Skip to main content
SpringerLink
Log in

Deep Percutaneous Penetration into Muscles and Joints: Update

  • Chapter
  • First Online:
Topical Drug Bioavailability, Bioequivalence, and Penetration

  • 1628 Accesses

Abstract

Transdermal drug delivery is a multifactorial process with variable penetration mechanisms. Adverse effects associated with nonsteroidal anti-inflammatory drugs’ (NSAIDs) use in treatment for joint and muscle diseases are sufficiently severe to consider topical application. A drug’s lipophilicity, fraction unbound, and permeability found in the viable skin are some of the physiochemical factors influencing the delivery mechanism of transdermal absorption. These and other variables play a role in determining if the drug reaches the deep tissues via direct penetration from dermal or systemic blood redistribution. Pharmacokinetic models have been developed to help elucidate penetration routes and efficacy for various drugs. Improvements in modes of transdermal delivery through active research projects including relevant animal models and human translational research may introduce advances in clinical development of treatments.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

  1. Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis. 2013;73(9):1659–64. doi:10.1136/annrheumdis-2013–203355.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Singh P. Percutaneous penetration as a method of delivery to skin and underlying tissues. In: Bronaugh RL, Maibach HI, editors. Percutaneous absorption: drugs-cosmetics-mechanisms-methodology. 7th ed. New York: Marcel Dekker Inc.; 1999. pp. 597–613.

    Google Scholar 

  3. Guy RH. Transdermal drug delivery. In: Schafer-Korting M, editor. Drug delivery. 197th ed. Vol. 197. Berlin: Springer; 2010. pp. 399–410.

    Chapter  Google Scholar 

  4. Stanos SP. Osteoarthritis guidelines: a progressive role for topical nonsteroidal anti-inflammatory drugs. J Multidiscip Healthc. 2013;6:133–7.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Lee CM, Maibach HI. Deep percutaneous penetration into muscles and joints. J Pharm Sci. 2006;95(7):1405–13.

    Article  CAS  PubMed  Google Scholar 

  6. Jepps OG, Dancik Y, Anissimov YG, Roberts MS. Modeling the human skin barrier—towards a better understanding of dermal absorption. Adv Drug Deliv Rev. 2013;65(2):152–68.

    Article  CAS  PubMed  Google Scholar 

  7. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J Pharmacol Exp Ther. 1994a;268(1):144–51.

    Google Scholar 

  8. Singh P, Roberts MS. Deep tissue penetration of bases and steroids after dermal application in rat. J Pharm Pharmacol. 1994b;46(12):956–64.

    Google Scholar 

  9. Baldwin JR, Carrano RA, Imondi AR. Penetration of trolamine salicylate into the skeletal muscle of the pig. J Pharm Sci. 1984;73(7):1002–4.

    Article  CAS  PubMed  Google Scholar 

  10. Herndon CM. Topical delivery of nonsteroidal anti-inflammatory drugs for osteoarthritis. J Pain Palliat Care Pharmacother. 2012;26(1):18–23.

    Article  PubMed  Google Scholar 

  11. Roberts MS, Anderson RA, Swarbrick J. Permeability of human epidermis to phenolic compounds. J Pharm Pharmacol. 1977;29(11):677–83.

    Article  CAS  PubMed  Google Scholar 

  12. Swarbrick J, Lee G, Brom J, Gensmantel NP. Drug permeation through human skin II: permeability of ionizable compounds. J Pharm Sci. 1984;73(10):1352–5.

    Article  CAS  PubMed  Google Scholar 

  13. Magnusson BM, Anissimov YG, Cross SE, Roberts MS. Molecular size as the main determinant of solute maximum flux across the skin. J Invest Dermatol. 2004;122(4):993–9.

    Article  CAS  PubMed  Google Scholar 

  14. Higaki K, Asai M, Suyama T, Nakayama K, Ogawara K, Kimura T. Estimation of intradermal disposition kinetics of drugs: II. factors determining penetration of drugs from viable skin to muscular layer. Int J Pharm. 2002;239(1–2):129–41.

    Article  CAS  PubMed  Google Scholar 

  15. Yagi S, Nakayama K, Kurosaki Y, Higaki K, Kimura T. Factors determining drug residence in skin during transdermal absorption: studies on beta-blocking agents. Biol Pharm Bull. 1998;21(11):1195–201.

    Article  CAS  PubMed  Google Scholar 

  16. Guy RH, Hadgraft J, Maibach HI. A pharmacokinetic model for percutaneous absorption. Int J Pharm. 1982;11(2):119–129.

    Article  CAS  Google Scholar 

  17. Barry B. Transdermal drug delivery. In: Aulton M, editor. Pharmaceutics: the science of dosage form design. London: Harcourt; 1988. p. 499–533.

    Google Scholar 

  18. Higaki K, Nakayama K, Suyama T, Amnuaikit C, Ogawara K, Kimura T. Enhancement of topical delivery of drugs via direct penetration by reducing blood flow rate in skin. Int J Pharm. 2005;288(2):227–33.

    Article  CAS  PubMed  Google Scholar 

  19. Singh P, Roberts MS. Dermal and underlying tissue pharmacokinetics of salicylic acid after topical application. J Pharmacokinet Biopharm. 1993a;21(4):337–73.

    Google Scholar 

  20. Singh P, Roberts MS. Iontophoretic transdermal delivery of salicylic acid and lidocaine to local subcutaneous structures. J Pharm Sci. 1993b;82(2):127–31.

    Google Scholar 

  21. Kretsos K, Kasting GB, Nitsche JM. Distributed diffusion-clearance model for transient drug distribution within the skin. J pharm Sci. 2004;93(11):2820–35.

    Article  CAS  PubMed  Google Scholar 

  22. Kretsos K, Kasting GB. A geometrical model of dermal capillary clearance. Math Biosci. 2007;208(2):430–53.

    Article  PubMed  Google Scholar 

  23. Schaefer H, Stüttgen G. Absolute concentrations of an antimycotic agent, econazole, in the human skin after local application. Arzneimittelforschung. 1976;26(3):432–5.

    CAS  PubMed  Google Scholar 

  24. Schaefer H, Zesch A. Penetration of vitamin A acid into human skin. Acta Derm Venereol Suppl (Stockh). 1975;74:50–5.

    CAS  Google Scholar 

  25. Zesch A, Schaefer H. [Penetration of radioactive hydrocortisone in human skin from various ointment bases. II. In vivo-experiments (author’s transl)]. Arch Dermatol Forsch. 1975;252(4):245–56.

    Article  CAS  PubMed  Google Scholar 

  26. Schaefer H, Zesch A, Stüttgen G. Penetration, permeation, and absorption of triamcinolone acetonide in normal and psoriatic skin. Arch Dermatol Res (Archiv für dermatologische Forschung). 1977;258(3):241–9.

    Article  CAS  Google Scholar 

  27. Schaefer H, Stüttgen G, Zesch A, Schalla W, Gazith J. Quantitative determination of percutaneous absorption of radiolabeled drugs in vitro and in vivo by human skin. Curr Probl Dermatol. 1978;7:80–94.

    CAS  PubMed  Google Scholar 

  28. Anissimov YG, Roberts MS. Modelling dermal drug distribution after topical application in human. Pharm Res. 2011;28(9):2119–29.

    Article  CAS  PubMed  Google Scholar 

  29. Dancik Y, Anissimov YG, Jepps OG, Roberts MS. Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application. Br J Clin Pharmacol. 2012;73(4):564–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Yanagimoto G, Hayashi T, Hasegawa T, Seki T, Juni K, Sugibayashi K, Morimoto Y. Skin disposition of drugs after topical application in hairless rats. Chem Pharm Bull (Tokyo). 1999;47(6):749–54.

    Article  CAS  Google Scholar 

  31. Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frölich JC. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol. 1991;31(5):537–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Müller M, Rastelli C, Ferri P, Jansen B, Breiteneder H, Eichler HG. Transdermal penetration of diclofenac after multiple epicutaneous administration. J Rheumatol. 1998;25(9):1833–6.

    PubMed  Google Scholar 

  33. Miyatake S, Ichiyama H, Kondo E, Yasuda K. Randomized clinical comparisons of diclofenac concentration in the soft tissues and blood plasma between topical and oral applications. Br J Clin Pharmacol. 2009;67(1):125–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Kai S, Kondo E, Kawaguchi Y, Kitamura N, Yasuda K. Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration. Br J Clin Pharmacol. 2013;75(3):799–804.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Rabinowitz JL, Baker D. Absorption of labeled triethanolamine salicylate in human and canine knee joints. II. J Clin Pharmacol. 1984;24(11–12):532–9.

    Article  CAS  PubMed  Google Scholar 

  36. Mills PC, Magnusson BM, Cross SE. Penetration of a topically applied nonsteroidal anti-inflammatory drug into local tissues and synovial fluid of dogs. Am J Vet Res. 2005;66(7):1128–32.

    Article  CAS  PubMed  Google Scholar 

  37. Yoshida D, Hasegawa T, Sugibayashi K. Targeting of salicylate to skin and muscle following topical injections in rats. Int J Pharm. 2002;231(2):177–84.

    Article  CAS  PubMed  Google Scholar 

  38. Skazik C, Wenzel J, Marquardt Y, Kim A, Merk HF, Bickers DR, Baron JM. P-glycoprotein (ABCB1) expression in human skin is mainly restricted to dermal components. Exp Dermatol. 2011;20(5):450–2.

    Article  PubMed  Google Scholar 

  39. Polat BE, Hart D, Langer R, Blankschtein D. Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Release. 2011;152(3):330–48.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Kigasawa K, Kajimoto K, Watanabe M, Kanamura K, Saito A, Kogure K. In vivo transdermal delivery of diclofenac by ion-exchange iontophoresis with geraniol. Biol Pharm Bull. 2009;32(4):684–7.

    Article  CAS  PubMed  Google Scholar 

  41. Sammeta SM, Murthy SN. “ChilDrive”: a technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid. Pharm Res. 2009;26(11):2535–40.

    Article  CAS  PubMed  Google Scholar 

  42. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31(10):2002–12.

    CAS  PubMed  Google Scholar 

  43. Simon LS, Grierson LM, Naseer Z, Bookman AAM, Zev Shainhouse J. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–45.

    Article  CAS  PubMed  Google Scholar 

  44. Roth SH, Fuller P. Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis. J Pain Res. 2011;4:159–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Bookman AAM, Williams KS, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ. 2004;171(4):333–8.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Carnes D, Anwer Y, Underwood M, Harding G, Parsons S. Influences on older people’s decision making regarding choice of topical or oral NSAIDs for knee pain: qualitative study. BMJ. 2008;336(7636):142–5.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol. 2010;37(6):1236–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Haisch C. Photoacoustic spectroscopy for analytical measurements. Meas Sci Technol. 2012;23.

    Google Scholar 

  49. De Melo JO, Pedrochi F, Baesso ML, Hernandes L, Truiti MC, Barons S, Bersani-Amado CA. Evidence of deep percutaneous penetration associated with anti-inflammatory activity of topically applied Helicteres gardneriana extract: a photoacoustic spectroscopy study. Pharm Res. 2011;28(2):331–6.

    Article  PubMed  Google Scholar 

  50. Xi H, Cun D, Xiang R, Guan Y, Zhang Y, Li Y, Fang L. Intra-articular drug delivery from an optimized topical patch containing teriflunomide and lornoxicam for rheumatoid arthritis treatment: does the topical patch really enhance a local treatment? J Control Release. 2013;169(1–2):73–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, School of Medicine, University of California San Francisco, San Francisco, CA, USA

    Vladyslava Doktor MA

  2. Texas Oncology, The Woodlands, TX, USA

    Christine M. Lee MD

  3. Department of Dermatology, School of Medicine, University of California, San Francisco, CA, USA

    Howard I. Maibach MD

Authors
  1. Vladyslava Doktor MA
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine M. Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard I. Maibach MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vladyslava Doktor MA .

Editor information

Editors and Affiliations

  1. Pharmaceutical Consultant, North Potomac, Maryland, USA

    Vinod P. Shah

  2. University of California, San Francisco School of Medicine, Department of Dermatology, San Francisco, California, USA

    Howard I. Maibach

  3. The Defence Science and Technology Laboratory, Biomedical Sciences Department, Salisbury, United Kingdom

    John Jenner

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Doktor, V., Lee, C., Maibach, H. (2014). Deep Percutaneous Penetration into Muscles and Joints: Update. In: Shah, V., Maibach, H., Jenner, J. (eds) Topical Drug Bioavailability, Bioequivalence, and Penetration. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1289-6_13

Download citation

Publish with us

Policies and ethics

Search

Navigation