Abstract
The skin is a formidable diffusion barrier that restricts passive diffusion to small (<500 Da) lipophilic molecules. Methods used to permeabilize this barrier for the purpose of drug delivery are maturing as an alternative to oral drug delivery and hypodermic injections. Ultrasound can reversibly and non-invasively permeabilize the diffusion barrier posed by the skin. This review discusses the mechanisms of ultrasound-permeability enhancement, and presents technological innovations in equipment miniaturization and recent advances in permeabilization capabilities. Additionally, potentially exciting applications, including protein delivery, vaccination, gene therapy and sensing of blood analytes, are discussed. Finally, the future challenges and opportunities associated with the use of ultrasound are discussed. It is stressed that developing ultrasound for suitable applications is key to ensure commercial success.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp. Dermatol. 9(3), 165–169 (2000).
- 2 . Enhanced skin permeation of sex hormones with novel topical spray vehicles. J. Pharm. Sci. 87(10), 1213–1218 (1998).
- 3 . Drug permeation through human skin: Theory and in vitro experimental measurement. AIChE J. 21(5), 985–996 (1975).
- 4 . Transdermal administration of nicotine. Drug Alcohol Depend. 13(3), 209–213 (1984).
- 5 . Transdermal drug delivery. Nat. Biotechnol. 26(11), 1261–1268 (2008).•• Excellent review on the history and developments in the field of transdermal drug delivery.
- 6 . Current status and future potential of transdermal drug delivery. Nat. Rev. Drug Discov. 3(2), 115–124 (2004).
- 7 . Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin. Drug Deliv. 7(12), 1415–1432 (2010).
- 8 . An analysis of the gastro-intestinal side-effects of non-steroidal anti-inflammatory drugs, with particular reference to comparative studies in man and laboratory species. Rheumatol. Int. 2(1), 1–10 (1982).
- 9 . The cost of unsafe injections. Bulletin World Health Organisation. (1999). www.who.int/entity/injection_safety/toolbox/Miller.pdf
- 10 . Needle Phobia: Etiology, Adverse Consequences, and Patient Management. Dent Clin. North Am. 54(4), 731–744 (2010)
- 11 . Fear of injections in young adults: Prevalence and associations. Am. J. Trop. Med. Hyg. 68(3), 341–344 (2003).
- 12 . Structure and Function of the Skin Barrier: An Introduction. In: Skin, Hair, and Nails Structure and Function. Forslind B, Lindberg M (Eds.). Marcel Dekker, Inc., New York, NY, USA, 9–21 (2004).
- 13 . Cytokine regulation of the epidermal barrier. Clin. Exp. Allergy 43, 586–589 (2012).
- 14 Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J. Control. Rel. 164(1), 26–40 (2012).
- 15 . Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin. Drug Deliv. 11(3), 393–407 (2014).
- 16 . Sonophoresis in transdermal drug deliverys. Ultrasonics 54(1), 56–65 (2014).
- 17 . Ultrasound mediated transdermal drug delivery. Adv. Drug Deliv. Rev. 72, 127–143 (2014).
- 18 . Novel mechanisms and devices to enable successful transdermal drug delivery. Eur. J. Pharm. Sci. 14(2), 101–114 (2001).
- 19 . The role of electroosmotic flow in transdermal iontophoresis. Adv. Drug Deliv. Rev. 46(1–3), 281–305 (2001).
- 20 . The effects of electric current applied to skin: a review for transdermal drug delivery. Adv. Drug Deliv. Rev. 18(3), 395–425 (1996).
- 21 . Iontophoresis in drug delivery – basic principles and applications. Crit. Rev. Ther. Drug Carrier Syst. 11(2–3), 161–213 (1994).
- 22 . Molecular interactions of penetration enhancers within ceramides organization: a FTIR approach. Eur. J. Pharm. Sci. 36(2–3), 192–199 (2009).
- 23 . Chemical Penetration Enhancers for Transdermal Drug Delivery Systems. Trop. J. Pharm. Res. 8(2), 173–179 (2009).
- 24 . Design principles of chemical penetration enhancers for transdermal drug delivery. Proc. Natl Acad. Sci. USA 102(13), 4688–4693 (2005).
- 25 . Nanotechnology and the transdermal route. J. Control. Rel. 141(3), 277–299 (2010).
- 26 . Gene transfer and drug delivery with electric pulse generators. Curr. Drug Metab. 14(3), 319–323 (2013).
- 27 . Laser microporation of the skin: prospects for painless application of protective and therapeutic vaccines. Expert Opin. Drug Deliv. 10(6), 761–773 (2013).
- 28 . Microporation applications for enhancing drug delivery. Expert Opin. Drug Deliv. 6(4), 343–354 (2009).
- 29 . Klinik und Therapie des chronischen Gelenkrheumatismus. Monatsschrift für Allgemeinmedizin 549–552 (1954).
- 30 . Sonophoresis: a 50-year journey. Drug Discov. Today 9(17), 735–736 (2004).
- 31 . Phonophoresis: efficiency, mechanisms and skin tolerance. Int. J. Pharm. 243(1–2), 1–15 (2002).
- 32 . Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J. Control. Rel. 152(3), 330–348 (2011).
- 33 . Ultrasound-mediated transdermal protein delivery. Science 269(5225), 850–853 (1995).
- 34 . Transdermal drug delivery using low-frequency sonophoresis. Pharmaceut. Res. 13(3), 411–420 (1996).
- 35 . Transdermal and tipical drug delivery today. In: Transdermal and Topical Drug Delivery: Principles and Practice. Benson HAC, Watkinson AC (Eds). John Wiley & Sons, Inc., Hoboken, NJ, USA, 357–366 (2012).
- 36 . Ultrasound with topical anesthetic rapidly decreases pain of intravenous cannulation. Academic Emerg. Med. 12(4), 289–295 (2005).• Clinical study with US FDA-approved ultrasound device displaying an excellent safety profile.
- 37 Clinical, histologic, and electron microscopy study of skin exposed to low-frequency ultrasound. Anat. Rec. 264(1), 114–119 (2001).
- 38 . Dependence of low-frequency sonophoresis on ultrasound parameters; distance of the horn and intensity. Int. J. Pharm. 235(1–2), 35–42 (2002).• Investigation of the effect of different ultrasound exposure parameters.
- 39 . An investigation of the role of cavitation inlow-frequency ultrasound-mediated transdermal drug transport. Pharmaceutical Res. 19(8), 1160–1169 (2002).
- 40 . Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy. J. Pharm. Sci. 91(2), 444–453 (2002).
- 41 . Dependence of optimal seed bubble size on pressure amplitude at therapeutic pressure levels. Ultrasonics 51(2), 115–122 (2011).
- 42 . The chemical effects of ultrasound. Scientific American 260(2), 80–86 (1989).
- 43 . Chemical bubble dynamics and quantitative sonochemistry. J. Phys. Chem. A. 102(35), 6927–6934 (1998).
- 44 Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J. Pharm. Sci. 89(7), 892–900 (2000).
- 45 . Synergistic effect of enhancers for transdermal drug delivery. Pharma. Res. 17(11), 1354–1359 (2000).
- 46 . Application of the aqueous porous pathway model to quantify the effect of sodium lauryl sulfate on ultrasound-induced skin structural perturbation. J. Pharm. Sci. 100(4), 1387–1397 (2011).
- 47 . Effects of low-frequency ultrasound on the transdermal permeation of mannitol: Comparative studies with in vivo and in vitro skin. J. Pharm. Sci. 91(8), 1776–1794 (2002).
- 48 Frequency dependence of sonophoresis. Pharma. Res. 18(12), 1694–1700 (2001).
- 49 . Experimental demonstration of the existence of highly permeable localized transport regions in low-frequency sonophoresis. J. Pharm. Sci. 93(11), 2733–2745 (2004).
- 50 . Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles. J. Pharm. Sci. 102(10), 3614–3622 (2013).
- 51 . A physical method to enhance transdermal delivery of a tissue optical clearing agent: combination of microneedling and sonophoresis. Lasers Surg. Med. 42(5), 412–417 (2010).
- 52 . Sonophoretic enhanced microneedles array (SEMA)—Improving the efficiency of transdermal drug delivery. Sensors and Actuators B: Chemical 145(1), 54–60 (2010).
- 53 . Mechanisms of synergistic skin penetration by sonophoresis and iontophoresis. Biol. Pharm. Bull. 32(5), 905–909 (2009).
- 54 . Transdermal delivery of a similar to 13 kDa protein-an in vivo comparison of physical enhancement methods. J. Drug Target 18(2), 141–147 (2010).
- 55 . Single-transducer dual-frequency ultrasound generation to enhance acoustic cavitation. Ultrason. Sonochem. 16(3), 431–438 (2009).
- 56 Rapid skin permeabilization by the simultaneous application of dual-frequency, high-intensity ultrasound. J. Control. Rel. 163(2), 154–160 (2012).
- 57 . Cavitation activation by dual-frequency ultrasound and shock waves. Phys. Chem. 11(43), 10029–10034 (2009).
- 58 . Microbubble contrast agents: a new era in ultrasound. BMJ 322(7296), 1222–1225 (2001).
- 59 . Ultrasound contrast agents - Basic principles. Eur. J. Radiol. 27, S157–S160 (1998).
- 60 . Physical basis and principles of action ofmicrobubble-based contrast agents. In: Contrast Media in Ultrasonography. Quaia E (Ed.). Springer, Berlin Heidelberg, Germany, 15–30 (2005).
- 61 . Transdermal drug delivery aided by an ultrasound contrast agent: an in vitro experimental study. Open Biomed. Eng. J. 4, 56–62 (2010).
- 62 Sonophoresis using ultrasound contrast agents for transdermal drug delivery: an in vivo experimental study. Ultrasound Med. Biology 38(4), 642–650 (2012).
- 63 . Influence of bubble size distribution on the echogenicity of ultrasound contrast agents– a study of SonoVue (TM). Invest. Radiol. 35(11), 661–671 (2000).
- 64 . Perspectives on transdermal ultrasound mediated drug delivery. Int. J. Nanomedicine 2(4), 585 (2007).
- 65 . Ultrasonic drug delivery – a general review. Expert Opin. Drug Deliv. 1(1), 37–56 (2004).
- 66 . Finite element analysis of the cymbal-type flextensional transducer. Ultrasonics 45(5), 1363–1369 (1998).
- 67 . Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).
- 68 Optimization of un-tethered, low voltage, 20–100kHz flexural transducers for biomedical ultrasonics applications. Ultrasonics 52(7), 943–948 (2012).
- 69 Finite element static displacement optimization of 20–100kHz flexural transducers for fully portable ultrasound applicator. Ultrasonics 53(2), 511–517 (2013).
- 70 . Noninvasive ultrasonic transdermal insulin delivery inrabbits using the light-weight cymbal array. Diabetes Technol. Ther. 6(6), 808–815 (2004).
- 71 . Ultrasound mediated transdermal insulin delivery inpigs using a lightweight transducer. Pharma. Res. 24(7), 1396–1401 (2007).
- 72 . Sonoporation delivery of monoclonal antibodies againsthuman papillomavirus 16 E6 restores p53 expression in transformed cervical keratinocytes. PLoS ONE (2012).• Ultrasound- assisted therapeutic intracellular antibody delivery.
- 73 . T-cell mediated immunity. In: Immunobiology The Immunesystem In Health And Disease (6th Edition). Janeway CA, Travers P, Walport M, Shlomchik MJ (Eds). Garland Science Publishing, NY, USA, 319–387 (2005).
- 74 Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340(6132), 635–639 (2013).
- 75 . Synthetic adjuvants for vaccine formulations: phytol derivatives. Expert Opin. Drug Deliv. 10(4), 437–450 (2013).
- 76 . Adjuvants for human vaccines – current status, problems and future prospects. Vaccine 13(14), 1263–1276 (1995).
- 77 . Vaccine adjuvants: current state and future trends. Immunol. Cell Biol. 82(5), 488–496 (2004).
- 78 Epidermal powder immunization induces both cytotoxicT-lymphocyte and antibody responses to protein antigens of influenza and hepatitis B viruses. J. Virol. 75(23), 11630–11640 (2001).
- 79 . Morphological and quantitative analyses of normal epidermal Langerhans cells using confocal scanning laser microscopy. Br. J. Dermatol. 131(6), 843–848 (1994).
- 80 . Low-frequency ultrasound as a transcutaneous immunization adjuvant. Vaccine 23(29), 3800–3807 (2005).• First report on ultrasound assisted cutaneous immunization.
- 81 . Transcutaneous immunisation assisted by low-frequency ultrasound. Int. J. Pharm. 368(1–2), 123–128 (2009).
- 82 . Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J. Clin. Invest. 90(2), 482–487 (1992).
- 83 . Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J. Exp. Med. 203(5), 1249–1258 (2006).
- 84 Intradermal Immunization Triggers Epidermal Langerhans Cell Mobilization Required for CD8 T-Cell Immune Responses. J. Invest. Dermatol. 132(3), 615–625 (2011).
- 85 . Glucose sensors: a review of current and emerging technology. Diabet. Med. 26(3), 197–210 (2009).
- 86 . Clinical evaluation of a continuous minimally invasive glucose flux sensor placed over ultrasonically permeated skin. Diabetes Technol. Ther. 6(1), 21–30 (2004).
- 87 American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care 26(Suppl. 1), S25–S27 (2003).
- 88 . Transdermal monitoring of glucose and other analytes using ultrasound. Nature Med. 6(3), 347–350 (2000).
- 89 . Pilot studies of transdermal continuous glucose measurement in outpatient diabetic patients and in patients during and after cardiac surgery. J. Diabetes Sci. Technol. 2(4), 595–602 (2008).
- 90 . Timing of changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes 52(11), 2790–2794 (2003).
- 91 Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observation in blood. Anal. Chem. 68(21), 3822–3826 (1996).
- 92 . Noninvasive ultrasonic glucose sensing with large pigs (approximately 200 pounds) using a lightweight cymbal transducer array and biosensors. J. Diabetes Sci. Technol. 3(3), 517–523 (2009).
- 93 . Cell experimental studies on sonoporation: State of the art and remaining problems. J. Control. Rel. 174, 151–160 (2014).
- 94 . Selective clinical ultrasound signals mediate differential gene transfer and expression in two human prostate cancer cell lines: LnCap and PC-3. Biochem. Biophys. Res. Commun. 234(1), 64–67 (1997).•• Intracellular delivery of pDNA that translate to functional proteins.
- 95 Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation 105(10), 1233–1239 (2002).
- 96 . Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharma. Res. 21(12), 2219–2225 (2004).
- 97 Targeting B-V600E-Raf and AW using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res. 68(18), 7638–7649 (2008).
- 98 Lipid-mediated gene delivery to the skin. Eur. J. Pharm. Sci. 43(4), 199–211 (2011).
- 99 . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 46(1–3), 3–26 (2001).
- 100 . Principles of protein-protein interactions: what are the preferred ways for proteins to interact? Chem. Rev. 108(4), 1225–1244 (2008).