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Dimethylamino Acid Esters as Biodegradable and Reversible Transdermal Permeation Enhancers: Effects of Linking Chain Length, Chirality and Polyfluorination

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Abstract

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.

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Acknowledgements

This work was supported by the Centre for New Antivirals and Antineoplastics (1M0508), the Ministry of Education of the Czech Republic (MSM0021620822) and the Grant Agency of the Charles University (286/2006/B-CH/FaF).

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Authors and Affiliations

  1. Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic

    Jakub Novotný, Michal Novotný, Barbora Janůšová, Alexandr Hrabálek & Kateřina Vávrová

  2. Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic

    Petra Kovaříková

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  1. Jakub Novotný
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  2. Petra Kovaříková
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Correspondence to Kateřina Vávrová.

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Novotný, J., Kovaříková, P., Novotný, M. et al. Dimethylamino Acid Esters as Biodegradable and Reversible Transdermal Permeation Enhancers: Effects of Linking Chain Length, Chirality and Polyfluorination. Pharm Res 26, 811–821 (2009). https://doi.org/10.1007/s11095-008-9780-3

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