Skip to main content
SpringerLink
Log in

Transdermal Macromolecular Delivery: Real-Time Visualisation of Iontophoretic and Chemically Enhanced Transport Using Two-Photon Excitation Microscopy

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. To investigate the transdermal delivery of a modelmacromolecule by passive and iontophoretic means following pretreatment withC12-penetration enhancers and to visualise transport across humanstratum corneum (SC) in real time.

Methods. Transport studies of dextran, labelled with fluorescentCascade Blue® (D-CB; MR = 3 kDa) across human stratum corneum,were conducted during passive and iontophoretic modes of deliveryfollowing pretreatment with either dodecyltrimethylammoniumbromide (DTAB), sodium dodecyl sulphate (SDS) or Azone®.Size-exclusion chromatography was used to assess maintenance of dextranstructural integrity throughout experimental lifetime. Two-photonexcitation microscopy was employed to visualise real-time dextran transportduring current application.

Results. The positively charged C12-enhancer DTAB elevated passiveD-CB steady-state flux (Jss) and was the only enhancer to do soabove control during iontophoresis. The negatively charged SDS had theleast effect during both stages. On-line macromolecular transport wasvisualised, indicating both inter- and intra-cellular pathways across SCduring current application. No transport was visible across untreatedSC during passive transport.

Conclusions. Use of a positively charged enhancer may improve Jssof anionic macromolecular penetrants during passive and iontophoreticdelivery. On-line visualisation of iontophoresis across SC was possibleand can provide mechanistic insight into SC transport pathways.

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

Similar content being viewed by others

REFERENCES

  1. E. W. Smith and H. I. Maibach. Percutaneous Penetration Enhancers, CRC Press, Boca Raton, 1995.

    Google Scholar 

  2. B. J. Aungst, N. J. Rogers, and E. Sheffer. Enhancement of Naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int. J. Pharm. 33:225–234 (1986).

    Google Scholar 

  3. J. A. Bouwstra, G. S. Gooris, J. Brussee, M. A. Salomons-de Vries, and W. Bras. The influence of alkyl-azones on the ordering of the lamellae in human stratum corneum. Int. J. Pharm. 79:141–148 (1992).

    Google Scholar 

  4. P. K. Wotton, B. MØ llgaard, J. Hadgraft, and A. Hoelgaard. Vehicle effect on topical drug delivery. III. Effect of Azone on the cutaneous permeation of metronidazole and propylene glycol. Int. J. Pharm. 24:19–26 (1985).

    Google Scholar 

  5. A. Naik, L. A. R. M. Pechtold, R. O. Potts, and R. H. Guy. Mechanism of oleic acid induced skin penetration enhancement. J. Contr. Rel. 37:299–306 (1995).

    Google Scholar 

  6. J.-Y. Fang, C.-L. Fang, Y.-B. Huang, and Y.-H. Tsai. Transdermal iontophoresis of sodium nonivamide acetate. III. Combined effect of pretreatment by penetration enhancers. Int. J. Pharm. 149:183–193 (1997).

    Google Scholar 

  7. J. Hirvonen, K. Kontturi, L. Murtomaki, P. Paronen, and A. Urrti. Transdermal Iontophoresis of Sotalol and Salicylate; the effect of skin charge and penetration enhancers J. Contr. Rel. 26:109–117 (1993).

    Google Scholar 

  8. C. L. Gay, P. G. Green, and M. L. Francoeur. Iontophoretic delivery of piroxicam across the skin in vitro. J. Contr. Rel. 22:57–68 (1992).

    Google Scholar 

  9. L. Wearley and Y. W. Chien. Enhancement of the in vitro skin permeability of Azidothymidine (AZT) via iontophoresis and chemical enhancer Pharm. Res. 7:34–40 (1990).

    Google Scholar 

  10. N. Yoshida and M. Roberts. Solute molecular size and transdermal iontophoresis across excised human skin. J. Contr. Rel. 25:177–195 (1993).

    Google Scholar 

  11. P. G. Green, B. Shroot, F. Bernerd, W. R. Pilgrim, and R. H. Guy. In vitro and in vivo iontophoresis of a tripeptide across nude rat skin. J. Contr. Rel. 20:209–218 (1992).

    Google Scholar 

  12. P. G. Green, M. Flanagan, B. Shroot, and R. H. Guy. Iontophoretic Drug Delivery. In K. A. Walters and J. Hadgraft (eds), Pharmaceutical Skin Penetration Enhancement, Marcel Dekker Inc, New York, 1993, pp. 311–333.

    Google Scholar 

  13. B. Berner and S. M. Dinh. Electronically assisted drug delivery: An overview. In B. Berner and S. M. Dinh (eds), Electronically controlled drug delivery, CRC Press, New York, 1998, pp. 3–7.

    Google Scholar 

  14. C. Cullander and R. H. Guy. Visualization of iontophoretic pathways with confocal microscopy and the vibrating probe electrode. Solid-state Ionics 53:197–206 (1992).

    Google Scholar 

  15. N. G. Turner and R. H. Guy. Iontophoretic transport pathways: Dependance on penetrant physicochemical properties. J. Pharm. Sci. 86:1385–1389 (1997).

    Google Scholar 

  16. N. G. Turner, L. Ferry, M. Price, C. Cullander, and R. H. Guy. Iontophoresis of Poly-L-lysines: The role of molecular weight? Pharm. Res. 14:1322–1331 (1997).

    Google Scholar 

  17. J. Vroom. Two-photon excitation fluorescence lifetime imaging: development and biological applications. PhD Thesis, Universiteit Utrecht, Faculteit Natuuren Sterrenkunde, pp. 1–93 (1998).

  18. C. Cullander, Confocal microscopy in the study of skin permeation: Utility and limitations. In K. A. Walters, K. Brain and V. J. James (eds), Prediction of Percutaneous Penetration, STS Publishing, Cardiff, 1996, pp. 5–6.

    Google Scholar 

  19. K. König P. T. C. So, W. W. Mantulin, and E. Gratton. Cellular response to near-infrared femtosecond laser pulses in two-photon microscopes. Optics Letts. 22:135–136 (1997).

    Google Scholar 

  20. L. A. Geddes, L. E. Baker, and A. G. Moore. Optimum electrolytic chloriding of silver electrodes. Med. Biol. Eng. 7:49–56 (1969).

    Google Scholar 

  21. R. Van der Geest, M. Danhof, and H. E. Boddé. Validation and testing of a new iontophoretic continuous flow through transport cell. J. Contr. Rel. 51:85–91 (1998).

    Google Scholar 

  22. C. J. de Grauw, J. M. Vroom, H. T. M. van der Voort, and H. C. Gerritsen. Imaging properties of in two-photon excitation microscropy and effects of refractive index mismatch in thick specimens, Applied Optics 38:5995–6003 (1999).

    Google Scholar 

  23. N. M. Volpato, P. Santi, and P. Colombo. Iontophoresis enhances the transport of acyclovir through nude mouse skin by electrorepulsion and electroosmosis. Pharm. Res. 12:1623–1626 (1995).

    Google Scholar 

  24. J. A. Bouwstra and H. E. Bodde, Human SC barrier impairment by N-alkyl-azacycloheptanones: A mechanistic study of drug flux enhancement, Azone mobility, and protein-and lipid-perturbation. In: Percutaneous Penetration Enhancers, E. W. Smith, and H. I. Maibach (eds.), New York: CRC Press, pp. 137–157, (1995).

    Google Scholar 

  25. Y. N. Kalia and R. H. Guy, The interaction between penetration enhancers and iontophoresis: Effect on human skin impedance in vivo, J. Contr. Rel. 44:33–42 (1997).

    Google Scholar 

  26. P. Ashton, K. A. Walters, K. R. Brain, and J. Hadgraft. Surfactant effects in percutaneous absorption I. Effects on the transdermal flux of methyl nicotinate. Int. J. Pharm. 87:261–264 (1992).

    Google Scholar 

  27. J. Hadgraft, D. G. Williams, and G. Allan. Azone®, Mechanisms of action and clinical effect. In K. A. Walters and J. Hadgraft (eds), Pharmaceutical Skin Penetration Enhancement, Marcel Dekker, New York, 1993

    Google Scholar 

  28. R. R. Burnette and B. Ongpipattanakul. Characterization of the permselective properties of excised human skin during iontophoresis. J. Pharm. Sci. 76:765–773 (1987).

    Google Scholar 

  29. A. Kim, P. G. Green, G. Rao, and R. H. Guy. Convective solvent flow across the skin during iontophoresis. Pharm. Res. 10:1315–1320 (1993).

    Google Scholar 

  30. L. D. Rhein, C. R. Robbins, K. Fernee, and R. Cantore. Surfactant structure effects on swelling of isolated human stratum corneum. J. Soc. Cosmet. Chem. 37:125 (1986).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Sciences Research Institute, Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK

    Burrinder S. Grewal

  2. Leiden/Amsterdam Centre for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands

    Burrinder S. Grewal, Gert Gooris & Joke A. Bouwstra

  3. Centre Interuniversitaire de Recherche et d'Enseignement, Archamps, France

    Aarti Naik

  4. Pharmaceutical Sciences Research Institute, Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK

    William J. Irwin

  5. Debye Institute, Department of Molecular Biophysics, Utrecht University, The Netherlands

    Cees J. de Grauw & Hans G. Gerritsen

Authors
  1. Burrinder S. Grewal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aarti Naik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William J. Irwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gert Gooris
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cees J. de Grauw
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hans G. Gerritsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joke A. Bouwstra
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grewal, B.S., Naik, A., Irwin, W.J. et al. Transdermal Macromolecular Delivery: Real-Time Visualisation of Iontophoretic and Chemically Enhanced Transport Using Two-Photon Excitation Microscopy. Pharm Res 17, 788–795 (2000). https://doi.org/10.1023/A:1007595822786

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007595822786

Search

Navigation