Purpose
Series of N,N-dimethylamino acid esters was synthesized to study their transdermal permeation-enhancing potency, biodegradability and reversibility
of action. Effects of chirality, linking chain length and polyfluorination were investigated.
Materials and Methods
In vitro activities were evaluated using porcine skin and four model drugs—theophylline, hydrocortisone, adefovir and indomethacin.
Biodegradability was determined using porcine esterase, reversibility was measured using electrical resistance.
Results
No differences in activity were found between (R), (S) and racemic dodecyl 2-(dimethylamino)propanoate (DDAIP). Substitution of hydrocarbon tail by fluorocarbon one resulted in
loss of activity. Replacement of branched linking chain between nitrogen and ester of DDAIP by linear one markedly improved
penetration-enhancing activity with optimum in 4–6C acid derivatives. Dodecyl 6-(dimethylamino)hexanoate (DDAK) was more potent
than clinically used skin absorption enhancer DDAIP for theophylline (enhancement ratio of DDAK and DDAIP was 17.3 and 5.9,
respectively), hydrocortisone (43.2 and 11.5) and adefovir (13.6 and 2.8), while DDAIP was better enhancer for indomethacin
(8.7 and 22.8). DDAK was rapidly metabolized by porcine esterase, and displayed low acute toxicity. Electrical resistance
of DDAK-treated skin barrier promptly recovered to control values.
Conclusion
DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate
for future research.
KEY WORDS biodegradability - permeation enhancers - reversibility - structure–activity relationships - transdermal drug delivery