Polymer Gels pp 343-375 | Cite as

Polymeric Gels: Vehicles for Enhanced Drug Delivery Across Skin

  • Rachna Prasad
  • Veena KoulEmail author
Part of the Gels Horizons: From Science to Smart Materials book series (GHFSSM)


Polymeric gels have emerged as promising vehicles for drug delivery across the skin. Stratum corneum, the topmost layer of the skin, does not allow hydrophilic and high molecular weight drugs to permeate without enhancing techniques. A number of enhancement techniques are being developed to increase the transdermal drug permeation. The transdermal route has many advantages and has therefore evolved as an attractive and convenient alternative to the existing routes of drug delivery that causes many side effects. In the present chapter, we shall be focusing on the physical enhancement techniques of iontophoresis, electroporation and sonophoresis for transport of drug molecules across skin using polymeric gels.


Polymeric gels Transdermal drug delivery Skin Iontophoresis Electroporation Sonophoresis 


  1. Albery WJ, Hadgraft J (1979) Percutaneous absorption: theoretical description. J Pharm Pharmacol 31:129–139PubMedCrossRefPubMedCentralGoogle Scholar
  2. Alexander A, Dwivedi S, Ajazuddin GTK, Saraf S, Saraf S, Tripathi DK (2012) Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Rel 164:26–40CrossRefGoogle Scholar
  3. Aliyar H, Huber R, Loubert G, Schalau G (2014) Efficient ibuprofen delivery from anhydrous semisolid formulation based on a novel cross-linked silicone polymer network: an in vitro and in vivo study. J Pharm Sci 103:2005–2011PubMedCrossRefPubMedCentralGoogle Scholar
  4. Allenby AC, Fletcher J, Schock C, Tees TFS (1969) The effect of heat, pH and organic solvents on the electrical impedance and permeability of excised human skin. Br J Dermatol 81:31–39CrossRefGoogle Scholar
  5. Alvarez-Figueroa MJ, Blanco-Méndez J (2001) Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions. Int J Pharm 215:57–65PubMedCrossRefPubMedCentralGoogle Scholar
  6. Arora A, Hakim I, Baxter J, Rathnasingham R, Srinivasan R, Fletcher DA, Mitragotri S (2007) Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets. Proc Natl Acad Sci USA 104:4255–4260PubMedCrossRefPubMedCentralGoogle Scholar
  7. Arunkumar S, Ashok P, Desai BG, Shivakumar HN (2015) Effect of chemical penetration enhancer on transdermal iontophoretic delivery of diclofenac sodium under constant voltage. J Drug Del Sci Technol 30:171–179CrossRefGoogle Scholar
  8. Azagury A, Khoury L, Enden G, Kost J (2014) Ultrasound mediated transdermal drug delivery. Adv Drug Del Rev 72:127–143CrossRefGoogle Scholar
  9. Bagniefski T, Burnette RR (1990) A comparison of pulsed and continuous current iontophoresis. J Control Rel 11:113–122CrossRefGoogle Scholar
  10. Banga AK, Chien YW (1998) Iontophoretic delivery of drugs: fundamentals, developments and biomedical applications. J Control Rel 7:1–24CrossRefGoogle Scholar
  11. Banga AK, Bose S, Ghosh TK (1999) Iontophoresis and electroporation: comparisons and contrasts. Int J Pharm 179:1–19PubMedCrossRefPubMedCentralGoogle Scholar
  12. Banga AK, Chien YW (1993) Hydrogel-based iontotherapeutic delivery devices for transdermal delivery of peptide/protein drugs. Pharm Res 10:697–702PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bani D, Bencini A, Bergonzi MC, Bilia AR, Guccione C, Severi M, Udisti R, Valtancoli B (2015) Enhanced intra-cutaneous delivery of a Mn-containing antioxidant drug by high-frequency ultrasounds. J Pharm Biomed Anal 106:197–203PubMedCrossRefPubMedCentralGoogle Scholar
  14. Barry BW (1983) Properties that influence percutaneous absorption. In: Barry BW (ed) Dermatological formulations; percutaneous absorption. Marcel Dekker, New York, pp 127–233Google Scholar
  15. Barry BW (2001) Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci 14:101–114PubMedCrossRefPubMedCentralGoogle Scholar
  16. Bashir SJ, Chew AL, Anigbogu A, Dreher F, Maibach HI (2001) Physical and physiological effects of stratum corneum tape stripping. Skin Res Technol 7:40–48PubMedCrossRefPubMedCentralGoogle Scholar
  17. Batheja P, Thakur R, Michniak B (2006) Transdermal iontophoresis. Expert Opin Drug Deliv 3:127–138PubMedCrossRefPubMedCentralGoogle Scholar
  18. Bhoyar TKGN, Tripathi DK, Alexander A, Ajazuddin (2012) Recent advances in novel drug delivery system through gels: review. J Pharm Allied Health Sci 2:21–39Google Scholar
  19. Blagus T, Markelc B, Cemazar M, Kosjek T, Preat V, Miklavcic D, Sersa G (2013) In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery. J Control Rel 172:862–871CrossRefGoogle Scholar
  20. Burnette RR, Ongpipattanakul B (1988) Characterisation of the pore transport properties and tissue alteration of excised human skin during iontophoresis. J Pharm Sci 77:132–137PubMedCrossRefPubMedCentralGoogle Scholar
  21. Cameroy BM (1966) Ultrasound enhanced local anesthesia. Am J Orthop 8:47Google Scholar
  22. Cevc G, Blumeb G, Schtitzlein A, Gebaue D, Paul A (1996) The skin: a pathway for systemic treatment with patches and lipid-based agent carriers. Adv Drug Deliv Rev 18:349–378CrossRefGoogle Scholar
  23. Chang F, Swartzendruber DC, Wertz PW, Squier CA (1993) Covalently bound lipids in keratinizing epithelia. Biochim Biophys Acta 1150:98–102PubMedCrossRefPubMedCentralGoogle Scholar
  24. Chen Y, Zahui T, Alberti I, Kalia YN (2016) Cutaneous biodistribution of ionizable, biolabile aciclovir prodrugs after short duration topical iontophoresis: targeted intraepidermal drug delivery. Eur J Pharm Biopharm 99:94–102PubMedCrossRefPubMedCentralGoogle Scholar
  25. Choi EH, Lee SH, Ahn SK, Hwang SM (1999) The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis. Skin Pharmacol Appl Skin Physiol 12:326–335PubMedCrossRefPubMedCentralGoogle Scholar
  26. Christophers E, Schubert C, Goes M (1989) The epidermis. In: Greaves MW, Shuster S (eds) Pharmacology of the skin, vol I. Springer-Verlag, Berlin, pp 3–30CrossRefGoogle Scholar
  27. Christophers E, Wolff HH, Laurence EB (1974) The formation of epidermal cell columns. J Invest Dermatol 62:555–559PubMedCrossRefPubMedCentralGoogle Scholar
  28. Coodley GL (1960) Bursitis and post-traumatic lesions. Am Pract 11:181–187Google Scholar
  29. Coury AJ, Fogt EJ, Norenberg MS, Untereker DF (1983) Development of a screening system for cystic fibrosis. Clin Chem 29:1593–1597PubMedPubMedCentralGoogle Scholar
  30. Craane-van-Hinsberg WHM, Bax L, Flinterman NHM, Verhoef J, Junginger HE, Bodde HE (1994) Iontophoresis of a model peptide across human skin in vitro: effects of iontophoresis protocol, pH, and ionic strength on peptide flux and skin impedance. Pharm Res 11:1296–1300PubMedCrossRefPubMedCentralGoogle Scholar
  31. Cullander C (1992) What are the pathways of iontophoretic current flow through mammalian skin? Adv Drug Del Rev 9:119–135Google Scholar
  32. Davis SP, Landis BJ, Adams ZH, Allen MG, Prausnitz MR (2004) Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. J Biomech 37:1155–1163PubMedCrossRefPubMedCentralGoogle Scholar
  33. Denet AR, Preat V (2003) Transdermal delivery of timolol by electroporation through human skin. J Control Rel 88:253–262CrossRefGoogle Scholar
  34. Denet A-R, Vanbever R, Préat V (2004) Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev 56:659–674PubMedCrossRefPubMedCentralGoogle Scholar
  35. DeNuzzio JD, Bemer B (1990) Electrochemical and iontophoretic studies of human skin. J Control Rel 11:105–112CrossRefGoogle Scholar
  36. Dinh SM, Luo C-W, Bemer B (1993) Upper and lower limits of human skin electrical resistance in iontophoresis. AIChE J 39:2011–2018CrossRefGoogle Scholar
  37. Donnelly RF, Singh TRR, Garland MJ, Migalska K, Majithiya R, McCrudden CM, Kole PR, Mahmood TMT, McCarthy HO, Woolfson AD (2012) Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv Funct Mater 22:4879–4890PubMedPubMedCentralCrossRefGoogle Scholar
  38. Donnelly RF, Singh TR, Alkilani AZ, McCrudden MT, O’Neill S, O’Mahony C, Armstrong K, McLoone N, Kole P, Woolfson AD (2013) Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. Int J Pharm 451:76–91PubMedPubMedCentralCrossRefGoogle Scholar
  39. Drury JL, Mooney DJ (2003) Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24:4337–4351PubMedCrossRefGoogle Scholar
  40. Dujardin N, Staes E, Kalia Y, Clarys P, Guy R, Preat V (2002) In vivo assessment of skin electroporation using square wave pulses. J Control Rel 79:219–227CrossRefGoogle Scholar
  41. El Maghraby GMM, Williams AC, Barry BW (2006) Can drug-bearing liposomes penetrate intact skin? J Pharm Pharmacol 58:415–429PubMedCrossRefPubMedCentralGoogle Scholar
  42. Elias PM, Menon GK (1991) Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24:1–26PubMedCrossRefPubMedCentralGoogle Scholar
  43. Fang J-Y, Huang Y-B, Lin HH, Tsai Y-H (1998a) Transdermal iontphoresis of sodium nonivamide acetate IV: effect of polymer formulations. Int J Pharm 173:127–140CrossRefGoogle Scholar
  44. Fang J-Y, Huang Y-B, Wu PC, Tsai Y-H (1996) Transdermal iontphoresis of sodium nonivamide acetate II: optimisation and evaluation of solutions and gels. Int J Pharm 145:175–186CrossRefGoogle Scholar
  45. Fang J-Y, Kuo CT, Huang Y-B, Wu PC, Tsai Y-H (1998b) Transdermal iontphoresis of sodium nonivamide propionate by iontophoresis. Biol Pharm Bull 21:1117–1120PubMedCrossRefPubMedCentralGoogle Scholar
  46. Fang J-Y, Sung SC, Lin HH, Fang CL (1999) Transdermal iontophoretic delivery of diclofenac sodium from various polymer formulations: in vitro and in vivo studies. Int J Pharm 178:83–92PubMedCrossRefPubMedCentralGoogle Scholar
  47. Fellinger K, Schmidt J (1954) Klinik and Therapies des Chromischen Gelenkreumatismus. Maudrich Vienna, Austria, pp 549–552Google Scholar
  48. Gehrke SH, Lee PI (1990) Hydrogels for drug delivery. In: Tyle P (ed) Specialized drug delivery systems, manufacturing and production technology. Marcel Dekker, New York, pp 333–392Google Scholar
  49. Golberg A, Rubinsky B (2012) Towards electroporation based treatment planning considering electric field induced muscle contractions. Technol Cancer Res Treat 11:189–201PubMedCrossRefPubMedCentralGoogle Scholar
  50. Gong JP, Komatsu N, Nitta T, Osada Y (1997) Electrical conductance of polyelectrolyte gels. J Phys Chem B 101:740–745CrossRefGoogle Scholar
  51. Gratieri T, Alberti I, Lapteva M, Kalia YN (2013) Next generation intra- and transdermal therapeutic systems: using non- and minimally-invasive technologies to increase drug delivery into and across the skin. Eur J Pharm Sci 18:609–622CrossRefGoogle Scholar
  52. Gupta J, Prausnitz MR (2009) Recovery of skin barrier properties after sonication in human subjects. Ultrasound Med Biol 35:1405–1408PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gupta SK, Kumar S, Bolton S, Behl CR (1994) Optimization of iontophoretic transdermal delivery of a peptide and a non-peptide drug. J Control Rel 30:253–261CrossRefGoogle Scholar
  54. Guy RH (1996) Current status and future prospects of transdermal drug delivery. Pharm Res 13:1765–1769PubMedCrossRefPubMedCentralGoogle Scholar
  55. Guy RH (1998) Iontophoresis−recent developments. J Pharm Pharmacol 50:371–374PubMedCrossRefPubMedCentralGoogle Scholar
  56. Guy RH, Hadgraft J (1991) Principles of skin permeability relevant to chemical exposure. In: Hobson DW (ed) Dermal and ocular toxicology: fundamentals and methods. CRC Press, Boca-Raton, FL, pp 221–246Google Scholar
  57. Hao J (2014) Topical iontophoresis for local therapeutic effects. J Drug Del Sci Technol 24:255–258CrossRefGoogle Scholar
  58. Heller R, Gilbert R, Jaroszeski MJ (1999) Clinical applications of electrochemotherapy. Adv Drug Del Rev 35:119–129CrossRefGoogle Scholar
  59. Hoare TR, Kohane DS (2008) Hydrogels in drug delivery: progress and challenges. Polymer 49:1993–2007CrossRefGoogle Scholar
  60. Hofmann GA, Dev SB, Nanda GS (1996) Electrochemotherapy: transition from laboratory to the clinic. IEEE Eng Med Biol Mag 15:124–132CrossRefGoogle Scholar
  61. Hofmann GA, Rustrum WV, Suder KS (1995) Electro-incorporation of microcarriers as a method for the transdermal delivery of large molecules. Bioelectrochem Bioenerg 38:209–222CrossRefGoogle Scholar
  62. Huang J-F, Sung KC, Hu OY-P, Wang J-J, Lin Y-H, Fang J-Y (2005) The effects of electrically assisted methods on transdermal delivery of nalbuphine benzoate and sebacoyl dinalbuphine ester from solutions and hydrogels. Int J Pharm 29:162–171Google Scholar
  63. Inada H, Ghanem A-H, Higuchi WI (1994) Studies on the effects of applied voltage and duration on human epidermal membrane alteration/recovery and the resultant effects upon iontophoresis. Pharm Res 11:687–697PubMedCrossRefPubMedCentralGoogle Scholar
  64. Indulekha S, Arunkumar P, Bahadur D, Srivastava R (2016) Thermoresponsive polymeric gel as an on-demand transdermal drug delivery system for pain management. Material Sci Engg: C 62:113–122CrossRefGoogle Scholar
  65. Ita KB (2014) Transdermal drug delivery: progress and challenges. J Drug Delivery Sci Technol 24:245–250CrossRefGoogle Scholar
  66. Jadoul A, Bouwstra J, Preat V (1999) Effects of iontophoresis and electroporation on the stratum corneum: review of the biophysical studies. Adv Drug Del Rev 35:89–105CrossRefGoogle Scholar
  67. Jagur-Grodzinski J (2010) Polymeric gels and hydrogels for biomedical and pharmaceutical applications. Polym Adv Technol 21:27–47Google Scholar
  68. Jeong B, Kim SW, Bae YH (2002) Thermosensitive sol-gel reversible hydrogels. Adv Drug Deliv Rev 54:37–51PubMedCrossRefPubMedCentralGoogle Scholar
  69. Jeong WL, Park JH, Prausnitz MR (2008) Dissolving microneedles for transdermal drug delivery. Biomaterials 29:2113CrossRefGoogle Scholar
  70. Jepps OG, Dancik Y, Anissimov YG, Roberts MS (2013) Modeling the human skin barrier—towards a better understanding of dermal absorption. Adv Drug Del Rev 65:152–168CrossRefGoogle Scholar
  71. Jiang H, Tovar-Carrillo K, Kobayashi T (2016) Ultrasound stimulated release of mimosa medicine from cellulose hydrogel matrix. Ultrason Sonochem 32:398–406PubMedCrossRefPubMedCentralGoogle Scholar
  72. Jodar KSP, Balcao VM, Chaud MV, Tubino M, Yoshida VMH, Oliveira JM Jr, Vila MMDC (2015) Development and characterization of a hydrogel containing silver sulfadiazine for antimicrobial topical applications. J Pharm Sci 104:2241–2254PubMedCrossRefPubMedCentralGoogle Scholar
  73. Johnson PG, Gallo SA, Hui SW, Oseroff AR (1998) A pulsed electric field enhances cutaneous delivery of methylene blue in excised full-thickness porcine skin. J Invest Dermatol 111:457–463PubMedCrossRefPubMedCentralGoogle Scholar
  74. Kalia Y, Nonato LB, Guy RH (1996) The effect of iontophoresis on skin barrier integrity: non-invasive evaluation by impedance spectroscopy and transepidermal water loss. Pharm Res 13:957–961PubMedCrossRefPubMedCentralGoogle Scholar
  75. Kalia YN, Merino V, Guy RH (1998) Transdermal drug delivery: clinical aspects. Dermatol Clin 16:289–299PubMedCrossRefPubMedCentralGoogle Scholar
  76. Kalia YN, Naik A, Garrison J, Guy RH (2004) Iontophoretic drug delivery. Adv Drug Deliv Rev 56:619–658PubMedCrossRefPubMedCentralGoogle Scholar
  77. Karande P, Jain A, Mitragotri S (2004) Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol 22:192–197Google Scholar
  78. Kearney M-C, Caffarel-Salvador E, Fallows SJ, McCarthy HO, Donnelly RF (2016) Microneedle-mediated delivery of donepezil: potential for improved treatment options in Alzheimer’s disease. Eur J Pharm Biopharm 103:43–50PubMedCrossRefPubMedCentralGoogle Scholar
  79. Khademhosseini A, Langer R (2007) Microengineered hydrogels for tissue engineering. Biomaterials 28:5087–5092PubMedCrossRefPubMedCentralGoogle Scholar
  80. Kikuchi A, Okano T (2002) Pulsatile drug release control using hydrogels. Adv Drug Deliv Rev 54:53–77PubMedCrossRefPubMedCentralGoogle Scholar
  81. Kim D, Choi S, Kwak Y (2012) The effect of SonoPrep on EMLA cream application for pain relief prior to intravenous cannulation. Eur J Pediatr 171:985–988PubMedCrossRefPubMedCentralGoogle Scholar
  82. Kong BJ, Kim A, Park SN (2016) Properties and in vitro drug release of hyaluronic acid-hydroxyethyl cellulose hydrogels for transdermal delivery of isoliquiritigenin. Carbohyd Polym 147:473–481CrossRefGoogle Scholar
  83. Kopeček J (2007) Hydrogel biomaterials: a smart future? Biomaterials 28:5185–5192PubMedPubMedCentralCrossRefGoogle Scholar
  84. Kost J, Katz N, Shapiro D, Herr_mann T, Kellogg S, Warner N, Custer L (2003) Ultrasound skin permeation pretreatment to accelerate the onset of topical anesthesia. Proc Inter Symp Bioact MaterGoogle Scholar
  85. Kost J, Langer R (2001) Responsive polymeric delivery systems. Adv Drug Deliv Rev 53:125–148CrossRefGoogle Scholar
  86. Lane ME (2013) The transdermal delivery of fentanyl. Eur J Pharm Biopharm 84:449–455PubMedCrossRefPubMedCentralGoogle Scholar
  87. Langer R (2003) Where a pill won’t go. Sci Am 288:50–57PubMedCrossRefPubMedCentralGoogle Scholar
  88. Langer R (2004) Transdermal drug delivery: past progress, current status and future prospects. Adv Drug Del Rev 56:557–558CrossRefGoogle Scholar
  89. Langkjaer L, Brange J, Grodsky GM, Guy RH (1998) Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. J Control Rel 51:47–56CrossRefGoogle Scholar
  90. Lark MR, Gangarosa LP Sr (1990) Iontophoresis: an effective modality for the treatment of inflammatory disorders of the temporomandibular joint and myofascial pain. Cranio 8:108–119PubMedCrossRefPubMedCentralGoogle Scholar
  91. Law S, Wertz PW, Swartzendruber DC, Squier CA (1995) Regional variation in content, composition and organization of porcine epithelial barrier lipids revealed by thin-layer chromatography and transmission electron microscopy. Arch Oral Biol 40:1085–1091PubMedCrossRefPubMedCentralGoogle Scholar
  92. Le L, Kost J, Mitragotri S (2000) Combined effect of low-frequency ultrasound and iontophoresis: applications for transdermal heparin delivery. Pharm Res 17:1151–1154PubMedCrossRefPubMedCentralGoogle Scholar
  93. Leduc S (1900) Introduction of medicinal substances into the depth of tissues by electric current. Ann d’ Electrobiol 3:545–560Google Scholar
  94. Lee KY, Mooney DJ (2001) Hydrogels for tissue engineering. Chem Rev 101:1869–1880PubMedCrossRefPubMedCentralGoogle Scholar
  95. Lee S, Newnham RE, Smith NB (2004a) Short ultrasound exposure times for noninvasive insulin delivery in rats using the lightweight cymbal array. IEEE Trans Ultrason Ferroelectr Freq Control 51:176–180PubMedCrossRefPubMedCentralGoogle Scholar
  96. Lee S, Snyder B, Newnham RE, Smith NB (2004b) Non-invasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array. Diabetes Technol Ther 6:808–815PubMedCrossRefPubMedCentralGoogle Scholar
  97. Levy D, Kost J, Meshulam Y, Langer R (1989) Effect of ultrasound on transdermal drug delivery to rats and guinea pigs. J Clin Invest 83:2074–2078PubMedPubMedCentralCrossRefGoogle Scholar
  98. Lopez RFV, Seto JE, Blankschtein D, Langer R (2011) Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate. Biomaterials 32:933–941PubMedCrossRefPubMedCentralGoogle Scholar
  99. Luis J, Park EJ, Meyer RJ, Smith NB (2007) Rectangular cymbal arrays for improved ultrasonic transdermal insulin delivery. J Acoust Soc Am 122:2022–2030PubMedCrossRefPubMedCentralGoogle Scholar
  100. Maione E, Shung KK, Meyer RJ Jr, Hughes JW, Newnham RE, Smith NB (2002) Transducer design for a portable ultrasound enhanced transdermal drug-delivery system. IEEE Trans Ultrason Ferroelectr Freq Control 49:1430–1436PubMedCrossRefPubMedCentralGoogle Scholar
  101. Menczel E (1985) Skin delipidization and percutaneous absorption. In: Bronaugh RL, Maibach HI (eds) Percutaneous absorption: mechanisms–methodology–drug delivery. Marcel Dekker, New York, pp 231–242Google Scholar
  102. Meshali M, Abdel-Aleem H, Sakr F, Nazzal S, El-Malah Y (2011) Effect of gel composition and phonophoresis on the transdermal delivery of ibuprofen: in vitro and in vivo evaluation. Pharm Dev Technol 16:93–101PubMedCrossRefPubMedCentralGoogle Scholar
  103. Mitragotri S (2000) Synergistic effect of enhancers for transdermal drug delivery. Pharm Res 17:1354–1359PubMedCrossRefPubMedCentralGoogle Scholar
  104. Mitragotri S (2004) Breaking the skin barrier. Adv Drug Deliv Rev 56:555–556PubMedCrossRefPubMedCentralGoogle Scholar
  105. Mitragotri S (2013) Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers. Adv Drug Del Rev 65:100–103CrossRefGoogle Scholar
  106. Mitragotri S, Blankschtein D, Langer R (1995a) Ultrasound-mediated transdermal protein delivery. Science 269:850–853PubMedCrossRefPubMedCentralGoogle Scholar
  107. Mitragotri S, Blankschtein D, Langer R (1996) Transdermal drug delivery using low-frequency sonophoresis. Pharm Res 13:411–420PubMedCrossRefPubMedCentralGoogle Scholar
  108. Mitragotri S, Edwards DA, Blankschtein D, Langer (1995b) A mechanistic study of ultrasonically-enhanced transdermal drug delivery. J Pharm Sci 84:697–706Google Scholar
  109. Mitragotri S, Kost J (2004) Low-frequency sonophoresis a review. Adv Drug Del Rev 56:589–601CrossRefGoogle Scholar
  110. Miyata T, Uragami T, Nakamae K (2002) Biomolecule sensitive hydrogels. Adv Drug Deliv Rev 54:79–98PubMedCrossRefPubMedCentralGoogle Scholar
  111. Murthy SN, Zhao YL, Marlan K, Hui SW, Kazim AL, Sen A (2006) Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation. J Pharm Sci 95:2041–2050PubMedCrossRefPubMedCentralGoogle Scholar
  112. Naik A, Kalia YN, Guy RH (2000) Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technol Today 3:318–326PubMedCrossRefPubMedCentralGoogle Scholar
  113. Nair V, Pillai O, Ramarao P, Panchagnula R (1999) Transdermal iontophoresis. Part I: basic principles and considerations methods find exp. Clin Pharmacol 21:139–151Google Scholar
  114. Neumann E, Rosenheck K (1972) Permeability changes induced by electrical pulses in vesicular membranes. J Membr Biol 10:279–290PubMedCrossRefPubMedCentralGoogle Scholar
  115. Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH (1982) Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J 1:841–845PubMedPubMedCentralCrossRefGoogle Scholar
  116. Odia S, Vocks E, Rakoski J, Ring J (1996) Successful treatment of dyshidrotic hand eczema using tap water iontophoresis with pulsed direct current. Acta Derm Venereol (Stockh) 76:472–474Google Scholar
  117. Ogura M, Paliwal S, Mitragotri S (2008) Low-frequency sonophoresis: current status and future prospects. Adv Drug Del Rev 60:1218–1223CrossRefGoogle Scholar
  118. Oh SY, Leung L, Bommannan D, Guy RH, Potts RO (1993) Effect of current, ionic strength and temperature on the electrical properties of skin. J Control Rel 27:115–125CrossRefGoogle Scholar
  119. Oosawa F (1957) A simple theory of thermodynamic properties of polyelectrolyte solutions. J Polymer Sci 23:421–430CrossRefGoogle Scholar
  120. Osada Y, Gong J-P (1998) Soft and wet materials: polymer gels. Adv Mater 10:827–837CrossRefGoogle Scholar
  121. Panchagnula R, Pillai I, Nair VB, Ramarao P (2000) Transdermal iontophoresis revisited. Curr Opin Chem Biol 4:468–473PubMedCrossRefPubMedCentralGoogle Scholar
  122. Park D, Park H, Seo J, Lee S (2014) Sonophoresis in transdermal drug deliverys Ultrasonics 54:56–65PubMedPubMedCentralGoogle Scholar
  123. Park EJ, Dodds J, Smith NB (2008) Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection. Int J Nanomed 3:335–341Google Scholar
  124. Park EJ, Werner J, Smith NB (2007) Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer. Pharm Res 24:1396–1401PubMedCrossRefPubMedCentralGoogle Scholar
  125. Park H, Park K, Shalaby WSW (2011) Biodegradable hydrogels for drug delivery. CRC PressGoogle Scholar
  126. Park K, Shalaby WSW, Park H (1993) Biodegradable hydrogels for controlled drug delivery. Technomic Publishing Co., Inc., Lancaster, PA Chapter 1Google Scholar
  127. Patel MP, Churchmana ST, Cruchley AT, Bradena M, Williams DM (2013) Delivery of macromolecules across oral mucosa from polymeric hydrogels is enhanced by electrophoresis (iontophoresis). Dental Mat 29:e299–e307CrossRefGoogle Scholar
  128. Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb AL (2010) Challenges and opportunities in dermal/transdermal delivery. Ther Deliv 1:109–131PubMedPubMedCentralCrossRefGoogle Scholar
  129. Peppas NA, Keys KB, Torres-Lugo M, Lowman AM (1999) Poly(ethylene glycol)-containing hydrogels in drug delivery. J Control Rel 62:81–87CrossRefGoogle Scholar
  130. Peppas NA, Ritger PL (1987a) A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Rel 5:23–36CrossRefGoogle Scholar
  131. Peppas NA, Ritger PL (1987b) A simple equation for description of solute release II. Fickian and anamolous release from swellable device. J Control Rel 5:37–42CrossRefGoogle Scholar
  132. Petchsangsai M, Rojanarata T, Opanasopit P, Ngawhirunpat T (2014) The combination of microneedles with electroporation and sonophoresis to enhance hydrophilic macromolecule skin penetration. Biol Pharm Bull 37:1373–1382PubMedCrossRefPubMedCentralGoogle Scholar
  133. Pikal MJ (1992) The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev 9:137–176CrossRefGoogle Scholar
  134. Pikal MJ, Shah S (1991) Study of the mechanisms of flux enhancement through hairless mouse skin by pulsed DC iontophoresis. Pharm Res 8:365–369PubMedCrossRefPubMedCentralGoogle Scholar
  135. Pillai O, Panchagnula R (2003) Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. J Control Rel 89:127–140CrossRefGoogle Scholar
  136. Pliquett U, Weaver JC (1996) Transport of a charged molecule across the human epidermis due to electroporation. J Control Rel 38:1–10CrossRefGoogle Scholar
  137. Polat BE, Hart D, Langer R, Blankschtein D (2011) Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Rel 152:330–348Google Scholar
  138. Prasad R, Anand S, Khar RK, Dinda AK, Koul V (2009) Studies on in vitro and in vivo transdermal flux enhancement of methotrexate by a combinational approach in comparison to oral delivery. Drug Dev Ind Pharm 11:1281–1292CrossRefGoogle Scholar
  139. Prasad R, Koul V (2012) Transdermal delivery of methotrexate: past, present and future prospects. Ther Del 3:315–325CrossRefGoogle Scholar
  140. Prasad R, Koul V, Anand S, Khar RK (2007) Effect of DC/mDC iontophoresis and terpenes on transdermal permeation of methotrexate: in vitro study. Int J Pharm 333:70–78PubMedCrossRefPubMedCentralGoogle Scholar
  141. Prausnitz MR (1998) Electroporation. In: Berner B, Dinh SM (eds) Electronically controlled drug delivery. CRC Press, Boca Raton, FL, pp 185–214Google Scholar
  142. Prausnitz MR (1999) A practical assessment of transdermal drug delivery by skin electroporation. Adv Drug Deliv Rev 35:61–76PubMedCrossRefPubMedCentralGoogle Scholar
  143. Prausnitz MR, Bose VG, Langer R, Weaver JC (1993) Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci USA 90:10504–10508PubMedCrossRefPubMedCentralGoogle Scholar
  144. Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotech 26:1261–1268CrossRefGoogle Scholar
  145. Prausnitz MR, Mitragotri S, Langer R (2004) Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov 3:115–124PubMedCrossRefPubMedCentralGoogle Scholar
  146. Prausnitz MR (1997) Reversible skin permeabilization for transdermal delivery of macromolecules. Crit Rev Ther Drug Carrier Syst 14:455–483PubMedCrossRefPubMedCentralGoogle Scholar
  147. Qiu Y, Park K (2001) Environment -sensitive hydrogels for drug delivery. Adv Drug Deliv Rev 53:321–339PubMedCrossRefPubMedCentralGoogle Scholar
  148. Quinn HL, Hughes CM, Donnelly RF (2016) Novel methods of drug administration for the treatment and care of older patients. Int J Pharm. In PressGoogle Scholar
  149. Raiman J, Koljonen M, Huikko K, Kostiainen R, Hirvonen J (2004) Delivery and stability of LHRH and Nafarelin in human skin: the effect of constant/pulsed iontophoresis. Eur J Pharm Sci 21:371–377PubMedCrossRefPubMedCentralGoogle Scholar
  150. Rastogi R, Anand S, Koul V (2010a) Electroporation of polymeric nanoparticles: an alternative technique for transdermal delivery of insulin. Drug Dev Ind Pharm 36:1303–1311PubMedCrossRefPubMedCentralGoogle Scholar
  151. Rastogi R, Anand S, Dinda AK, Koul V (2010b) Investigation on the synergistic effect of a combination of chemical enhancers and modulated iontophoresis for transdermal delivery of insulin. Drug Dev Ind Pharm 36:993–1004PubMedCrossRefPubMedCentralGoogle Scholar
  152. Rehman K, Zulfakar MH (2014) Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev Ind Pharm 40:433–440PubMedCrossRefPubMedCentralGoogle Scholar
  153. Rosendal T (1943) Studies on the conducting properties of the human skin to direct current. Acta Physiol Scand 5:130–151CrossRefGoogle Scholar
  154. Sale AJH, Hamilton WA (1967) Effects of electric fields on microorganisms killing of bacteria and yeasts. Biochim Biophys Acta 118:781–788CrossRefGoogle Scholar
  155. Samchenko Y, Ulberg Z, Korotych O (2011) Multipurpose smart hydrogel systems. Adv Colloid Interface Sci 168:247–262PubMedCrossRefPubMedCentralGoogle Scholar
  156. Sardesai NY, Weiner DB (2011) Electroporation delivery of DNA vaccines: prospects for success. Curr Opin Immunol 23:421–429PubMedPubMedCentralCrossRefGoogle Scholar
  157. Saroha K, Singh S, Aggarwal A, Nanda S (2013) Transdermal gels—an alternative vehicle for drug delivery. Int J Pharm Chem Biol Sci IJPCBS 3:495–503Google Scholar
  158. Scheuplein RJ (1965) Mechanism of percutaneous absorption: I. Routes of penetration and the influence of solubility. J Invest Dermatol 29:131–149Google Scholar
  159. Scheuplein RJ (1967) Mechanism of percutaneous absorption: II. Transient diffusion and the relative importance of various routes of skin penetration. J Invest Dermatol 48:79–88PubMedCrossRefPubMedCentralGoogle Scholar
  160. Schreier H, Bouwstra J (1994) Liposomes and niosomes as topical drug carriers-dermal and transdermal drug-delivery. J Control Rel 30:1–15CrossRefGoogle Scholar
  161. Schuetz YB, Naik A, Guy RH, Kalia YN (2005) Emerging strategies for the transdermal delivery of peptide and protein drugs. Expert Opin Drug Deliv 2:533–548PubMedCrossRefPubMedCentralGoogle Scholar
  162. Scott ER, Laplaza AI, White HS, Phipps JB (1993) Transport of ionic species in skin: contribution of pores to the overall skin conductance. Pharm Res 10:1699–1709PubMedCrossRefPubMedCentralGoogle Scholar
  163. Sen A, Daly MS, Hui SW (2002) Transdermal insulin delivery using lipid enhanced electroporation. Biochim Biophys Acta 1564:5–8PubMedCrossRefPubMedCentralGoogle Scholar
  164. Shipton EA (2012) Advances in delivery systems and routes for local anaesthetics. Trends Anaesth Critical Care 2:228–233CrossRefGoogle Scholar
  165. Sieg A, Guy RH, Delgado-Charro MB (2004) Electroosmosis in transdermal iontophoresis: implications for noninvasive and calibration-free glucose monitoring. Biophys J 87:3344–3350PubMedPubMedCentralCrossRefGoogle Scholar
  166. Sims SM, Higuchi WI, Srinivasan V (1991) Skin alteration and convective solvent flow effects during iontophoresis: I. Neutral solute transport across human skin. Int J Pharm 69:109–121CrossRefGoogle Scholar
  167. Sirsi SR, Borden MA (2014) State-of-the-art materials for ultrasound-triggered drug delivery. Adv Drug Del Rev 72:3–14CrossRefGoogle Scholar
  168. Smith NB, Lee S, Maione E, Roy RB, McElligott S, Shung KK (2003a) Ultrasound-mediated transdermal transport of insulin in vitro through human skin using novel transducer designs. Ultrasound Med Biol 29:311–317PubMedCrossRefPubMedCentralGoogle Scholar
  169. Smith NB, Lee S, Shung KK (2003b) Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays. Ultrasound Med Biol 29:1205–1210PubMedCrossRefPubMedCentralGoogle Scholar
  170. Spierings EL, Brevard JA, Katz NP (2008) Two-minute skin anesthesia through ultrasound pretreatment and iontophoretic delivery of a topical anesthetic: a feasibility study. Pain Med 9:55–59PubMedCrossRefPubMedCentralGoogle Scholar
  171. Swartzendruber DC, Wertz PW, Madison KC (1987) Evidence that the corneocyte has a chemically bound lipid envelope. J Invest Dermatol 88:709–713PubMedCrossRefPubMedCentralGoogle Scholar
  172. Tachibana K, Tachibana S (1991) Transdermal delivery of insulin by ultrasonic vibration. J Pharm Pharmacol 43:270–271PubMedCrossRefPubMedCentralGoogle Scholar
  173. Tachibana K, Tachibana S (1993) Use of ultrasound to enhance the local anesthetic effect of topically applied aqueous lidocaine. Anestheiology 78:1091–1096CrossRefGoogle Scholar
  174. Tagami H, Ohi M, Iwatsuki K, Kanamaru Y, Yamada M, Ichijo B (1980) Evaluation of the skin surface hydration in vivo by electrical measurement. J Invest Dermatol 75:500–507PubMedCrossRefPubMedCentralGoogle Scholar
  175. Tezel A, Sens A, Mitragotri S (2002) Incorporation of lipophilic pathways into the porous pathway model for describing skin permeabilization during low frequency sonophoresis. J Control Rel 83:183–188CrossRefGoogle Scholar
  176. Tezel A, Sens A, Tuchscherer J, Mitragotri S (2001) Frequency dependence of sonophoresis. Pharm Res 18:1694–1700PubMedCrossRefPubMedCentralGoogle Scholar
  177. Tuncel A, Demiroz PS, Piskin E (2002) A novel approach for albumin determination in aqueous media by using temperature and pH sensitive N-isopropyl acrylamide-co-N-[3-(dimethylamino)-propyl] methacrylamide random co-polymers. J Appl Polym Sci 84:2060–2070CrossRefGoogle Scholar
  178. Uma DS, Ganesan M, Mohanta GP, Manavalan R (2002) Design and evaluation of tetracycline hydrochloride gels. Indian Drugs 39:552–554Google Scholar
  179. Valenta C, Auner BG (2004) The use of polymers for dermal andtransdermal delivery. Eur J Pharms Biopharm 58:279–289CrossRefGoogle Scholar
  180. Wang YM, Allen LV, Li LC (2000) Effect of sodium dodecyl sulphate on iontophoresis of hydrocortisone across hairless mouse skin. Pharm Dev T 5:533–542CrossRefGoogle Scholar
  181. Weaver JC, Chizmadzhev YA (1996) Theory of electroporation: a review. Bioelectrochem Bioenerg 41:135–160CrossRefGoogle Scholar
  182. Wichterle O, Lim D (1960) Hydrophilic gels for biological use. Nature 1185:117–118CrossRefGoogle Scholar
  183. Williams AC (2003) Structure and function of human skin. In: Transdermal and topical drug delivery-from theory to clinical practice. Pharmaceutical press, London, pp 1–25Google Scholar
  184. Wong TW (2014) Electrical, magnetic, photomechanical and cavitational waves to overcome skin barrier for transdermal drug delivery. J Control Rel 193:257–269CrossRefGoogle Scholar
  185. Wong TW, Chen TY, Huang CC, Tsai JC, Hui SW (2011) Painless skin electroporation as a novel way for insulin delivery. Diabetes Technol Ther 13:929–935PubMedCrossRefPubMedCentralGoogle Scholar
  186. Yamamoto T, Yamamoto Y (1976) Electrical properties of the epidermal stratum corneum. Med Biol Eng Comput 14:151–158CrossRefGoogle Scholar
  187. Yarmush ML, Golberg A, Serša G, Kotnik T, Miklavci D (2014) Electroporation based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng 16:295–320PubMedCrossRefPubMedCentralGoogle Scholar
  188. Zhang I, Shung KK, Edwards DA (1996) Hydrogels with enhanced mass transfer for transdermal drug delivery. J Pharm Sci 85:1312–1316PubMedCrossRefPubMedCentralGoogle Scholar
  189. Zorec B, Becker S, Reberšek M, Miklavci D, Pavšelj N (2013) Skin electroporation for transdermal drug delivery: the influence of the order of different square wave electric pulses. Int J Pharm 457:214–223PubMedCrossRefPubMedCentralGoogle Scholar
  190. Zorec B, Jelenc J, Miklavčič D, Pavšelj N (2015) Ultrasound and electric pulses for transdermal drug delivery enhancement: ex vivo assessment of methods with in vivo oriented experimental protocols. Int J Pharm 490:65–73PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Centre for Biomedical Engineering, Indian Institute of TechnologyNew DelhiIndia
  2. 2.Biomedical Engineering UnitAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations