Pharmaceutical Research

, Volume 30, Issue 4, pp 1099–1109 | Cite as

Transdermal Delivery of Molecules is Limited by Full Epidermis, Not Just Stratum Corneum

  • Samantha N. Andrews
  • Eunhye Jeong
  • Mark R. Prausnitz
Research Paper

ABSTRACT

Purpose

Most methods to increase transdermal drug delivery focus on increasing stratum corneum permeability, without addressing the need to increase permeability of viable epidermis. Here, we assess the hypothesis that viable epidermis offers a significant permeability barrier that becomes rate limiting upon sufficient permeabilization of stratum corneum.

Methods

We tested this hypothesis by using calibrated microdermabrasion to selectively remove stratum corneum or full epidermis in pig and human skin, and then measuring skin permeability to a small molecule (sulforhodamine) and macromolecules (bovine serum albumin, insulin, inactivated influenza vaccine) in vitro.

Results

We found that removal of stratum corneum dramatically increased skin permeability to all compounds tested. However, removal of full epidermis increased skin permeability by another 1–2 orders of magnitude. We also studied the effects of removing skin tissue only from localized spots on the skin surface by covering skin with a mask containing 125-μm holes during tissue removal. Skin permeabilized in this less-invasive way showed similar results. This suggests that microdermabrasion of skin using a mask may provide an effective way to increase skin permeability.

Conclusions

We conclude that viable epidermis offers a significant permeability barrier that becomes rate limiting upon removal of stratum corneum.

KEY WORDS

insulin microdermabrasion skin stratum corneum transdermal drug delivery viable epidermis 

REFERENCES

  1. 1.
    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Bolognia J, Jorizzo J, Schaffer J. Dermatology. Philadelphia: Saunders; 2012.Google Scholar
  3. 3.
    Kirschner N, Houdek P, Fromm M, Moll I, Brandner JM. Tight junctions form a barrier in human epidermis. Eur J Cell Biol. 2010;89:839–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Karande P, Jain A, Ergun K, Kispersky V, Mitragotri S. Design principles of chemical penetration enhancers for transdermal drug delivery. Proc Natl Acad Sci USA. 2005;102:4688–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Smithand E, Maibach H. Percutaneous penetration enhancers. Boca Raton, FL: CRC Press; 2005.CrossRefGoogle Scholar
  6. 6.
    Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol. 2004;22:192–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by magainin pore-forming peptide. J Control Release. 2007;122:375–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Polat BE, Hart D, Langer R, Blankschtein D. Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Release. 2011;152:330–48.PubMedCrossRefGoogle Scholar
  9. 9.
    Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364:227–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Fujimoto T, Shirakami K, Tojo K. Effect of microdermabrasion on barrier capacity of stratum corneum. Chem Pharm Bull. 2005;53:1014–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Karimipour DJ, Kang S, Johnson TM, Orringer JS, Hamilton T, Hammerberg C, et al. Microdermabrasion with and without aluminum oxide crystal abrasion: a comparative molecular analysis of dermal remodeling. J Am Acad Dermatol. 2006;54:405–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Lew BL, Cho Y, Lee MH. Effect of serial microdermabrasion on the ceramide level in the stratum corneum. Dermatol Surg. 2006;32:376–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bhallaand M, Thami G. Microdermabrasion: reappraisal and brief review of literature. Dermatol Surg. 2006;32:809–14.CrossRefGoogle Scholar
  14. 14.
    Freedman BM, Rueda-Pedraza E, Earley RV. Clinical and histologic changes determine optimal treatment regimens for microdermabrasion. J Dermatol Treat. 2002;13:193–200.CrossRefGoogle Scholar
  15. 15.
    Andrews SN, Lee JW, Choi SO, Prausnitz MR. Transdermal insulin delivery using microdermabrasion. Pharm Res. 2011;28:2110–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Fang JY, Lee WR, Shen SC, Fang YP, Hu CH. Enhancement of topical 5-aminolaevulinic acid delivery by erbium: YAG laser and microdermabrasion: a comparison with iontophoresis and electroporation. Br J Dermatol. 2004;151:132–40.PubMedCrossRefGoogle Scholar
  17. 17.
    Lee WR, Shen SC, Wang KH, Hu CH, Fang JY. Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J Invest Dermatol. 2003;121:1118–25.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee WR, Tsai RY, Fang CL, Liu CJ, Hu CH, Fang JY. Microdermabrasion as a novel tool to enhance drug delivery via the skin: An animal study. Dermatol Surg. 2006;32:1013–22.PubMedCrossRefGoogle Scholar
  19. 19.
    Andrews SN, Zarnitsyn V, Bondy B, Prausnitz MR. Optimization of microdermabrasion for controlled removal of stratum corneum. Int J Pharm. 2011;407:95–104.PubMedCrossRefGoogle Scholar
  20. 20.
    Koutsonanos DG, Martin MD, Zarnitsyn VG, Sullivan SP, Compans RW, Prausnitz MR, et al. Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS One. 2009;4:e4773.PubMedCrossRefGoogle Scholar
  21. 21.
    Jacques SL, McAuliffe DJ, Blank IH, Parrish JA. Controlled removal of human stratum-corneum by pulsed laser. J Invest Dermatol. 1987;88:88–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Sintov AC, Krymberk I, Daniel D, Hannan T, Sohn Z, Levin G. Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs. J Control Release. 2003;89:311–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Badkar AV, Smith AM, Eppstein JA, Banga AK. Transdermal delivery of interferon alpha-2B using microporation and iontophoresis in hairless rats. Pharm Res. 2007;24:1389–95.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee JW, Gadiraju P, Park JH, Allen MG, Prausnitz MR. Microsecond thermal ablation of skin for transdermal drug delivery. J Control Release. 2011;154:58–68.PubMedCrossRefGoogle Scholar
  25. 25.
    Bachhav YG, Heinrich A, Kalia YN. Using laser microporation to improve transdermal delivery of diclofenac: increasing bioavailability and the range of therapeutic applications. Eur J Pharm Biopharm. 2011;78:408–14.PubMedCrossRefGoogle Scholar
  26. 26.
    Bachhav YG, Summer S, Heinrich A, Bragagna T, Bohler C, Kalia YN. Effect of controlled laser microporation on drug transport kinetics into and across the skin. J Control Release. 2010;146:31–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliver Rev. 2012;64:1547–68.Google Scholar
  28. 28.
    Crichton ML, Ansaldo A, Chen XF, Prow TW, Fernando GJP, Kendall MAF. The effect of strain rate on the precision of penetration of short densely-packed microprojection array patches coated with vaccine. Biomaterials. 2010;31:4562–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Fernando GJP, Chen XF, Prow TW, Crichton ML, Fairmaid EJ, Roberts MS, et al. Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model. PLoS One. 2010;5:e10266.PubMedCrossRefGoogle Scholar
  30. 30.
    Andrews SN, Lee JW, Prausnitz MR. Recovery of skin barrier after stratum corneum removal by microdermabrasion. AAPS PharmSciTech. 2011;12:1393–400.PubMedCrossRefGoogle Scholar
  31. 31.
    Gill HS, Denson DD, Burris BA, Prausnitz MR. Effect of microneedle design on pain in human volunteers. Clin J Pain. 2008;24:585–94.PubMedCrossRefGoogle Scholar
  32. 32.
    Pettisand RJ, Harvey AJ. Microneedle delivery: clinical studies and emerging medical applications. Ther Deliv. 2012;3:357–71.CrossRefGoogle Scholar
  33. 33.
    Hoesly FJ, Borovicka J, Gordon J, Nardone B, Holbrook JS, Pace N, et al. Safety of a novel microneedle device applied to facial skin: a subject- and rater-blinded, sham-controlled, randomized trial. Arch Dermatol. 2012;148:711–17.Google Scholar
  34. 34.
    Levin G, Gershonowitz A, Sacks H, Stern M, Sherman A, Rudaev S, et al. Transdermal delivery of human growth hormone through RF-microchannels. Pharm Res. 2005;22:550–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Bissett, D. Ch 3: anatomy and biochemistry of skin. In: Kydonieus AF, Berner B, editors. Transdermal delivery of drugs, vol. I. Boca Raton, FL: CRC Press, Inc.; 1987. p. 160.Google Scholar
  36. 36.
    Khalil E, Kretsos K, Kasting GB. Glucose partition coefficient and diffusivity in the lower skin layers. Pharm Res. 2006;23:1227–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Tojo K, Chiang CC, Chien YW. Drug permeation across the skin—effect of penetrant hydrophilicity. J Pharm Sci. 1987;76:123–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Kretsos K, Miller MA, Zamora-Estrada G, Kasting GB. Partitioning, diffusivity and clearance of skin permeants in mammalian dermis. Int J Pharm. 2008;346:64–79.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Samantha N. Andrews
    • 1
  • Eunhye Jeong
    • 2
  • Mark R. Prausnitz
    • 1
    • 2
  1. 1.Wallace Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyAtlantaUSA
  2. 2.School of Chemical and Biomolecular EngineeringGeorgia Institute of TechnologyAtlantaUSA

Personalised recommendations