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Current status and future potential of transdermal drug delivery

Key Points

  • Transdermal delivery of drugs, proteins and other bioactive molecules is an attractive alternative for compounds that cannot be administered orally due to degradation in the gastrointestinal tract and liver. As a result, transdermal patches exist in the United States to administer twelve different drugs or drug combinations to treat a variety of indications.

  • Although it would be beneficial to deliver more drugs from patches, the skin's outer layer of stratum corneum provides a barrier to transport that prevents transdermal delivery of most compounds at therapeutic levels. A broad variety of chemical enhancers has been used to increase drug penetration across skin, but their efficacy has been limited by associated skin irritation and toxicity.

  • Electrical and acoustical energy have been used to increase transdermal delivery. Iontophoresis, involving increased transport across skin mediated primarily by electrophoretic migration, is used in a few FDA-approved products and is poised to have increased impact. Additional research has shown that short, high-voltage pulses causing electroporation can increase transdermal transport not only by electrophoretic movement, but also through short-lived nanometre pores created within the skin. Also of commercial interest, ultrasound and acoustic shock waves have been shown to increase skin permeability by a mechanism believed to involve transient disruption of skin nanostructure.

  • Skin can also be disrupted on the micron scale to increase permeability. Arrays of microscopic needles inserted painlessly into skin have been shown to increase skin permeability for the delivery of small drugs, macromolecules and microparticles, which has stimulated increasing industrial activity. Jet injectors, thermal ablation methods and very small hypodermic needles are also the subject of renewed and on-going commercial interest.

  • After an initial period of development that led to passive systems like the nicotine patch, transdermal drug delivery is experiencing a resurgence of activity using active enhancement methods base on nano- and micro-scale disruption of skin structure. Synergistic combinations of these methods could provide still better results.

Abstract

The past twenty five years have seen an explosion in the creation and discovery of new medicinal agents. Related innovations in drug delivery systems have not only enabled the successful implementation of many of these novel pharmaceuticals, but have also permitted the development of new medical treatments with existing drugs. The creation of transdermal delivery systems has been one of the most important of these innovations, offering a number of advantages over the oral route. In this article, we discuss the already significant impact this field has made on the administration of various pharmaceuticals; explore limitations of the current technology; and discuss methods under exploration for overcoming these limitations and the challenges ahead.

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Figure 1: Schematic representation of a cross section through human skin.
Figure 2: Images of selected transdermal products (marketed or under development).

References

  1. 1

    Rein, H. Experimental electroendosmotic studies on living human skin. Z. Biol. 81, 124– (1924).

    Google Scholar 

  2. 2

    Blank, I. H. Penetration of low-molecular-weight alcohols into skin. I. Effect of concentration of alcohol and type of vehicle. J. Invest. Dermatol. 43, 415–420 (1964).

    CAS  PubMed  Google Scholar 

  3. 3

    Scheuplein, R. J. Mechanism of percutaneous adsorption I. Routes of penetration and the influence of solubility. J. Invest. Dermatol. 45, 334–345 (1965).

    CAS  PubMed  Google Scholar 

  4. 4

    Scheuplein, R. J. & Blank, I. H. Permeability of the skin. Physiol. Rev. 51, 702–747 (1971).

    CAS  PubMed  Google Scholar 

  5. 5

    Michaels, A. S., Chandrasekaran, S. K. & Shaw, J. E. Drug permeation through human skin: theory and in vitro experimental measurement. AIChE J. 21, 985–996 (1975). Rigorous modelling of transdermal transport that provided the foundation for subsequent models.

    CAS  Google Scholar 

  6. 6

    Sifton, D. W. (ed.) Physicians' Desk Reference (Thomson PDR, Montvale, 2003).

    Google Scholar 

  7. 7

    Cramer, M. P. & Saks, S. R. Translating safety, efficacy and compliance into economic value for controlled release dosage forms. Pharmacoeconomics 5, 482–504 (1994).

    CAS  PubMed  Google Scholar 

  8. 8

    Henningfield, J. E. Nicotine medications for smoking cessation. N. Engl. J. Med. 333, 1196–1203 (1995).

    CAS  PubMed  Google Scholar 

  9. 9

    Zaffaroni, A. Overview and evolution of therapeutic systems. Ann. NY Acad. Sci. 618, 405–421 (1991).

    CAS  PubMed  Google Scholar 

  10. 10

    Wertz, P. W. & Downing, D. T. in Transdermal Drug Delivery: Developmental Issues and Research Intiatives (eds Hadgraft, J. & Guy, R. H.) 1–17 (Marcel Dekker, 1989).

    Google Scholar 

  11. 11

    Champion, R. H., Burton, J. L., Burns, D. A. & Breathnach, S. M. (eds). Textbook of Dermatology (Blackwell Science, London, 1998).

    Google Scholar 

  12. 12

    Elias, P. M. & Feingold, K. R. Coordinate regulation of epidermal differentiation and barrier homeostasis. Skin Pharmacol. Appl. Skin Physiol. 14 (Suppl. 1), 28–34 (2001).

    CAS  PubMed  Google Scholar 

  13. 13

    Marrink, S. J. & Berendsen, J. C. Permeation process of small molecules across lipid membranes studied by molecular dynamics simulations. J. Phys. Chem. 100, 16729–16738 (1996).

    CAS  Google Scholar 

  14. 14

    Peck, K. D., Ghanem, A. H. & Higuchi, W. I. Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane. Pharm. Res. 11, 1306–1314 (1994).

    CAS  PubMed  Google Scholar 

  15. 15

    Mitragotri, S. Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. J. Control. Release 86, 69–92 (2003).

    CAS  PubMed  Google Scholar 

  16. 16

    Fiserova-Bergerova, V., Pierce, J. T. & Droz, P. O. Dermal absoprtion potential of industrial chemicals: criteria for skin notation. Am. J. Ind. Med. 17, 617–635 (1990).

    CAS  PubMed  Google Scholar 

  17. 17

    McKone, T. E. & Howard, R. A. Estimating dermal uptake of non-ionic organic chemicals from water and soil: I. Unified fugacity-based models for risk assessment. Risk Analysis 12, 543–557 (1992).

    CAS  PubMed  Google Scholar 

  18. 18

    Potts, R. O. & Guy, R. H. Predicting skin permeability. Pharm. Res. 9, 663–669 (1992). Broadly predictive semi-empirical model of skin permeability.

    CAS  PubMed  Google Scholar 

  19. 19

    Moss, G. P., Dearden, J. C., Patel, H. & Cronin, M. T. D. Quantitative structure–permeability relationships (QSPRs) for percutaneous absorption. Toxicol. In Vitro 16, 299–317 (2002).

    CAS  PubMed  Google Scholar 

  20. 20

    Anderson, B. D. & Raykar, P. V. Solute structure-permeability relationships in human stratum corneum. J. Invest. Dermatol. 93, 280–286 (1989).

    CAS  PubMed  Google Scholar 

  21. 21

    Cleek, R. L. & Bunge, A. L. A new method for estiamting dermal absorption from chemical exposure. 1. General approach. Pharm. Res. 10, 497–506 (1993).

    CAS  PubMed  Google Scholar 

  22. 22

    Abraham, M. H., Martins, F. & Mitchell, R. C. Algorithms for skin permeability using hydrogen bond descriptors: the problem of steroids. J. Pharm. Pharmac. 49, 858–865 (1997).

    CAS  Google Scholar 

  23. 23

    Buchwald, P. & Bodor, N. A simple, predictive, structure-based skin permeability model. J. Pharm. Pharmacol. 53, 1087–1098 (2001).

    CAS  PubMed  Google Scholar 

  24. 24

    Barrat, M. D. Quantitative structure–activity relationships for skin permeability. Toxicol. In Vitro 9, 27–37 (1995).

    Google Scholar 

  25. 25

    Pugh, W. J., Hadgraft, J. & Roberts, M. S. in Dermal Absorption and Toxicity Assessment (eds Roberts, M. S. & Walters, K.) 245–268 (Marcek Dekker, New York, 1998).

    Google Scholar 

  26. 26

    Lim, C. W., Fujiwara, S., Yamashita, F. & Hashida, M. Prediction of human skin permeability using a combination of molecular orbital calculations and artificial neural network. Biol. Pharm. Bull. 25, 361–366 (2002).

    CAS  PubMed  Google Scholar 

  27. 27

    Frasch, H. F. A Random-walk model for skin permeation. Risk. Anal. 22, 265–276 (2002).

    PubMed  Google Scholar 

  28. 28

    Kasting, G. B., Smith, R. L. & Cooper, E. R. Effect of lipid solubility and molecular size on percutaneous absorption. Pharmacol. Skin 1, 138–153 (1987).

    Google Scholar 

  29. 29

    French, E., Potton, C. & Walters, K. in Pharmaceutical Skin Penetration Enhnacement (eds Walters, K. & Hadgraft, J.) 113–144 (Marcel Dekker, New York, 1993).

    Google Scholar 

  30. 30

    Kanikkannan, N., Kanimalla, K., Lamba, S. S. & Singh, M. Structure–activity relationship of chemical penetration enhancers in transdermal drug delivery. Curr. Med. Chem. 7, 593–608 (2000).

    CAS  PubMed  Google Scholar 

  31. 31

    Lashmar, U. T., Hadgraft, J. & Thomas, N. Topical application of penetration enhancers to the skin of nude mice: a histophatholgical study. J. Pharm. Pharmacol. 41, 118–122 (1989).

    CAS  PubMed  Google Scholar 

  32. 32

    Takanashi, Y., Higashiyama, K., Komiya, H., Takayama, K. & Nagai, T. Thiomenthol derivatives as novel percutaneous absorption enhancers. Drug Dev. Ind. Pharm. 25, 89–94 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Akimoto, T. & Nagase, Y. Novel transdermal drug penetration enhancer: synthesis and enhancing effect of alkyldisiloxane comounds containign glucopyranosyl group. J. Control. Rel. 88, 243–252 (2003).

    CAS  Google Scholar 

  34. 34

    McVary, K. T., Polepalle, S., Riggi, S. & Pelham, R. W. Topical prostaglandin E1 SEPA gel for the treatment of erectile dysfunction. J. Urol. 162, 726–730 (1999).

    CAS  PubMed  Google Scholar 

  35. 35

    Williams, A. C. & Barry, B. W. Skin absorption enhancers. Crit. Rev. Ther. Drug Carrier Syst. 9, 305–353 (1992).

    CAS  PubMed  Google Scholar 

  36. 36

    Finin, B. C. & Morgan, T. M. Transdermal penetration enhancers: applications, limitations, and potential. J. Pharm. Sci. 88, 955–958 (1999).

    Google Scholar 

  37. 37

    Ongpipattnakul, B., Burnette, R. R., Potts, R. O. & Francoeur, M. L. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm. Res. 8, 350–354 (1991).

    Google Scholar 

  38. 38

    Cevc, G. Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 13, 257–388 (1996). Overview of lipid-based systems for transdermal delivery.

    CAS  PubMed  Google Scholar 

  39. 39

    Karande, P., Jain, A. & Mitragotri, S. Discovery of transdermal penetration enhancers by high-throughput screening. Nature Biotechnol. 4 Jan 2004 (doi:10.1038/nbt928). Study establishing high-throughput screening methods for transdermal formulations.

  40. 40

    Costello, C. T. & Jeske, A. H. Iontophoresis: applications in transdermal medication delivery. Phys. Ther. 75, 554–563 (1995).

    CAS  PubMed  Google Scholar 

  41. 41

    Warwick, W. J. et al. Evaluation of a cystic fibrosis screening system incorporating a miniature sweat stimulator and disposable chloride sensor. Clin. Chem. 32, 850–853 (1986).

    CAS  PubMed  Google Scholar 

  42. 42

    Hölzle, E. & Alberti, N. Long-term efficacy and side effects of tap water iontophoresis of palmoplantar hyperhidrosis — the usefulness of home therapy. Dermatologica 175, 126–135 (1987).

    PubMed  Google Scholar 

  43. 43

    Miller, K. A., Balakrishnan, G., Eichbauer, G. & Betley, K. 1% lidocaine injection, EMLA cream, or 'numby stuff' for topical analgesia associated with peripheral intravenous cannulation. AANA J. 69, 185–187 (2001).

    CAS  PubMed  Google Scholar 

  44. 44

    Tamada, J. et al. Noninvasive glucose monitoring: comprehensive clinical results. Cygnus Research Team. JAMA 282, 1839–1844 (1999).

    CAS  PubMed  Google Scholar 

  45. 45

    Ledger, P. W. Skin biological issues in electrically enhanced transdermal delivery. Adv. Drug Deliv. Rev. 9, 289–307 (1992). Overview of biological issues associated with transdermal delivery, especially in iontophoresis.

    CAS  Google Scholar 

  46. 46

    Banga, A. K. Electrically-Assisted Transdermal and Topical Drug Delivery (Taylor & Francis, London, 1998).

    Google Scholar 

  47. 47

    Amsden, B. G. & Goosen, M. F. A. Transdermal delivery of peptide and protein drugs: an overview. AIChE J. 41, 1972–1997 (1995). Overview of challenges associated with transdermal delivery of macromolecules, especially in iontophoresis.

    CAS  Google Scholar 

  48. 48

    Pikal, M. J. The role of electroosmotic flow in transdermal iontophoresis. Adv. Drug Deliv. Rev. 46, 281–305 (2001).

    CAS  PubMed  Google Scholar 

  49. 49

    Higuchi, W. I., Li, S. K., Ghanem, A. H., Zhu, H. & Song, Y. Mechanistic aspects of iontophoresis in human epidermal membrane. J. Control. Release 62, 13–23 (1999).

    CAS  PubMed  Google Scholar 

  50. 50

    Prausnitz, M. R. The effects of electric current applied to the skin: a review for transdermal drug delivery. Adv. Drug Deliv. Rev. 18, 395–425 (1996).

    CAS  Google Scholar 

  51. 51

    Chizmadzhev, Y. A. et al. Electrical properties of skin at moderate voltages: contribution of appendegeal macropores. Biophys. J. 74, 843–856 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Prausnitz, M. R., Bose, V. G., Langer, R. & Weaver, J. C. Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc. Natl Acad. Sci. USA 90, 10504–10508 (1993). Study that established skin electroporation for transdermal delivery.

    CAS  PubMed  Google Scholar 

  53. 53

    Prausnitz, M. R. A practical assessment of transdermal drug delivery by skin electroporation. Adv. Drug Deliv. Rev. 35, 61–76 (1999).

    CAS  PubMed  Google Scholar 

  54. 54

    Weaver, J. C., Vaughan, T. E. & Chizmadzhev, Y. Theory of electrical creation of aqueous pathways across skin transport barriers. Adv. Drug Deliv. Rev. 35, 21–40 (1999).

    CAS  PubMed  Google Scholar 

  55. 55

    Prausnitz, M. R., Pliquett, U. & Vanbever, R. in Electrochemotherapy, Electrogenetherapy, and Transdermal Drug Delivery (eds Jaroszeski, M. J., Heller, R. & Gilbert, R.) 213–245 (Humana Press, Totowa, 2000).

    Google Scholar 

  56. 56

    Vanbever, R. & Preat, V. In vivo efficacy and safety of skin electroporation. Adv. Drug Deliv. Rev. 35, 77–88 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Wallace, M. S. et al. Topical delivery of lidocaine in healthy volunteers by electroporation, electroincorporation, or iontophoresis: an evaluation of skin anesthesia. Reg. Anesth. Pain Med. 26, 229–238 (2001).

    CAS  PubMed  Google Scholar 

  58. 58

    Prausnitz, M. R., Edelman, E. R., Gimm, J. A., Langer, R. & Weaver, J. C. Transdermal delivery of heparin by skin electroporation. Bio/Technology 13, 1205–1209 (1995).

    CAS  PubMed  Google Scholar 

  59. 59

    Sen, A., Daly, M. E. & Hui, S. W. Transdermal insulin delivery using lipid enhanced electroporation. Biochim. Biophys. Acta 1564, 5–8 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Misra, A., Ganga, S. & Upadhyay, P. Needle-free, non-adjuvanted skin immunization by electroporation-enhanced transdermal delivery of diphtheria toxoid and a candidate peptide vaccine against hepatitis B virus. Vaccine 18, 517–523 (1999).

    CAS  PubMed  Google Scholar 

  61. 61

    Zewert, T. E., Pliquett, U. F., Langer, R. & Weaver, J. C. Transdermal transport of DNA antisense oligonucleotides by electroporation. Biochem. Biophys. Res. Com. 212, 286–292 (1995).

    CAS  PubMed  Google Scholar 

  62. 62

    Zhang, L., Li, L., Hofmann, G. A. & Hoffman, R. M. Depth-targeted efficient gene delivery and expression in the skin by pulsed electric fields: an approach to gene therapy of skin aging and other diseases. Biochem. Biophys. Res. Comm. 220, 633–636 (1996).

    CAS  PubMed  Google Scholar 

  63. 63

    Hofmann, G. A., Rustrum, W. V. & Suder, K. S. Electro-incorporation of microcarriers as a method for the transdermal delivery of large molecules. Bioelectrochem. Bioenerg. 38, 209–222 (1995).

    CAS  Google Scholar 

  64. 64

    Prausnitz, M. R., Pliquett, U., Langer, R. & Weaver, J. C. Rapid temporal control of transdermal drug delivery by electroporation. Pharm. Res. 11, 1834–1837 (1994).

    CAS  PubMed  Google Scholar 

  65. 65

    Heller, R., Gilbert, R. & Jaroszeski, M. J. Clinical applications of electrochemotherapy. Adv. Drug Deliv. Rev. 35, 119–130 (1999).

    CAS  PubMed  Google Scholar 

  66. 66

    Pliquett, U. Mechanistic studies of molecular transdermal transport due to skin electroporation. Adv. Drug Deliv. Rev. 35, 41–60 (1999).

    CAS  PubMed  Google Scholar 

  67. 67

    Prausnitz, M. R. et al. Imaging of transport pathways across human stratum corneum during high-voltage and low-voltage electrical exposures. J. Pharm. Sci. 85, 1363–1370 (1996).

    CAS  PubMed  Google Scholar 

  68. 68

    Fellinger, K. & Schmidt, J. Klinik and therapies des chromischen gelenkreumatismus. Maudrich Vienna, Austria 549–552 (1954).

  69. 69

    Tyle, P. & Agrawala, P. Drug delivery by phonophoresis. Pharm. Res. 6, 355–361 (1989).

    CAS  PubMed  Google Scholar 

  70. 70

    Merino, G., Kalia, Y. N. & Guy, R. H. Ultrasound-enhanced transdermal transport. J. Pharm. Sci. 92, 1125–1137 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    Mitragotri, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850–853 (1995). Study demonstrating transdermal protein delivery using ultrasound.

    CAS  PubMed  Google Scholar 

  72. 72

    Mitragotri, S. & Kost, J. Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound. Pharm. Res. 18, 1151–1156 (2000).

    Google Scholar 

  73. 73

    Tachibana, K. Transdermal delivery of insulin to alloxan-diabetc rabits by ultrasound exposure. Pharm. Res. 9, 952–954 (1992).

    CAS  PubMed  Google Scholar 

  74. 74

    Mitragotri, S. & Kost, J. Low-frequency sonophoresis: a non-invasive method for drug delivery and diagnostics. Biotech. Progress 16, 488–492 (2000).

    CAS  Google Scholar 

  75. 75

    Kost, J., Mitragotri, S., Gabbay, R., Pishko, M. & Langer, R. Transdermal extraction of glucose and other analytes using ultrasound. Nature Med. 6, 347–350 (2000).

    CAS  PubMed  Google Scholar 

  76. 76

    Mitragotri, S., Edwards, D. A., Blankschtein, D. & Langer, R. A mechanistic study of ultrasonically enhanced transdermal drug delivery. J. Pharm. Sci. 84, 697–706 (1995).

    CAS  PubMed  Google Scholar 

  77. 77

    Mitragotri, S., Blankschtein, D. & Langer, R. in Encyclopedia of Pharmaceutical Technology. (ed. Boylan, J.) 103–122 (Marcel Dekker, New York, 1996).

    Google Scholar 

  78. 78

    Menon, G. K., Kollias, N. & Doukas, A. G. Ultrastructural evidence of stratum corneum permeabilization induced by photomechanical waves. J. Invest. Dermatol. 121, 104–109 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Lee, S., McAuliffe, D. J., Mulholland, S. E. & Doukas, A. G. Photomechanical transdermal delivery of insulin in vivo. Lasers Surg. Med. 28, 282–285 (2001).

    CAS  PubMed  Google Scholar 

  80. 80

    McAllister, D. V., Allen, M. G. & Prausnitz, M. R. Microfabricated microneedles for gene and drug delivery. Annu. Rev. Biomed. Eng. 2, 289–313 (2000).

    CAS  Google Scholar 

  81. 81

    Henry, S., McAllister, D., Allen, M. G. & Prausnitz, M. R. Microfabricated microneedles: a novel method to increase transdermal drug delivery. J. Pharm. Sci. 87, 922–925 (1998).

    CAS  PubMed  Google Scholar 

  82. 82

    McAllister, D. V. et al. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc. Natl Acad. Sci. USA 100, 13755–13760 (2003). Study describing fabrication methods and transdermal delivery using microneedles.

    CAS  PubMed  Google Scholar 

  83. 83

    Lin, W. et al. Transdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux) technology. Pharm. Res. 18, 1789–1793 (2001).

    CAS  PubMed  Google Scholar 

  84. 84

    Martanto, W. et al. Transdermal delivery of insulin using microneedles in vivo. Proc. Intl. Symp. Control. Rel. Bioact. Mater. A666 (2003).

  85. 85

    Cormier, M. & Daddona, P. E. in Modified-Release Drug Delivery Technology (eds Rathbone, M. J., Hadgraft, J. & Roberts, M. S.) 589–598 (Marcel Dekker, New York, 2003).

    Google Scholar 

  86. 86

    Matriano, J. A. et al. Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm. Res. 19, 63–70 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Mikszta, J. A. et al. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nature Med. 8, 415–419 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Kaushik, S. et al. Lack of pain associated with microfabricated microneedles. Anesth. Analg. 92, 502–504 (2001).

    CAS  Google Scholar 

  89. 89

    Gerstel, M. S. & Place, V. A. Drug delivery device. US Patent 3,964,482 (1976).

  90. 90

    Sintov, A. C. et al. Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs. J. Control. Release 89, 311–320 (2003).

    CAS  PubMed  Google Scholar 

  91. 91

    Bramson, J. et al. Enabling topical immunization via microporation: a novel method for pain-free and needle-free delivery of adenovirus-based vaccines. Gene Ther. 10, 251–260 (2003).

    CAS  PubMed  Google Scholar 

  92. 92

    Gebhart, S. et al. Glucose sensing in transdermal body fluid collected under continuous vacuum pressure via micropores in the stratum corneum. Diabetes Technol. Ther. 5, 159–166 (2003).

    CAS  PubMed  Google Scholar 

  93. 93

    Hingson, R. A. & Figge, F. H. A survey of the development of jet injection in parenteral therapy. Curr. Res. Anesth. Analg. 31, 361–366 (1952).

    CAS  PubMed  Google Scholar 

  94. 94

    Bremseth, D. L. & Pass, F. Delivery of insulin by jet injection: recent observations. Diabetes Technol. Ther. 3, 225–232 (2001). Evaluation of jet injection for transdermal delivery.

    CAS  PubMed  Google Scholar 

  95. 95

    Burkoth, T. L. et al. Transdermal and transmucosal powdered drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 16, 331–384 (1999).

    CAS  PubMed  Google Scholar 

  96. 96

    Mikkelsen Lynch, P. et al. A pharmacokinetic and tolerability evaluation of two continuous subcutaneous infusion systems compared to an oral controlled-release morphine. J. Pain Symptom Manage. 19, 348–356 (2000).

    CAS  PubMed  Google Scholar 

  97. 97

    Mitragotri, S. Synergistic effect of enhancers for transdermal drug delivery. Pharm. Res. 17, 1354–1359 (2000). Overview of enhancer combinations for transdermal delivery.

    CAS  PubMed  Google Scholar 

  98. 98

    Srinivasan, V., Su, M. H., Higuchi, W. I. & Behl, C. R. Iontophoresis of polypeptides: effect of ethanol pretreatment of human skin. J. Pharm. Sci. 79, 588–591 (1990).

    CAS  PubMed  Google Scholar 

  99. 99

    Oh, S. Y., Jeong, S. Y., Park, T. G. & Lee, J. H. Enhanced transdermal delivery of AZT (Zidovudine) using iontophoresis and penetration enhancer. J. Control. Release 51, 161–168 (1998).

    CAS  PubMed  Google Scholar 

  100. 100

    Wearley, L. & Chien, Y. W. Enhancement of the in vitro skin permeability of azidothymidine (AZT) via iontophoresis and chemical enhancers. Pharm. Res. 7, 34–40 (1990).

    CAS  PubMed  Google Scholar 

  101. 101

    Ganga, S., Ramarao, J. & Singh, J. Effect of azone on the iontophoretic transdermal delivery of metoprolol tartarate through human epidermis in vitro. J. Control. Rel. 42, 57–64 (1996).

    CAS  Google Scholar 

  102. 102

    Bhatia, K. S., Gao, S. & Singh, J. Effetct of penetration enhancers and iontophoresis on the FT-IR spectroscopy and LHRH permeability. J. Control. Rel. 47, 81–89 (1997).

    CAS  Google Scholar 

  103. 103

    Johnson, M. E., Mitragotri, S., Patel, A., Blankschtein, D. & Langer, R. Synergistic effect of ultrasound and chemical enhancers on transdermal drug delivery. J. Pharm. Sci. 85, 670–679 (1996).

    CAS  PubMed  Google Scholar 

  104. 104

    Mitragotri, S. et al. Synergistic effect of ultrasound and sodium lauryl sulfate on transdermal drug delivery. J. Pharm. Sci. 89, 892–900 (2000).

    CAS  PubMed  Google Scholar 

  105. 105

    Le, L., Kost, J. & Mitragotri, S. Combined effect of low-frequency ultrasound and iontophoresis: applications for transdermal heparin delivery. Pharm. Res. 17, 1151–1154 (2000).

    CAS  PubMed  Google Scholar 

  106. 106

    Vanbever, R., Prausnitz, M. R. & Preat, V. Macromolecules as novel transdermal transport enhancers for skin electroporation. Pharm. Res. 14, 638–644 (1997).

    CAS  PubMed  Google Scholar 

  107. 107

    Zewert, T. E., Pliquett, U. F., Vanbever, R., Langer, R. & Weaver, J. C. Creation of transdermal pathways for macromolecule transport by skin electroporation and a low toxicity, pathway-enlarging molecule. Bioelectrochem. Bioenerg. 49, 11–20 (1999).

    CAS  PubMed  Google Scholar 

  108. 108

    Bommanon, D. B., Tamada, J., Leung, L. & Potts, R. O. Effects of electroporation on transdermal iontophoretic delivery of leutinizing hormone releasing hormone. Pharm. Res. 11, 1809–1814 (1994).

    Google Scholar 

  109. 109

    Benowitz, N. L. Drug therapy. Pharmacologic aspects of cigarette smoking and nicotine addition. N. Engl. J. Med. 319, 1318–1330 (1988).

    CAS  PubMed  Google Scholar 

  110. 110

    Centers Disease Control and Prevention. Cigarette smoking among adults — United States, 1988. MMWR Morb. Mortal. Wkly Rep. 40, 757–759, 765 (1991).

  111. 111

    Gora, M. L. Nicotine transdermal systems. Ann. Pharmacother. 27, 742–750 (1993).

    CAS  PubMed  Google Scholar 

  112. 112

    Cordoba-Diaz, M. et al. Validation protocol of an automated in-line flow-through diffusion equipment for in vitro permeation studies. J. Control. Release 69, 357–367 (2000).

    CAS  PubMed  Google Scholar 

  113. 113

    Moody, R. P. Automated In Vitro Dermal Absorption (AIVDA): predicting skin permeation of atrazine with finite and infinite (swimming/bathing) exposure models. Toxicol. In Vitro 14, 467–474 (2000).

    CAS  PubMed  Google Scholar 

  114. 114

    Karande, P. & Mitragotri, S. Dependence of skin permeability on contact area. Pharm. Res. 20, 257–263 (2003).

    CAS  PubMed  Google Scholar 

  115. 115

    Cima, M., Chen, H. & Gyory, J. R. System and method for optimizing tissue barrier transfer of compounds. WO 02/06518 (2002).

  116. 116

    Pritchard, J. F. et al. Making better drugs: decision gates in non-clinical drug development. Nature Rev. Drug Discov. 2, 542–553 (2003).

    CAS  Google Scholar 

  117. 117

    Leduc, S. Introduction of medicinal substances into the depth of tissues by electric current. Ann. d'Electrobiol. 3, 545–560 (1900).

    Google Scholar 

  118. 118

    Tachibana, K. & Tachibana, S. Transdermal delivery of insulin by ultrasonic vibration. J. Pharm. Pharmocol. 43, 270–271 (1991).

    CAS  Google Scholar 

  119. 119

    Lee, S., McAuliffe, D. J., Flotte, T. J., Kollias, N. & Doukas, A. G. Photomechanical transcutaneous delivery of macromolecules. J. Invest. Dermatol. 111, 925–929 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Gale for helpful discussions. This work was supported in part by National Institutes of Health grants.

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Competing interests

M.R.P. owns shares in BioValve Technologies. S.M. owns shares and is an advisor or consultant to Sontra Medical Corp. and fqubed. R.L. owns shares and is an advisor to Sontra Medical Corp. and TransForm Pharmaceuticals. All authors are inventors on patents on the subject of transdermal delivery that are owned by their current or former academic or industrial employers.

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FURTHER INFORMATION

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Glossary

TRANSDERMAL DELIVERY

The movement of compounds across the stratum corneum and into systemic circulation.

STRATUM CORNEUM

The outer layer of epidermis, consisting of several layers of corneocytes in a lipid-rich matrix.

EPIDERMIS

The outer, epithelial portion of the skin.

CORNEOCYTE

The non-living, keratin-filled squamous cell of the stratum corneum.

DESQUAMATED

Shed from the surface of the skin.

SURFACTANT

A molecule typically containing separate hydrophilic and hydrophobic domains that reduces surface tension of water.

OLEIC ACID

A carboxylic acid with a linear chain of 18 carbon atoms and one double bond (C18H34O2).

TOPICAL DELIVERY

The movement of compounds across the stratum corneum and locally into the skin.

IONTOPHORESIS

The movement of molecules across the skin or other tissue under the influence of an electric field.

HYPERHIDROSIS

Excessive sweating, especially of the hands and feet.

ELECTROPHORESIS

The migration of molecules with a net charge under the influence of an electric field.

ELECTRO-OSMOSIS

The movement in an electric field of liquid within a porous medium having a fixed net charge.

ELECTROPORATION

The formation of aqueous pathways across a lipid bilayer by a pulsed electric field.

ULTRASOUND

A sound (that is, pressure) wave at a frequency greater than 20 kHz.

SONOPHORESIS

The movement of molecules across the skin or other tissue under the influence of an acoustic field.

CAVITATION

The formation of gaseous bubbles within a liquid by ultrasound or other mechanical forces.

MICRONEEDLE

A needle of micrometre dimensions usually fabricated using techniques derived from the microelectronics industry.

LANGERHANS' CELL

Dendritic clear cells in the epidermis believed to be antigen fixing and processing cells of monocytic origin.

THERMAL PORATION

The formation of aqueous pathways across stratum corneum by the application of pulsed heat.

JET INJECTION

The high-velocity penetration into or across the skin of liquid droplets (or solid particles) often containing a drug.

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Prausnitz, M., Mitragotri, S. & Langer, R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov 3, 115–124 (2004). https://doi.org/10.1038/nrd1304

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