Painless skin electroporation as a novel way for insulin delivery.

BACKGROUND Rigorous research efforts have been undertaken worldwide to develop a needle-free insulin delivery for many decades with limited success. This translational study aims to deliver insulin through skin with painless electroporation. METHODS A recently designed microelectrode array was used to deliver insulin in mice with diabetes under electroporation conditions that are painless and harmless on human skin. RESULTS Under such condition, a therapeutic amount of insulin was delivered successfully through mouse skin. Electroporation alone increased insulin transport around 100-fold compared with passive diffusion. Increased skin temperature to 40°C for 20 min augmented insulin transport to 237-fold more than the control value. Repeated electroporation showed no harm on human skin. CONCLUSION The results indicate the potential of painless delivery of insulin through human skin in future clinical practice.

[1]  Julie Gehl,et al.  Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. , 2003, Cancer treatment reviews.

[2]  P. Ramarao,et al.  Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[3]  S W Hui,et al.  Time-dependent ultrastructural changes to porcine stratum corneum following an electric pulse. , 1999, Biophysical Journal.

[4]  P. Elias,et al.  Transepidermal water loss: the signal for recovery of barrier structure and function. , 1989, Journal of lipid research.

[5]  J. Weaver,et al.  Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  John C Rutledge,et al.  The challenge of type 1 diabetes mellitus. , 2004, ILAR journal.

[7]  S. Mitragotri,et al.  Current status and future potential of transdermal drug delivery , 2004, Nature Reviews Drug Discovery.

[8]  James C. Weaver,et al.  Feasibility of an Electrode-Reservoir Device for Transdermal Drug Delivery by Noninvasive Skin Electroporation , 2007, IEEE Transactions on Biomedical Engineering.

[9]  K. Goa,et al.  Spotlight on Insulin Aspart in Type 1 and 2 Diabetes Mellitus , 2003, Treatments in endocrinology.

[10]  S. Mitragotri,et al.  Ultrasound-mediated transdermal protein delivery , 1995, Science.

[11]  S. Hui,et al.  Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation. , 2006, Journal of pharmaceutical sciences.

[12]  H. Kato,et al.  Pilot study of topical delivery of mono-L-aspartyl chlorin e6 (NPe6): implication of topical NPe6-photodynamic therapy. , 2003, Journal of pharmacological sciences.

[13]  S. Hui,et al.  Pilot study of topical delivery of methotrexate by electroporation , 2005, The British journal of dermatology.

[14]  V. Wong,et al.  Evaluation of the WHO criteria for 75 g oral glucose tolerance test in pregnancy , 1987, British journal of obstetrics and gynaecology.

[15]  S. Hui,et al.  Temperature influences the postelectroporation permeability state of the skin. , 2004, Journal of pharmaceutical sciences.

[16]  J. Holst,et al.  Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. , 2004, Diabetes.

[17]  M. Daly,et al.  Transdermal insulin delivery using lipid enhanced electroporation. , 2002, Biochimica et biophysica acta.

[18]  D. L. Wilson,et al.  Increased atherosclerosis in streptozotocin-induced diabetic mice. , 1996, The Journal of clinical investigation.

[19]  S. Hui,et al.  pH influences the postpulse permeability state of skin after electroporation. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[20]  R. Guy,et al.  Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Yoshinori Onuki,et al.  Current challenges in non-invasive insulin delivery systems: a comparative review. , 2007, Advanced drug delivery reviews.

[22]  J. Lau,et al.  Meta-Analysis: Efficacy and Safety of Inhaled Insulin Therapy in Adults with Diabetes Mellitus , 2006, Annals of Internal Medicine.

[23]  S. Hui,et al.  Painless electroporation with a new needle-free microelectrode array to enhance transdermal drug delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[24]  Roman Hovorka,et al.  Interstitial glucose kinetics in subjects with type 1 diabetes under physiologic conditions. , 2004, Metabolism: clinical and experimental.

[25]  Robert Langer,et al.  Transdermal drug delivery , 2008, Nature Biotechnology.

[26]  Lei Zhang,et al.  Enhanced transdermal transport by electroporation using anionic lipids. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[27]  P. Elias,et al.  Epidermal lipids, barrier function, and desquamation. , 1983, The Journal of investigative dermatology.

[28]  A. Bråve,et al.  Plasmid DNA vaccination using skin electroporation promotes poly‐functional CD4 T‐cell responses , 2011, Immunology and cell biology.

[29]  D. Hubble.  The Action of Glucagon on the Blood Sugar in Normal and Diabetic Persons , 1955, Diabetes.

[30]  M. J. Alvarez-Figueroa,et al.  Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions. , 2001, International journal of pharmaceutics.