Pharmaceutical Research

, Volume 26, Issue 4, pp 811–821 | Cite as

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

  • Jakub Novotný
  • Petra Kovaříková
  • Michal Novotný
  • Barbora Janůšová
  • Alexandr Hrabálek
  • Kateřina Vávrová
Research Paper



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.


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.


DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate for future research.


biodegradability permeation enhancers reversibility structure–activity relationships transdermal drug delivery 



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).


  1. 1.
    M. R. Prausnitz, S. Mitragotri, and R. Langer. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3:115–124 (2004). doi: 10.1038/nrd1304.PubMedCrossRefGoogle Scholar
  2. 2.
    B. J. Thomas, and B. C. Finnin. The transdermal revolution. Drug Discov. Today. 9:697–703 (2004). doi: 10.1016/S1359-6446(04)03180-0.PubMedCrossRefGoogle Scholar
  3. 3.
    H. Y. Thong, H. Zhai, and H. I. Maibach. Percutaneous penetration enhancers: an overview. Skin Pharmacol. Physiol. 20:272–282 (2007). doi: 10.1159/000107575.PubMedCrossRefGoogle Scholar
  4. 4.
    A. C. Williams, and B. W. Barry. Penetration enhancers. Adv. Drug Deliv. Rev. 56:603–618 (2004). doi: 10.1016/j.addr.2003.10.025.PubMedCrossRefGoogle Scholar
  5. 5.
    K. Vavrova, J. Zbytovska, and A. Hrabalek. Amphiphilic transdermal permeation enhancers: structure-activity relationships. Curr. Med. Chem. 12:2273–2291 (2005). doi: 10.2174/0929867054864822.PubMedCrossRefGoogle Scholar
  6. 6.
    S. Buyuktimkin, N. Buyuktimkin, and J. H. Rytting. Synthesis and enhancing effect of dodecyl 2-(N,N-dimethylamino)propionate on the transepidermal delivery of indomethacin, clonidine, and hydrocortisone. Pharm. Res. 10:1632–1637 (1993). doi: 10.1023/A:1018980905312.PubMedCrossRefGoogle Scholar
  7. 7.
    T. M. Suhonen, L. Pirskanen, M. Raisanen, K. Kosonen, J. H. Rytting, P. Paronen, and A. Urtti. Transepidermal delivery of beta-blocking agents: Evaluation of enhancer effects using stratum corneum lipid liposomes. J. Control. Release. 43:251–259 (1997). doi: 10.1016/S0168-3659(96)01495-2.CrossRefGoogle Scholar
  8. 8.
    A. M. Wolka, J. H. Rytting, B. L. Reed, and B. C. Finnin. The interaction of the penetration enhancer DDAIP with a phospholipid model membrane. Int. J. Pharm. 271:5–10 (2004). doi: 10.1016/j.ijpharm.2003.09.018.PubMedCrossRefGoogle Scholar
  9. 9.
    T. M. Turunen, A. Urtti, P. Paronen, K. L. Audus, and J. H. Rytting. Effect of some penetration enhancers on epithelial membrane lipid domains: evidence from fluorescence spectroscopy studies. Pharm. Res. 11:288–294 (1994). doi: 10.1023/A:1018919811227.PubMedCrossRefGoogle Scholar
  10. 10.
    N. Buyuktimkin, S. Buyuktimkin, and J. H. Rytting. Alkyl N,N-Disubstituted-Amino acetates. In E. W. Smith, and H. I. Maibach (eds.), Percutaneous Penetration Enhancers, CRC, New York, 1995, pp. 91–102.Google Scholar
  11. 11.
    S. Buyuktimkin, N. Buyuktimkin, and J. H. Rytting. Interaction of indomethacin with a new penetration enhancer, dodecyl 2-(N,N-dimethylamino)propionate (DDAIP): Its effect on transdermal delivery. Int. J. Pharm. 127:245–253 (1996). doi: 10.1016/0378–5173(96)80691-0.CrossRefGoogle Scholar
  12. 12.
    W. Pfister, M. Li, and D. Frank. Development of the novel permeation enhancers dodecyl-2-N,N-dimethylaminopropionate (DDAIP) and HCl salt: physiochemical properties, preclinical safety and in vitro permeation enhancement. AAPS J. 8:(2006).Google Scholar
  13. 13.
    E. Touitou, B. Godin, T. R. Kommuru, M. I. Afouna, and I. K. Reddy. Transport of chiral molecules across the skin. In I. K. Reddy, and R. Mehvar (eds.), Chirality in Drug Design and Development, Marcel Dekker, New York, 2004, pp. 67–99.Google Scholar
  14. 14.
    K. Vavrova, A. Hrabalek, and P. Dolezal. Enhancement effects of (R) and (S) enantiomers and the racemate of a model enhancer on permeation of theophylline through human skin. Arch. Dermatol. Res. 294:383–385 (2002).PubMedGoogle Scholar
  15. 15.
    N. Kanikkannan, K. Kandimalla, S. S. Lamba, and M. Singh. Structure–activity relationship of chemical penetration enhancers in transdermal drug delivery. Curr. Med. Chem. 7:593–608 (2000).PubMedGoogle Scholar
  16. 16.
    K. Vavrova, A. Hrabalek, P. Dolezal, T. Holas, and J. Klimentova. Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers. J. Control. Release. 104:41–49 (2005). doi: 10.1016/j.jconrel.2005.01.002.PubMedCrossRefGoogle Scholar
  17. 17.
    P. Vierling, C. Santaella, and J. Greiner. Highly fluorinated amphiphiles as drug and gene carrier and delivery systems. J. Fluorine Chem. 107:337–354 (2001). doi: 10.1016/S0022-1139(00)00378-X.CrossRefGoogle Scholar
  18. 18.
    K. Wang, G. Karlsson, M. Almgren, and T. Asakawa. Aggregation behavior of cationic fluorosurfactants in water and salt solutions. A cryoTEM survey. J. Phys. Chem. B. 103:9237–9246 (1999). doi: 10.1021/jp990821u.CrossRefGoogle Scholar
  19. 19.
    J. G. Riess, and M. P. Krafft. Advanced fluorocarbon-based systems for oxygen and drug delivery, and diagnosis. Artif. Cells Blood Substit. Immobil. Biotechnol. 25:43–52 (1997).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Hrabalek, P. Dolezal, O. Farsa, Z. Sklubalova, and J. Kunes. Esters of 6-dimethylaminohexanoic acid as skin penetration enhancers. Pharmazie. 55:759–761 (2000).PubMedGoogle Scholar
  21. 21.
    K. Vavrova, K. Lorencova, J. Klimentova, J. Novotny, A. N. Holy, and A. Hrabalek. Transdermal and dermal delivery of adefovir: effects of pH and permeation enhancers. Eur. J. Pharm. Biopharm. 69:597–604 (2008). doi: 10.1016/j.ejpb.2007.12.005.PubMedCrossRefGoogle Scholar
  22. 22.
    K. Vavrová, K. Lorencová, J. Novotný, A. Holý, and A. Hrabálek. Permeation enhancer dodecyl 6-(dimethylamino)hexanoate increases transdermal and topical delivery of adefovir; influence of pH, ion-pairing and skin species. Eur. J. Pharm. Biopharm. 70:901–907 (2008), doi: 10.1016/j.ejpb.2008.07.002
  23. 23.
    A. Hrabalek, P. Dolezal, K. Vavrova, J. Zbytovska, T. Holas, J. Klimentova, and J. Novotny. Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin. Pharm. Res. 23:912–919 (2006). doi: 10.1007/s11095-006-9782-y.PubMedCrossRefGoogle Scholar
  24. 24.
    A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, and R. D. Shah. Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures. J. Org. Chem. 61:3849–3862 (1996). doi: 10.1021/jo960057x.PubMedCrossRefGoogle Scholar
  25. 25.
    C. Herkenne, A. Naik, Y. N. Kalia, J. Hadgraft, and R. H. Guy. Pig ear skin ex vivo as a model for in vivo dermatopharmacokinetic studies in man. Pharm. Res. 23:1850–1856 (2006). doi: 10.1007/s11095-006-9011-8.PubMedCrossRefGoogle Scholar
  26. 26.
    U. Jacobi, M. Kaiser, R. Toll, S. Mangelsdorf, H. Audring, N. Otberg, W. Sterry, and J. Lademann. Porcine ear skin: an in vitro model for human skin. Skin Res. Technol. 13:19–24 (2007). doi: 10.1111/j.1600-0846.2006.00179.x.PubMedCrossRefGoogle Scholar
  27. 27.
    A. Williams. Alternative membranes for in-vitro studies. Transdermal and Topical Drug Delivery: From Theory to Clinical Practice, Pharmaceutical Press, London, 2003, pp. 54–58Google Scholar
  28. 28.
    K. Vavrova, K. Lorencova, J. Klimentova, J. Novotny, and A. Hrabalek. HPLC method for determination of in vitro delivery through and into porcine skin of adefovir (PMEA). J. Chrom. B. 853:198–203 (2007). doi: 10.1016/j.jchromb.2007.03.012.CrossRefGoogle Scholar
  29. 29.
    W. J. Fasano, S. C. Carpenter, S. A. Gannon, T. A. Snow, J. C. Stadler, G. L. Kennedy, R. C. Buck, S. H. Korzeniowski, P. M. Hinderliter, and R. A. Kemper. Absorption, distribution, metabolism, and elimination of 8–2 fluorotelomer alcohol in the rat. Toxicol. Sci. 91:341–355 (2006). doi: 10.1093/toxsci/kfj160.PubMedCrossRefGoogle Scholar
  30. 30.
    R. Fraginals, M. Schaeffer, J. L. Stampf, and C. Benezra. Perfluorinated analogues of poison ivy allergens. Synthesis and skin tolerogenic activity in mice. J. Med. Chem. 34:1024–1027 (1991). doi: 10.1021/jm00107a022.PubMedCrossRefGoogle Scholar
  31. 31.
    B. J. Aungst. Structure/effect studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm. Res. 6:244–247 (1989). doi: 10.1023/A:1015921702258.PubMedCrossRefGoogle Scholar
  32. 32.
    J. Klimentova, P. Kosak, K. Vavrova, T. Holas, and A. Hrabalek. Influence of terminal branching on the transdermal permeation-enhancing activity in fatty alcohols and acids. Bioorg. Med. Chem. 14:7681–7687 (2006). doi: 10.1016/j.bmc.2006.08.013.PubMedCrossRefGoogle Scholar
  33. 33.
    J. Klimentova, P. Kosak, K. Vavrova, T. Holas, J. Novotny, and A. Hrabalek. Transkarbams with terminal branching as transdermal permeation enhancers. Bioorg. Med. Chem. Lett. 18:1712–1715 (2008). doi: 10.1016/j.bmcl.2008.01.040.PubMedCrossRefGoogle Scholar
  34. 34.
    D. Chantasart, S. K. Li, N. He, K. S. Warner, S. Prakongpan, and W. I. Higuchi. Mechanistic studies of branched-chain alkanols as skin permeation enhancers. J. Pharm. Sci. 93:762–779 (2004). doi: 10.1002/jps.10550.PubMedCrossRefGoogle Scholar
  35. 35.
    A. Hrabalek, K. Vavrova, P. Dolezal, and M. Machacek. Esters of 6-aminohexanoic acid as skin permeation enhancers: The effect of branching in the alkanol moiety. J. Pharm. Sci. 94:1494–1499 (2005). doi: 10.1002/jps.20376.PubMedCrossRefGoogle Scholar
  36. 36.
    J. J. Prusakiewicz, C. Ackermann, and R. Voorman. Comparison of skin esterase activities from different species. Pharm. Res. 23:1517–1524 (2006). doi: 10.1007/s11095-006-0273-y.PubMedCrossRefGoogle Scholar
  37. 37.
    W. Montagna. Histology and cytochemistry of human skin. IX. The distribution of non-specific esterases. J. Biophys. Biochem. Cytol. 1:13–16 (1955).PubMedCrossRefGoogle Scholar
  38. 38.
    D. J. Davies, R. J. Ward, and J. R. Heylings. Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. Toxicol. In Vitro. 18:351–358 (2004). doi: 10.1016/j.tiv.2003.10.004.PubMedCrossRefGoogle Scholar
  39. 39.
    A. Holy, J. Gunter, H. Dvorakova, M. Masojidkova, G. Andrei, R. Snoeck, J. Balzarini, and E. De Clercq. Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base. J. Med. Chem. 42:2064–2086 (1999). doi: 10.1021/jm9811256.PubMedCrossRefGoogle Scholar
  40. 40.
    V. Kopecky Jr., P. Mojzes, J. V. Burda, and L. Dostal. Raman spectroscopy study of acid-base and structural properties of 9-[2-(phosphonomethoxy)ethyl]adenine in aqueous solutions. Biopolymers. 67:285–288 (2002). doi: 10.1002/bip.10111.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jakub Novotný
    • 1
  • Petra Kovaříková
    • 2
  • Michal Novotný
    • 1
  • Barbora Janůšová
    • 1
  • Alexandr Hrabálek
    • 1
  • Kateřina Vávrová
    • 1
  1. 1.Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic
  2. 2.Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec KrálovéCharles University in PragueHradec KrálovéCzech Republic

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