Volume 29, Issue 4 (4-2025)                   IBJ 2025, 29(4): 189-205 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Ahmadpour Emshi Z, Roostayi M M, Daryabor A, Niajalili M, Naimi S S. Transdermal Iontophoresis Insulin in Laboratory Animals: A Systematic Review. IBJ 2025; 29 (4) :189-205
URL: http://ibj.pasteur.ac.ir/article-1-5127-en.html
Abstract:  
Insulin therapy is essential for regulating glucose levels in diabetic patients. However, subcutaneous insulin injection, despite being a standard procedure, is invasive and often painful and can lead to complications such as skin damage and infections. These issues often result in poor patient compliance and inadequate glycemic control. Recently, transdermal insulin administration has been explored as an alternative to subcutaneous methods; however, no universally accepted protocol has been developed for its use. This systematic review aimed to evaluate the effect of iontophoresis on transdermal insulin administration in laboratory animals. Using the PICO search strategy and in accordance with PRISMA guidelines, relevant articles published from January 1980 to May 2025 were retrieved from Scopus, PubMed, ISI Web of Science, PEDro, Science Direct, and Google Scholar databases. The findings from these studies suggest that combining iontophoresis with physical enhancers of skin penetration can effectively regulate blood glucose levels while minimizing the risk of hypoglycemia.
Type of Study: Systematic Review | Subject: Related Fields

References
1. Yoo M, D'Silva LJ, Martin K, Sharma NK, Pasnoor M, LeMaster JW, et al. Pilot study of exercise therapy on painful diabetic peripheral neuropathy. Pain Med. 2015;16(8):1482-9. [DOI:10.1111/pme.12743]
2. Magliano DJ, Boyko EJ. IDF Diabetes Atlas. 10th edition. Brussels: International diabetes federation; 2021.
3. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358(9283):739-46. [DOI:10.1016/S0140-6736(01)05842-1]
4. Hayward RA, Manning WG, Kaplan SH, Wagner EH, Greenfield S. Starting insulin therapy in patients with type 2 diabetes: Effectiveness, complications, and resource utilization. JAMA. 1997;278(20):1663-9. [DOI:10.1001/jama.1997.03550200039029]
5. Larrañeta E, Lutton RE, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Mater Sci Eng. 2016;104:1-32. [DOI:10.1016/j.mser.2016.03.001]
6. Wang QL, Zhu DD, Chen Y, Guo XD. A fabrication method of microneedle molds with controlled microstructures. Mater Sci Eng C Mater Biol Appl. 2016;65:135-42. [DOI:10.1016/j.msec.2016.03.097]
7. Bae W-G, Ko H, So J-Y, Yi H, Lee C-H, Lee D-H, et al. Snake fang-inspired stamping patch for transdermal delivery of liquid formulations. Sci Transl Med. 2019;11(503):3329. [DOI:10.1126/scitranslmed.aaw3329]
8. Ma G, Wu C. Microneedle, bio-microneedle and bio-inspired microneedle: A review. J Control Release. 2017;251:11-23. [DOI:10.1016/j.jconrel.2017.02.011]
9. Liu D, Yu B, Jiang G, Yu W, Zhang Y, Xu B. Fabrication of composite microneedles integrated with insulin-loaded CaCO3 microparticles and PVP for transdermal delivery in diabetic rats. Mater Sci Eng C Mater Biol Appl. 2018;90:180-8. [DOI:10.1016/j.msec.2018.04.055]
10. Wang J, Ye Y, Yu J, Kahkoska AR, Zhang X, Wang C, et al. Core-shell microneedle gel for self-regulated insulin delivery. ACS Nano. 2018;12(3):2466-73. [DOI:10.1021/acsnano.7b08152]
11. Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. 2003;20(11):886-98. [DOI:10.1046/j.1464-5491.2003.01076.x]
12. Khafagy E-S, Morishita M, Onuki Y, Takayama K. Current challenges in non-invasive insulin delivery systems: A comparative review. Adv Drug Deliv Rev. 2007;59(15):1521-46. [DOI:10.1016/j.addr.2007.08.019]
13. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies. Nat Rev Drug Discov. 2014;13(9):655-72. [DOI:10.1038/nrd4363]
14. Yang R, Wei T, Goldberg H, Wang W, Cullion K, Kohane DS. Getting drugs across biological barriers. Adv Mater. 2017;29(37):1002. [DOI:10.1002/adma.201606596]
15. Dharadhar S, Majumdar A, Dhoble S, Patravale V. Microneedles for transdermal drug delivery: A systematic review. Drug Dev Ind Pharm. 2019;45(2):188-201. [DOI:10.1080/03639045.2018.1539497]
16. Simmons JA, Davis J, Thomas J, Lopez J, Le Blanc A, Allison H, et al. Characterization of skin blebs from intradermal jet injection: Ex-vivo studies. J Control Release. 2019;307:200-10. [DOI:10.1016/j.jconrel.2019.06.032]
17. Ita K. Transdermal iontophoretic drug delivery: Advances and challenges. J Drug Target. 2016;24(5):386-91. [DOI:10.3109/1061186X.2015.1090442]
18. Ita K. Perspectives on transdermal electroporation. Pharmaceutics. 2016;8(1):9. [DOI:10.3390/pharmaceutics8010009]
19. Polat BE, Hart D, Langer R, Blankschtein D. Ultrasound-mediated transdermal drug delivery: Mechanisms, scope, and emerging trends. J Control Release. 2011;152(3):330-48. [DOI:10.1016/j.jconrel.2011.01.006]
20. Szunerits S, Boukherroub R. Heat: A highly efficient skin enhancer for transdermal drug delivery. Front Bioeng Biotechnol. 2018;6:15. [DOI:10.3389/fbioe.2018.00015]
21. Ahad A, Raish M, Bin Jardan YA, Al-Mohizea AM, Al-Jenoobi FI. Delivery of insulin via skin route for the management of diabetes mellitus: Approaches for breaching the obstacles. Pharmaceutics. 2021;13(1):100. [DOI:10.3390/pharmaceutics13010100]
22. Dixit N, Bali V, Baboota S, Ahuja A, Ali J. Iontophoresis-an approach for controlled drug delivery: A review. Curr Drug Deliv. 2007;4(1):1-10. [DOI:10.2174/156720107779314802]
23. Tomoda K, Terashima H, Suzuki K, Inagi T, Terada H, Makino K. Enhanced transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis in vivo. Colloids Surf B Biointerfaces. 2012;92:50-4. [DOI:10.1016/j.colsurfb.2011.11.016]
24. Liang W, Pan HW, Vllasaliu D, Lam JK. Pulmonary delivery of biological drugs. Pharmaceutics. 2020;12(11):1025. [DOI:10.3390/pharmaceutics12111025]
25. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-84. [DOI:10.1136/jech.52.6.377]
26. Meyer BR, Katzeff HL, Eschbach JC, Trimmer J, Zacharias SB, Rosen S, et al. Transdermal delivery of human insulin to albino rabbits using electrical current. Am J Med Sci. 1989;297(5):321-5. [DOI:10.1097/00000441-198905000-00009]
27. Chien YW, Lelawongs P, Siddiqui O, Sun Y, Shi W. Facilitated transdermal delivery of therapeutic peptides and proteins by iontophoretic delivery devices. J Control Release. 1990;13(2-3):263-78. [DOI:10.1016/0168-3659(90)90017-N]
28. Huang Y-Y, Wu S-M. Stability of peptides during iontophoretic transdermal delivery. Int J pharm. 1996;131(1):19-23. [DOI:10.1016/0378-5173(95)04263-6]
29. Yang J, Li Y, Ye R, Zheng Y, Li X, Chen Y, et al. Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery. Microsyst Nanoeng. 2020;6(1):112. [DOI:10.1038/s41378-020-00224-z]
30. Li Y, Yang J, Zheng Y, Ye R, Liu B, Huang Y, et al. Iontophoresis-driven porous microneedle array patch for active transdermal drug delivery. Acta Biomater. 2021;121:349-58. [DOI:10.1016/j.actbio.2020.12.023]
31. Rastogi SK, Singh J. Passive and iontophoretic transport enhancement of insulin through porcine epidermis by depilatories: Permeability and Fourier transform infrared spectroscopy studies. AAPS PharmSciTech. 2003;4(3):1-9. [DOI:10.1208/pt040329]
32. Rastogi SK, Singh J. Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis. Pharm Dev Technol. 2005;10(1):97-104. [DOI:10.1081/PDT-49679]
33. Murthy SN, Zhao Y-L, Hui S-W, Sen A. Synergistic effect of anionic lipid enhancer and electroosmosis for transcutaneous delivery of insulin. Int J Pharm. 2006;326(1-2):1-6. [DOI:10.1016/j.ijpharm.2006.06.039]
34. Rastogi R, Anand S, Dinda AK, Koul V. Investigation on the synergistic effect of a combination of chemical enhancers and modulated iontophoresis for transdermal delivery of insulin. Drug Dev Ind Pharm. 2010;36(8):993-1004. [DOI:10.3109/03639041003682012]
35. Chen H, Zhu H, Zheng J, Mou D, Wan J, Zhang J, et al. Iontophoresis-driven penetration of nanovesicles through microneedle-induced skin microchannels for enhancing transdermal delivery of insulin. J Control Release. 2009;139(1):63-72. [DOI:10.1016/j.jconrel.2009.05.031]
36. Li X, Huang X, Mo J, Wang H, Huang Q, Yang C, et al. A fully integrated closed‐loop system based on mesoporous microneedles‐iontophoresis for diabetes treatment. Adv Sci. 2021;8(16):2100827. [DOI:10.1002/advs.202100827]
37. Srinivasan V, Higuchi W, Sims S, Ghanem A, Behl C. Transdermal iontophoretic drug delivery: Mechanistic analysis and application to polypeptide delivery. J Pharm Sci. 1989;78(5):370-5. [DOI:10.1002/jps.2600780506]
38. Tari K, Khamoushian S, Madrakian T, Afkhami A, Łos MJ, Ghoorchian A, et al. Controlled transdermal iontophoresis of insulin from water-soluble polypyrrole nanoparticles: An in vitro study. Int J Mol Sci. 2021;22(22):12479. [DOI:10.3390/ijms222212479]
39. 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. [DOI:10.1016/S0168-3659(03)00094-4]
40. Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of insulin: IV. Influence of chemical enhancers. Int J Pharm. 2004;269(1):109-20. [DOI:10.1016/j.ijpharm.2003.09.032]
41. Panchagnula R, Bindra P, Kumar N, Shanker Dey C, Pillai O. Stability of insulin under iontophoretic conditions. Pharmazie. 2006;61(12):1014-8.
42. Tomohira Y, Machida Y, Onishi H, Nagai T. Iontophoretic transdermal absorption of insulin and calcitonin in rats with newly-devised switching technique and addition of urea. Int J pharm. 1997;155(2):231-9. [DOI:10.1016/S0378-5173(97)00171-3]
43. Thirunavukkarasu A, Nithya R, Jeyanthi J. Transdermal drug delivery systems for the effective management of type 2 diabetes mellitus: A review. Diabetes Res Clin Pract. 2022:194:109996. [DOI:10.1016/j.diabres.2022.109996]
44. Qin G, Gao Y, Wu Y, Zhang S, Qiu Y, Li F, et al. Simultaneous basal-bolus delivery of fast-acting insulin and its significance in diabetes management. Nanomedicine. 2012;8(2):221-7. [DOI:10.1016/j.nano.2011.05.017]
45. Cheng Y, Gong X, Yang J, Zheng G, Zheng Y, Li Y, et al. A touch-actuated glucose sensor fully integrated with microneedle array and reverse iontophoresis for diabetes monitoring. Biosens Bioelectron. 2022;203:114026. [DOI:10.1016/j.bios.2022.114026]
46. Kanikkannan N, Singh J, Ramarao P. Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue. J Control release. 1999;59(1):99-105. [DOI:10.1016/S0168-3659(98)00184-9]
47. Pillai O, Borkute SD, Sivaprasad N, Panchagnula R. Transdermal iontophoresis of insulin. II. Physicochemical considerations. Int J Pharm. 2003;254(2):271-80. [DOI:10.1016/S0378-5173(03)00034-6]
48. Pillai O, Kumar N, Dey CS, Borkute S, Nagalingam S, Panchagnula R. Transdermal iontophoresis of insulin. Part 1: A study on the issues associated with the use of platinum electrodes on rat skin. J Pharm pharmacol. 2003;55(11):1505-13. [DOI:10.1211/0022357022197]
49. Pillai O, Panchagnula R. Transdermal iontophoresis of insulin. V. Effect of terpenes. J Control Release. 2003;88(2):287-96. [DOI:10.1016/S0168-3659(03)00065-8]
50. Tokumoto S, Higo N, Sugibayashi K. Effect of electroporation and pH on the iontophoretic transdermal delivery of human insulin. Int J Pharm. 2006;326(1-2):13-9. [DOI:10.1016/j.ijpharm.2006.07.002]
51. Kajimoto K, Yamamoto M, Watanabe M, Kigasawa K, Kanamura K, Harashima H, et al. Noninvasive and persistent transfollicular drug delivery system using a combination of liposomes and iontophoresis. Int J Pharm. 2011;403(1-2):57-65. [DOI:10.1016/j.ijpharm.2010.10.021]
52. Akram M, Naqvi SB, Khan A. Design and development of insulin emulgel formulation for transdermal drug delivery and its evaluation. Pak J Pharm Sci. 2013;26(2):323-32.
53. Cawley P, Zakzewski C, Wasilewski J, Ford W. Effect of skin preparation on transdermal insulin delivery. IEEE. 1996:50-1. [DOI:10.1109/NEBC.1996.503212]
54. Zakzewski C, Wasilewski J, Cawley P, Ford W. Electrically enhanced transdermal delivery of insulin to chronic diabetic rats.IEEE. 1997:756813.
55. Federation ID: IDF diabetes atlas 9th edition. Http://www.Idf Diabetes Atlas. 2015.
56. Rawat S, Vengurlekar S, Rakesh B, Jain S, Srikarti G. Transdermal delivery by iontophoresis. Indian J Pharm Sci. 2008;70(1):5-10. [DOI:10.4103/0250-474X.40324]
57. Whitley HP, Lee R, Steil C, Pillion D. Student pharmacists' service-oriented learning at a camp for children with type 1 diabetes mellitus. Cur Pharm Teach Learn. 2019;11(8):825-31. [DOI:10.1016/j.cptl.2019.04.010]
58. Lee H, Song C, Baik S, Kim D, Hyeon T, Kim D-H. Device-assisted transdermal drug delivery. Adv Drug Deliv Rev. 2018;127:35-45. [DOI:10.1016/j.addr.2017.08.009]
59. Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov. 2019;18(1):19-40. [DOI:10.1038/nrd.2018.183]
60. Nayak AK, Hasnain MS, Aminabhavi TM, Torchilin VP. Systems of nanovesicular drug delivery: Nanovesicular systems in drug delivery. London: Elsevier Academic Press; 2022. [DOI:10.1016/B978-0-323-91864-0.00026-7]
61. Junaid MSA, Banga AK. Transdermal delivery of baclofen using iontophoresis and microneedles. AAPS PharmSciTech. 2022;23(3):84. [DOI:10.1208/s12249-022-02232-w]
62. Pikal MJ. The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev. 2001;46(1-3):281-305. [DOI:10.1016/S0169-409X(00)00138-1]
63. Matos BN, Pereira MN, Bravo M, Cunha-Filho M, Saldanha-Araújo F, Gratieri T, et al. Chitosan nanoparticles loading oxaliplatin as a mucoadhesive topical treatment of oral tumors: Iontophoresis further enhances drug delivery ex vivo. Int J Biol Macromol. 2020;154:1265-75. [DOI:10.1016/j.ijbiomac.2019.11.001]
64. Sakunpongpitiporn P, Naeowong W, Sirivat A. Enhanced transdermal insulin basal release from silk fibroin (SF) hydrogels via iontophoresis. Drug Deliv. 2022;29(1):2234-44. [DOI:10.1080/10717544.2022.2096717]
65. Jue-Chen L, Ying S, Siddiqui O, Wei-min S, John L. Blood glucose control in diabetic rats by transdermal iontophoretic delivery of insulin. Int J Pharm. 1988;44(1-3):197-204. [DOI:10.1016/0378-5173(88)90116-0]
66. 66. Vadlapatla R, Wong EY, Gayakwad SG. Electronic drug delivery systems: An overview. J Drug Deliv Sci Technol. 2017;41:359-66. [DOI:10.1016/j.jddst.2017.08.008]
67. Banga A, Chien YW. Iontophoretic delivery of drugs: fundamentals, developments and biomedical applications. J Control Release. 1988;7:1-24. [DOI:10.1016/0168-3659(88)90075-2]
68. Lau DT, Sharkey JW, Petryk L, Mancuso FA, Yu Z, Tse FL. Effect of current magnitude and drug concentration on lontophoretic delivery of octreotide acetate (Sandostatin) in the rabbit. Pharm Res. 1994;11(12):1742-6. [DOI:10.1023/A:1018963300092]
69. Sieg A, Jeanneret F, Fathi M, Hochstrasser D, Rudaz S, Veuthey J-L, et al. Extraction of amino acids by reverse iontophoresis in vivo. Eur J Pharm Biopharm. 2009;72(1):226-31. [DOI:10.1016/j.ejpb.2008.12.012]
70. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: Overcoming the skin's barrier function. Pharm Sci Technol Today. 2000;3(9):318-26. [DOI:10.1016/S1461-5347(00)00295-9]
71. Sage Jr BH. Insulin iontophoresis. Pharm Biotechnol. 1997:10:319-41. [DOI:10.1007/0-306-46803-4_12]
72. Stephen RL, Petelenz TJ, Jacobsen SC. Potential novel methods for insulin administration: I. Iontophoresis. Biomed Biochim Acta. 1984;43(5):553-8.
73. Chien YW, Siddiqui O, Sun Y, Shi WM, Liu JC. Transdermal iontophoretic delivery of therapeutic peptides/proteins I: insulin. Ann N Y Acad Sci. 1987;507:32-51. [DOI:10.1111/j.1749-6632.1987.tb45790.x]
74. Mao X, Liang B, Fang S. Reduced blood glucose in diabetic rats by pulse current iontophoretic transdermal delivery of insulin. Chin Pharm J. 1995;30(11):660-3.
75. Chien YW, Banga AK. Characterization of in vitro transdermal iontophoretic delivery of insulin. Drug Dev Ind Pharm. 1993;19(16):2069-87. [DOI:10.3109/03639049309069342]
76. Mao XM, Liang BW, Fang ZS, Li Q, Yao YP, Zhou MW. Facilitated transdermal delivery of insulin by pulse current iontophoresis. Yao Xue Xue Bao. 1995;30(4):302-6.
77. Bakshi P, Vora D, Hemmady K, Banga AK. Iontophoretic skin delivery systems: Success and failures. Int J Pharm. 2020;586:119584. [DOI:10.1016/j.ijpharm.2020.119584]
78. Fukuta T, Oshima Y, Michiue K, Tanaka D, Kogure K. Non-invasive delivery of biological macromolecular drugs into the skin by iontophoresis and its application to psoriasis treatment. J Control Release. 2020;323:323-32. [DOI:10.1016/j.jconrel.2020.04.044]
79. Peña-Juárez MC, Guadarrama-Escobar OR, Escobar-Chávez JJ. Transdermal delivery systems for biomolecules. J Pharm Innov. 2021;17(2):319-32.. [DOI:10.1007/s12247-020-09525-2]
80. Langkjær 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. [DOI:10.1016/S0168-3659(97)00155-7]
81. Wang H, Cai R, Wang S, Yang Y, Sheng T, Zhang W, et al. A wearable transdermal device for on-demand drug delivery. Matter. 2025;8(4):102040. [DOI:10.1016/j.matt.2025.102040]
82. Khamoushian S, Madrakian T, Afkhami A, Ghoorchian A, Ghavami S, Tari K, et al. Transdermal delivery of insulin using combination of iontophoresis and deep eutectic solvents as chemical penetration enhancers: In vitro and in vivo evaluations. J Pharm Sci. 2023;112(8):2249-59. [DOI:10.1016/j.xphs.2023.03.005]

Add your comments about this article : Your username or Email:
CAPTCHA

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2025 CC BY-NC 4.0 | Iranian Biomedical Journal

Designed & Developed by : Yektaweb