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 formation. 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 microg/cm(2)/h. This rate of percutaneous absorption would allow for reaching effective plasma concentrations. After the topical application, adefovir concentrated in the stratum corneum with low penetration into the deeper skin layers from either aqueous or isopropyl myristate vehicle 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 administration of adefovir and other acyclic nucleoside phosphonates.
Subject(s)
Adenine/analogs & derivatives , Antiviral Agents/administration & dosage , Caproates/pharmacology , Methylamines/pharmacology , Organophosphonates/administration & dosage , Skin Absorption/drug effects , Skin/drug effects , Adenine/administration & dosage , Adenine/chemistry , Adenine/metabolism , Administration, Cutaneous , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Caproates/chemistry , Chemistry, Pharmaceutical , Diffusion Chambers, Culture , Dimethylamines , Dodecanol , Female , Humans , Hydrogen-Ion Concentration , Kinetics , Methylamines/chemistry , Organophosphonates/chemistry , Organophosphonates/metabolism , Permeability , Pharmaceutical Vehicles/chemistry , Skin/metabolism , Species Specificity , SwineABSTRACT
The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.
Subject(s)
Adenine/analogs & derivatives , Antiviral Agents/pharmacokinetics , Organophosphonates/pharmacokinetics , Adenine/administration & dosage , Adenine/pharmacokinetics , Administration, Cutaneous , Antiviral Agents/administration & dosage , Chromatography, High Pressure Liquid , Drug Delivery Systems , Excipients , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Organophosphonates/administration & dosage , Permeability , Skin Absorption/drug effects , SolventsABSTRACT
A simple HPLC/UV method for the determination of the transdermal permeation and dermal penetration of a broad-spectrum antiviral drug adefovir (PMEA) was developed. The separation was achieved on a C18 column with the mobile phase composed of 10 mM KH2PO4 and 2 mM Bu4NHSO4 at pH 6.0 and 7% acetonitrile. The method was validated with respect to selectivity, linearity (0.1-50 microg/ml), precision, accuracy, and stability. Transdermal permeation of 2% PMEA was studied in vitro using the Franz diffusion cell and porcine skin. The flux values were 1.8, 3.0, and 0.6 microg/cm2/h from aqueous donor samples at pH 3.4 and 7.4, and isopropyl myristate, respectively. The respective skin concentrations at 48 h were 294, 263, and 971 microg/g from these vehicles. These results will serve as a lead for further studies on transdermal and topical delivery of antivirals from the group of acyclic nucleoside phosphonates.
