Quantitative Structure–Enhancement Relationship and the Microenvironment of the Enhancer Site of Action

  • S. Kevin LiEmail author
  • William I. Higuchi


In the last several decades, a large number of studies on chemical permeation enhancers were performed to assist the development of topical and transdermal products. The mechanisms of chemical permeation enhancers on skin transport have been investigated and quantitative structure–enhancement relationships for permeation enhancers have been examined. The understanding of the enhancer mechanisms of action would allow effective prediction of the effects of skin permeation enhancers, minimize chemical permeation enhancer screening, and improve topical and transdermal formulation development. Based on the systematic approaches in our previous studies, it was determined that enhancer-induced permeation enhancement across the skin lipoidal pathway was directly related to the concentration of the enhancers in the stratum corneum lipid domain. Relationships between skin permeation enhancer potency (based on either enhancer aqueous concentration in the diffusion cell chamber or enhancer concentration in the stratum corneum lipids) and enhancer lipophilicity (enhancer n-octanol–water partition coefficient) were established. The nature of the microenvironment of the enhancer site of action in the stratum corneum was found to be mimicked by n-octanol. The present chapter summarizes these findings and reviews the quantitative structure–enhancement relationship deduced in these systematic studies.


Chemical permeation enhancer Quantitative structure–enhancement relationship Enhancer potency Transdermal delivery Skin 



The authors thank Drs. Kevin S. Warner, Ning He, Doungdaw Chantasart, and Sarah A. Ibrahim for their contributions in the project and the financial support by NIH Grants GM 043181 and GM 063559.


  1. Anderson BD, Raykar PV (1989) Solute structure-permeability relationships in human stratum corneum. J Invest Dermatol 93:280–286CrossRefPubMedGoogle Scholar
  2. Anderson BD, Higuchi WI, Raykar PV (1988) Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum. Pharm Res 5:566–573CrossRefPubMedGoogle Scholar
  3. Aungst BJ (1989) Structure/effect studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm Res 6:244–247CrossRefPubMedGoogle Scholar
  4. Aungst BJ, Rogers NJ, Shefter E (1986) Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int J Pharm 33:225–234CrossRefGoogle Scholar
  5. Barry BW (1987) Mode of action of penetration enhancers in human skin. J Control Release 6:85–97CrossRefGoogle Scholar
  6. Bouwstra JA, Pilgram GSK, Ponec M (2002a) Does the single gel phase exist in stratum corneum? J Invest Dermatol 118:897–898CrossRefPubMedGoogle Scholar
  7. Bouwstra JA, Gooris GS, Dubbelaar FER, Ponec M (2002b) Phase behavior of stratum corneum lipid mixtures based on human ceramides: the role of natural and synthetic ceramide 1. J Invest Dermatol 118:606–617CrossRefPubMedGoogle Scholar
  8. Brain KR, Walters KA (1993) Molecular modeling of skin permeation enhancement by chemical agents. In: Walters KA, Hadgraft J (eds) Pharmaceutical skin penetration enhancement. Marcel Dekker, New York, pp 389–416Google Scholar
  9. Chantasart D, Li SK, He N, Warner KS, Prakongpan S, Higuchi WI (2004) Mechanistic studies of branched-chain alkanols as skin permeation enhancers. J Pharm Sci 93:762–779CrossRefPubMedGoogle Scholar
  10. Chantasart D, Sa-Nguandeekul P, Prakongpan S, Li SK, Higuchi WI (2007) Comparison of the effects of chemical permeation enhancers on the lipoidal pathways of human epidermal membrane and hairless mouse skin and the mechanism of enhancer action. J Pharm Sci 96:2310–2326CrossRefPubMedGoogle Scholar
  11. Chantasart D, Pongjanyakul T, Higuchi WI, Li SK (2009) Effects of oxygen-containing terpenes as skin permeation enhancers on the lipoidal pathways of human epidermal membrane. J Pharm Sci 98:3617–3632CrossRefPubMedGoogle Scholar
  12. Chantasart D, Li SK (2010) Relationship between the enhancement effects of chemical permeation enhancers on the lipoidal transport pathway across human skin under the symmetric and asymmetric conditions in vitro. Pharm Res 27:1825–1836Google Scholar
  13. Cooper ER (1984) Increased skin permeability for lipophilic molecules. J Pharm Sci 73:1153–1156Google Scholar
  14. Goates CY, Knutson K (1994) Enhanced permeation of polar compounds through human epidermis. I. Permeability and membrane structural changes in the presence of short chain alcohols. Biochim Biophys Acta 1195:169–179CrossRefPubMedGoogle Scholar
  15. He N, Li SK, Suhonen TM, Warner KS, Higuchi WI (2003) Mechanistic study of alkyl azacycloheptanones as skin permeation enhancers by permeation and partition experiments with hairless mouse skin. J Pharm Sci 92:297–310CrossRefPubMedGoogle Scholar
  16. He N, Warner KS, Chantasart D, Shaker DS, Higuchi WI, Li SK (2004) Mechanistic study of chemical skin permeation enhancers with different polar and lipophilic functional groups. J Pharm Sci 93:1415–1430CrossRefPubMedGoogle Scholar
  17. Ibrahim SA, Li SK (2009) Effects of chemical enhancers on human epidermal membrane: structure enhancement relationship based on maximum enhancement (E max). J Pharm Sci 98:926–944Google Scholar
  18. Ibrahim SA, Li SK (2010a) Efficiency of fatty acids as chemical penetration enhancers: mechanisms and structure enhancement relationship. Pharm Res 27:115–125PubMedCentralCrossRefPubMedGoogle Scholar
  19. Ibrahim SA, Li SK (2010b) Chemical enhancer solubility in human stratum corneum lipids and enhancer mechanism of action on stratum corneum lipid domain. Int J Pharm 383:89–98PubMedCentralCrossRefPubMedGoogle Scholar
  20. Kim YH, Ghanem AH, Mahmoud H, Higuchi WI (1992) Short chain alkanols as transport enhancers for lipophilic and polar/ionic permeants in hairless mouse skin: mechanism(s) of action. Int J Pharm 80:17–31CrossRefGoogle Scholar
  21. Klimentová J, Kosák P, Vávrová K, Holas T, Hrabálek A (2006) Influence of terminal branching on the transdermal permeation enhancing activity in fatty alcohol and acids. Bioorg Med Chem 14:7681–7687CrossRefPubMedGoogle Scholar
  22. Kuempel D, Swartzendruber DC, Squier CA, Wertz P (1998) In vitro reconstitution of stratum corneum lipid lamellae. Biochim Biophys Acta 1372:135–140CrossRefPubMedGoogle Scholar
  23. Lee VHL, Yamamoto A, Kompella UB (1991) Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit Rev Ther Drug Carrier Syst 8:91–192PubMedGoogle Scholar
  24. Liu P, Higuchi WI, Ghanem A-H, Kurihara-Bergstrom T, Good WR (1992) Assessing the influence of ethanol in simultaneous diffusion and metabolism of estradiol in hairless mouse skin for the ‘asymmetric’ situation in vitro. Int J Pharm 78:123–136CrossRefGoogle Scholar
  25. Norlen L (2001) Skin barrier structure and function: the single gel phase model. J Invest Dermatol 117:830–836CrossRefPubMedGoogle Scholar
  26. Novotný J, Janůsová B, Novotný M, Hrabálek A, Vávrová K (2009a) Short-chain ceramides decrease skin barrier properties. Skin Pharmacol Physiol 22:22–30CrossRefPubMedGoogle Scholar
  27. Novotný M, Hrabálek A, Janůsová B, Novotný J, Vávrová K (2009b) Dicarboxylic acid esters as transdermal permeation enhancers: effects of chain number and geometric isomers. Bioorg Med Chem Lett 19:344–347Google Scholar
  28. Ogiso T, Iwaki M, Paku T (1995) Effect of various enhancers on transdermal penetration of indomethacin and urea, and relationship between penetration parameters and enhancement factors. J Pharm Sci 84:482–488CrossRefPubMedGoogle Scholar
  29. Potts RO, Guy RH (1997) Mechanisms of transdermal drug delivery. Marcel Dekker, New YorkGoogle Scholar
  30. Raykar PV, Fung MC, Anderson BD (1988) The role of protein and lipid domains in the uptake of solutes by human stratum corneum. Pharm Res 5:140–150CrossRefPubMedGoogle Scholar
  31. Smith EW, Maibach HI (1995) Percutaneous penetration enhancers. CRC Press, Inc., Boca RatonGoogle Scholar
  32. Vávrová K, Zbytovská J, Hrabálek A (2005) Amphiphilic transdermal permeation enhancers: structure-activity relationships. Curr Med Chem 12:2273–2291CrossRefPubMedGoogle Scholar
  33. Walters KA, Hadgraft J (1993) Pharmaceutical skin penetration enhancers. Marcel Dekker, New YorkGoogle Scholar
  34. Warner KS, Li SK, Higuchi WI (2001) Influences of alkyl group chain length and polar head group on chemical skin permeation enhancement. J Pharm Sci 90:1143–1153CrossRefPubMedGoogle Scholar
  35. Warner KS, Li SK, He N, Suhonen TM, Chantasart D, Bolikal D, Higuchi WI (2003) Structure-activity relationship for chemical skin permeation enhancers: probing the chemical microenvironment of the site of action. J Pharm Sci 92:1305–1322CrossRefPubMedGoogle Scholar
  36. Warner KS, Shaker DS, Molokhia S, Xu Q, Hao J, Higuchi WI, Li SK (2008) Silicone elastomer uptake method for determination of free 1-alkyl-2-pyrrolidone concentration in micelle and hydroxypropyl-β-cyclodextrin systems used in skin transport studies. J Pharm Sci 97:368–380CrossRefPubMedGoogle Scholar
  37. White SH, Mirejovsky D, King GI (1988) Structure of lamellar lipid domains and corneocyte envelopes of murine stratum corneum. An x-ray diffraction study. Biochemistry 27:3725–3732CrossRefPubMedGoogle Scholar
  38. Williams AC, Barry BW (1992) Skin absorption enhancers. Crit Rev Ther Drug Carrier Syst 9:305–353PubMedGoogle Scholar
  39. Yoneto K, Ghanem AH, Higuchi WI, Peck KD, Li SK (1995) Mechanistic studies of the 1-alkyl-2-pyrrolidones as skin permeation enhancers. J Pharm Sci 84:312–317CrossRefPubMedGoogle Scholar
  40. Yoneto K, Li SK, Higuchi WI, Jiskoot W, Herron JN (1996) Fluorescent probe studies of the interactions of 1-alkyl-2-pyrrolidones with stratum corneum lipid liposomes. J Pharm Sci 85:511–517CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Division of Pharmaceutical SciencesCollege of Pharmacy, University of CincinnatiCincinnatiUSA
  2. 2.Pharmaceutics and Pharmaceutical ChemistryCollege of Pharmacy, University of UtahSalt Lake CityUSA

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