Skip to main content

Advertisement

SpringerLink
Log in

Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The maximum flux of solutes penetrating the epidermis has been known to depend predominantly on solute molecular weight. Here we sought to establish the mechanistic dependence of maximum flux on other solute physicochemical parameters.

Methods

Maximum fluxes, stratum corneum solubilities and estimated diffusivities through human epidermis were therefore determined for 10 phenols with similar molecular weights and hydrogen bonding but varying in lipophilicity.

Results

Maximum flux and stratum corneum solubilities of the phenolic compounds both showed a bilinear dependence on octanol-water partition coefficient (P), with solutes having a maximum solubility in the stratum corneum when 2.7<log P<3.1. In contrast, lag times and diffusivities were relatively independent of P. Stratum corneum-water partition coefficients and epidermal permeability coefficients were consistent with previously reported data.

Conclusion

A key finding is that the convex dependence of maximum flux on lipophilicity arises primarily from variations in stratum corneum solubility, and not from diffusional or partitioning barrier effects at the stratum corneum–viable epidermis interface for the more lipophilic phenols. Our data support a solute structure-skin transport model for aqueous solutions in which permeation rates depend on both partitioning and diffusivity: partitioning is related to P, and diffusivity to solute size and hydrogen bonding. (199 words)

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

α/β :

hydrogen-bond acidity/basicity

C v :

the concentration in the vehicle

D :

diffusion coefficient

F d :

the fraction of the initial solute concentration remaining in the donor

F r :

recovered in the receptor phase as a fraction of the receptor phase solubility

HPLC:

high-performance liquid chromatography

J max :

maximum skin flux

J max,estimated :

maximum fluxes estimated from the dilute solutions

J max,observed :

flux observed for saturated solutions

J SS :

steady-state flux

k p :

epidermal permeability coefficient

K SC :

stratum corneum-water partition coefficient

log P :

logarithmic (base 10) form of octanol-water partition coefficient

P :

octanol-water partition coefficient

PSA :

polar surface area

S aq :

solute solubility in water

S SC :

solute solubility in the stratum corneum

t lag :

lag time

π :

dipolarity/polarisability of solute

References

  1. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14:101–14. doi:10.1016/S0928-0987(01) 00167-1.

    CAS  Google Scholar 

  2. Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem. 1960;11:85–97.

    Google Scholar 

  3. Magnusson BM, Anissimov YG, Cross SE, Roberts MS. Molecular size as the main determinant of solute maximum flux across the skin. J Invest Dermatol. 2004;122:993–9. doi:10.1111/j.0022-202X.2004.22413.x.

    Article  PubMed  CAS  Google Scholar 

  4. Lien EJ, Tong GL. Physicochemical properties and percutaneous absorption of drugs. J Soc Cosmet Chem. 1971;24:371–84.

    Google Scholar 

  5. Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev. 1971;51:702–47.

    CAS  Google Scholar 

  6. Roberts MS, Anderson RA, Swarbrick J. Permeability of human epidermis to phenolic compounds. J Pharm Pharmacol. 1977;29:677–83.

    PubMed  CAS  Google Scholar 

  7. Michaels AS, Chandrasekaran SK, Shaw JE. Drug permeation through human skin: theory and in vitro experimental measurement. AIChE Journal. 1975;21:985–96. doi:10.1002/aic.690210522.

    Article  CAS  Google Scholar 

  8. du Plessis J, Pugh WJ, Judefeind A, Hadgraft J. Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups. Eur J Pharm Sci. 2002;16:107–12. doi:10.1016/S0928-0987(02) 00085-4.

    Article  PubMed  Google Scholar 

  9. Roberts MS. Percuteneous absorption of phenolic compounds. PhD Thesis University of Sydney;1976.

  10. Pugh WJ, Roberts MS, Hadgraft J. Epidermal permeability—Penetrant structure relationships: 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum. Int J Pharm. 1996;138:149–65. doi:10.1016/0378-5173(96)04533-4.

    Article  CAS  Google Scholar 

  11. Potts RO, Guy RH. A predictive algorithm for skin permeability: the effects of molecular size and hydrogen bond activity. Pharm Res. 1995;12:1628–33. doi:10.1023/A:1016236932339.

    Article  PubMed  CAS  Google Scholar 

  12. Yotsuyanagi T, Higuchi WI. A two phase series model for the transport of steroids across the fully hydrated stratum corneum. J Pharm Pharmacol. 1972;24:934–41.

    PubMed  CAS  Google Scholar 

  13. Bunge AL, Cleek RL. A new method for estimating dermal absorption from chemical exposure: 2. Effect of molecular weight and octanol-water partitioning. Pharm Res. 1995;12:88–95. doi:10.1023/A:1016242821610.

    Article  PubMed  CAS  Google Scholar 

  14. Kasting GB, Smith RL, Cooper ER. Effect of lipid solubility and molecular size on percuatenous absorption. In: Shroot B, Schaefer H, editors. Skin Pharmacokinetics. Basel: Karger; 1987. p. 138–53.

    Google Scholar 

  15. Huq AS, Ho NF, Husari N, Flynn GL, Jetzer WE, Condie L Jr. Permeation of water contaminative phenols through hairless mouse skin. Arch Environ Contam Toxicol. 1986;15:557–66. doi:10.1007/BF01056570.

    Article  PubMed  CAS  Google Scholar 

  16. Cross SE, Roberts MS. Use of in vitro human skin membranes to model and predict the effect of changing blood flow on the flux and retention of topically applied solutes. J Pharm Sci. 2008;97:3442–50. doi:10.1002/jps.21253.

    Article  PubMed  CAS  Google Scholar 

  17. Elias PM, Friend DS. The permeability barrier in mammalian epidermis. J Cell Biol. 1975;65:180–91. doi:10.1083/jcb.65.1.180.

    Article  PubMed  CAS  Google Scholar 

  18. Albery WJ, Hadgraft J. Percutaneous absorption: in vivo experiments. J Pharm Pharmacol. 1979;31:140–7.

    PubMed  CAS  Google Scholar 

  19. Anderson BD, Raykar PV. Solute structure-permeability relationships in human stratum corneum. J Invest Dermatol. 1989;93:280–6. doi:10.1111/1523-1747.ep12277592.

    Article  PubMed  CAS  Google Scholar 

  20. Guy RH, Potts RO. Structure-permeability relationships in percutaneous penetration. J Pharm Sci. 1992;81:603–4. doi:10.1002/jps.2600810629.

    Article  PubMed  CAS  Google Scholar 

  21. Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992;9:663–9. doi:10.1023/A:1015810312465.

    Article  PubMed  CAS  Google Scholar 

  22. Pugh WJ, Hadgraft J. Ab initio prediction of human skin permeability coefficients. Int J Pharm. 1994;103:163–78. doi:10.1016/0378-5173(94)90097-3.

    Article  CAS  Google Scholar 

  23. Wang TF, Kasting GB, Nitsche JM. A multiphase microscopic diffusion model for stratum corneum permeability. II. Estimation of physicochemical parameters, and application to a large permeability database. J Pharm Sci. 2007;96:3024–51. doi:10.1002/jps.20883.

    Article  PubMed  CAS  Google Scholar 

  24. Nitsche JM, Kasting GB. Biophysical models for skin transport and absorption. In: Roberts MS, Walters KA, editors. Dermal Absorption and Toxicity Assessment (2nd ed.). New York: Informa Healthcare USA; 2007. p. 251–69.

    Google Scholar 

  25. Yu B, Kim KH, So PT, Blankschtein D, Langer R. Visualization of oleic acid-induced transdermal diffusion pathways using two-photon fluorescence microscopy. J Invest Dermatol. 2003;120:448–55. doi:10.1046/j.1523-1747.2003.12061.x.

    Article  PubMed  CAS  Google Scholar 

  26. Hanson KM, Behne MJ, Barry NP, Mauro TM, Gratton E, Clegg RM. Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient. Biophys J. 2002;83:1682–90. doi:10.1016/S0006-3495(02) 73936-2.

    Article  PubMed  CAS  Google Scholar 

  27. Winckle G, Anissimov YG, Cross SE, Wise G, Roberts MS. An integrated pharmacokinetic and imaging evaluation of vehicle effects on solute human epidermal flux and, retention characteristics. Pharm Res. 2008;25:158–66. doi:10.1007/s11095-007-9416-z.

    Article  PubMed  CAS  Google Scholar 

  28. Cross SE, Thompson MJ, Roberts MS. Transdermal penetration of vasoconstrictors–present understanding and assessment of the human epidermal flux and retention of free bases and ion-pairs. Pharm Res. 2003;20:270–4. doi:10.1023/A:1022235507186.

    Article  PubMed  CAS  Google Scholar 

  29. Cross SE, Magnusson BM, Winckle G, Anissimov Y, Roberts MS. Determination of the effect of lipophilicity on the in vitro permeability and tissue reservoir characteristics of topically applied solutes in human skin layers. J Invest Dermatol. 2003;120:759–64. doi:10.1046/j.1523-1747.2003.12131.x.

    Article  PubMed  CAS  Google Scholar 

  30. Magnusson BM, Cross SE, Winckle G, Roberts MS. Percutaneous absorption of steroids: determination of in vitro permeability and tissue reservoir characteristics in human skin layers. Skin Pharmacol Physiol. 2006;19:336–42. doi:10.1159/000095254.

    Article  PubMed  CAS  Google Scholar 

  31. Diez I, Colom H, Moreno J, Obach R, Peraire C, Domenech J. A comparative in vitro study of transdermal absorption of a series of calcium channel antagonists. J Pharm Sci. 1991;80:931–4. doi:10.1002/jps.2600801006.

    Article  PubMed  CAS  Google Scholar 

  32. Hinz RS, Lorence CR, Hodson CD, Hansch C, Hall LL, Guy RH. Percutaneous penetration of para-substituted phenols in vitro. Fundam Appl Toxicol. 1991;17:575–83. doi:10.1016/0272-0590(91) 90207-K.

    Article  PubMed  CAS  Google Scholar 

  33. Bucks D, Maibach HI. Occlusion dose not uniformly enhance penetration in vivo. In: Bronaugh RL, Maibach HI, editors. Percutaneous Absorption: drugs, cosmetics, mechanisms, methodology. Boca Raton: Taylor & Francis; 2005. p. 65–83.

    Google Scholar 

  34. Yano T, Nakagawa A, Tsuji M, Noda K. Skin permeability of various non-steroidal anti-inflammatory drugs in man. Life Sci. 1986;39:1043–50. doi:10.1016/0024-3205(86) 90195-5.

    Article  PubMed  CAS  Google Scholar 

  35. Liron Z, Cohen S. Percutaneous absorption of alkanoic acids II: Application of regular solution theory. J Pharm Sci. 1984;73:538–42. doi:10.1002/jps.2600730426.

    Article  PubMed  CAS  Google Scholar 

  36. Ando HY, Schultz TW, Schnaare RL, Sugita ET. Percutaneous absorption: a new physicochemical predictive model for maximum human in vivo penetration rates. J Pharm Sci. 1984;73:461–7. doi:10.1002/jps.2600730409.

    Article  PubMed  CAS  Google Scholar 

  37. Anissimov YG, Roberts MS. Diffusion modeling of percutaneous absorption kinetics. 1. Effects of flow rate, receptor sampling rate, and viable epidermal resistance for a constant donor concentration. J Pharm Sci. 1999;88:1201–9. doi:10.1021/js990053i.

    Article  PubMed  CAS  Google Scholar 

  38. Pellett MA, Roberts MS, Hadgraft J. Supersaturated solutions evaluated with an in vitro stratum corneum tape stripping technique. Int J Pharm. 1997;151:91–8. doi:10.1016/S0378-5173(97) 04897-7.

    Article  CAS  Google Scholar 

  39. Roberts MS, Anissimov YG. Mathematical models in percutaneous absorption. In: Bronaugh RL, Maibach HI, editors. Percutaneous Absorption: drugs, cosmetics, mechanisms, methodology. Boca Raton: Taylor & Francis; 2005. p. 1–44.

    Google Scholar 

  40. Kim MK, Lee CH, Kim DD. Skin permeation of testosterone and its ester derivatives in rats. J Pharm Pharmacol. 2000;52:369–75. doi:10.1211/0022357001774101.

    Article  PubMed  CAS  Google Scholar 

  41. Hansch C, Clayton JM. Lipophilic character and biological activity of drugs. II. The parabolic case. J Pharm Sci. 1973;62:1–21. doi:10.1002/jps.2600620102.

    Article  PubMed  CAS  Google Scholar 

  42. Kubinyi H. Quantitative structure-activity relationships. IV. Non-linear dependence of biological activity on hydrophobic character: a new model. Arzneimittelforschung. 1976;26:1991–7.

    PubMed  CAS  Google Scholar 

  43. Kubinyi H. Drug partitioning: relationships between forward and reverse rate constants and partition coefficient. J Pharm Sci. 1978;67:262–3. doi:10.1002/jps.2600670237.

    Article  PubMed  CAS  Google Scholar 

  44. Leo A, Hansch C, Elkins D. Partition coefficients and their uses. Chem Rev. 1971;71:525–616. doi:10.1021/cr60274a001.

    Article  CAS  Google Scholar 

  45. Anderson BD, Higuchi WI, Raykar PV. Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum. Pharm Res. 1988;5:566–73. doi:10.1023/A:1015989929342.

    Article  PubMed  CAS  Google Scholar 

  46. Takacs-Novak K, Avdeef A. Interlaboratory study of log P determination by shake-flask and potentiometric methods. J Pharm Biomed Anal. 1996;14:1405–13. doi:10.1016/0731-7085(96) 01773-6.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  48. Anderson RA, Triggs EJ, Roberts MS. The percutaneous absorption of phenolic compounds. 3. Evaluation of permeability through human stratum corneum using a desorption technique. Aust J Pharm Sci. 1976;5:107–10.

    CAS  Google Scholar 

  49. Roberts MS, Triggs EJ, Anderson RA. Permeability of solutes through biological membranes measured by a desorption technique. Nature. 1975;257:225–7. doi:10.1038/257225a0.

    Article  PubMed  CAS  Google Scholar 

  50. Mitragotri S. In situ determination of partition and diffusion coefficients in the lipid bilayers of stratum corneum. Pharm Res. 2000;17:1026–9. doi:10.1023/A:1007547809430.

    Article  PubMed  CAS  Google Scholar 

  51. Abraham MH. Scales of solute hydrogen-bonding-their construction and application to physicochemical and biochemical processes. Chem Soc Rev. 1993;22:73–83. doi:10.1039/cs9932200073.

    Article  CAS  Google Scholar 

  52. Abraham MH, Chadha HS, Mitchell RC. The factors that influence skin penetration of solutes. J Pharm Pharmacol. 1995;47:8–16.

    CAS  Google Scholar 

  53. Mintz C, Acree WE, Abraham MH. Correlation of minimum inhibitory concentrations toward oral bacterial growth based on the Abraham model. QSAR Comb Sci. 2006;25:912–20. doi:10.1002/qsar.200630011.

    Article  CAS  Google Scholar 

  54. Brain KR, Waters KA, Watkinson AC. Investigation of skin permeation in vitro. In: Roberts MS, Walters KA, editors. Dermal Absorption and Toxicity Assessment. New York: Marcel Dekker; 1998. p. 161–88.

    Google Scholar 

  55. Roberts MS, Anderson RA, Moore DE, Swarbrick J. The distribution of non-electrolytes between human stratum corneum and water. Aust J Pharm Sci. 1977;6:77–82.

    CAS  Google Scholar 

  56. Blank IH. Penetration of low-molecular-weight alcohols into skin. I. effect of concentration of alcohol and type of vehicle. J Invest Dermatol. 1964;43:415–20.

    PubMed  CAS  Google Scholar 

  57. Roberts MS, Cross SE, Pellett MA. Skin transport. In: Walters KA, editor. Dermatological and Transdermal Formulations. New York: Marcel Dekker; 2002. p. 89–195.

    Google Scholar 

  58. Zhang Y, Lukacova V, Reindl K, Balaz S. Quantitative characterization of binding of small molecules to extracellular matrix. J Biochem Biophys Methods. 2006;67:107–22. doi:10.1016/j.jbbm.2006.01.007.

    Article  PubMed  CAS  Google Scholar 

  59. Ogata N, Shibata T. Binding of alkyl- and alkoxy-substituted simple phenolic compounds to human serum proteins. Res Commun Mol Pathol Pharmacol. 2000;107:167–73.

    PubMed  CAS  Google Scholar 

  60. Mellick GD, Roberts MS. Structure-hepatic disposition relationships for phenolic compounds. Toxicol Appl Pharmacol. 1999;158:50–60. doi:10.1006/taap.1999.8682.

    Article  PubMed  CAS  Google Scholar 

  61. Guy RH, Hadgraft J. Physicochemical aspects of percutaneous penetration and its enhancement. Pharm Res. 1988;5:753–8. doi:10.1023/A:1015980516564.

    Article  PubMed  CAS  Google Scholar 

  62. Sloan KB, Koch SA, Siver KG, Flowers FP. Use of solubility parameters of drug and vehicle to predict flux through skin. J Invest Dermatol. 1986;87:244–52. doi:10.1111/1523-1747.ep12696635.

    Article  PubMed  CAS  Google Scholar 

  63. Kasting GB, Smith RL, Anderson BD. Prodrugs for dermal delivery: solubility, molecular size, and functional group effects. In: Sloan KB, editor. Produgs. New York: Marcel Dekker; 1992. p. 117–61.

    Google Scholar 

  64. Roberts MS, Walters KA. The relationship between structure and barrier function of skin. In: Roberts MS, Walters KA, editors. Dermal Absorption and Toxicity Assessment. New York: Marcel Dekker; 1998. p. 1–42.

    Google Scholar 

  65. Roberts MS, Anderson RA, Swarbrick J, Moore DE. The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum. J Pharm Pharmacol. 1978;30:486–90.

    PubMed  CAS  Google Scholar 

  66. Jetzer WE, Huq AS, Ho NF, Flynn GL, Duraiswamy N, Condie L Jr. Permeation of mouse skin and silicone rubber membranes by phenols: relationship to in vitro partitioning. J Pharm Sci. 1986;75:1098–103. doi:10.1002/jps.2600751116.

    Article  PubMed  CAS  Google Scholar 

  67. Stenberg P, Norinder U, Luthman K, Artursson P. Experimental and computational screening models for the prediction of intestinal drug absorption. J Med Chem. 2001;44:1927–37. doi:10.1021/jm001101a.

    Article  PubMed  CAS  Google Scholar 

  68. Winiwarter S, Ax F, Lennernas H, Hallberg A, Pettersson C, Karlen A. Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability. J Mol Graph Model. 2003;21:273–87. doi:10.1016/S1093-3263(02) 00163-8.

    Article  PubMed  CAS  Google Scholar 

  69. Bartzatt R. Alkylation activity and molecular properties of two antineoplastic agents that utilise indometacin and a conjugate of aspirin with 2-aminonicotinic acid to transport nitrogen mustard groups. Drugs R D. 2007;8:363–72. doi:10.2165/00126839-200708060-00004.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the National Health and Medical Research Council of Australia, National“863”Project (No. 2003AA2Z347A) from P.R China and National Nature Science Fund (30630076) from P.R China for financial support for this work. O.G. Jepps thanks the Australian Research Council for financial support (APD Fellowship) during this work. We also thank Prof M.H. Abraham from Department of Chemistry, University College London, for providing the solvatochromic parameters for methyl salicylate.

Author information

Authors and Affiliations

  1. Therapeutics Research Unit, School of Medicine, Princess Alexandra Hospital, The University of Queensland, Woolloongabba, QLD 4102, Australia

    Qian Zhang, Jeffrey E. Grice, Peng Li & Michael S. Roberts

  2. Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210038, China

    Qian Zhang & Guang-Ji Wang

  3. School of Biomolecular and Physical Sciences, Griffith University, Brisbane, QLD 4111, Australia

    Owen G. Jepps

  4. School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia

    Michael S. Roberts

Authors
  1. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey E. Grice
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Owen G. Jepps
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guang-Ji Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael S. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Roberts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Q., Grice, J., Li, P. et al. Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules. Pharm Res 26, 1974–1985 (2009). https://doi.org/10.1007/s11095-009-9912-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9912-4

KEY WORDS

Search

Navigation