Skip to main content

Advertisement

SpringerLink
Log in

Topical Delivery of a Naproxen-Dithranol Co-drug: In Vitro Skin Penetration, Permeation, and Staining

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

ABSTRACT

Purpose

This work probed the topical delivery and skin-staining properties of a novel co-drug, naproxyl-dithranol (Nap-DTH), which comprises anti-inflammatory (naproxen) and anti-proliferative (dithranol) moieties.

Method

Freshly excised, full-thickness porcine ear skin was dosed with saturated solutions of the compounds. After 24 h, the skin was recovered and used to prepare comparative depth profiles by the tape-stripping technique and to examine the extent of skin staining.

Results

Depth profiles showed that Nap-DTH led to a 5-fold increase in drug retention in the skin compared to dithranol. The application of Nap-DTH also demonstrated improved stability, resulting in lower levels of dithranol degradation products in the skin. Furthermore, significantly less naproxen from hydrolysed Nap-DTH permeated into the receptor phase compared to naproxen when applied alone (0.08 ± 0.03 nmol cm-² and 180 ± 60 nmol cm-², respectively). Moreover, the reduced staining of the skin was very apparent for Nap-DTH compared to dithranol.

Conclusions

Topical delivery of Nap-DTH not only improves the delivery of naproxen and dithranol, but also reduces unwanted effects of the parent moieties, in particular the skin staining, which is a major issue concerning the use of dithranol.

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

Similar content being viewed by others

Abbreviations

HMPA:

Hexamethylphosphoramide

IPM:

Isopropyl myristate

LOD:

limit of detection

MW:

molecular weight

Nap-DTH:

Naproxyl-dithranol

SC:

stratum corneum

THF:

Tetrahydrofuran

REFERENCES

  1. National Psoriasis Foundation. About psoriasis: statistics. http://www.psoriasis.org/about/stats/ (accessed 19 May 2008).

  2. Jullien D. Psoriasis physiopathology. J Eur Acad Dermatol Venereol. 2006;20:10–23.

    Article  Google Scholar 

  3. McKay IA, Leigh IM. Altered keratinocyte growth and differentiation in psoriasis. Clin Dermatol. 1995;13:105–14.

    Article  CAS  PubMed  Google Scholar 

  4. Tschachler E. Psoriasis: the epidermal component. Clin Dermatol. 2007;25:589–95.

    Article  PubMed  Google Scholar 

  5. Albanesi C, De Pità O, Girolomoni G. Resident skin cells in psoriasis: a special look at the pathogenetic functions of keratinocytes. Clin Dermatol. 2007;25:581–8.

    Article  PubMed  Google Scholar 

  6. Gaspari A. Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol. 2006;54:S67–80.

    Article  PubMed  Google Scholar 

  7. Gerritsen MJP. Dithranol. In: van de Kerkhof P, editor. Textbook of Psoriasis. Oxford: Blackwell; 2003. p. 170–85.

    Chapter  Google Scholar 

  8. Müller K, Leukel P, Mayer KK, Wiegrebe W. Modification of DNA bases by anthralin and related compounds. Biochem Pharmacol. 1995;49:1607–13.

    Article  PubMed  Google Scholar 

  9. McGill A, Frank A, Emmett N, Leech SN, Turnbull DM, Birch-Machin MA, Reynolds NJ. The antipsoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria. FASEB J. 2005;04-2664.

  10. Peus D, Beyerle A, Vasa M, Pott M, Meves A, Pittelkow MR. Antipsoriatic drug anthralin induces EGF receptor phosphorylation in keratinocytes: requirement for H2O2 generation. Exp Dermatol. 2004;13:78–85.

    Article  CAS  PubMed  Google Scholar 

  11. Reichert U, Jacques Y, Grangeret M, Schmidt R. Antirespiratory and antiproliferative activity of anthralin in cultured human keratinocytes. J Invest Dermatol. 1985;84:130–4.

    Article  CAS  PubMed  Google Scholar 

  12. Thomaand K, Holzmann C. Photostability of dithranol. Eur J Pharm Biopharm. 1998;46:201–8.

    Article  Google Scholar 

  13. DiSepio D, Chandraratna RAS, Nagpal S. Novel approaches for the treatment of psoriasis. Drug Discov Today. 1999;4:222–31.

    Article  CAS  PubMed  Google Scholar 

  14. Menterand A, Griffiths CEM. Current and future management of psoriasis. Lancet. 2007;370:272–84.

    Article  Google Scholar 

  15. Lau WM, White AW, Gallagher SJ, Donaldson M, McNaughton G, Heard CM. Scope and limitations of the co-drug approach to topical drug delivery. Curr Pharm Des. 2008;14:794–802.

    Article  CAS  PubMed  Google Scholar 

  16. Bonina FP, Puglia C, Barbuzzi T, de Caprariis P, Palagiano F, Rimoli MG, et al. In vitro and in vivo evaluation of polyoxyethylene esters as dermal prodrugs of ketoprofen, naproxen and diclofenac. Eur J Pharm Sci. 2001;14:123–34.

    Article  CAS  PubMed  Google Scholar 

  17. Gillard SE, Finlay AY. Current management of psoriasis in the United Kingdom: patterns of prescribing and resource use in primary care. Int J Clin Pract. 2005;59:1260–7.

    Article  CAS  PubMed  Google Scholar 

  18. Lau WM. Improved topical therapeutic systems based on co-drugs. Welsh School of Pharmacy. PhD thesis. 2008.

  19. International Conference of Harmonisation. Guidance for industry: Q1A(R2) stability testing of new drug substances and products. www.fda.gov/CbER/gdlns/ichstab.htm (accessed 12 Apr 2008).

  20. Sekkat N, Kalia YN, Guy RH. Porcine ear skin as a model for the assessment of transdermal drug delivery to premature neonates. Pharm Res. 2004;21:1390–7.

    Article  CAS  PubMed  Google Scholar 

  21. Thomas CP, Heard CM. Probing the skin permeation of eicosapentaenoic acid and ketoprofen: 2. Comparative depth profiling and metabolism of eicosapentaenoic acid. Eur J Pharm Biopharm. 2007;67:156–65.

    Article  CAS  PubMed  Google Scholar 

  22. Vallet V, Cruz C, Josse D, Bazire A, Lallement G, Boudry I. In vitro percutaneous penetration of organophosphorus compounds using full-thickness and split-thickness pig and human skin. Toxicol In Vitro. 2007;21:1182–90.

    Article  CAS  PubMed  Google Scholar 

  23. Simonand GA, Maibach HI. The pig as an experimental animal model of percutaneous permeation in man: qualitative and quantitative observations—an overview. Skin Pharmacol Appl Skin Physiol. 2000;13:229–34.

    Google Scholar 

  24. Meyer W, Kacza J, Zschemisch N-H, Godynicki S, Seeger J. Observations on the actual structural conditions in the stratum superficiale dermidis of porcine ear skin, with special reference to its use as model for human skin. Annals of Anatomy—Anatomischer Anzeiger. 2007;189:143–56.

    Article  Google Scholar 

  25. Schmook FP, Meingassner JG, Billich A. Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int J Pharm. 2001;215:51–6.

    Article  CAS  PubMed  Google Scholar 

  26. Bos JD, Meinardi MMHM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9:165–9.

    Article  CAS  PubMed  Google Scholar 

  27. Willson RJ. A thermodynamic exploration into pharmaceutical drug solubility. Drug Discov Today. 2001;6:985–6.

    Article  PubMed  Google Scholar 

  28. Leung DYM, Szfler SJ, Noman PS, Apter A, Eichenfield LF, Beck L. Elidel (pimecrolimus) cream 1%: A nonsteroidal topical agent for the treatment of atopic dermatitis. J Allergy Clin Immunol. 2003;111:1154–68.

    Google Scholar 

  29. Alaiti S, Kang S, Fiedler VC, Ellis CN, Spurlin DV, Fader D, et al. Tacrolimus (FK506) ointment for atopic dermatitis: A phase I study in adults and children. J Am Acad Dermatol. 1998;38:69–76.

    Article  CAS  PubMed  Google Scholar 

  30. The British Pharmacopoeia Commission. British Pharmacopoeia 2008 The Stationery Office, London, 2007.

  31. Arellano A, Santoyo S, Martin C, Ygartua P. Influence of propylene glycol and isopropyl myristate on the in vitro percutaneous penetration of diclofenac sodium from carbopol gels. Eur J Pharm Sci. 1999;7:129–35.

    Article  CAS  PubMed  Google Scholar 

  32. Goldberg-Cettina M, Liu P, Nightingale J, Kurihara-Bergstrom T. Enhanced transdermal delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols. Int J Pharm. 1995;114:237–45.

    Article  CAS  Google Scholar 

  33. Bealland HD, Sloan KB. Topical delivery of 5-fluorouracil (5-Fu) by 3-alkylcarbonyl-5-Fu prodrugs. Int J Pharm. 2001;217:127–37.

    Article  Google Scholar 

  34. Mahrle G. Dithranol. Clin Dermatol. 1997;15:723–37.

    Article  CAS  PubMed  Google Scholar 

  35. Sasaki H, Takahashi T, Mori Y, Nakamura J, Shibasaki J. Transdermal delivery of 5-fluorouracil and its alkylcarbamoyl derivatives. Int J Pharm. 1990;60:1–9.

    Article  CAS  Google Scholar 

  36. Wang JJ, Sung KC, Huang JF, Yeh CH, Fang JY. Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study. J Pharm Pharmacol. 2007;59:917–25.

    Article  CAS  PubMed  Google Scholar 

  37. Bickers DR, Dutta-Choudhury T, Mukhtar H. Epidermis: a site of drug metabolism in neonatal rat skin. Studies on cytochrome P-450 content and mixed-function oxidase and epoxide hydrolase activity. Mol Pharmacol. 1982;21:239–47.

    CAS  PubMed  Google Scholar 

  38. Das M, Bickers DR, Mukhtar H. Epidermis: the major site of cutaneous benzo(a)pyrene and benzo(a)pyrene 7, 8-diol metabolism in neonatal BALB/c mice. Drug Metab Disposition. 1986;14:637–42.

    CAS  Google Scholar 

  39. Ziboh VA, Miller CC, Cho Y. Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: generation of antiinflammatory and antiproliferative metabolites. Am J Clin Nutr. 2000;71:361S–6S.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

The authors would like to acknowledge the financial support from Stiefel Laboratories, UK.

Conflict of interest

None declared.

Author information

Author notes

  1. Wing Man Lau

    Present address: School of Pharmacy, University of Reading, Whiteknights, PO Box 226, Reading, RG6 6AP, UK

Authors and Affiliations

  1. Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK

    Wing Man Lau, Alex W White & Charles M Heard

Authors
  1. Wing Man Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex W White
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles M Heard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wing Man Lau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lau, W.M., White, A.W. & Heard, C.M. Topical Delivery of a Naproxen-Dithranol Co-drug: In Vitro Skin Penetration, Permeation, and Staining. Pharm Res 27, 2734–2742 (2010). https://doi.org/10.1007/s11095-010-0274-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0274-8

KEY WORDS

Search

Navigation