRefGoogle Scholar
  17. 17.
    Rowland M, Tozer TN. Clinical pharmacokinetics: concept and applications. Philadelphia: Lea&Febiger; 1980.Google Scholar
  18. 18.
    Hadgraft J. Skin deep. Eur J Pharm Biopharm. 2004;58:291–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Herkenne C, Alberti I, Naik A, Kalia YN, Mathy F-X, Préat V, et al. In vivo methods for the assessment of topical drug bioavailablity. Pharm Res. 2008;25(1):87–103.PubMedCrossRefGoogle Scholar
  20. 20.
    Russell LM, Guy RH. Measurement and prediction of the rate and extent of drug delivery into and through the skin. Expert Opin Drug Deliv. 2009;6(4):355–69.PubMedCrossRefGoogle Scholar
  21. 21.
    Ortiz PG, Hansen SH, Shah VP, Menné T, Benfeldt E. Impact of adult atopic dermatitis on topical drug penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm Venereol. 2009;89:33–8.Google Scholar
  22. 22.
    Davies MI. A review of microdialysis sampling for pharmacokinetic applications. Anal Chim Acta. 1999;379:227–49.CrossRefGoogle Scholar
  23. 23.
    Kunin CM, Dornbush AC, Finland M. Distribution and excretion of four tetracycline analogues in normal young men. J Clin Invest. 1959;38(11):1950–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Benfeldt E, Serup J, Menné T. Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function. Br J Dermatol. 1999;140:739–48.PubMedCrossRefGoogle Scholar
  25. 25.
    Müller M, Mascher H, Kikuta C, Schäfer S, Brunner M, Dorner G, et al. Diclofenac concentrations in defined tissue layers after topical administration. Clin Pharmacol Ther. 1997;62:293–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Stagni G, O’Donnell D, Liu YJ, Kellogg DL, Morgan T, Shepherd AMM. Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in forearm dermis. J Control Release. 2000;63:331–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Hegemann L, Forstinger C, Partsch B, Lagler I, Krotz S, Wolff K. Microdialysis in cutaneous pharmacology: kinetic analysis of transdermally delivered nicotine. J Invest Dermatol. 1995;104:839–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Müller M, Schmid R, Wagner O, Osten B, Shayganfar H, Eichler HG. In vivo characterization of transdermal drug transport by microdialysis. J Control Release. 1995;37:49–57.CrossRefGoogle Scholar
  29. 29.
    Boelsma E, Anderson C, Karlsson AMJ, Ponec M. Microdialysis technique as a method to study the percutaneous penetration of methyl nicotinate through excised human skin, reconstructed epidermis, and human skin in vivo. Pharm Res. 2000;17(2):141–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Brunner M, Dehghanyar P, Seigfried B, Martin W, Menke G, Müller M. Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation. Br J Clin Pharmacol. 2005;60(5):573–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Cross SE, Anderson C, Roberts MS. Topical penetration of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies. Br J Clin Pharmacol. 1998;46:29–35.PubMedCrossRefGoogle Scholar
  32. 32.
    Kreilgaard M, Kemme MJB, Burggraaf J, Schoemaker RC, Cohen AF. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics. Pharm Res. 2001;18(5):593–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Tegeder I, Bräutigam L, Podda M, Meier S, Kaufmann R, Geisslinger G, et al. Time course of 8-methoxypsoralen concentrations in skin and plasma after topical (bath and cream) and oral administration of 8-methoxypsoralen. Clin Pharmacol Ther. 2002;71:153–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Benfeldt E, Hansen SH, Vølund A, Menné T, Shah VP. Bioequivalence of topical formulations in humans: evaluation by dermal microdialysis sampling and the dermatopharmacokinetic method. J Invest Dermatol. 2007;127:170–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Tettey-Amlalo RNO, Kanfer I, Skinner MF, Benfeldt E, Verbeeck RK. Application of dermal microdialysis for the evaluation of bioequivalence of a ketoprofen topical gel. Eur J Pharm Sci. 2009;36:219–25.PubMedCrossRefGoogle Scholar
  36. 36.
    Ortiz PG, Hansen SH, Shah VP, Sonne J, Benfeldt E. Are marketed topical metronidazole creams bioequivalent? Evaluation by in vivo microdialysis sampling and tape stripping methodology. Skin Pharmacol Physiol. 2011;24(1):44–53.CrossRefGoogle Scholar
  37. 37.
    Müller M. Science, medicine, and the future. Microdialysis BMJ. 2002;324:588–91.CrossRefGoogle Scholar
  38. 38.
    Midha KK, Shah VP, Singh GJP, Patnaik R. Conference report: Bio-International 2005. J Pharm Sci. 2007;96(4):747–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Pershing LK, Bakhtian S, Poncelet CE, Corlett JL, Shah VP. Comparison of skin stripping, in vitro release, and skin blanching response methods to measure dose response and similarity of triamcinolone acetonide cream strengths from two manufactured sources. J Pharm Sci. 2002;91(5):1312–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Lademann J, Jacobi U, Surber C, Weigmann H-J, Fluhr JW. The tape stripping procedure-evaluation of some critical parameters. Eur J Pharm Biopharm. 2009;72:317–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Breternitz M, Flach M, Präβler J, Elsner P, Fluhr JW. Acute barrier disruption by adhesive tapes is influenced by pressure, time and anatomical location: integrity and cohesion assessed by sequential tape stripping; a randomized, controlled study. Br J Dermatol. 2007;156:231–40.PubMedCrossRefGoogle Scholar
  42. 42.
    Löffler H, Dreher F, Maibach HI. Stratum corneum adhesive tape stripping: influence of anatomical site, application pressure, duration and removal. Br J Dermatol. 2004;151:746–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Boix-Montanes A. Relevance of equivalence assessment of topical products based on the dermatopharmacokinetics approach. Eur J Pharm Sci. 2011;42:173–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Caron D, Queille-Roussel C, Shah VP, Schaefer H. Correlation between the drug penetration and the blanching effect of topically applied hydrocortisone creams in human beings. J Am Acad Dermatol. 1990;23(3):458–62.PubMedCrossRefGoogle Scholar
  45. 45.
    Hadgraft J, Lane ME. Skin permeation: the years of enlightenment. Int J Pharm. 2005;305:2–12.PubMedCrossRefGoogle Scholar
  46. 46.
    Korting-Schäfer M, Mehnert W, Korting H-C. Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv Drug Deliv Rev. 2007;59:427–43.CrossRefGoogle Scholar
  47. 47.
    Morgan CJ, Renwick AG, Friedmann PS. The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis. Br J Dermatol. 2003;148:434–43.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Tuba Incecayir
    • 1
  • Ilbeyi Agabeyoglu
    • 1
  • Ulver Derici
    • 2
  • Sukru Sindel
    • 2
  1. 1.Department of Pharmaceutical Technology, Faculty of PharmacyGazi UniversityAnkaraTurkey
  2. 2.Department of Nephrology, Faculty of MedicineGazi UniversityAnkaraTurkey

Personalised recommendations