Skip to main content
SpringerLink
Log in

Transkarbams: Transdermal Penetration-Enhancing Carbamates

  • Chapter
Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement

  • 1696 Accesses

Abstract

Transkarbams (TRANSdermal penetration-enhancing CARBAMates) are a structurally unusual class of compounds that facilitate drug delivery through the skin. These two-chain amphiphiles containing an ammonium carbamate polar head are formed by the reaction of ω-amino acid derivatives (in particular, 6-aminohexanoates) with carbon dioxide. Transkarbams, e.g., 6-dodecyloxy-6-oxohexylammonium 6-dodecyloxy-6-oxohexylcarbamate (transkarbam 12 or T12), are up to an order of magnitude more active than Azone® (N-dodecylazepan-2-one or laurocapram) in enhancing the percutaneous penetration of a broad spectrum of drugs. Transkarbams act by a dual mechanism: first, the parent carbamate salt decomposes in the stratum corneum, which increases skin permeability, and second, the released protonated amino acid ester continues acting as an enhancer. The advantage of this dual effect is that the “daughter” enhancer, despite being less active, broadens the scope of action of the parent carbamate because it also enhances the permeation of hydrophilic drugs. Transkarbams are then degraded by esterases, which account for their low toxicity and low skin irritation. Due to these favorable properties, transkarbams meet the requirements for an ideal enhancer for transdermal or dermal drug delivery.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahad A, Aqil M, Kohli K, Chaudhary H, Sultana Y, Mujeeb M, Talegaonkar S (2009) Chemical penetration enhancers: a patent review. Expert Opin Ther Pat 19(7):969–988

    Article  CAS  PubMed  Google Scholar 

  • Albery WJ, Hadgraft J (1979) Percutaneous absorption: in vivo experiments. J Pharm Pharmacol 31(3):140–147

    Article  CAS  PubMed  Google Scholar 

  • Aoyagi T, Yamamura M, Suzuki N, Matsui K, Nagase Y (1991) Preparation of alkyl-substituted pyrrolidone derivatives and their evaluation as transdermal penetration enhancers. Drug Des Discov 8(1):37–46

    CAS  PubMed  Google Scholar 

  • Asbill CS, El-Kattan AF, Michniak B (2000) Enhancement of transdermal drug delivery: chemical and physical approaches. Crit Rev Ther Drug Carrier Syst 17(6):621–658

    Article  CAS  PubMed  Google Scholar 

  • Aungst BJ (2011) Absorption enhancers: applications and advances. AAPS J 14(1):10–18

    Article  PubMed Central  PubMed  Google Scholar 

  • Barry BW (1983) Dermatological formulations: percutaneous absorption. Marcel Dekker, New York

    Google Scholar 

  • Barry BW (2001) Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci 14(2):101–114

    Article  CAS  PubMed  Google Scholar 

  • Buyuktimkin S, Buyuktimkin N, Rytting JH (1993) Synthesis and enhancing effect of dodecyl 2-(N, N-dimethylamino)propionate on the transepidermal delivery of indomethacin, clonidine, and hydrocortisone. Pharm Res 10(11):1632–1637

    Article  CAS  PubMed  Google Scholar 

  • Dell’Amico DB, Calderazzo F, Labella L, Marchetti F, Pampaloni G (2003) Converting carbon dioxide into carbamato derivatives. Chem Rev 103(10):3857–3897

    Article  PubMed  Google Scholar 

  • Dolezal P, Hrabalek A, Mericka P, Klimesova V, Klimes J, Sochor J, Semecky V, Budnikova R (1989) Urychlovač transdermální penetrace. CZ Pat 276300

    Google Scholar 

  • Dolezal P, Hrabalek A, Semecky V (1993) epsilon-Aminocaproic acid esters as transdermal penetration enhancing agents. Pharm Res 10(7):1015–1019

    Article  CAS  PubMed  Google Scholar 

  • Farsa O, Dolezal P, Hrabalek A (2010) Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers. J Serb Chem Soc 75(5):595–603

    Article  CAS  Google Scholar 

  • Folbrova J (2007) Hodnocení transkarbamu 12 a jeho nečistot pomocí HPLC s MS detekcí. PharmD. thesis, Charles University in Prague, Hradec Kralove

    Google Scholar 

  • Fuhrman LC, Michniak BB, Behl CR, Malick AW (1997) Effect of novel penetration enhancers on the transdermal delivery of hydrocortisone: an in vitro species comparison. J Control Release 45(2):199–206

    Article  CAS  Google Scholar 

  • Geers C, Gros G (2000) Carbon dioxide transport and carbonic anhydrase in blood and muscle. Phys Rev 80(2):681–715

    CAS  Google Scholar 

  • Guy RH (2010) Transdermal drug delivery. Handb Exp Pharmacol 197:399–410

    Article  CAS  PubMed  Google Scholar 

  • Hadgraft J (1999) Passive enhancement strategies in topical and transdermal drug delivery. Int J Pharm 184(1):1–6

    Article  CAS  PubMed  Google Scholar 

  • Holas T, Vavrova K, Klimentova J, Hrabalek A (2006a) Synthesis and transdermal permeation-enhancing activity of ketone, amide, and alkane analogs of Transkarbam 12. Bioorg Med Chem 14(9):2896–2903

    Article  CAS  PubMed  Google Scholar 

  • Holas T, Vavrova K, Sima M, Klimentova J, Hrabalek A (2006b) Synthesis and transdermal permeation-enhancing activity of carbonate and carbamate analogs of Transkarbam 12. Bioorg Med Chem 14(23):7671–7680

    Article  CAS  PubMed  Google Scholar 

  • Holas T, Zbytovska J, Vavrova K, Berka P, Madlova M, Klimentova J, Hrabalek A (2006c) Thermotropic phase behavior of long-chain alkylammonium-alkylcarbamates. Thermochim Acta 441(2):116–123

    Article  CAS  Google Scholar 

  • Hrabalek A (1992) Potenciální akceleranty transdermální penetrace na bázi isosterních obměn substituovaných cyklických amidů (Potential transdermal penetration enhancers based on isosteric modifications of substituted cyclic amides) [Ph.D. thesis]. Charles University in Prague, Hradec Kralove

    Google Scholar 

  • Hrabalek A, Dolezal P, Farsa O, Sklubalova Z, Kunes J (2000) Esters of 6-dimethylaminohexanoic acid as skin penetration enhancers. Pharmazie 55(10):759–761

    CAS  PubMed  Google Scholar 

  • Hrabalek A, Dolezal P, Farsa O, Krebs A, Kroutil A, Roman M, Sklubalova Z (2001) Omega-amino acid derivatives, processes of their preparation and their use. US 6187938

    Google Scholar 

  • Hrabalek A, Vavrova K, Dolezal P, Machacek M (2005) Esters of 6-aminohexanoic acid as skin permeation enhancers: the effect of branching in the alkanol moiety. J Pharm Sci 94(7):1494–1499

    Article  CAS  PubMed  Google Scholar 

  • Hrabalek A, Dolezal P, Vavrova K, Zbytovska J, Holas T, Klimentova J, Novotny J (2006) Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin. Pharm Res 23(5):912–919

    Article  CAS  PubMed  Google Scholar 

  • Janůšová B, Školová B, Tükörová K, Wojnarová L, Šimůnek T, Mladěnka P, Filipský T, Říha M, Roh J, Palát K, Hrabálek A, Vávrová K (2013) Amino acid derivatives as transdermal permeation enhancers. J Control Release 165(2):91–100

    Article  PubMed  Google Scholar 

  • Kanikkannan N, Kandimalla K, Lamba SS, Singh M (2000) Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery. Curr Med Chem 7(6):593–608

    Article  CAS  PubMed  Google Scholar 

  • Kaushik D, Batheja P, Kilfoyle B, Rai V, Michniak-Kohn B (2008) Percutaneous permeation modifiers: enhancement versus retardation. Expert Opin Drug Deliv 5(5):517–529

    Article  CAS  PubMed  Google Scholar 

  • Klimentova J, Hrabalek A, Vavrova K, Holas T, Kroutil A (2006a) Synthesis and transdermal penetration-enhancing activity of carbonic and carbamic acid esters–comparison with transkarbam 12. Bioorg Med Chem Lett 16(7):1981–1984

    Article  CAS  PubMed  Google Scholar 

  • Klimentova J, Kosak P, Vavrova K, Holas T, Hrabalek A (2006b) Influence of terminal branching on the transdermal permeation-enhancing activity in fatty alcohols and acids. Bioorg Med Chem 14(23):7681–7687

    Article  CAS  PubMed  Google Scholar 

  • Klimentova J, Kosak P, Vavrova K, Holas T, Novotny J, Hrabalek A (2008) Transkarbams with terminal branching as transdermal permeation enhancers. Bioorg Med Chem Lett 18(5):1712–1715

    Article  CAS  PubMed  Google Scholar 

  • Krebs A (2001) Akceleranty transdermální penetrace na bázi derivátů močoviny (Transdermal penetration enhancers based on urea derivatives) [Ph.D. thesis]. Charles University in Prague, Hradec Kralove

    Google Scholar 

  • Kroutil A (1995) Estery bazických alkoholů jako potenciální akceleranty transdermální penetrace (Esters of basic alcohols as potential transdermal penetration enhancers). Master thesis, Charles University in Prague, Hradec Kralove

    Google Scholar 

  • Marjukka Suhonen T, Bouwstra JA, Urtti A (1999) Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J Control Release 59(2):149–161

    Article  CAS  PubMed  Google Scholar 

  • Michniak BB, Player MR, Godwin DA, Lockhart CC, Sowell JW (1998) In vitro evaluation of azone analogs as dermal penetration enhancers – V. Miscellaneous compounds. Int J Pharm 161(2):169–178

    Article  CAS  Google Scholar 

  • Miyazaki K, Kaiho F, Inagaki A, Dohi M, Hazemoto N, Haga M, Hara H, Kato Y (1992) Enantiomeric difference in percutaneous penetration of propranolol through rat excised skin. Chem Pharm Bull 40(4):1075–1076

    Article  CAS  PubMed  Google Scholar 

  • Montagna W (1955) Histology and cytochemistry of human skin. 9. The distribution of non-specific esterases. J Biophys Biochem Cytol 1(1):13–16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Novotny J, Kovarikova P, Novotny M, Janusova B, Hrabalek A, Vavrova K (2009) Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination. Pharm Res 26(4):811–821

    Article  CAS  PubMed  Google Scholar 

  • Novotny M, Hrabalek A, Janusova B, Novotny J, Vavrova K (2010) Transkarbams as transdermal permeation enhancers: effects of ester position and ammonium carbamate formation. Bioorg Med Chem Lett 20(9):2726–2728

    Article  CAS  PubMed  Google Scholar 

  • Novotny M, Klimentova J, Janusova B, Palat K, Hrabalek A, Vavrova K (2011) Ammonium carbamates as highly active transdermal permeation enhancers with a dual mechanism of action. J Control Release 150(2):164–170

    Article  CAS  PubMed  Google Scholar 

  • Pasakova I, Klimes J, Sochor J, Hrabalek A (2006a) Optimization of HPLC chromatographic conditions for determination of Transkarbam 12 and its degradation products. J Pharm Biomed Anal 42(1):136–142

    Article  CAS  PubMed  Google Scholar 

  • Pasakova I, Sochor J, Klimes J, Hrabalek A (2006b) Preliminary pharmaceutico-analytical evaluation of transkarbam 12 using liquid chromatography. J Sep Sci 29(11):1595–1599

    Article  CAS  PubMed  Google Scholar 

  • Potts RO, Guy RH (1992) Predicting skin permeability. Pharm Res 9(5):663–669

    Article  CAS  PubMed  Google Scholar 

  • Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26(11):1261–1268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Quan DY, Higuchi RI, Takayama K, Higashiyama K, Nagai T (1990) Enhancing effect of piperidone derivatives on the percutaneous absorption of indomethacin. Drug Des Deliv 6(1):61–71

    CAS  PubMed  Google Scholar 

  • Rajadhyaksha VJ (1976) Inventor Vehicle composition containing 1-substituted azacycloheptan-2-ones. US Patent 3,989,816

    Google Scholar 

  • Sasaki H, Kojima M, Nakamura J, Shibasaki J (1990) Acute toxicity and skin irritation of pyrrolidone derivatives as transdermal penetration enhancer. Chem Pharm Bull (Tokyo) 38(8):2308–2310

    Article  CAS  Google Scholar 

  • Sasaki H, Kojima M, Mori Y, Nakamura J, Shibasaki J (1991) Enhancing effect of pyrrolidone derivatives on transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen. J Pharm Sci 80(6):533–538

    Article  CAS  PubMed  Google Scholar 

  • Smith EW, Maibach HI (1995) Percutaneous penetration enhancers. CRC Press, Boca Raton

    Google Scholar 

  • Stoughton RB (1982) Enhanced percutaneous penetration with 1-dodecylazacycloheptan-2-one. Arch Dermatol 118(7):474–477

    Article  CAS  PubMed  Google Scholar 

  • Svozil M, Dolezal P, Hrabalek A, Mericka P (2007) In vitro studies on transdermal permeation of butorphanol. Drug Dev Ind Pharm 33(5):559–567

    Article  CAS  PubMed  Google Scholar 

  • Vavrova K, Hrabalek A, Dolezal P (2002) 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(8):383–385

    CAS  PubMed  Google Scholar 

  • Vavrova K, Hrabalek A, Dolezal P, Holas T, Klimentova J (2005a) Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers. J Control Release 104(1):41–49

    Article  CAS  PubMed  Google Scholar 

  • Vavrova K, Zbytovska J, Hrabalek A (2005b) Amphiphilic transdermal permeation enhancers: structure-activity relationships. Curr Med Chem 12(19):2273–2291

    Article  CAS  PubMed  Google Scholar 

  • Vavrova K, Lorencova K, Klimentova J, Novotny J, Holy AN, Hrabalek A (2008a) Transdermal and dermal delivery of adefovir: effects of pH and permeation enhancers. Eur J Pharm Biopharm 69(2):597–604

    Article  CAS  PubMed  Google Scholar 

  • Vavrova K, Lorencova K, Novotny J, Holy A, Hrabalek A (2008b) 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(3):901–907

    Article  CAS  PubMed  Google Scholar 

  • Vavrova K, Kovarikova P, Skolova B, Libalova M, Roh J, Cap R, Holy A, Hrabalek A (2011) Enhanced topical and transdermal delivery of antineoplastic and antiviral acyclic nucleoside phosphonate cPr-PMEDAP. Pharm Res 28(12):3105–3115

    Article  CAS  PubMed  Google Scholar 

  • Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56(5):603–618

    Article  CAS  PubMed  Google Scholar 

  • Wong O, Tsuzuki N, Nghiem B, Kuehnhoff J, Itoh T, Masaki K, Huntington J, Konishi R, Rytting JH, Higuchi T (1989) Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers. II. Evaluation study. Int J Pharm 52(3):191–202

    Article  CAS  Google Scholar 

  • Zbytovska J, Raudenkolb S, Wartewig S, Hubner W, Rettig W, Pissis P, Hrabalek A, Dolezal P, Neubert RH (2004) Phase behaviour of transkarbam 12. Chem Phys Lipids 129(1):97–109

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Czech Science Foundation for its financial support (project 207/11/0365).

Author information

Authors and Affiliations

  1. Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 50005, Hradec Králové, Czech Republic

    Alexandr Hrabálek & Kateřina Vávrová

Authors
  1. Alexandr Hrabálek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kateřina Vávrová
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexandr Hrabálek .

Editor information

Editors and Affiliations

  1. Department of Manufacturing, Apoteka "Beograd", Belgrade, Serbia

    Nina Dragicevic

  2. Dermatology Clinic, University of California San Francisco Dermatology Clinic, San Francisco, USA

    Howard I. Maibach

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Hrabálek, A., Vávrová, K. (2015). Transkarbams: Transdermal Penetration-Enhancing Carbamates. In: Dragicevic, N., Maibach, H. (eds) Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-47039-8_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-47039-8_19

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-47038-1

  • Online ISBN: 978-3-662-47039-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation