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

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• 作者：Denisa Diblíková (1)
  Monika Kope?ná (1)
  Barbora ?kolová (1)
  Marcela Kre?merová (2)
  Jaroslav Roh (1)
  Alexandr Hrabálek (1)
  Kate?ina Vávrová (1)
  
• 关键词：acyclic nucleoside phosphonate antivirals ; lysolipid prodrug ; penetration enhancer ; skin absorption ; transdermal drug delivery
• 刊名：Pharmaceutical Research
• 出版年：2014
• 出版时间：April 2014
• 年：2014
• 卷：31
• 期：4
• 页码：1071-1081
• 全文大小：348 KB
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• 作者单位：Denisa Diblíková (1)
  Monika Kope?ná (1)
  Barbora ?kolová (1)
  Marcela Kre?merová (2)
  Jaroslav Roh (1)
  Alexandr Hrabálek (1)
  Kate?ina Vávrová (1)
  
  1. Skin Barrier Research Group, Charles University in Prague Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005, Hradec Králové, Czech Republic
  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i, Prague, Czech Republic
  
• ISSN：1573-904X

文摘

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-.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?±-.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.