Skip to main content

Advertisement

SpringerLink
Log in

Screening of Chemical Penetration Enhancers for Transdermal Drug Delivery Using Electrical Resistance of Skin

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

Abstract

Purpose

A novel technique is presented for identifying potential chemical penetration enhancers (CPEs) based on changes in the electrical resistance of skin.

Methods

Specifically, a multi-well resistance chamber was designed and constructed to facilitate more rapid determination of the effect of CPEs on skin resistance. The experimental setup was validated using nicotine and decanol on porcine skin in vitro. The multi-well resistance chambers were capable of operating at 37°C in order to simulate the physiological temperature of the human body. Further, the utility of the multi-well resistance chamber technique was validated using standard Franz diffusion cells. Electrical resistance measurements were used to evaluate the potency of seven new potential CPEs, identified using virtual screening algorithms. From the resistance measurements, the chemicals 1-dodecyl-2-pyrrolidinone (P), menthone (M) and R(+)-3-amino-1-hydroxy-2-pyrrolidinone (C) were identified as the better penetration enhancers among the seven tested. Further, traditional permeation experiments were performed in Franz diffusion cells to confirm our findings.

Results

The permeation test results indicated that, of the three CPEs deemed potentially viable using the newly-developed resistance screening technique, both P and M increased the permeation of the test drug (melatonin) through skin in 48 h.

Conclusion

In summary, this resistance technique can be used to effectively pre-evaluate potential CPEs, thereby reducing the time required to conduct the permeability studies.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. S. A. Gallo, A. R. Oseroff, P. G. Johnson, and S. W. Hui. Characterization of electric-pulse-induced permeabilization of porcine skin using surface electrodes. Biophys. J. 72:2805–2811 (1997)

    Article  PubMed  CAS  Google Scholar 

  2. P. Karande, A. Jain, and S. Mitragotri. Relationships between skin’s electrical impedance and permeability in the presence of chemical enhancers. J. Control. Release. 110:307–313 (2006) doi:10.1016/j.jconrel.2005.10.012.

    Article  PubMed  CAS  Google Scholar 

  3. A. C. Williams, and B. W. Barry. Penetration enhancers. Adv. Drug Deliv. Rev. 56:603–618 (2004) doi:10.1016/j.addr.2003.10.025.

    Article  PubMed  CAS  Google Scholar 

  4. C. Y. Goates, and K. Knutson. Enhanced permeation of polar compounds through human epidermis. I. Permeability and membrane structural changes in the presence of short chain alcohols. Biochim. Biophys. Acta. 1195:169–179 (1994) doi:10.1016/0005-2736(94)90024-8.

    Article  PubMed  CAS  Google Scholar 

  5. S. Andega, N. Kanikkannan, and M. Singh. Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. J. Control. Release. 77:17–25 (2001) doi:10.1016/S0168-3659(01)00439-4.

    Article  PubMed  CAS  Google Scholar 

  6. L. M. Nolan, J. Corish, O. I. Corrigan, and D. Fitzpatrick. Iontophoretic and chemical enhancement of drug delivery. Part I: across artificial membranes. Int. J. Pharm. 257:41–55 (2003) doi:10.1016/S0378-5173(03)00108-X.

    Article  PubMed  CAS  Google Scholar 

  7. R. E. Baynes, J. D. Brooks, M. Mumtaz, and J. E. Riviere. Effect of chemical interactions in pentachlorophenol mixtures on skin and membrane transport. Toxicol. Sci. 69:295–305 (2002) doi:10.1093/toxsci/69.2.295.

    Article  PubMed  CAS  Google Scholar 

  8. D. J. Davies, R. J. Ward, and J. R. Heylings. Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. Toxicol. In Vitro. 18:351–358 (2004) doi:10.1016/j.tiv.2003.10.004.

    Article  PubMed  CAS  Google Scholar 

  9. W. J. Fasano, and P. M. Hinderliter. The Tinsley LCR Databridge Model 6401 and electrical impedance measurements to evaluate skin integrity in vitro. Toxicol. In Vitro. 18:725–729 (2004) doi:10.1016/j.tiv.2004.01.003.

    Article  PubMed  CAS  Google Scholar 

  10. J. H. Fentem, G. E. B. Archer, M. Balls, P. A. Botham, R. D. Curren, L. K. Earl, D. J. Esdaile, H. G. Holzhutter, and M. Liebsch. The ECVAM International Validation Study on in vitro tests for skin corrosivity. 2. Results and evaluation by the management team. Toxicol. In Vitro. 12:483–524 (1998) doi:10.1016/S0887-2333(98)00019-8.

    Article  CAS  Google Scholar 

  11. P. Karande, A. Jain, and S. Mitragotri. Discovery of transdermal penetration enhancers by high-throughput screening. Nat. Biotechnol. 22:192–197 (2004) doi:10.1038/nbt928.

    Article  PubMed  CAS  Google Scholar 

  12. P. Karande, and S. Mitragotri. High throughput screening of transdermal formulations. Pharm. Res. 19:655–660 (2002) doi:10.1023/A:1015362230726.

    Article  PubMed  CAS  Google Scholar 

  13. S. Pappinen, S. Tikkinen, S. Pasonen-Seppanen, L. Murtomaki, M. Suhonen, and A. Urtti. Rat epidermal keratinocyte organotypic culture (ROC) compared to human cadaver skin: the effect of skin permeation enhancers. Eur. J. Pharm. Sci. 30:240–250 (2007) doi:10.1016/j.ejps.2006.11.013.

    Article  PubMed  CAS  Google Scholar 

  14. K. Kandimalla, N. Kanikkannan, S. Andega, and M. Singh. Effect of fatty acids on the permeation of melatonin across rat and pig skin in-vitro and on the transepidermal water loss in rats in-vivo. J. Pharm. Pharmacol. 51:783–790 (1999) doi:10.1211/0022357991773140.

    Article  PubMed  CAS  Google Scholar 

  15. S. S. Godavarthy, R. L. Robinson, and K. A. M. Gasem. An improved structure–property model for predicting melting-point temperatures. Ind. Eng. Chem. Res. 45:5117–5126 (2006) doi:10.1021/ie051130p.

    Article  CAS  Google Scholar 

  16. S. S. Godavarthy, R. L. Robinson, and K. A. M. Gasem. SVRC-QSPR model for predicting saturated vapor pressures of pure fluids. Fluid Phase Equilib. 246:39–51 (2006) doi:10.1016/j.fluid.2006.05.020.

    Article  CAS  Google Scholar 

  17. D. Ravindranath, B. J. Neely, R. L. Robinson, and K. A. M. Gasem. QSPR generalization of activity coefficient models for predicting vapor–liquid equilibrium behavior. Fluid Phase Equilibria. 257:53–62 (2007) doi:10.1016/j.fluid.2007.05.014.

    Article  CAS  Google Scholar 

  18. S. Mitragotri, D. Ray, J. Farrell, H. Tang, B. Yu, J. Kost, D. Blankschtein, and R. Langer. Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J. Pharm. Sci. 89:892–900 (2000) doi:10.1002/1520-6017(200007)89:7<892::AID-JPS6>3.0.CO;2-V.

    Article  PubMed  CAS  Google Scholar 

  19. P. Karande, and S. Mitragotri. Dependence of skin permeability on contact area. Pharm. Res. 20:257–263 (2003) doi:10.1023/A:1022231406277.

    Article  PubMed  CAS  Google Scholar 

  20. P. J. Lee, N. Ahmad, R. Langer, S. Mitragotri, and V. Prasad Shastri. Evaluation of chemical enhancers in the transdermal delivery of lidocaine. Int. J. Pharm. 308:33–39 (2006) doi:10.1016/j.ijpharm.2005.10.027.

    Article  PubMed  CAS  Google Scholar 

  21. J. R. Heylings, H. M. Clowes, and L. Hughes. Comparison of tissue sources for the skin integrity function test (SIFT). Toxicol. In Vitro. 15:597–600 (2001) doi:10.1016/S0887-2333(01)00069-8.

    Article  PubMed  CAS  Google Scholar 

  22. S. S. Godavarthy. Design of improved solvents for extractive distillation, Ph.D. Thesis, Oklahoma State University, Stillwater, 2004.

  23. L. Kikwai, N. Kanikkannan, R. J. Babu, and M. Singh. Effect of vehicles on the transdermal delivery of melatonin across porcine skin in vitro. J. Control. Release. 83:307–311 (2002) doi:10.1016/S0168-3659(02)00202-X.

    Article  PubMed  CAS  Google Scholar 

  24. S. Daya, R. B. Walker, B. D. Glass, and S. Anoopkumar-Dukie. The effect of variations in pH and temperature on stability of melatonin in aqueous solution. J. Pineal. Res. 31:155–158 (2001) doi:10.1034/j.1600-079x.2001.310209.x.

    Article  PubMed  CAS  Google Scholar 

  25. H.-J. Oh, Y.-K. Oh, and C.-K. Kim. Effects of vehicles and enhancers on transdermal delivery of melatonin. Int. J. Pharm. 212:63–71 (2001) doi:10.1016/S0378-5173(00)00598-6.

    Article  PubMed  CAS  Google Scholar 

  26. M. K. Nair, D. J. Chetty, H. Ho, and Y. W. Chien. Biomembrane permeation of nicotine: mechanistic studies with porcine mucosae and skin. J. Pharm. Sci. 86:257–262 (1997) doi:10.1021/js960095w.

    Article  PubMed  CAS  Google Scholar 

  27. N. Ohara, K. Takayama, and T. Nagai. Combined effect of d-limonene pretreatment and temperature on the rat skin permeation of lipophilic and hydrophilic drugs. Biol. Pharm. Bull. 18:439–442 (1995).

    PubMed  CAS  Google Scholar 

  28. I. V. Tetko, J. Gasteiger, R. Todeschini, A. Mauri, D. Livingstone, P. Ertl, V. A. Palyulin, E. V. Radchenko, N. S. Zefirov, A. S. Makarenko, V. Y. Tanchuk, and V. V. Prokopenko. Virtual computational chemistry laboratory—design and description. J. Comput. Aided Mol. Des. 19:453–463 (2005) doi:10.1007/s10822-005-8694-y.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

Financial support for this research was provided by the National Institutes of Health (#1R21EB005749-01A1).

Author information

Authors and Affiliations

  1. School of Chemical Engineering, Oklahoma State University, Stillwater, Oklahoma, 74078, USA

    Vijay Krishna Rachakonda, Krishna Mohan Yerramsetty, Sundararajan V. Madihally, Robert L. Robinson Jr. & Khaled A. M. Gasem

Authors
  1. Vijay Krishna Rachakonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krishna Mohan Yerramsetty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sundararajan V. Madihally
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert L. Robinson Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Khaled A. M. Gasem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khaled A. M. Gasem.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rachakonda, V.K., Yerramsetty, K.M., Madihally, S.V. et al. Screening of Chemical Penetration Enhancers for Transdermal Drug Delivery Using Electrical Resistance of Skin. Pharm Res 25, 2697–2704 (2008). https://doi.org/10.1007/s11095-008-9696-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9696-y

KEY WORDS

Search

Navigation