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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

KEY WORDS

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

Abbreviations

ANP

acyclic nucleoside phosphonate

(S)-8-azaHPMPDAP

(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diamino-8-azapurine

(S)-cHPMPDAP

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

CMV

cytomegalovirus

DDAK

dodecyl ester of 6-(dimethylamino)hexanoic acid

EBV

Epstein-Barr virus

HILIC

hydrophilic interaction liquid chromatography

HIV

human immunodeficiency virus

HDP

hexadecyloxypropyl ester

HDP-(S)-HPMPDAP

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

HDP-(R)-PMPDAP

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

HHV

human herpesviruses

HPLC

high-performance liquid chromatography

(S)-HPMPDAP

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

HSV

herpes simplex virus

PBS

phosphate-buffered saline

PG

propylene glycol

(R)-PMPDAP

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

(S)-PMPDAP

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

SC

stratum corneum

VZV

varicella-zoster virus

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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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