Research paper Permeation enhancer dodecyl 6-(dimethylamino)hexanoate increases transdermal and topical delivery of adefovir: Influence of pH, ion-pairing and skin species Kater ˇina Vávrová a, * , Kater ˇina Lorencová a , Jakub Novotny ´ a , Antonín Holy ´ b , Alexandr Hrabálek a a Centre for New Antivirals and Antineoplastics, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Czech Republic b Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic article info Article history: Received 5 May 2008 Accepted in revised form 9 July 2008 Available online 15 July 2008 Keywords: Adefovir Acyclic nucleoside phosphonates Antiviral Transdermal drug delivery Permeation enhancer abstract Adefovir (9-(2-phosphonomethoxyethyl)adenine) is an acyclic nucleoside phosphonate currently used for the treatment of hepatitis B. The aim of this study was to evaluate the effect of permeation enhancer DDAK (6-dimethylaminohexanoic acid dodecyl ester) on the transdermal and topical delivery of adefovir. In porcine skin, DDAK enhanced adefovir flux 42 times with maximum at pH 5.8 suggesting ion pair for- mation. DDAK increased thermodynamic activity and stratum corneum/vehicle distribution coefficient of adefovir, as well as it directly decreased the skin barrier resistance. Maximal flux was observed already at 2% adefovir + 1% DDAK. The results were confirmed in freshly excised human skin where DDAK enhanced adefovir flux 179 times to 8.9 lg/cm 2 /h. This rate of percutaneous absorption would allow for reaching effective plasma concentrations. After the topical application, adefovir concentrated in the stratum cor- neum with low penetration into the deeper skin layers from either aqueous or isopropyl myristate vehi- cle without the enhancer. With 1% DDAK, adefovir concentrations in the viable epidermis and dermis were 33–61 times higher. These results offer an attractive alternative to established routes of administra- tion of adefovir and other acyclic nucleoside phosphonates. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction Adefovir (9-(2-phosphonomethoxyethyl)adenine, Fig. 1) is an acyclic nucleoside phosphonate with a broad-spectrum antiviral activity. In 2002, its bis(pivaloyloxymethyl) ester prodrug adefovir dipivoxil has been approved for treatment of hepatitis B in adult HBeAg-positive and negative patients as well as in adult patients with lamivudin-resistant HBV mutants, thereby providing a valu- able alternative to current treatments. The major drawbacks of adefovir are its low bioavailability, accumulation in the kidney with dose-dependent nephrotoxicity and the requirement for a long-term therapy. Currently, the search for new prodrug types or delivery options to enhance adefovir bioavailability and improve its pharmacokinetic profile is one of the perspectives in this field. For recent reviews on adefovir, see Refs. [1,2]. Transdermal drug delivery offers an attractive alternative to established routes of administration [3,4]. In adefovir as well as in other chronic therapies, percutaneous application may be bene- ficial due to less frequent application and achievement of sustained plasma levels. Particularly in adefovir therapy of hepatitis B, sub- stantial commitment from the patient is required as the discontin- uation of the therapy may result in severe acute hepatitis exacerbation. Apart from its activity against hepatitis B virus, ade- fovir is active against various herpes viruses, and possesses a cyto- static, antiparasitic and immunomodulatory properties [1]. Thus, it is a candidate drug for local treatment of various skin diseases as well. The major obstacle of the drug administration through the skin is the presence of the stratum corneum, the outermost layer of the skin, which provides an efficient barrier to drug penetration. However, the absorption of therapeutics either into the systemic circulation or to the deeper, viable skin layers may be increased by chemical substances known as transdermal permeation enhancers [5,6]. In our previous study [7], the effects of solvents of different polarity, donor pH and permeation enhancers including dodecanol, 1-dodecylazepan-2-one (Azone) [8], dodecyl 2-(dimethylamino)propionate (DDAIP) [9] and Transkarbam 12 (T12, 5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycar- bonyl)pentylcarbamate) [10,11] on the transport of adefovir through and into the porcine skin were investigated. The highest adefovir flux (11.3 ± 3.6 lg/cm 2 /h) and skin concentration (1549 ± 416 lg/g) was achieved with 1% T12 at pH 4. The activity of T12 at such acidic pH suggested that the presence of the unusual 0939-6411/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2008.07.002 * Corresponding author. Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 50005 Hradec Králové, Czech Republic. Tel.: +420 495 067497; fax: +420 495 067166. E-mail address: katerina.vavrova@faf.cuni.cz (K. Vávrová). European Journal of Pharmaceutics and Biopharmaceutics 70 (2008) 901–907 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb