Skip to main content

Advertisement

SpringerLink
Log in

Topical Iontophoresis of Valaciclovir Hydrochloride Improves Cutaneous Aciclovir Delivery

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

To investigate the topical iontophoresis of valaciclovir (VCV) as a means to improve cutaneous aciclovir (ACV) delivery.

Methods

ACV and VCV electrotransport experiments were conducted using excised porcine skin in vitro.

Results

While the charged nature of the prodrug, VCV, enabled it to be more efficiently iontophoresed into the skin than the parent molecule, ACV, only the latter was detectable in the receptor chamber, suggesting that VCV was enzymatically cleaved into the active metabolite during skin transit. Iontophoresis of VCV was significantly more efficient than that of ACV; the cumulative permeation of ACV after 1, 2 and 3 h of VCV iontophoresis at 0.5 mA cm−2 and using an aqueous 2 mM (∼0.06%) formulation was 20 ± 10, 104 ± 47 and 194 ± 82 μg cm−2, respectively (cf. non-quantifiable levels, 0.1 and 1.0 ± 0.7 μg cm−2 after ACV iontophoresis).

Conclusions

These delivery rates provide ample room to reduce either current density or the duration of current application. Preliminary in vitro data serve to emphasize the potential of VCV iontophoresis to improve the topical therapy of cutaneous herpes simplex infections and merit further investigation to demonstrate clinical efficacy.

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

Similar content being viewed by others

References

  1. S. L. Spruance, R. Nett, T. Marbury, R. Wolff, J. Johnson, and T. Spaulding. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob. Agents Chemother. 46:2238–2243 (2002).

    Article  PubMed  CAS  Google Scholar 

  2. G. W. Raborn and M. G. A. Grace. Recurrent herpes simplex labialis: selected therapeutic options. J. Can. Dent. Assoc. 69:498–503 (2003).

    PubMed  Google Scholar 

  3. S. L. Spruance and C.S. Crumpacker. Topical 5 percent acyclovir in polyethylene glycol for herpes simplex labialis. Antiviral effect without clinical benefit. Am. J. Med. 73:315–319 (1982).

    Article  PubMed  CAS  Google Scholar 

  4. S. L. Spruance, L. E. Schnipper, J. C. Overall Jr, E. R. Kern, B. Wester, J. Modlin, G. Wenerstrom, C. Burton, G. L. Chiu, and C. S. Crumpacker. Treatment of herpes simplex labialis with topical acyclovir in polyethylene glycol. J. Infect. Dis. 146:85–90 (1982).

    PubMed  CAS  Google Scholar 

  5. A. P. Fiddian and L. Ivanyi. Topical acyclovir in the management of recurrent herpes labialis. Br. J. Dermatol. 109:321–326 (1983).

    Article  PubMed  CAS  Google Scholar 

  6. J. M. Yeo and A. P. Fiddian. Acyclovir in the management of herpes labialis. J. Antimicrob. Chemother. 12:95–103 (1983).

    PubMed  Google Scholar 

  7. S. L. Spruance, C. S. Crumpacker, L. E. Schnipper, E. R. Kern, S. Marlowe, K. A. Arndt, and J. C. Overall Jr. Early, patient-initiated treatment of herpes labialis with topical 10% acyclovir. Antimicrob. Agents Chemother. 25:553–555 (1984).

    PubMed  CAS  Google Scholar 

  8. D. J. Freeman, N. V. Sheth, and S. L. Spruance. Failure of topical acyclovir in ointment to penetrate human skin. Antimicrob. Agents Chemother. 29:730–732 (1986).

    PubMed  CAS  Google Scholar 

  9. S. L. Spruance, M. B. McKeough, and J. R. Cardinal. Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection. Antimicrob. Agents Chemother. 25:10–15 (1984).

    PubMed  CAS  Google Scholar 

  10. S. L. Spruance, D. J. Freeman, and N. V. Sheth. Comparison of foscarnet cream, acyclovir cream, and acyclovir ointment in the topical treatment of experimental cutaneous herpes simplex virus type 1 infection. Antimicrob. Agents Chemother. 30:196–198 (1986).

    PubMed  CAS  Google Scholar 

  11. G. E. Parry, P. Dunn, V. P. Shah, and L. K. Pershing. Acyclovir bioavailability in human skin. J. Invest. Dermatol. 98:856–863 (1992).

    Article  PubMed  CAS  Google Scholar 

  12. J. Piret, A. Desormeaux, P. Gourde, J. Juhasz, and M. G. Bergeron. Efficacies of topical formulations of foscarnet and acyclovir and of 5-percent acyclovir ointment (Zovirax®) in a murine model of cutaneous herpes simplex virus type 1 infection. Antimicrob. Agents Chemother. 44:30–38 (2000).

    Article  PubMed  CAS  Google Scholar 

  13. Y. N. Kalia, A. Naik, J. Garrison, and R. H. Guy. Iontophoretic drug delivery. Adv. Drug Deliv. Rev. 56:619–658 (2004).

    Article  PubMed  CAS  Google Scholar 

  14. N. Abla, A. Naik, R. H. Guy, and Y. N. Kalia. Iontophoresis: clinical applications and future challenges. In E. W. Smith and H. I. Maibach (eds.), Percutaneous Penetration Enhancers, In Press, CRC, Boca Raton, Florida, 2005, pp. 177–219.

    Google Scholar 

  15. S. Gangarosa and J. M. Hill. Modern iontophoresis for local drug delivery. Int. J. Pharm. 123:159–171 (1995).

    Article  CAS  Google Scholar 

  16. N. M. Volpato, P. Santi, and P. Colombo. Iontophoresis enhances the transport of acyclovir through nude mouse skin by electrorepulsion and electroosmosis. Pharm. Res. 12:1623–1627 (1995).

    Article  PubMed  CAS  Google Scholar 

  17. N. M. Volpato, S. Nicoli, C. Laureri, P. Colombo, and P. Santi. In vitro acyclovir distribution in human skin layers after transdermal iontophoresis. J. Control. Release 50:291–296 (1998).

    Article  PubMed  CAS  Google Scholar 

  18. G. Stagni, M. E. Ali, and D. Weng. Pharmacokinetics of acyclovir in rabbit skin after IV-bolus, ointment, and iontophoretic administrations. Int. J. Pharm. 274:201–211 (2004).

    Article  PubMed  CAS  Google Scholar 

  19. C. Padula, F. Sartori, F. Marra, and P. Santi. The influence of iontophoresis on acyclovir transport and accumulation in rabbit ear skin. Pharm. Res. 22:1519–1524 (2005).

    Article  PubMed  CAS  Google Scholar 

  20. W. T. Zempsky, J. Sullivan, D. M. Paulson, and S. B. Hoath. Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial. Clin. Ther. 26:1110–1119 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. L. M. Beauchamp, G. F. Orr, P. de Miranda, T. Burnette, T. A. Krenitsky. Amino acid ester prodrugs of acyclovir. Antivir. Chem. Chemother. 3:157–164 (1992).

    CAS  Google Scholar 

  22. M. A. Jacobson. Valaciclovir (BW256U87): the l-valyl ester of acyclovir. J. Med. Virol. Suppl. 1:150–153 (1993).

    Article  PubMed  Google Scholar 

  23. J. Soul-Lawton, E. Seaber, N. On, R. Wootton, P. Rolan, and J. Posner. Absolute bioavailability and metabolic disposition of valaciclovir, the l-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 39:2759–2764 (1995).

    PubMed  CAS  Google Scholar 

  24. B. S. Anand, S. Katragadda, and A. K. Mitra. Pharmacokinetics of novel dipeptide ester prodrugs of acyclovir after oral administration: intestinal absorption and liver metabolism. J. Pharmacol. Exp. Ther. 311:659–667 (2004).

    Article  PubMed  CAS  Google Scholar 

  25. C. J. Martin and A. E. Axelrod. Proteolytic enzyme system of skin. II. Characterization of esterase activities. Biochim. Biophys. Acta 26:490–501 (1957).

    Article  PubMed  CAS  Google Scholar 

  26. J. Boehnlein, A. Sakr, J. L. Lichtin, and R. L. Bronaugh. Characterization of esterase and alcohol dehydrogenase activity in skin. Metabolism of retinyl palmitate of retinol (vitamin A) during percutaneous absorption. Pharm. Res. 11:1155–1159 (1994).

    Article  PubMed  CAS  Google Scholar 

  27. N. Abla, A. Naik, R. H. Guy, and Y. N. Kalia. Effect of charge and molecular weight on transdermal peptide delivery by iontophoresis. Pharm. Res. 22:2069–2078 (2005).

    Article  PubMed  CAS  Google Scholar 

  28. S. Gerscher, J. P. Connelly, J. Griffiths, S. B. Brown, A. J. MacRobert, G. Wong, and L. E. Rhodes. Comparison of the pharmacokinetics and phototoxicity of protoporphyrin IX metabolized from 5-aminolevulinic acid and two derivatives in human skin in vivo. Photochem. Photobiol. 72:569–574 (2000).

    Article  PubMed  CAS  Google Scholar 

  29. K. C. Sung, J. Y. Fang, and O. Yoa-Pu Hu. Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis. J. Control. Release 67:1–8 (2000).

    Article  PubMed  CAS  Google Scholar 

  30. S. Gerscher, J. P. Connelly, G. M. J. Beijersbergen Van Henegouwen, A. J. MacRobert, P. Watt, and L. E. Rhodes. A quantitative assessment of protoporphyrin IX metabolism and phototoxicity in human skin following dose-controlled delivery of the prodrugs 5-aminolaevulinic acid and 5-aminolaevulinic acid-n-pentylester. Br. J. Dermatol. 144:983–990 (2001).

    Article  PubMed  CAS  Google Scholar 

  31. R. F. V. Lopez, M. V. Bentley, M. B. Delgado-Charro, D. Salomon, H. van den Bergh, N. Lange, and R. H. Guy. Enhanced delivery of 5-aminolevulinic acid esters by iontophoresis in vitro. Photochem. Photobiol. 77:304–308 (2003).

    Article  PubMed  CAS  Google Scholar 

  32. S. Laneri, A. Sacchi, E. Abignente di Frassello, E. Luraschi, P. Colombo, and P. Santi. Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic delivery. Pharm. Res. 16:1818–1824 (1999).

    Article  PubMed  CAS  Google Scholar 

  33. I. P. Dick and R. C. Scott. Pig ear skin as an in-vitro model for human skin permeability. J. Pharm. Pharmacol. 44:640–645 (1992).

    PubMed  CAS  Google Scholar 

  34. N. Sekkat, Y. N. Kalia, and R. H. Guy. Biophysical study of porcine ear skin in vitro and its comparison to human skin in vivo. J. Pharm. Sci. 91:2376–2381 (2002).

    Article  PubMed  CAS  Google Scholar 

  35. B. S. Anand and A. K. Mitra. Mechanism of corneal permeation of l-valyl ester of acyclovir: targeting the oligopeptide transporter on the rabbit cornea. Pharm. Res. 19:1194–1202 (2002).

    Article  PubMed  CAS  Google Scholar 

  36. I. Steinstrasser and H. P. Merkle. Dermal metabolism of topically applied drugs: pathways and models reconsidered. Pharm. Acta Helv. 70:3–24 (1995).

    Article  PubMed  CAS  Google Scholar 

  37. Calculated using Advanced Chemistry Development (ACL/Labs) Software v,8.14 for Solaris (1994–2005 ACD/Labs).

  38. F. Yamashita, Y. Koyama, H. Sezaki, and M. Hashida. Estimation of a concentration profile of acyclovir in the skin after topical administration. Int. J. Pharm. 89:199–206 (1993).

    Article  CAS  Google Scholar 

  39. R. V. Padmanabhan, J. B. Phipps, G. A. Lattin, and R. J. Sawchuk. In vitro and in vivo evaluation of transdermal iontophoretic delivery of hydromorphone. J. Control. Release 11:123–135 (1990).

    Article  CAS  Google Scholar 

  40. P. Singh, S. Boniello, P. Liu, and S. Dinh. Transdermal iontophoretic delivery of methylphenidate HCl in vitro. Int. J. Pharm. 178:121–128 (1999).

    Article  PubMed  CAS  Google Scholar 

  41. D. Marro, Y. N. Kalia, M. B. Delgado-Charro, and R. H. Guy. Contributions of electromigration and electroosmosis to iontophoretic drug delivery. Pharm. Res. 18:1701–1708 (2001).

    Article  PubMed  CAS  Google Scholar 

  42. G. B. Kasting and J. C. Keister. Application of electrodiffusion theory for a homogeneous membrane to iontophoretic transport through skin. J. Control. Release 8:195–210 (1989).

    Article  CAS  Google Scholar 

  43. B. H. Sage Jr. Iontophoresis. In E. W. Smith and H. I. Maibach (eds.), Percutaneous Penetration Enhancers, CRC, Boca Raton, Florida, 1995, pp. 351–368.

    Google Scholar 

  44. Y. B. Schuetz, A. Naik, R. H. Guy, E. Vuaridel, and Y. N. Kalia. Transdermal iontophoretic delivery of vapreotide acetate across porcine skin in vitro. Pharm. Res. 22:1305–1312 (2005).

    Article  PubMed  CAS  Google Scholar 

  45. A. L. Stinchcomb, A. Paliwal, R. Dua, H. Imoto, R. W. Woodward, and G. L. Flynn. Permeation of buprenorphine and its 3-alkyl-ester prodrugs through human skin. Pharm. Res. 13:1519–1523 (1996).

    Article  PubMed  CAS  Google Scholar 

  46. H. Bundgaard, N. Mork, and A. Hoelgaard. Enhanced delivery of nalidixic acid through human skin via acyloxymethyl ester prodrugs. Int. J. Pharm. 55:91–97 (1989).

    Article  CAS  Google Scholar 

  47. G. Nicolau and A. Yacobi. Transdermal absorption and skin metabolism of viprostol, a synthetic prostaglandin E2 analogue. Drug Metab. Rev. 21:401–425 (1990).

    Article  CAS  Google Scholar 

  48. T. Seki, T. Kawaguchi, and K. Juni. Enhanced delivery of zidovidudine through rat and human skin via ester prodrugs. Pharm. Res. 7:948–952 (1990).

    Article  PubMed  CAS  Google Scholar 

  49. U. Täuber and K. L. Rost. Esterase activity of the skin including species variation. In B. Shroot and H. Schaefer (eds.), Pharmacology and the Skin Vol. 1, Skin Pharmacokinetics, Karger, Basel, 1987, pp. 170–183.

    Google Scholar 

  50. G. C. Santus, N. Watari, R. S. Hinz, L. Z. Benet, and R. H. Guy. Cutaneous metabolism of transdermally delivered nitroglycerin in vitro. In B. Shroot and H. Schaefer (eds.), Pharmacology and the Skin Vol. 1, Skin Pharmacokinetics, Karger, Basel, 1987, pp. 240–244.

    Google Scholar 

  51. P. W. Ledger. Skin biological issues in electrically enhanced transdermal delivery. Adv. Drug Deliv. Rev. 9:289–307 (1992).

    Article  CAS  Google Scholar 

  52. R. O. Potts, S. C. McNeill, C. R. Desbonnet, and E. Wakshull. Transdermal drug transport and metabolism. II. The role of competing kinetic events. Pharm. Res. 6:119–124 (1989).

    Article  PubMed  CAS  Google Scholar 

  53. P. Boderke, H. P. Merkle, C. Cullander, M. Ponec, and H. E. Bodde. Localization of aminopeptidase activity in freshly excised human skin: direct visualization by confocal laser scanning microscopy. J. Invest. Dermatol. 108:83–86 (1997).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

AN would like to thank the Fonds National Suisse (Swiss National Science Foundation) for financial support.

Author information

Author notes

  1. Richard H. Guy

    Present address: Department of Pharmacy & Pharmacology, University of Bath, Bath, BA2 7AY, England, UK

Authors and Affiliations

  1. School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 1211, Geneva, Switzerland

    Nada Abla, Aarti Naik, Richard H. Guy & Yogeshvar N. Kalia

  2. Centre Interuniversitaire de Recherche et d'Enseignement, «Pharmapeptides» Site d'Archamps, F-74160, Archamps, France

    Nada Abla, Aarti Naik & Yogeshvar N. Kalia

Authors
  1. Nada Abla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aarti Naik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard H. Guy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yogeshvar N. Kalia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yogeshvar N. Kalia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abla, N., Naik, A., Guy, R.H. et al. Topical Iontophoresis of Valaciclovir Hydrochloride Improves Cutaneous Aciclovir Delivery. Pharm Res 23, 1842–1849 (2006). https://doi.org/10.1007/s11095-006-9017-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9017-2

Key words

Search

Navigation