Preparations of phosphonate, phosphoramidate and phosphate derivatives and their evaluation as transdermal penetration enhancers

Phosphonate, phosphoramidate and phosphate derivatives containing long alkyl groups were prepared, and their activities enhancing drug penetration through the skin were evaluated by means of in vitro experiments. The effect of chemical structure of these compounds on enhancing activity was investigated. Among the phosphonate and phosphoramidate derivatives, compounds having a hexadecyl group showed the most effective enhancement of transdermal penetration of indomethacin. For the phosphate derivatives, the enhancing activities were almost equal in the compounds containing dodecyl, tetradecyl and hexadecyl group. All the compounds having an octyl group were not effective in penetration enhancement. Diethyl hexadecylphosphonate and diethyl hexadecylphosphoramidate brought about the highest enhancing activities among these compounds, and the permeability coefficient of indomethacin was about 10-fold as much as that without enhancer. The relationship between the enhancing activities and the lipophilicities of these compounds was discussed.