Pharmaceutical Research

, Volume 31, Issue 4, pp 1071–1081 | Cite as

Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

  • Denisa Diblíková
  • Monika Kopečná
  • Barbora Školová
  • Marcela Krečmerová
  • Jaroslav Roh
  • Alexandr Hrabálek
  • Kateřina Vávrová
Research Paper



In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin.


The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin.


The ability of ANPs to cross the human skin barrier was very low (0.5–1.4 nmol/cm2/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm2/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption.


By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.


acyclic nucleoside phosphonate antivirals lysolipid prodrug penetration enhancer skin absorption transdermal drug delivery 



acyclic nucleoside phosphonate




cyclic (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine




dodecyl ester of 6-(dimethylamino)hexanoic acid


Epstein-Barr virus


hydrophilic interaction liquid chromatography


human immunodeficiency virus


hexadecyloxypropyl ester


hexadecyloxypropyl ester of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine


hexadecyloxypropyl ester of (R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine


human herpesviruses


high-performance liquid chromatography




herpes simplex virus


phosphate-buffered saline


propylene glycol






stratum corneum


varicella-zoster virus


Acknowledgments AND DISCLOSURES

This work is dedicated to the memory of Professor Antonín Holý. This work was supported by the Czech Science Foundation (207/11/0365) and Charles University (1404213) and the Subvention for development of research organization RVO 61388963. M.K. and B.Š. thank SVV 2013-267-001.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Denisa Diblíková
    • 1
  • Monika Kopečná
    • 1
  • Barbora Školová
    • 1
  • Marcela Krečmerová
    • 2
  • Jaroslav Roh
    • 1
  • Alexandr Hrabálek
    • 1
  • Kateřina Vávrová
    • 1
  1. 1.Skin Barrier Research Group, Charles University in Prague Faculty of Pharmacy in Hradec KrálovéHradec KrálovéCzech Republic
  2. 2.Institute of Organic Chemistry and BiochemistryAcademy of Sciences of the Czech Republic v.v.iPragueCzech Republic

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