Pharmaceutical Research

, 35:70 | Cite as

Effect of Permeation Enhancers on the Buccal Permeability of Nicotine: Ex vivo Transport Studies Complemented by MALDI MS Imaging

  • Eva Marxen
  • Liang Jin
  • Jette Jacobsen
  • Christian Janfelt
  • Birgitte Hyrup
  • Joseph A. Nicolazzo
Research Paper



The purpose of this study was to assess the effect of several chemical permeation enhancers on the buccal permeability of nicotine and to image the spatial distribution of nicotine in buccal mucosa with and without buccal permeation enhancers.


The impact of sodium taurodeoxycholate (STDC), sodium dodecyl sulphate (SDS), dimethyl sulfoxide (DMSO) and Azone® on the permeability of [3H]-nicotine and [14C]-mannitol (a paracellular marker) across porcine buccal mucosa was studied ex vivo in modified Ussing chambers. The distribution of nicotine, mannitol and permeation enhancers was imaged using using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI).


Despite STDC significantly increasing permeability of [14C]-mannitol, no enhancing effect was seen on [3H]-nicotine permeability with any of the permeation enhancers. Rather, SDS and DMSO retarded nicotine permeability, likely due to nicotine being retained in the donor compartment. The permeability results were complemented by the spatial distribution of nicotine and mannitol determined with MALDI MSI.


The buccal permeability of nicotine was affected in an enhancer specific manner, suggesting that nicotine primarily diffuses via the transcellular pathway. MALDI MSI was shown to complement ex vivo permeability studies and to be a useful qualitative tool for visualizing drug and penetration enhancer distribution in buccal mucosa.


buccal mucosa mass spectrometry imaging nicotine permeability permeation enhancer 





Critical micelle concentration


Dimethyl sulfoxide


Enhancement ratio


Hematoxylin and eosin


Krebs-Ringer bicarbonate buffer


Matrix-assisted laser desorption ionization


Apparent permeability coefficient


Standard deviation


Sodium dodecyl sulfate


Sodium taurodeoxycholate


Acknowledgments and Disclosures

The Nicotine Science Center, Fertin Pharma A/S, Vejle, Denmark is thankfully acknowledged for their funding of this project. Assistant Professor Andrew Richard Williams is acknowledged for kind donation of porcine cheeks from experimental control pigs for the MALDI studies. The authors gratefully acknowledge the Oticon Foundation, the Lundbeck Foundation and the Graduate School of Health and Medical Sciences for grants enabling the travel to Melbourne, Australia where the permeability studies were performed. Support for the MALDI imaging from the Carlsberg Foundation and The Danish Council for Independent Research | Medical Sciences (grant no. DFF – 4002-00391) is gratefully acknowledged.

Supplementary material

11095_2017_2332_MOESM1_ESM.docx (2.5 mb)
ESM 1 (DOCX 2533 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Eva Marxen
    • 1
  • Liang Jin
    • 2
  • Jette Jacobsen
    • 1
  • Christian Janfelt
    • 1
  • Birgitte Hyrup
    • 3
  • Joseph A. Nicolazzo
    • 2
  1. 1.Department of Pharmacy, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia
  3. 3.Fertin Pharma A/SVejleDenmark

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