Skip to main content

Confocal Raman Spectroscopy as a Tool to Investigate the Action of Penetration Enhancers Inside the Skin

  • Chapter
  • First Online:
Percutaneous Penetration Enhancers Drug Penetration Into/Through the Skin

Abstract

Confocal Raman microspectroscopy (CRM) is a new method aimed at investigating in vitro or in vivo the penetration of substances in the skin (either active substances, contaminants, or even other ingredients) provided that they have a Raman signature that can be isolated from the spectral background. This technique allows monitoring the permeant absorption into the skin up to 100 μm depth, but also simultaneous investigation of the modification of endogenous skin components resulting from interactions between the permeants and skin lipids or proteins. Penetration enhancers have been studied for a long time by several techniques; tracking enhancers in the skin by CRM is a new field of investigation. Water is the first enhancer widely studied by the CRM technique. Numerous studies explored the moisturization of stratum corneum (SC) and its consequences to drug penetration. Retinol was the most common model drug used to investigate the impact of classical enhancers such as dimethylsulfoxide, oleic acid, and surfactants on drug absorption. Measurements by CRM of the enhancing effect of surfactants on retinol penetration allowed sorting them with respect to their penetration enhancer power. The modification of the stratum corneum lipids packing after application of such formulations has also been pointed out in few studies. More recently, the development of stimulated Raman scattering microscopy improved the sensitivity of Raman microscopy imaging of skin.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

  • Anigbogu ANC, Williams AC, Barry BW, Edwards HGM (1995) Fourier transform Raman spectroscopy of interactions between the penetration enhancer dimethyl sulfoxide and human stratum corneum. Int J Pharm 125:265–282

    Article  CAS  Google Scholar 

  • Aqil M, Ahad A, Sultana Y, Ali A (2007) Status of terpenes as skin penetration enhancers. Drug Discov Today 12:1061–1067

    Article  CAS  PubMed  Google Scholar 

  • Ashtikara M (2013) Matthäus, Schmitt M, Krafft C, Fahr a, Popp J. Non-invasive depth profile imaging of the stratum corneum using confocal Raman microscopy: first insights into the method. Eur J Pharm Sci 50:601–608

    Article  Google Scholar 

  • Babita K, Kumar V, Rana V, Jain S, Tiwary AK (2006) Thermotropic and spectroscopic behavior of skin: relationship with percutaneous permeation enhancement. Curr Drug Deliv 3:95–113

    Article  CAS  PubMed  Google Scholar 

  • Barry BW, Edwards H, Williams A (1992) Fourier transform Raman and infrared vibrational study of human skin: assignment of spectral bands. J Raman Spectrosc 23:641–645

    Article  CAS  Google Scholar 

  • Benson HAE (2005) Transdermal drug delivery: penetration enhancement techniques. Curr Drug Deliv 2:23–33

    Article  CAS  PubMed  Google Scholar 

  • Bolzinger MA, Briancon S, Pelletier J, Fessi H, Chevalier Y (2008) Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms. Eur J Pharm Biopharm 68:446–451

    Article  CAS  PubMed  Google Scholar 

  • Bolzinger MA, Briançon S, Pelletier J, Chevalier Y (2012) Penetration of drugs through skin, a complex rate-controlling membrane. Curr Opin Colloid Interface Sci 17:156–165

    Article  CAS  Google Scholar 

  • Boncheva M, Damien F, Normand V (2008) Molecular organization of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy. Biochim Biophys Acta 1778:1344–1355

    Article  CAS  PubMed  Google Scholar 

  • Bouwstra JA, Ponec M (2006) The skin barrier in healthy and diseased state. Biochim Biophys Acta 1758:2080–2095

    Article  CAS  PubMed  Google Scholar 

  • Bouwstra JA, Gooris GS, van der Spek JA, Bras W (1991) Structural investigations of human stratum corneum by small angle X-ray scattering. J Invest Dermatol 97:1005–1012

    Article  CAS  PubMed  Google Scholar 

  • Bouwstra JA, Cheng K, Gooris GS, Weerheim A, Ponec M (1996) Phase behavior of isolated skin lipids. Biochim Biophys Acta 1300:177–186

    Article  PubMed  Google Scholar 

  • Bouwstra JA, Honeywell-Nguyen PL, Gooris GS, Ponec M (2003) Structure of the skin barrier and its modulation by vesicular formulations. Prog Lipid Res 42:1–36

    Article  CAS  PubMed  Google Scholar 

  • Bouwstra JA, Gooris GS, Ponec M (2007) Skin lipid organization, composition and barrier function. IFSCC Magazine 10:297–307

    CAS  Google Scholar 

  • Bronaugh RL, Maibach HI (1999) Percutaneous absorption. Drugs – cosmetics – mechanisms – methodology, 3rd edn. Marcel Dekker, New York

    Google Scholar 

  • Cappel MJ, Kreuter J (1991) Effect of nonionic surfactants on transdermal drug delivery: I. Polysorbates. Int J Pharm 69:143–153

    Article  CAS  Google Scholar 

  • Caspers P, Lucassen G, Bruining H, Puppels G (2000) Automated depth-scanning confocal Raman microspectrometer for rapid in vivo determination of water concentration profiles in human skin. J Raman Spectrosc 31:813–818

    Article  CAS  Google Scholar 

  • Caspers PJ, Lucassen GW, Carter EA, Bruining HA, Puppels GJ (2001) In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles. J Invest Dermatol 116:434–442

    Article  CAS  PubMed  Google Scholar 

  • Caspers PJ, Williams AC, Carter EA, Edwards HG, Barry BW, Bruining HA, Puppels GJ (2002) Monitoring the penetration enhancer dimethyl sulfoxide in human stratum corneum in vivo by confocal Raman spectroscopy. Pharm Res 19:1577–1580

    Article  CAS  PubMed  Google Scholar 

  • Caspers PJ, Lucassen GW, Puppels GJ (2003) Combined in vivo confocal Raman spectroscopy and confocal microscopy of human skin. Biophys J 85:572–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandrasekharan SK, Campbell PS, Michaels AS (1977) Effect of dimethylsulfoxide on drug permeation through human skin. AICHE J 23:810–815

    Article  Google Scholar 

  • Ciampi E, van Ginkel M, McDonald PJ, Pitts S, Bonnist EYM, Singleton S, Williamson A-M (2011) Dynamic in vivo mapping of model moisturiser ingress into human skin by GARfield MRI. NMR Biomed 24:135–144

    Article  CAS  PubMed  Google Scholar 

  • Crowther JM, Sieg A, Blenkiron P, Marcott C, Matts PJ, Kaczvinsky JR, Rawlings AV (2008) Measuring the effects of topical moisturizers on changes in stratum corneum thickness, water gradients and hydration in vivo. Br J Dermatol 159:567–577

    CAS  PubMed  Google Scholar 

  • Damien F, Boncheva M (2010) The extent of orthorhombic lipid phases in the stratum corneum determines the barrier efficiency of human skin in vivo. J Invest Dermatol 130:611–614

    Article  CAS  PubMed  Google Scholar 

  • Darlenski R, Sassning S, Tsankov N, Fluhr JW (2009) Non-invasive in vivo methods for investigation of the skin barrier physical properties. Eur J Pharm Biopharm 72:295–303

    Article  CAS  PubMed  Google Scholar 

  • Downes A, Elfick A (2010) Raman spectroscopy and related techniques in biomedicine. Sensors 10:1871–1889

    Article  PubMed  PubMed Central  Google Scholar 

  • Egawa M, Kajikawa T (2009) Changes in the depth profile of water in the stratum corneum treated with water. Skin Res Technol 15:242–249

    Article  PubMed  Google Scholar 

  • Egawa M, Hirao T, Takahashi M (2007) In vivo estimation of stratum corneum thickness from water concentration profiles obtained with Raman spectroscopy. Acta Derm Venereol 87:4–8

    Article  PubMed  Google Scholar 

  • Evans CL, Xie XS (2008) Coherent anti-stokes Raman scattering microscopy: chemical imaging for biology and medicine. Annu Rev Anal Chem 1:883–909

    Article  CAS  Google Scholar 

  • Failloux N, Bonnet I, Perrier E, Baron M-H (2004) Effects of light, oxygen and concentration on vitamin A1. J Raman Spectrosc 2:140–147

    Article  Google Scholar 

  • Förster M, Bolzinger MA, Montagnac G, Briançon S (2011a) Confocal Raman microspectroscopy of the skin. Eur J Dermatol 21:851–863

    PubMed  Google Scholar 

  • Förster M, Bolzinger MA, Ach D, Montagnac G, Briançon S (2011b) Ingredients tracking of cosmetic formulations in the skin: a confocal Raman microscopy investigation. Pharm Res 28:858–872

    Article  PubMed  Google Scholar 

  • Francoeur ML, Golden GM, Potts RO (1990) Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery. Pharm Res 7:621–627

    Article  CAS  PubMed  Google Scholar 

  • Freudiger CW, Min W, Saar BG, Lu S, Holtom GR, He C, Tsai JC, Kang JX, Xie XS (2008) Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322:1857–1861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu D, Lu F-K, Zhang X, Freudiger C, Pernik DR, Holtom G, Xie XS (2012) Quantitative chemical imaging with multiplex stimulated Raman scattering microscopy. J Am Chem Soc 134:3623–3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gay CL, Guy RH, Golden GM, Mak VHW, Francoeur ML (1994) Characterization of low temperature (i.E., < 65 degrees C) lipid transitions in human stratum corneum. J Invest Dermatol 103:233–239

    Article  CAS  PubMed  Google Scholar 

  • Groen D, Poole DS, Gooris GS, Bouwstra JA (2011) Is an orthorhombic lateral packing and a proper lamellar organization important for the skin barrier function? Biochim Biophys Acta - Biomembranes 1808:1529–1537

    Article  CAS  Google Scholar 

  • Hancewicz TM, Xiao C, Weissman J, Foy V, Zhang S, Misra M (2012) A consensus modeling approach for the determination of stratum corneum thickness using in-vivo confocal Raman spectroscopy. J Cosmet Dermatol Sci Appl 2:241–251

    Google Scholar 

  • Herkenne C, Alberti I, Naik A, Kalia YN, Mathy F-X, Préat V, Guy RH (2008) In vivo methods for the assessment of topical drug bioavailability. Pharm Res 25:87–103

    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 5:517–529

    Article  CAS  PubMed  Google Scholar 

  • Li L, Wang H, Cheng J-X (2005) Quantitative coherent anti-stokes Raman scattering imaging of lipid distribution in coexisting domains. Biophys J 89:3480–3490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu F-K, Ji M, Fu D, Ni X, Freudiger CW, Holtom G, Xie XS (2012) Multicolor stimulated Raman scattering microscopy. Mol Phys 110:1927–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mélot M, Pudney PDA, Williamson AM, Caspers PJ, Van Der Pol A, Puppels GJ (2009) Studying the effectiveness of penetration enhancers to deliver retinol through the stratum cornum by in vivo confocal Raman spectroscopy. J Control Release 138:32–39

    Article  PubMed  Google Scholar 

  • Min W, Freudiger CW, Lu S, Xie XS (2011) Coherent nonlinear optical imaging: beyond fluorescence microscopy. Annu Rev Phys Chem 62:507–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montes LF, Day JL, Wand CJ (1967) Kennedy L. Ultrastructural changes in the horny layer following local application of DMSO to Guinea pig skin. J Invest Dermatol 48:184–189

    Google Scholar 

  • Naik A, Pechtold LARM, Potts RO, Guy RH (1995) Mechanism of oleic acid-induced skin penetration in vivo in humans. J Control Release 37:299–306

    Article  CAS  Google Scholar 

  • Nandakumar P, Kovalev A, Volkmer A (2009) Vibrational imaging based on stimulated Raman scattering microscopy. New J Phys 11:033026

    Article  Google Scholar 

  • Norlén L (2001) Skin barrier structure and function: the single gel phase model. J Invest Dermatol 117:830–836

    Article  PubMed  Google Scholar 

  • Ongpipattanakul B, Burnette RR, Potts RO, Francoeur ML (1991) Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm Res 8:350–354

    Article  CAS  PubMed  Google Scholar 

  • Pilgram GSK, Engelsma-van Pelt AM, Bouwstra JA, Koerten HK (1999) Electron diffraction provides new information on human stratum corneum lipid organisation studied in relation to depth and temperature. J Invest Dermatol 113:403–409

    Article  CAS  PubMed  Google Scholar 

  • Pudney PDA, Mélot M, Caspers PJ, Van Der Pol A, Puppels GJ (2007) An in vivo confocal Raman study of the delivery of trans-retinol to the skin. Appl Spectrosc 61:804–811

    Article  CAS  PubMed  Google Scholar 

  • Saar BG, Freudiger CW, Reichman J, Stanley CM, Holtom GR, Xie XS (2010) Video-rate molecular imaging in vivo with stimulated Raman scattering. Science 330:1368–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saar BG, Contreras-Rojas LR, Xie XS, Guy RH (2011) Imaging drug delivery to skin with stimulated Raman scattering microscopy. Mol Pharm 8:969–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slipchenko MN, Chen H, Ely DR, Jung Y, Carvajal MT, Cheng J-X (2010) Vibrational imaging of tablets by epi-detected stimulated Raman scattering microscopy. Analyst 135:2613–2619

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Xiao C, Mendelsohn R, Zheng T, Strekowski L, Michniak B (2005) Investigation of iminosulfuranes as novel transdermal penetration enhancers: enhancement activity and cytotoxicity. Pharm Res 22:1918–1925

    Article  CAS  PubMed  Google Scholar 

  • Stoughton RB, McClure WO (1983) Azone – a new non-toxic enhancer of cutaneous penetration. Drug Dev Ind Pharm 9:725–744

    Article  CAS  Google Scholar 

  • Tfaili S, Gobinet C, Josse G, Angiboust JF, Baillet A, Manfait M, Piot O (2013) Vibrational spectroscopies for the analysis of cutaneous permeation: experimental limiting factors identified in the case of caffeine penetration. Anal Bioanal Chem 405:1325–1332

    Article  CAS  PubMed  Google Scholar 

  • Tfayli A, Piot O, Pitre F, Manfait M (2007) Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy. Eur J Biophys 36:1049–1058

    Article  CAS  Google Scholar 

  • Tfayli A, Piot O, Manfait M (2008) Confocal Raman microspectroscopy on excised human skin: uncertainties in depth profiling and mathematical correction applied to dermatological drug permeation. J Biophoton 1:140–153

    Article  CAS  Google Scholar 

  • Tfayli A, Guillard E, Manfait M, Baillet-Guffroy A (2010) Thermal dependence of Raman descriptors of ceramides. Part I: effect of double bonds in hydrocarbon chains. Anal Bioanal Chem 397:1281–1296

    Article  CAS  PubMed  Google Scholar 

  • Tfayli S, Josse G, Gobinet C, Angiboust JF, Manfait M, Piot O (2012a) Shedding light on the laser wavelength effect in Raman analysis of skin epidermises. Analyst 137:4241–4246

    Article  Google Scholar 

  • Tfayli S, Gobinet C, Josse G, Angiboust JF, Manfait M, Piot O (2012b) Confocal Raman microspectroscopy for skin characterization: a comparative study between human skin and pig skin. Analyst 137:3673–3682

    Article  Google Scholar 

  • Tfayli A, Guillard E, Manfait M, Baillet-Guffroy A (2012c) Molecular interactions of penetration enhancers within ceramides organization: a Raman spectroscopy approach. Analyst 137:5002–5010

    Article  CAS  PubMed  Google Scholar 

  • Tfayli A, Guillard E, Manfait M, Baillet-Guffroy A (2012d) Raman spectroscopy: feasibility of in vivo survey of stratum corneum lipids, effect of natural aging. Eur J Dermatol 22:36–41

    CAS  PubMed  Google Scholar 

  • Touitou E, Meidan VM, Horwitz E (1998) Methods for quantitative determination of drug localized in the skin. J Control Release 56:7–21

    Article  CAS  PubMed  Google Scholar 

  • Walker RB, Smith EW (1996) The role of percutaneous penetration enhancers. Adv Drug Deliv Rev 18:295–301

    Article  CAS  Google Scholar 

  • van Hal DA, Jeremiasse E, Junginger HE, Spies F, Bouwstra JA (1996) Structure of fully hydrated human stratum corneum: a freeze-fracture electron microscopy study. J Invest Dermatol 106:89–95

    Article  PubMed  Google Scholar 

  • van der Pol A, de Sterke J, Caspers PJ (2007) Modeling and interpretation of water concentration gradients in the stratum corneum as measured by confocal Raman microspectroscopy. Int J Cosmet Sci 29:235

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Windheuser JJ, Haslam JL, Caldwell L, Shaffer RD (1982) The use of N,N-diethyl-m-toluamide to enhance dermal and transdermal delivery of drugs. J Pharm Sci 71:1211–1213

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Polefka TG (2008) Confocal Raman microspectroscopy of stratum corneum: a pre-clinical validation study. Int J Cosmet Sci 30:47–56

    Article  CAS  PubMed  Google Scholar 

  • Xiao C, Flach CR, Marcott C, Mendelsohn R (2004) Uncertainties in depth determination and comparison of multivariate with univariate analysis in confocal Raman studies of a laminated polymer and skin. Appl Spectrosc 58:382–389

    Article  CAS  PubMed  Google Scholar 

  • Yu B, Kim KH, So PTC, Blankschtein D, Langer R (2003) Visualization of oleic acid induced transdermal diffusion pathways using two photon fluorescence microscopy. J Invest Dermatol 120:448–455

    Article  CAS  PubMed  Google Scholar 

  • Zhang G, Flach CR, Mendelsohn R (2007a) Tracking the dephosphorylation of resveratrol triphosphate in skin by confocal Raman microscopy. J Control Release 123:141–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang G, Moore DJ, Flach CR, Mendelsohn R (2007b) Vibrational microscopy and imaging of skin: from single cells to intact tissue. Anal Bioanal Chem 387:1591–1599

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stéphanie Briançon .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Briançon, S., Bolzinger, MA., Chevalier, Y. (2017). Confocal Raman Spectroscopy as a Tool to Investigate the Action of Penetration Enhancers Inside the Skin. In: Dragicevic, N., I. Maibach, H. (eds) Percutaneous Penetration Enhancers Drug Penetration Into/Through the Skin. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-53270-6_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-53270-6_13

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-53268-3

  • Online ISBN: 978-3-662-53270-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics