Advertisement

Pharmaceutical Research

, Volume 22, Issue 11, pp 1918–1925 | Cite as

Investigation of Iminosulfuranes as Novel Transdermal Penetration Enhancers: Enhancement Activity and Cytotoxicity

  • Yifan Song
  • Chunhong Xiao
  • Richard Mendelsohn
  • Tao Zheng
  • Lucjan Strekowski
  • Bozena Michniak
Research Paper

Purpose

Very few chemical enhancers for transdermal drug delivery have been approved for clinical use due to irritancy and toxicity concerns. Novel chemical enhancers (iminosulfuranes) were synthesized and studied for their activity and toxicity.

Methods

Skin was treated with 0.4 M 15 for 1 h before hydrocortisone was applied. Samples were taken over 24 h and analyzed by high-performance liquid chromatography. Dermal fibroblasts and epidermal keratinocytes were treated with 0–1.2 M 15 for 24 h and cytotoxicity assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)] was performed. Furthermore, enhancement activity of 0–0.4 M 2 was studied. Partition coefficient of the model drugs into stratum corneum (SC) was measured and confocal Raman microscopy was used to study the penetration process and possible mechanisms of action of the enhancers. Quantitative structure–activity relationship (QSAR) was analyzed to study the contribution of different intramolecular descriptors to enhancement activity.

Results

Iminosulfurane 2 showed the highest enhancement activity. All compounds below 0.2 M were safe to skin cells, and 2 was effective at the concentration of 0.1 and 0.2 M. Mechanisms of action of 2 may include increasing partition coefficient of the model drug into SC and interaction between the enhancer and lipids and protein in the SC. QSAR study indicated contribution of several factors to activity: partition coefficient, hydrogen-bond acceptor, and optimal molecular size.

Conclusions

Enhancement activity of 2 was achieved without any cytotoxicity.

Key Words

chemical enhancers dimethyl sulfoxide iminosulfuranes percutaneous penetration transdermal drug delivery 

References

  1. 1.
    Asbill, C. S., El-Kattan, A. F., Michniak, B. 2000Enhancement of transdermal drug delivery: chemical and physical approachesCrit. Rev. Ther. Drug Carrier Syst.17621658PubMedGoogle Scholar
  2. 2.
    Guy, R. H. 1998Iontophoresis—recent developmentsJ. Pharm. Pharmacol.50371374PubMedGoogle Scholar
  3. 3.
    Henry, S., McAllister, D. V., Allen, M. G., Prausnitz, M. R. 1998Microfabricated microneedles: a novel approach to transdermal drug deliveryJ. Pharm. Sci.87922925CrossRefPubMedGoogle Scholar
  4. 4.
    Mitragotri, S., Edwards, D. A., Blankschtein, D., Langer, R. 1995A mechanistic study of ultrasonically-enhanced transdermal drug deliveryJ. Pharm. Sci.84697706PubMedGoogle Scholar
  5. 5.
    Weaver, J. C., Vaughan, T. E., Chizmadzhev, Y. 1999Theory of electrical creation of aqueous pathways across skin transport barriersAdv. Drug Deliv. Rev.352139CrossRefPubMedGoogle Scholar
  6. 6.
    Stoughton, R. B., Fritsch, W. 1964Influence of dimethylsulfoxide (DMSO) on human percutaneous absorptionArch. Dermatol.90512517PubMedGoogle Scholar
  7. 7.
    Kurihara-Bergstrom, T., Flynn, G. L., Higuchi, W. I. 1986Physicochemical study of percutaneous absorption enhancement by dimethyl sulfoxide: kinetic and thermodynamic determinants of dimethyl sulfoxide mediated mass transfer of alkanolsJ. Pharm. Sci.75479486PubMedGoogle Scholar
  8. 8.
    Barry, B. W. 1987Mode of action of penetration enhancers in human skinJ. Control. Release68597CrossRefGoogle Scholar
  9. 9.
    Kligman, A. M. 1965Topical pharmacology and toxicology of dimethyl sulfoxide. 1JAMA193796804PubMedGoogle Scholar
  10. 10.
    Sweeney, T. M., Downes, A. M., Matoltsy, A. G. 1966The effect of dimethyl sulfoxide on the epidermal water barrierJ. Invest. Dermatol.46300302PubMedGoogle Scholar
  11. 11.
    Skog, E., Wahlberg, J. E. 1967Effect of dimethyl sulfoxide on skin. A macroscopic and microscopic investigation on human skinActa Derm.-Venereol.47426434PubMedGoogle Scholar
  12. 12.
    Montes, L. F., Day, J. L., Wand, C. J., Kennedy, L. 1967Ultrastructural changes in the horny layer following local application of dimethyl sulfoxideJ. Invest. Dermatol.48184196PubMedGoogle Scholar
  13. 13.
    Shackleford, J. M., Yielding, K. L. 1984Ultrastructural studies of barrier restoration in epidermis of hairless mice following dimethyl sulfoxide applicationJ. Cutaneous Pathol.11259268Google Scholar
  14. 14.
    Kim, N., El-Khalili, M., Henary, M. M., Strekowski, L., Michniak, B. B. 1999Percutaneous penetration enhancement activity of aromatic S,S-dimethyliminosulfuranesInt. J. Pharm.187219229CrossRefPubMedGoogle Scholar
  15. 15.
    Strekowski, L., Henary, M., Kim, N., Michniak, B. B. 1999N-(4-Bromobenzoyl)-S,S-dimethyliminosulfurane, a potent dermal penetration enhancerBioorg. Med. Chem. Lett.910331034CrossRefPubMedGoogle Scholar
  16. 16.
    Mossman, T. 1983Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assaysJ. Immunol. Methods655563CrossRefPubMedGoogle Scholar
  17. 17.
    Watanabe, T., Hasegawa, T., Takahashi, H., Ishibashi, T., Itagaki, H., Sugibayashi, K. 2002Utility of MTT assay in three-dimensional cultured human skin model as an alternative for draize skin irritation test: approach using diffusion law of irritant in skin and toxicokinetics–toxicodynamics correlationPharm. Res.19669675CrossRefPubMedGoogle Scholar
  18. 18.
    Wester, R. C., Maibach, H. I., Sedik, L., Melendres, J., DiZio, S., Wade, M. 1992In vitro percutaneous absorption of cadmium from water and soil into human skinFundam. Appl. Toxicol.1915CrossRefPubMedGoogle Scholar
  19. 19.
    Kligman, A. M., Christophers, E. 1963Preparation of isolated sheets of human stratum corneumArch. Dermatol.887073Google Scholar
  20. 20.
    Vaddi, H. K., Ho, P. C., Chan, S. Y. 2002Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetryJ. Pharm. Sci.9116391651CrossRefPubMedGoogle Scholar
  21. 21.
    Accelrys Inc. Cerius2 Molecular Simulation Users Guide, Version 4.6, San Diego, 2001.Google Scholar
  22. 22.
    Rogers, D., Hopfinger, A. J. 1994Applications of genetic function approximation to quantitative structure–activity relationships and quantitative structure–property relationshipsJ. Chem. Inf. Comput. Sci.34854866CrossRefGoogle Scholar
  23. 23.
    Rogers, D. 1994WOLF 6.2 GFA ProgramMolecular Simulation Inc.San DiegoGoogle Scholar
  24. 24.
    Friedman, J. 1988Multivariate Adaptive Regression SplinesStanford UniversityStanfordGoogle Scholar
  25. 25.
    Fuhrman, L. C., Michniak, B., Behl, C. R., Malick, A. W. 1997Effect of novel penetration enhancers on the transdermal delivery of hydrocortisone: an in vitro species comparisonJ. Control. Release45199206CrossRefGoogle Scholar
  26. 26.
    Ghose, A. K., Viswanadhan, V. N., Wendoloski, J. J. 1998Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methodsJ. Phys. Chem.10237623772Google Scholar
  27. 27.
    Smith, E. W., Maibach, H. I. 1995Percutaneous Penetration EnhancersCRC PressBoca RatonGoogle Scholar
  28. 28.
    Anigbogu, A. N. C., Williams, A. C., Barry, B. W., Edwards, H. G. M. 1995Fourier transform Raman spectroscopy of interactions between the penetration enhancer dimethylsulfoxide and human SCInt. J. Pharm.125265282CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Yifan Song
    • 1
    • 6
  • Chunhong Xiao
    • 2
  • Richard Mendelsohn
    • 2
  • Tao Zheng
    • 3
  • Lucjan Strekowski
    • 4
  • Bozena Michniak
    • 1
    • 5
  1. 1.Laboratory for Drug Delivery, Department of Pharmacology and PhysiologyUniversity of Medicine and Dentistry of New Jersey, NJMSNewarkUSA
  2. 2.Department of Chemistry, RutgersThe State University of New JerseyNewarkUSA
  3. 3.NanuetUSA
  4. 4.Department of ChemistryGeorgia State UniversityAtlantaUSA
  5. 5.Department of Pharmaceutics, RutgersThe State University of New JerseyPiscatawayUSA
  6. 6.Schering Plough Research InstituteLafayetteUSA

Personalised recommendations