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

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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.

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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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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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Authors and Affiliations

  1. Skin Barrier Research Group, Charles University in Prague Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic

    Denisa Diblíková, Monika Kopečná, Barbora Školová, Jaroslav Roh, Alexandr Hrabálek & Kateřina Vávrová

  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i, Prague, Czech Republic

    Marcela Krečmerová

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  1. Denisa Diblíková
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  2. Monika Kopečná
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  4. Marcela Krečmerová
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  7. Kateřina Vávrová
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Correspondence to Kateřina Vávrová.

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Diblíková, D., Kopečná, M., Školová, B. et al. Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs. Pharm Res 31, 1071–1081 (2014). https://doi.org/10.1007/s11095-013-1228-8

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  • DOI: https://doi.org/10.1007/s11095-013-1228-8

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