Skip to main content
Log in

Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids

Pharmaceutical Research Aims and scope Submit manuscript

Cite this article



Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin.


To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of d-glucose derivatives, both hydrophilic and amphiphilic.


Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-d-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin.


Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7





Dodecyl ester of 6 (dimethylamino)hexanoic acid


Dulbecco’s modified Eagle’s medium


Enhancement ratio


High performance liquid chromatography


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Neutral red


Phosphate buffered saline


Propylene glycol


Stratum corneum


Sodium dodecyl sulfate

Span 20:

Sorbitan monolaurate


Transepidermal water loss



Transkarbam 12:

5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate


  1. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004;3(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  2. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14(2):101–14.

    Article  CAS  PubMed  Google Scholar 

  3. Vávrová K, Zbytovská J, Hrabálek A. Amphiphilic transdermal permeation enhancers: structure-activity relationships. Curr Med Chem. 2005;12(19):2273–91.

    Article  PubMed  Google Scholar 

  4. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.

    Article  Google Scholar 

  5. Hrabalek A, Dolezal P, Vavrova K, Zbytovska J, Holas T, Klimentova J, et al. Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin. Pharm Res. 2006;23(5):912–9.

    Article  CAS  PubMed  Google Scholar 

  6. Janůšová B, Školová B, Tükörová K, Wojnarová L, Šimůnek T, Mladěnka P, et al. Amino acid derivatives as transdermal permeation enhancers. J Control Release. 2013;165(2):91–100.

    Article  PubMed  Google Scholar 

  7. Novotny J, Kovarikova P, Novotny M, Janusova B, Hrabalek A, Vavrova K. Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination. Pharm Res. 2009;26(4):811–21.

    Article  CAS  PubMed  Google Scholar 

  8. Plat T, Linhardt RJ. Syntheses and applications of sucrose-based esters. J Surfactants Detergents. 2001;4(4):415–21.

    Article  Google Scholar 

  9. Som I, Bhatia K, Yasir M. Status of surfactants as penetration enhancers in transdermal drug delivery. J Pharm Bioal Sci. 2012;4(1):2.

    Article  Google Scholar 

  10. Cázares-Delgadillo J, Naik A, Kalia YN, Quintanar-Guerrero D, Ganem-Quintanar A. Skin permeation enhancement by sucrose esters: a pH-dependent phenomenon. Int J Pharm. 2005;297(1):204–12.

    Article  PubMed  Google Scholar 

  11. El-Laithy HM, Shoukry O, Mahran LG. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies. Eur J Pharm Biopharm. 2011;77(1):43–55.

    Article  CAS  PubMed  Google Scholar 

  12. Arellano A, Santoyo S, Martn C, Ygartua P. Surfactant effects on the in vitro percutaneous absorption of diclofenac sodium. Eur J Drug Metab Pharmacokinet. 1998;23(2):307–12.

    Article  CAS  PubMed  Google Scholar 

  13. López A, Llinares F, Cortell C, Herraez M. Comparative enhancer effects of Span® 20 with Tween® 20 and Azone® on the in vitro percutaneous penetration of compounds with different lipophilicities. Int J Pharm. 2000;202(1):133–40.

    Article  PubMed  Google Scholar 

  14. Femenia-Font A, Balaguer-Fernandez C, Merino V, Rodilla V, Lopez-Castellano A. Effect of chemical enhancers on the in vitro percutaneous absorption of sumatriptan succinate. Eur J Pharm Biopharm. 2005;61(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  15. Stoughton RB. Enhanced percutaneous penetration with 1-dodecylazacycloheptan-2-one. Arch Dermatol. 1982;118(7):474–7.

    Article  CAS  PubMed  Google Scholar 

  16. Wulff G, Clarkson G. On the synthesis of C-glycosyl compounds containing double bonds without the use of protecting groups. Carbohydrate Res. 1994;257(1):81–95.

    Article  CAS  Google Scholar 

  17. Plusquellec D, Baczko K. Sugar chemistry without protecting groups: a novel regioselective synthesis of 6-O-acyl-D-glucopyranoses and methyl-6-O-acyl-α-D-glucopyranosides. Tetrahedron Lett. 1987;28(33):3809–12.

    Article  CAS  Google Scholar 

  18. Poláková M, Belánová M, Mikušová KN, Lattová E, Perreault H. Synthesis of 1, 2, 3-triazolo-linked octyl (1 → 6)-α-D-oligomannosides and their evaluation in mycobacterial mannosyltransferase assay. Bioconjugate Chem. 2011;22(2):289–98.

    Article  Google Scholar 

  19. Milkereit G, Morr M, Thiem J, Vill V. Thermotropic and lyotropic properties of long chain alkyl glycopyranosides: part III: pH-sensitive headgroups. Chem Phys Lipids. 2004;127(1):47–63.

    Article  CAS  PubMed  Google Scholar 

  20. Šimák O, Staněk J, Moravcová J. A stereocontrolled synthesis of 3-acetamido-1, 3, 5-trideoxy-and 1, 3, 5, 6-tetradeoxy-1, 5-imino-d-glucitol. Carbohydrate Res. 2009;344(8):966–71.

    Article  Google Scholar 

  21. Burland PA, Osborn HM, Turkson A. Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes. Bioorg Med Chem. 2011;19(18):5679–92.

    Article  CAS  PubMed  Google Scholar 

  22. Novotný J, Janůšová B, Novotný M, Hrabálek A, Vávrová K. Short-chain ceramides decrease skin barrier properties. Skin Pharmacol Physiol. 2009;22(1):22–30.

    Article  PubMed  Google Scholar 

  23. Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch Dermatol. 1963;88:702–5.

    Article  CAS  PubMed  Google Scholar 

  24. Flynn GL, Stewart B. Percutaneous drug penetration: choosing candidates for transdermal development. Drug Dev Res. 1988;13(2‐3):169–85.

    Article  CAS  Google Scholar 

  25. Netzlaff F, Kaca M, Bock U, Haltner-Ukomadu E, Meiers P, Lehr C-M, et al. Permeability of the reconstructed human epidermis model Episkin® in comparison to various human skin preparations. Eur J Pharm Biopharm. 2007;66(1):127–34.

    Article  CAS  PubMed  Google Scholar 

  26. Zabawski Jr EJ. A review of topical and intralesional cidofovir. Dermatol Online J. 2000;6(1):3.

    PubMed  Google Scholar 

  27. Bernard G, Auger M, Soucy J, Pouliot R. Physical characterization of the stratum corneum of an in vitro psoriatic skin model by ATR-FTIR and Raman spectroscopies. Biochim Biophys Acta. 2007;1770(9):1317–23.

    Article  CAS  PubMed  Google Scholar 

  28. Mendelsohn R, Flach CR, Moore DJ. Determination of molecular conformation and permeation in skin via IR spectroscopy, microscopy, and imaging. Biochim Biophys Acta. 2006;1758(7):923–33.

    Article  CAS  PubMed  Google Scholar 

  29. Bárány E, Lindberg M, Lodén M. Biophysical characterization of skin damage and recovery after exposure to different surfactants. Contact Dermatitis. 1999;40(2):98–103.

    Article  PubMed  Google Scholar 

  30. Szűts A, Szabó-Révész P. Sucrose esters as natural surfactants in drug delivery systems—a mini-review. Int J Pharm. 2012;433(1):1–9.

    Article  PubMed  Google Scholar 

  31. Kim N, El-Kattan A, Asbill C, Kennette R, Sowell J, Latour R, et al. Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers: side chain length variation and molecular modeling. J Control Release. 2001;73(2):183–96.

    Article  CAS  PubMed  Google Scholar 

  32. Janůšová B, Zbytovská J, Lorenc P, Vavrysová H, Palát K, Hrabálek A, et al. Effect of ceramide acyl chain length on skin permeability and thermotropic phase behavior of model stratum corneum lipid membranes. Biochim Biophys Acta. 2011;1811(3):129–37.

    Article  PubMed  Google Scholar 

  33. Elsner P, Wigger-Alberti W, Pantini G. Perfluoropolyethers in the prevention of irritant contact dermatitis. Dermatology. 1998;197(2):141–5.

    Article  CAS  PubMed  Google Scholar 

  34. Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol. 2004;22(2):192–7.

    Article  CAS  PubMed  Google Scholar 

  35. De Clercq E, Holý A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat Rev Drug Discov. 2005;4(11):928–40.

    Article  PubMed  Google Scholar 

  36. Vávrová K, Lorencová K, Klimentová J, Novotný J, Hrabálek A. Transdermal and dermal delivery of adefovir: effects of pH and permeation enhancers. Eur J Pharm Biopharm. 2008;69(2):597–604.

    Article  PubMed  Google Scholar 

  37. Diblíková D, Kopečná M, Školová B, Krečmerová M, Roh J, Hrabálek A, et al. Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and lysolipid prodrugs. Pharm Res. 2014;31(4):1071–81.

    Article  PubMed  Google Scholar 

  38. Lin S-Y, Duan K-J, Lin T-C. Simultaneous determination of the protein conversion process in porcine stratum corneum after pretreatment with skin enhancers by a combined microscopic FT-IR/DSC system. Spectrochim Acta A Mol Biomol Spectrosc. 1996;52(12):1671–8.

    Article  Google Scholar 

  39. Moore DJ, Rerek ME, Mendelsohn R. FTIR spectroscopy studies of the conformational order and phase behavior of ceramides. J Phys Chem B. 1997;101(44):8933–40.

    Article  CAS  Google Scholar 

  40. López-Castellano A, Cortell-Ivars C, López-Carballo G, Herráez-Domınguez M. The influence of Span® 20 on stratum corneum lipids in Langmuir monolayers: comparison with Azone®. Int J Pharm. 2000;203(1):245–53.

    Article  PubMed  Google Scholar 

  41. Loffler H, Pirker C, Aramaki J, Frosch PJ, Happle R, Effendy I. Evaluation of skin susceptibility to irritancy by routine patch testing with sodium lauryl sulfate. Eur J Dermatol. 2001;11(5):416–9.

    CAS  PubMed  Google Scholar 

  42. Tanojo H, Boelsma E, Junginger HE, Ponec M, Boddé HE. In vivo human skin barrier modulation by topical application of fatty acids. Skin Pharmacol Physiol. 1998;11(2):87–97.

    Article  CAS  Google Scholar 

  43. Yang L, Mao‐Qiang M, Taljebini M, Elias P, Feingold K. Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment. Brit J Dermatol. 1995;133(5):679–85.

    Article  CAS  Google Scholar 

Download references


This work was supported by the Czech Science Foundation (13-23891S). MK was supported by Charles University (1404213 and SVV 206183).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Kateřina Vávrová.

Electronic supplementary material

Below is the link to the electronic supplementary material.


(DOCX 216 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kopečná, M., Macháček, M., Prchalová, E. et al. Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids. Pharm Res 34, 640–653 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: