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Pharmaceutical Research

, Volume 22, Issue 8, pp 1313–1319 | Cite as

Dermal, Subdermal, and Systemic Concentrations of Granisetron by Iontophoretic Delivery

  • Ayyappa Chaturvedula
  • Dipty P. Joshi
  • Carter Anderson
  • Russ Morris
  • Walter L. Sembrowich
  • Ajay K. Banga
Research Paper

Purpose

The purpose of this work was to demonstrate the iontophoretic delivery of granisetron hydrochloride by novel, self-contained iontophoretic patches and to determine the subcutaneous and dermal absorption kinetics using microdialysis.

Methods

In vitro iontophoretic delivery of granisetron hydrochloride was evaluated at 5, 10, or 20 mg/ml concentrations of donor using Franz diffusion cells and hairless rat skin as a membrane. In vivo studies were performed in hairless rats. Animals received either subcutaneous or dermal microdialysis probes and iontophoretic patches filled with drug formulation were applied on the abdominal area such that the probe lies below the anode chamber. Blood and microdialysate samples were collected at different time intervals. Intravenous administration of granisetron was also done to determine the basic pharmacokinetic parameters.

Results

Iontophoretic patches delivered current constantly throughout the patch application. The patches delivered granisetron hydrochloride at a rate of 14.91 ± 4.53 μg/min/kg. Similar concentrations of granisetron hydrochloride in dermal and subcutaneous tissue were observed. Depot formation was identified in the subcutaneous and dermal profiles, indicating that subcutaneous structures are also responsible for the depot formation of the drug in the dermis.

Conclusion

The patches successfully delivered granisetron hydrochloride by iontophoresis and depot formation was observed in the dermal and subcutaneous structures in the skin.

Key Words

granisetron iontophoresis microdialysis pharmacokinetics 

Abbreviations

AUC

area under the curve

ECF

extracellular fluid

HPLC

high-performance liquid chromatography

NCA

noncompartmental analysis

RF

recovery factor

Notes

Acknowledgments

This project was funded by Travanti Pharma Inc., Oakdale, MN 55128. We would like to thank Pharsight Inc., Mountain View, CA, for providing us the academic license for WinNonlin Pro software.

References

  1. 1.
    Guy, R. H., Kalia, Y. N., Delgado-Charro, M. B., Merino, V., Lopez, A., Marro, D. 2000Iontophoresis: electrorepulsion and electroosmosisJ. Control. Release64129132CrossRefPubMedGoogle Scholar
  2. 2.
    Conjeevaram, R., Banga, A. K., Zhang, L. 2002Electrically modulated transdermal delivery of fentanylPharm. Res.19440444CrossRefPubMedGoogle Scholar
  3. 3.
    Stagni, G., Shukla, C. 2003Pharmacokinetics of methotrexate in rabbit skin and plasma after i.v.-bolus and iontophoretic administrationsJ. Control. Release93283292CrossRefPubMedGoogle Scholar
  4. 4.
    Stagni, G., Ali, M. E., Weng, D. 2004Pharmacokinetics of acyclovir in rabbit skin after i.v.-bolus, ointment, and iontophoretic administrationsInt. J. Pharm.274201211CrossRefPubMedGoogle Scholar
  5. 5.
    Fang, J. Y., Sung, K. C., Lin, H. H., Fang, C. L. 1999Transdermal iontophoretic delivery of diclofenac sodium from various polymer formulations: in vitro and in vivo studiesInt. J. Pharm.1788392CrossRefPubMedGoogle Scholar
  6. 6.
    Fang, J. Y., Hsu, L. R., Huang, Y. B., Tsai, Y. H. 1999Evaluation of transdermal iontophoresis of enoxacin from polymer formulations: in vitro skin permeation and in vitro microdialysis using Wistar rat as an animal modelInt. J. Pharm.180137149CrossRefPubMedGoogle Scholar
  7. 7.
    Stagni, G., O’Donnell, D., Liu, Y. J., Kellogg, D. L., Morgan, T., Shepherd, A. M. 2000Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in forearm dermisJ. Control. Release63331339CrossRefPubMedGoogle Scholar
  8. 8.
    Graumlich, J. F., McLaughlin, R. G., Birkhahn, D., Shah, N., Burk, A., Jobe, P. C., Dailey, J. W. 2000Subcutaneous microdialysis in rats correlates with carbamazepine concentrations in plasma and brainEpilepsy Res.402532CrossRefPubMedGoogle Scholar
  9. 9.
    Groth, L., Jorgensen, A., Serup, J. 1998Cutaneous microdialysis in the rat: insertion trauma studied by ultrasound imagingActa Dermatol. Venereol.781014CrossRefGoogle Scholar
  10. 10.
    Groth, L., Serup, J. 1998Cutaneous microdialysis in man: effects of needle insertion trauma and anaesthesia on skin perfusion, erythema and skin thicknessActa Derm.-Venereol.7859CrossRefPubMedGoogle Scholar
  11. 11.
    Clarke, S. E., Austin, N. E., Bloomer, J. C., Haddock, R. E., Higham, F. C., Hollis, F. J., Nash, M., Shardlow, P. C., Tasker, T. C., Woods, F. R. 1994Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosingXenobiotica2411191131PubMedGoogle Scholar
  12. 12.
    Sintov, A. C., Krymberk, I., Daniel, D., Hannan, T., Sohn, Z., Levin, G. 2003Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugsJ. Control. Release89311320CrossRefPubMedGoogle Scholar
  13. 13.
    Ludden, T. M., Beal, S. L., Sheiner, L. B. 1994Comparison of the Akaike Information Criterion, the Schawarz criterion and the F test as guides to model selectionJ. Pharmacokinet. Biopharm.22431435PubMedGoogle Scholar
  14. 14.
    Marro, D., Kalia, Y. N., Delgado-Charro, M. B., Guy, R. H. 2001Contributions of electromigration and electroosmosis to iontophoretic drug deliveryPharm. Res.1817011708CrossRefPubMedGoogle Scholar
  15. 15.
    Kalia, Y. N., Naik, A., Garrison, J., Guy, R. H. 2004Iontophoretic drug deliveryAdv. Drug Deliv. Rev.56619658CrossRefPubMedGoogle Scholar
  16. 16.
    Williams, P. L., Riviere, J. E. 1995A biophysically based dermatopharmacokinetic compartment model for quantifying percutaneous penetration and absorption of topically applied agents. I. TheoryJ. Pharm. Sci.84599608PubMedGoogle Scholar
  17. 17.
    Luzardo-Alvarez, A., Delgado-Charro, M. B., Blanco-Mendez, J. 2003In vivo iontophoretic administration of ropinirole hydrochlorideJ. Pharm. Sci.9224412448CrossRefPubMedGoogle Scholar
  18. 18.
    Kankkunen, T., Sulkava, R., Vuorio, M., Kontturi, K., Hirvonen, J. 2002Transdermal iontophoresis of tacrine in vivoPharm. Res.19704707CrossRefPubMedGoogle Scholar
  19. 19.
    Prausnitz, M. R., Lee, C. S., Liu, C. H., Pang, J. C., Singh, T.-P., Langer, R., Weaver, J. C. 1996Transdermal transport efficiency during skin electroporation and iontophoresisJ. Control. Release38205217CrossRefGoogle Scholar
  20. 20.
    Singh, P., Roberts, M. S., Maibach, H. I. 1995Modelling of plasma levels of drugs following transdermal iontophoresisJ. Control. Release33293298CrossRefGoogle Scholar
  21. 21.
    Huang, C. T., Chen, C. F., Tsai, T. H. 1999Pharmacokinetics of granisetron in rat blood and brain by microdialysisLife Sci.6419211931CrossRefPubMedGoogle Scholar
  22. 22.
    Mathy, F. X., Denet, A. R., Vroman, B., Clarys, P., Barel, A., Verbeeck, R. K., Preat, V. 2003In vivo tolerance assessment of skin after insertion of subcutaneous and cutaneous microdialysis probes in the ratSkin Pharmacol. Appl. Skin Physiol.161827CrossRefPubMedGoogle Scholar
  23. 23.
    Singh, P., Roberts, M. S. 1993Iontophoretic transdermal delivery of salicylic acid and lidocaine to local subcutaneous structuresJ. Pharm. Sci.82127131PubMedGoogle Scholar
  24. 24.
    Banga, A. K., Bose, S., Ghosh, T. K. 1999Iontophoresis and electroporation: comparisons and contrastsInt. J. Pharm.179119CrossRefPubMedGoogle Scholar
  25. 25.
    Turner, N. G., Guy, R. H. 1997Iontophoretic transport pathways: dependence on penetrant physicochemical propertiesJ. Pharm. Sci.8613851389CrossRefPubMedGoogle Scholar
  26. 26.
    Li, S. K., Ghanem, A. H., Peck, K. D., Higuchi, W. I. 1999Pore induction in human epidermal membrane during low to moderate voltage iontophoresis: a study using AC iontophoresisJ. Pharm. Sci.88419427CrossRefPubMedGoogle Scholar
  27. 27.
    Singh, P., Roberts, M. S. 1993Blood flow measurements in skin and underlying tissues by microsphere method: application to dermal pharmacokinetics of polar nonelectrolytesJ. Pharm. Sci.82873879PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Ayyappa Chaturvedula
    • 1
    • 3
  • Dipty P. Joshi
    • 1
    • 4
  • Carter Anderson
    • 2
  • Russ Morris
    • 2
  • Walter L. Sembrowich
    • 2
  • Ajay K. Banga
    • 1
  1. 1.Department of Pharmaceutical SciencesMercer UniversityAtlantaUSA
  2. 2.Travanti Pharma Inc.OakdaleUSA
  3. 3.GlaxoSmithKlineParsipannyUSA
  4. 4.Vyteris Inc.FairlawnUSA

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