caa a22 4500 445312602 CHVBK 20180317142635.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s11095-011-0508-4 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0508-4 Enhanced Topical and Transdermal Delivery of Antineoplastic and Antiviral Acyclic Nucleoside Phosphonate cPr-PMEDAP [Elektronische Daten] [Kateřina Vávrová, Petra Kovaříková, Barbora Školová, Martina Líbalová, Jaroslav Roh, Robert Čáp, Antonín Holý, Alexandr Hrabálek] ABSTRACT: Purpose: Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP. Methods: In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin. Results: Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40ng/cm2/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed. Conclusions: Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound. Springer Science+Business Media, LLC, 2011 acyclic nucleoside phosphonates nationallicence antineoplastics nationallicence antivirals nationallicence permeation enhancer nationallicence topical skin application nationallicence transdermal delivery nationallicence cPr-PMEDAP : N 6 -cyclopropyl-2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine nationallicence DDAK : dodecyl 6-dimethylaminohexanoate nationallicence HBSS : Hanks balanced salt solution nationallicence PBS : phosphate-buffered saline nationallicence PMEDAP : 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine nationallicence PMEG : 9-[2-(phosphonomethoxy)ethyl]guanine nationallicence Vávrová Kateřina Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Kovaříková Petra Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Školová Barbora Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Líbalová Martina Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Roh Jaroslav Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Čáp Robert Clinics of Surgery, University Hospital, Hradec Králové, Czech Republic aut Holý Antonín Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry & Biochemistry AS CR, v.v.i., Prague, Czech Republic aut Hrabálek Alexandr Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3105-3115 0724-8741 28:12<3105 2011 28 11095 https://doi.org/10.1007/s11095-011-0508-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0508-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vávrová Kateřina Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Kovaříková Petra Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Školová Barbora Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Líbalová Martina Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Roh Jaroslav Department of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Čáp Robert Clinics of Surgery, University Hospital, Hradec Králové, Czech Republic aut NATIONALLICENCE 700 1- Holý Antonín Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry & Biochemistry AS CR, v.v.i., Prague, Czech Republic aut NATIONALLICENCE 700 1- Hrabálek Alexandr Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3105-3115 0724-8741 28:12<3105 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer