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.
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REFERENCES
Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8.
Bolognia J, Jorizzo J, Schaffer J. Dermatology. Philadelphia: Saunders; 2012.
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.
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.
Smithand E, Maibach H. Percutaneous penetration enhancers. Boca Raton, FL: CRC Press; 2005.
Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol. 2004;22:192–7.
Kim YC, Ludovice PJ, Prausnitz MR. Transdermal delivery enhanced by magainin pore-forming peptide. J Control Release. 2007;122:375–83.
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.
Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364:227–36.
Fujimoto T, Shirakami K, Tojo K. Effect of microdermabrasion on barrier capacity of stratum corneum. Chem Pharm Bull. 2005;53:1014–6.
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.
Lew BL, Cho Y, Lee MH. Effect of serial microdermabrasion on the ceramide level in the stratum corneum. Dermatol Surg. 2006;32:376–9.
Bhallaand M, Thami G. Microdermabrasion: reappraisal and brief review of literature. Dermatol Surg. 2006;32:809–14.
Freedman BM, Rueda-Pedraza E, Earley RV. Clinical and histologic changes determine optimal treatment regimens for microdermabrasion. J Dermatol Treat. 2002;13:193–200.
Andrews SN, Lee JW, Choi SO, Prausnitz MR. Transdermal insulin delivery using microdermabrasion. Pharm Res. 2011;28:2110–8.
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.
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.
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.
Andrews SN, Zarnitsyn V, Bondy B, Prausnitz MR. Optimization of microdermabrasion for controlled removal of stratum corneum. Int J Pharm. 2011;407:95–104.
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.
Jacques SL, McAuliffe DJ, Blank IH, Parrish JA. Controlled removal of human stratum-corneum by pulsed laser. J Invest Dermatol. 1987;88:88–93.
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.
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.
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.
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.
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.
Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliver Rev. 2012;64:1547–68.
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.
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.
Andrews SN, Lee JW, Prausnitz MR. Recovery of skin barrier after stratum corneum removal by microdermabrasion. AAPS PharmSciTech. 2011;12:1393–400.
Gill HS, Denson DD, Burris BA, Prausnitz MR. Effect of microneedle design on pain in human volunteers. Clin J Pain. 2008;24:585–94.
Pettisand RJ, Harvey AJ. Microneedle delivery: clinical studies and emerging medical applications. Ther Deliv. 2012;3:357–71.
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.
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.
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.
Khalil E, Kretsos K, Kasting GB. Glucose partition coefficient and diffusivity in the lower skin layers. Pharm Res. 2006;23:1227–34.
Tojo K, Chiang CC, Chien YW. Drug permeation across the skin—effect of penetrant hydrophilicity. J Pharm Sci. 1987;76:123–6.
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.
ACKNOWLEDGMENTS AND DISCLOSURES
We would like to thank Dr. Yeu-Chun Kim for supplying and preparing the fluorescently labeled influenza virus; Dr. Jeong-Woo Lee and Aritra Sengupta for advice on the sulforhodamine diffusion experiments; and Donna Bondy for administrative support. This work was carried out in the Center for Drug Design, Development and Delivery and the Institute for Bioengineering and Bioscience at Georgia Tech with financial support in part from the National Institutes of Health. Mark Prausnitz serves as a consultant and is an inventor on patents licensed to companies developing microneedle-based products. This potential conflict of interest has been disclosed and is being managed by the Georgia Institute of Technology and Emory University.
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Andrews, S.N., Jeong, E. & Prausnitz, M.R. Transdermal Delivery of Molecules is Limited by Full Epidermis, Not Just Stratum Corneum. Pharm Res 30, 1099–1109 (2013). https://doi.org/10.1007/s11095-012-0946-7
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DOI: https://doi.org/10.1007/s11095-012-0946-7