Skip to main content

Advertisement

Log in

Transdermal Delivery of Proteins

  • Review Article
  • Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Transdermal delivery of peptides and proteins avoids the disadvantages associated with the invasive parenteral route of administration and other alternative routes such as the pulmonary and nasal routes. Since proteins have a large size and are hydrophilic in nature, they cannot permeate passively across the skin due to the stratum corneum which allows the transport of only small lipophilic drug molecules. Enhancement techniques such as chemical enhancers, iontophoresis, microneedles, electroporation, sonophoresis, thermal ablation, laser ablation, radiofrequency ablation and noninvasive jet injectors aid in the delivery of proteins by overcoming the skin barrier in different ways. In this review, these enhancement techniques that can enable the transdermal delivery of proteins are discussed, including a discussion of mechanisms, sterility requirements, and commercial development of products. Combination of enhancement techniques may result in a synergistic effect allowing increased protein delivery and these are also discussed.

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

Access this article

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

Similar content being viewed by others

REFERENCES

  1. Antosova Z, Mackova M, Kral V, Macek T. Therapeutic application of peptides and proteins: parenteral forever? Trends Biotechnol. 2009;27(11):628–35.

    Article  PubMed  CAS  Google Scholar 

  2. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8.

    Article  PubMed  CAS  Google Scholar 

  3. van de Weert M, Jorgensen L, Horn Moeller E, Frokjaer S. Factors of importance for a successful delivery system for proteins. Expert Opin Drug Deliv. 2005;2(6):1029–37.

    Article  PubMed  Google Scholar 

  4. Steinstrasser I, Merkle HP. Dermal metabolism of topically applied drugs: pathways and models reconsidered. Pharm Acta Helv. 1995;70(1):3–24.

    Article  PubMed  CAS  Google Scholar 

  5. Tauber U. Drug metabolism in the skin: advantages and disadvantages. In: Hadgraft J, Guy RH, editors. Transdermal drug delivery: developmental issues and research initiatives. New York: Marcel Dekker; 1989. p. 99–112.

    Google Scholar 

  6. Magnusson BM, Runn P. Effect of penetration enhancers on the permeation of the thyrotropin releasing hormone analogue pGlu-3-methyl-His-Pro amide through human epidermis. Int J Pharm. 1999;178(2):149–59.

    Article  PubMed  CAS  Google Scholar 

  7. Chen Y, Shen Y, Guo X, Zhang C, Yang W, Ma M, et al. Transdermal protein delivery by a coadministered peptide identified via phage display. Nat Biotechnol. 2006;24(4):455–60.

    Article  PubMed  CAS  Google Scholar 

  8. Frankenburg S, Grinberg I, Bazak Z, Fingerut L, Pitcovski J, Gorodetsky R, et al. Immunological activation following transcutaneous delivery of HR-gp100 protein. Vaccine. 2007;25(23):4564–70.

    Article  PubMed  CAS  Google Scholar 

  9. Foldvari M, Baca-Estrada ME, He Z, Hu J, Attah-Poku S, King M. Dermal and transdermal delivery of protein pharmaceuticals: lipid-based delivery systems for interferon alpha. Biotechnol Appl Biochem. 1999;30(Pt 2):129–37.

    PubMed  CAS  Google Scholar 

  10. Caccetta R, Blanchfield JT, Harrison J, Toth I, Benson HAE. Epidermal penetration of a therapeutic peptide by lipid conjugation; stereo-selective peptide availability of a topical distereomeric lipopeptide. Int J Pept Res Ther. 2006;12:327–33.

    Article  CAS  Google Scholar 

  11. Jain S, Jain P, Umamaheshwari RB, Jain NK. Transfersomes—a novel vesicular carrier for enhanced transdermal delivery: development, characterization, and performance evaluation. Drug Dev Ind Pharm. 2003;29(9):1013–26.

    Article  PubMed  CAS  Google Scholar 

  12. Abla N, Naik A, Guy RH, Kalia YN. Contributions of electromigration and electroosmosis to peptide iontophoresis across intact and impaired skin. J Control Release. 2005;108(2–3):319–30.

    Article  PubMed  CAS  Google Scholar 

  13. Green PG. Iontophoretic delivery of peptide drugs. J Control Release. 1996;41:33–48.

    Article  CAS  Google Scholar 

  14. Lau DT, Sharkey JW, Petryk L, Mancuso FA, Yu Z, Tse FL. Effect of current magnitude and drug concentration on iontophoretic delivery of octreotide acetate (Sandostatin) in the rabbit. Pharm Res. 1994;11(12):1742–6.

    Article  PubMed  CAS  Google Scholar 

  15. Medi BM, Singh J. Electronically facilitated transdermal delivery of human parathyroid hormone (1–34). Int J Pharm. 2003;263(1–2):25–33.

    Article  PubMed  CAS  Google Scholar 

  16. Prausnitz MR, Lee CR, Liu CH, Pang JC, Singh TP, Langer R, et al. Transdermal transport efficiency during skin electroporation and iontophoresis. J Control Release. 1996;38:205–17.

    Article  CAS  Google Scholar 

  17. Miller LL, Kolaskie CJ, Smith GA, Rivier J. Transdermal iontophoresis of gonadotropin releasing hormone (LHRH) and two analogues. J Pharm Sci. 1990;79(6):490–3.

    Article  PubMed  CAS  Google Scholar 

  18. Schuetz YB, Naik A, Guy RH, Vuaridel E, Kalia YN. Transdermal iontophoretic delivery of triptorelin in vitro. J Pharm Sci. 2005;94(10):2175–82.

    Article  PubMed  CAS  Google Scholar 

  19. Nestor Jr JJ, Ho TL, Simpson RA, Horner BL, Jones GH, McRae GI, et al. Synthesis and biological activity of some very hydrophobic superagonist analogues of luteinizing hormone-releasing hormone. J Med Chem. 1982;25(7):795–801.

    Article  PubMed  CAS  Google Scholar 

  20. Pikal MJ. Penetration enhancement of peptide and protein drugs by electrochemical means: transdermal iontophoresis. In: Lee VHL, Hashida M, Mizushima Y, editors. Trends and future perspectives in peptide and protein drug delivery. Chur: Harwood Academic Publishers GmbH; 1995.

    Google Scholar 

  21. Vemulapalli V, Banga AK, Friden PM. Optimization of iontophoretic parameters for the transdermal delivery of methotrexate. Drug Deliv. 2008;15(7):437–42.

    Article  PubMed  CAS  Google Scholar 

  22. Langkjaer L, Brange J, Grodsky GM, Guy RH. Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. J Control Release. 1998;51(1):47–56.

    Article  PubMed  CAS  Google Scholar 

  23. Hoogstraate AJ, Srinivasan V, Sims SM, Higuchi WI. Iontophoretic enhancement of peptides: behaviour of leuprolide versus model permeants. J Control Release. 1994;31:41–7.

    Article  CAS  Google Scholar 

  24. Banga AK. Therapeutic peptides and proteins. 2nd ed. New York: Taylor & Francis; 2006.

    Google Scholar 

  25. Wang PM, Cornwell M, Hill J, Prausnitz MR. Precise microinjection into skin using hollow microneedles. J Invest Dermatol. 2006;126(5):1080–7.

    Article  PubMed  CAS  Google Scholar 

  26. Kalluri H, Banga AK. Microneedles and transdermal drug delivery. J Drug Del Sci Tech. 2009;19(5):303–10.

    CAS  Google Scholar 

  27. Li G, Badkar A, Kalluri H, Banga AK. Microchannels created by sugar and metal microneedles: characterization by microscopy, macromolecular flux and other techniques. J Pharm Sci. 2010;99(4):1931–41.

    PubMed  CAS  Google Scholar 

  28. Verbaan FJ, Bal SM, van den Berg DJ, Groenink WH, Verpoorten H, Luttge R, et al. Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. J Control Release. 2007;117(2):238–45.

    Article  PubMed  CAS  Google Scholar 

  29. Wu XM, Todo H, Sugibayashi K. Enhancement of skin permeation of high molecular compounds by a combination of microneedle pretreatment and iontophoresis. J Control Release. 2007;118(2):189–95.

    Article  PubMed  CAS  Google Scholar 

  30. Wermeling DP, Banks SL, Hudson DA, Gill HS, Gupta J, Prausnitz MR, et al. Microneedles permit transdermal delivery of a skin-impermeant medication to humans. Proc Natl Acad Sci USA. 2008;105(6):2058–63.

    Article  PubMed  CAS  Google Scholar 

  31. Lin W, Cormier M, Samiee A, Griffin A, Johnson B, Teng CL, et al. Transdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux) technology. Pharm Res. 2001;18(12):1789–93.

    Article  PubMed  CAS  Google Scholar 

  32. Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for transdermal delivery. Pharm Res. 2008;25(1):104–13.

    Article  PubMed  CAS  Google Scholar 

  33. Chabri F, Bouris K, Jones T, Barrow D, Hann A, Allender C, et al. Microfabricated silicon microneedles for nonviral cutaneous gene delivery. Br J Dermatol. 2004;150(5):869–77.

    Article  PubMed  CAS  Google Scholar 

  34. Gill HS, Prausnitz MR. Coating formulations for microneedles. Pharm Res. 2007;24(7):1369–80.

    Article  PubMed  CAS  Google Scholar 

  35. Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang DD, et al. Transdermal delivery of desmopressin using a coated microneedle array patch system. J Control Release. 2004;97(3):503–11.

    PubMed  CAS  Google Scholar 

  36. Widera G, Johnson J, Kim L, Libiran L, Nyam K, Daddona PE, et al. Effect of delivery parameters on immunization to ovalbumin following intracutaneous administration by a coated microneedle array patch system. Vaccine. 2006;24(10):1653–64.

    Article  PubMed  CAS  Google Scholar 

  37. Xie Y, Xu B, Gao Y. Controlled transdermal delivery of model drug compounds by MEMS microneedle array. Nanomedicine. 2005;1(2):184–90.

    PubMed  CAS  Google Scholar 

  38. Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, et al. Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm Res. 2002;19(1):63–70.

    Article  PubMed  CAS  Google Scholar 

  39. Ito Y, Hagiwara E, Saeki A, Sugioka N, Takada K. Feasibility of microneedles for percutaneous absorption of insulin. Eur J Pharm Sci. 2006;29(1):82–8.

    Article  PubMed  CAS  Google Scholar 

  40. Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2008;20:933–8.

    Article  CAS  Google Scholar 

  41. Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res. 2006;23(5):1008–19.

    Article  PubMed  CAS  Google Scholar 

  42. Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113–24.

    Article  PubMed  CAS  Google Scholar 

  43. Roxhed N, Griss P, Stemme G. Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery. Biomed Microdevices. 2008;10(2):271–9.

    Article  PubMed  CAS  Google Scholar 

  44. Paik SJ, Byun S, Lim JM, Park Y, Lee A, Chung S, et al. In-plane single-crystal-silicon microneedles for minimally invasive microfluid systems. Sens Actuators A. 2004;114:276–84.

    Article  Google Scholar 

  45. Martanto W, Moore JS, Kashlan O, Kamath R, Wang PM, O’Neal JM, et al. Microinfusion using hollow microneedles. Pharm Res. 2006;23(1):104–13.

    Article  PubMed  CAS  Google Scholar 

  46. Nordquist L, Roxhed N, Griss P, Stemme G. Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: an initial comparison with subcutaneous administration. Pharm Res. 2007;24(7):1381–8.

    Article  PubMed  CAS  Google Scholar 

  47. Teo MA, Shearwood C, Ng KC, Lu J, Moochhala S. In vitro and in vivo characterization of MEMS microneedles. Biomed Microdevices. 2005;7(1):47–52.

    Article  PubMed  Google Scholar 

  48. Martanto W, Moore JS, Couse T, Prausnitz MR. Mechanism of fluid infusion during microneedle insertion and retraction. J Control Release. 2006;112(3):357–61.

    Article  PubMed  CAS  Google Scholar 

  49. Ameri M, Wang X, Maa YF. Effect of irradiation on parathyroid hormone PTH(1–34) coated on a novel transdermal microprojection delivery system to produce a sterile product—adhesive compatibility. J Pharm Sci. 2010;99(4):2123–34.

    PubMed  CAS  Google Scholar 

  50. Kalluri H, Banga AK. Formation and Closure of Microchannels in Skin Following Microporation. Pharm Res [serial on the Internet]. 2010: Available from: http://www.ncbi.nlm.nih.gov/pubmed/20354766.

  51. Haq MI, Smith E, John DN, Kalavala M, Edwards C, Anstey A, et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed Microdevices. 2009;11(1):35–47.

    Article  PubMed  CAS  Google Scholar 

  52. Gupta J. Microneedles for transdermal drug delivery in human subjects. Atlanta: Georgia Institute of Technology; 2009.

    Google Scholar 

  53. Donnelly RF, Singh TR, Tunney MM, Morrow DI, McCarron PA, O’Mahony C, et al. Microneedle arrays allow lower microbial penetration than hypodermic needles in vitro. Pharm Res. 2009;26(11):2513–22.

    Article  PubMed  CAS  Google Scholar 

  54. Prausnitz MR. Do high-voltage pulses cause changes in skin structure? J Control Release. 1996;40:321–6.

    Article  CAS  Google Scholar 

  55. Edwards DA, Prausnitz MR, Langer R, Weaver JC. Analysis of enhanced transdermal transport by skin electroporation. J Control Release. 1995;34:211–21.

    Article  CAS  Google Scholar 

  56. Zhao YL, Murthy SN, Manjili MH, Guan LJ, Sen A, Hui SW. Induction of cytotoxic T-lymphocytes by electroporation-enhanced needle-free skin immunization. Vaccine. 2006;24(9):1282–90.

    Article  PubMed  CAS  Google Scholar 

  57. Chang SL, Hofmann GA, Zhang L, Deftos LJ, Banga AK. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J Control Release. 2000;66(2–3):127–33.

    Article  PubMed  CAS  Google Scholar 

  58. Prausnitz MR, Pliquett U, Langer R, Weaver JC. Rapid temporal control of transdermal drug delivery by electroporation. Pharm Res. 1994;11(12):1834–7.

    Article  PubMed  CAS  Google Scholar 

  59. Vanbever R, Lecouturier N, Preat V. Transdermal delivery of metoprolol by electroporation. Pharm Res. 1994;11(11):1657–62.

    Article  PubMed  CAS  Google Scholar 

  60. Prausnitz MR, Edelman ER, Gimm JA, Langer R, Weaver JC. Transdermal delivery of heparin by skin electroporation. Biotechnology (NY). 1995;13(11):1205–9.

    Article  CAS  Google Scholar 

  61. Prausnitz MR, Bose VG, Langer R, Weaver JC. Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci USA. 1993;90(22):10504–8.

    Article  PubMed  CAS  Google Scholar 

  62. Therapeutics A. PassPort Patch. 2010; Available from: http://www.alteatherapeutics.com/. Accessed June 2010

  63. Banga AK. Microporation applications for enhancing drug delivery. Expert Opin Drug Deliv. 2009;6(4):343–54.

    Article  PubMed  CAS  Google Scholar 

  64. TransPharma. ViaDerm system. 2010; Available from: http://www.transpharma-medical.com/viaderm_system.html. Accessed June 2010

  65. 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(4):550–5.

    Article  PubMed  CAS  Google Scholar 

  66. Mitragotri S, Kost J. Low-frequency sonophoresis: a review. Adv Drug Deliv Rev. 2004;56(5):589–601.

    Article  PubMed  CAS  Google Scholar 

  67. Luis J, Park EJ, Meyer RJ, Smith NB. Rectangular cymbal arrays for improved ultrasonic transdermal insulin delivery. J Acoust Soc Am. 2007;122(4):2022–30.

    Article  PubMed  CAS  Google Scholar 

  68. Lee S, Snyder B, Newnham RE, Smith NB. Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array. Diabetes Technol Ther. 2004;6(6):808–15.

    Article  PubMed  CAS  Google Scholar 

  69. Smith NB, Lee S, Shung KK. Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays. Ultrasound Med Biol. 2003;29(8):1205–10.

    Article  PubMed  Google Scholar 

  70. Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science. 1995;269(5225):850–3.

    Article  PubMed  CAS  Google Scholar 

  71. Tachibana K, Tachibana S. Use of ultrasound to enhance the local anesthetic effect of topically applied aqueous lidocaine. Anesthesiology. 1993;78:1091–6.

    Article  PubMed  CAS  Google Scholar 

  72. Mitragotri S, Kost J. Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound. Pharm Res. 2001;18(8):1151–6.

    Article  PubMed  CAS  Google Scholar 

  73. El-Kamel AH, Al-Fagih IM, Alsarra IA. Effect of sonophoresis and chemical enhancers on testosterone transdermal delivery from solid lipid microparticles: an in vitro study. Curr Drug Deliv. 2008;5(1):20–6.

    Article  PubMed  CAS  Google Scholar 

  74. Tezel A, Dokka S, Kelly S, Hardee GE, Mitragotri S. Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharm Res. 2004;21(12):2219–25.

    Article  PubMed  CAS  Google Scholar 

  75. Mitragotri S, Blankschtein D, Langer R. An explanation for the variation of the sonophoretic transdermal transport enhancement from drug to drug. J Pharm Sci. 1997;86(10):1190–2.

    Article  PubMed  CAS  Google Scholar 

  76. Banga AK. New technologies to allow transdermal delivery of therapeutic proteins and small water-soluble drugs. Am J Drug Deliv. 2006;4(4):221–30.

    Article  CAS  Google Scholar 

  77. Biosolutions P. P.L.E.A.S.E. platform. 2010; Available from: http://www.pantec-biosolutions.com/. Accessed June 2010

  78. Abbey N. Laser Assisted Drug Delivery (LAD). 2010; Available from: www.norwoodabbey.com. Accessed June 2010

  79. Koh JL, Harrison D, Swanson V, Norvell DC, Coomber DC. A comparison of laser-assisted drug delivery at two output energies for enhancing the delivery of topically applied LMX-4 cream prior to venipuncture. Anesth Analg. 2007;104(4):847–9.

    Article  PubMed  CAS  Google Scholar 

  80. Mitragotri S. Current status and future prospects of needle-free liquid jet injectors. Nat Rev Drug Discov. 2006;5(7):543–8.

    PubMed  Google Scholar 

  81. Dean HJ, Fuller D, Osorio JE. Powder and particle-mediated approaches for delivery of DNA and protein vaccines into the epidermis. Comp Immunol Microbiol Infect Dis. 2003;26(5–6):373–88.

    Article  PubMed  Google Scholar 

  82. Chen D, Payne LG. Targeting epidermal Langerhans cells by epidermal powder immunization. Cell Res. 2002;12(2):97–104.

    Article  PubMed  Google Scholar 

  83. Osorio JE, Zuleger CL, Burger M, Chu Q, Payne LG, Chen D. Immune responses to hepatitis B surface antigen following epidermal powder immunization. Immunol Cell Biol. 2003;81(1):52–8.

    Article  PubMed  CAS  Google Scholar 

  84. Kendall M, Rishworth S, Carter F, Mitchell T. Effects of relative humidity and ambient temperature on the ballistic delivery of micro-particles to excised porcine skin. J Invest Dermatol. 2004;122(3):739–46.

    Article  PubMed  CAS  Google Scholar 

  85. Pillai O, Panchagnula R. Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. J Control Release. 2003;89(1):127–40.

    Article  PubMed  CAS  Google Scholar 

  86. 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(7):1389–95.

    Article  PubMed  CAS  Google Scholar 

  87. Katikaneni S, Badkar A, Nema S, Banga AK. Molecular charge mediated transport of a 13 kD protein across microporated skin. Int J Pharm. 2009;378(1–2):93–100.

    Article  PubMed  CAS  Google Scholar 

  88. Vemulapalli V, Yang Y, Friden PM, Banga AK. Synergistic effect of iontophoresis and soluble microneedles for transdermal delivery of methotrexate. J Pharm Pharmacol. 2008;60(1):27–33.

    Article  PubMed  CAS  Google Scholar 

  89. Bommannan DB, Tamada J, Leung L, Potts RO. Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro. Pharm Res. 1994;11(12):1809–14.

    Article  PubMed  CAS  Google Scholar 

  90. Riviere JE, Monteiro-Riviere NA, Rogers RA, Bommannan D, Tamada JA, Potts RO. Pulsatile transdermal delivery of LHRH using electroporation: drug delivery and skin toxicology. J Control Release. 1995;36:229–33.

    Article  CAS  Google Scholar 

  91. Mutalik S, Parekh HS, Davies NM, Udupa N. A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride. Drug Deliv. 2009;16(2):82–91.

    Article  PubMed  CAS  Google Scholar 

  92. Kost J, Pliquett U, Mitragotri S, Yamamoto A, Langer R, Weaver J. Synergistic effect of electric field and ultrasound on transdermal transport. Pharm Res. 1996;13(4):633–8.

    Article  PubMed  CAS  Google Scholar 

  93. Le L, Kost J, Mitragotri S. Combined effect of low-frequency ultrasound and iontophoresis: applications for transdermal heparin delivery. Pharm Res. 2000;17(9):1151–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ajay K. Banga.

Additional information

Guest Editors: Lavinia Lewis, Jim Agalloco, Bill Lambert, Russell Madsen, and Mark Staples

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalluri, H., Banga, A.K. Transdermal Delivery of Proteins. AAPS PharmSciTech 12, 431–441 (2011). https://doi.org/10.1208/s12249-011-9601-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-011-9601-6

KEY WORDS

Navigation