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Clinical Evaluation of a Low-pain Long Microneedle for Subcutaneous Insulin Injection

  • Lee, Ghunil (Department of Biomaterials Science and Engineering, Yonsei University) ;
  • Ma, Yonghao (Department of Biotechnology, Yonsei University) ;
  • Lee, Yong-ho (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Jung, Hyungil (Department of Biomaterials Science and Engineering, Yonsei University)
  • Received : 2018.10.12
  • Accepted : 2018.11.27
  • Published : 2018.12.20

Abstract

Microneedles (MNs) are being developed to overcome the limitations of the conventional hypodermic needle, e.g. the injection pain. In this study, we conducted an analysis of clinical pain and bleeding at the site of MN insertion and evaluated the insulin pharmacodynamic profile compared with parameters obtained with a conventional pen needle. MN insertion into the skin of 25 healthy adults or 15 patients with type 2 diabetes (T2D) revealed significantly less pain relative to a conventional hypodermic pen needle, thus reducing pain scores from $2.1{\pm}1.9$ to $21.3{\pm}1.4$ ($mean{\pm}standard$ deviation [SD]). Besides, no bleeding was observed when the MN was used. In the insulin pharmacodynamic assay, no significant differences were observed in the blood glucose-lowering effect between the pen needle and MN. Based on these results, the MN is expected to be a good substitute for conventional hypodermic pen needles and improve the quality of life of patients by significantly reducing the pain associated with insulin treatment.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Fraser, R. Metabolic disorders in diabetes. Br. Med. J. 4, 591-596 (1972). https://doi.org/10.1136/bmj.4.5840.591
  2. Nathan, D.M. et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977-986 (1993). https://doi.org/10.1056/NEJM199309303291401
  3. Nathan, D.M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643-2653 (2005). https://doi.org/10.1056/NEJMoa052187
  4. Hameed, I. et al. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J. Diabetes 6, 598-612 (2015). https://doi.org/10.4239/wjd.v6.i4.598
  5. Thrasher, J. Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies. Am. J. Cardiol. 120, S4-S16 (2017). https://doi.org/10.1016/j.amjcard.2017.05.009
  6. CADTH Therapeutic Reviews. in Third-line Drugs for Type 2 Diabetes - Project Protocol (Canadian Agency for Drugs and Technologies in Health. Copyright (c) 2017 Canadian Agency for Drugs and Technologies in Health., Ottawa (ON), 2017).
  7. Humphrey, M.J. The Oral Bioavailability of Peptides and Related Drugs. in Delivery Systems for Peptide Drugs (eds. Davis, S.S., Illum, L. & Tomlinson, E.) 139-151 (Springer US, Boston, MA, 1986).
  8. Shaji, J. & Patole, V. Protein and Peptide Drug Delivery: Oral Approaches. Indian J. Pharm. Sci. 70, 269-277 (2008). https://doi.org/10.4103/0250-474X.42967
  9. Rubin, R.R., Peyrot, M., Kruger, D.F. & Travis, L.B. Barriers to insulin injection therapy: patient and health care provider perspectives. Diabetes Educ. 35, 1014-1022 (2009). https://doi.org/10.1177/0145721709345773
  10. Aronson, R. The Role of Comfort and Discomfort in Insulin Therapy. Diabetes Technol. Ther. 14, 741-747 (2012). https://doi.org/10.1089/dia.2012.0038
  11. Oleck, J., Kassam, S. & Goldman, J.D. Commentary: Why Was Inhaled Insulin a Failure in the Market? Diabetes Spectr. 29, 180-184 (2016). https://doi.org/10.2337/diaspect.29.3.180
  12. Kling, J. Inhaled insulin's last gasp? Nat. Biotechnol. 26, 479-480 (2008). https://doi.org/10.1038/nbt0508-479
  13. Mohanty, R.R. & Das, S. Inhaled Insulin - Current Direction of Insulin Research. J. Clin. Diagn. Res. 11, OE01-OE02 (2017).
  14. Gill, H.S., Denson, D.D., Burris, B.A. & Prausnitz, M.R. Effect of microneedle design on pain in human subjects. Clin. J. Pain 24, 585-594 (2008). https://doi.org/10.1097/AJP.0b013e31816778f9
  15. Martanto, W. et al. Transdermal delivery of insulin using microneedles in vivo. Pharm. Res. 21, 947-952 (2004). https://doi.org/10.1023/B:PHAM.0000029282.44140.2e
  16. Gill, H.S. & Prausnitz, M.R. Coated microneedles for transdermal delivery. J. Control. Release 117, 227-237 (2007). https://doi.org/10.1016/j.jconrel.2006.10.017
  17. Martin, C.J., Allender, C.J., Brain, K.R., Morrissey, A. & Birchall, J.C. Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications. J. Control. Release 158, 93-101 (2012). https://doi.org/10.1016/j.jconrel.2011.10.024
  18. Gill, H.S. & Prausnitz, M.R. Pocketed Microneedles for Drug Delivery to the Skin. J. Phys. Chem. Solids 69, 1537-1541 (2008). https://doi.org/10.1016/j.jpcs.2007.10.059
  19. Gupta, J., Felner, E.I. & Prausnitz, M.R. Rapid pharmacokinetics of intradermal insulin administered using microneedles in type 1 diabetes subjects. Diabetes Technol. Ther. 13, 451-456 (2011). https://doi.org/10.1089/dia.2010.0204
  20. Pettis, R.J. et al. Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection. Diabetes Technol. Ther. 13, 435-442 (2011). https://doi.org/10.1089/dia.2010.0184
  21. 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). https://doi.org/10.1073/pnas.2331316100
  22. Akkus, O., Oguz, A., Uzunlulu, M. & Kizilgul, M. Evaluation of skin and subcutaneous adipose tissue thickness for optimal insulin injection. J. Diabetes Metab. 3, 2 (2012).
  23. Norman, J.J., Brown, M.R., Raviele, N.A., Prausnitz, M.R. & Felner, E.I. Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes. Pediatr Diabetes 14, 459-465 (2013). https://doi.org/10.1111/pedi.12031
  24. Gupta, J., Felner, E.I. & Prausnitz, M.R. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. Diabetes Technol. Ther. 11, 329-337 (2009). https://doi.org/10.1089/dia.2008.0103
  25. Li, C.G. et al. A Novel Ultrafine Needle (UN) for Innocuous and Efficient Subcutaneous Insulin Delivery. Advanced Functional Materials 27, (2017).
  26. Pettis, R.J. et al. Microneedle-based intradermal versus subcutaneous administration of regular human insulin or insulin lispro: pharmacokinetics and postprandial glycemic excursions in patients with type 1 diabetes. Diabetes Technol. Ther. 13, 443-450 (2011). https://doi.org/10.1089/dia.2010.0183
  27. Kochba, E., Levin, Y., Raz, I. & Cahn, A. Improved Insulin Pharmacokinetics Using a Novel Microneedle Device for Intradermal Delivery in Patients with Type 2 Diabetes. Diabetes Technol. Ther. 18, 525-531 (2016). https://doi.org/10.1089/dia.2016.0156
  28. Lee, C.Y., Lee, K., You, Y.S., Lee, S.H. & Jung, H. Tower microneedle via reverse drawing lithography for innocuous intravitreal drug delivery. Adv. Healthc. Mater. 2, 812-816 (2013). https://doi.org/10.1002/adhm.201200239
  29. McKay, M., Compion, G. & Lytzen, L. A comparison of insulin injection needles on patients' perceptions of pain, handling, and acceptability: A randomized, open-label, crossover study in subjects with diabetes. Diabetes Technol. Ther. 11, 195-201 (2009) https://doi.org/10.1089/dia.2008.0054
  30. Miwa, T. et al. Comparison of the effects of a new 32-gauge x 4-mm pen needle and a 32-gauge x 6-mm pen needle on glycemic control, safety, and patient ratings in Japanese adults with diabetes. Diabetes Technol. Ther. 14, 1084-1090 (2012). https://doi.org/10.1089/dia.2012.0170
  31. Lee, K., Lee, H.C., Lee, D.S. & Jung, H. Drawing lithography: three-dimensional fabrication of an ultrahigh-aspect-ratio microneedle. Adv. Mater. 22, 483-486 (2010). https://doi.org/10.1002/adma.200902418

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