Rapid reconstitution packages (RRPs) for stable storage and delivery of glucagon

  • Sebastian D’hers
  • Agustín N. Abad Vazquez
  • Pablo Gurman
  • Noel M. ElmanEmail author
Original Article


Current emergency injectors of glucagon require manual reconstitution, which involves several steps that may lead to dosage errors. Rapid reconstitution packages (RRPs) are new devices, designed using computational fluid dynamics (CFD) to optimize fluid mixing, integrating physical properties of active pharmaceutical ingredients (APIs), excipients and diluents. RRPs improve drug stability for long-term storage and ease of delivery. Device prototypes were manufactured using advanced stereolithography apparatus (SLA) 3D printing technology. Reconstitution of glucagon with RRPs was evaluated by high-performance liquid chromatography (HPLC) and optical spectroscopy methods. Enzyme-linked immunosorbent assays were performed to test in vitro activity. Experimental results showed that RRPs effectively reconstituted glucagon even after exposure to 60 °C for a 24-h period. RRPs exhibited improved performance at maintaining drug stability compared to lyophilized glucagon stored in a standard glass vial under the same temperature conditions. RRPs represent a portable platform for rapid reconstitution of lyophilized drugs, compatible with standard syringes available in any clinical setting. The RRP provides an alternative to manual reconstitution process, especially designed for medical emergencies.


Reconstitution Hypoglycemia Glucagon Microfluidics Computational fluid dynamics (CFD) Stability Drug delivery Diabetes Emergency medicine Ambulatory settings 


Funding information

This research work was partially supported by GearJump Technologies, LLC, and the US Army Research Office via the Institute for Soldier Nanotechnologies (ISN) at the Massachusetts Institute of Technology (MIT), contract: W911NF-07-D-0004. The corresponding author’s former affiliation was the Institute for Soldier Nanotechnologies (ISN) at MIT.

Compliance with ethical standards

Conflict of interest

N. M. Elman works at GearJump Technologies, LLC. S. D’hers, A. N. Abad Vazquez, and P. Gurman declare that they have no conflict of interest.


  1. 1.
    Powers AC, Endocrine Pancreas D’A, D. Pharmacotherapy of diabetes mellitus and hypoglycemia. In: Brunton L, Chabner BA, Knollmann BC, editors. Goodman and Gilman’s the pharmacological basis of therapeutics, twelfth edition. New York: Mc Graw Hill; 2011.Google Scholar
  2. 2.
    Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes. Diabet Med. 2008;25(3):245–54.CrossRefGoogle Scholar
  3. 3.
    Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902–12.CrossRefGoogle Scholar
  4. 4.
    Cryer PE. Hierarchy of physiological responses to hypoglycemia: relevance to clinical hypoglycemia in type I (insulin dependent) diabetes mellitus. Horm Metab Res. 1997;29(3):92–6.CrossRefGoogle Scholar
  5. 5.
    Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes, Metab Syndr Obes: Targets Ther. 2011;4:337–46.CrossRefGoogle Scholar
  6. 6.
    Stephani TC, Haymond WM. Minimizing morbidity of hypoglycemia in diabetes: a review of mini-dose glucagon. J Diabetes Sci Technol. 2015;9(1):44–51.CrossRefGoogle Scholar
  7. 7.
    Shafiee G, Mohajeri-Tehrani M, Pajouhi M, Larijani B. The importance of hypoglycemia in diabetic patients. J Diabetes Metab Disord. 2012;11:17.CrossRefGoogle Scholar
  8. 8.
  9. 9.
    Lilly glucagon official site:[Accessed September 3, 2017] 2017.
  10. 10.
    GlucaGen official site: [Accessed September 3, 2017] 2017.
  11. 11.
    McDowell SE, Mt-Isa S, Ashby D, Ferner RE. Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis. Qual Saf Health Care. 2010;19(4):341–5.CrossRefGoogle Scholar
  12. 12.
    Grissinger M. Reducing errors with injectable medications. P T. 2010;35(8):428–51.Google Scholar
  13. 13.
    Wheeler DW, Degnan BA, Sehmi JS, Burnstein RW, Menon DK, Gupta AK. Variability in the concentrations of intravenous drug infusions prepared in a critical care unit. Intensive Care Med. 2008;34(8):1441–7.CrossRefGoogle Scholar
  14. 14.
    Parshuram CS, To T, Seto W, Trope A, Koren G, Laupacis A. Systematic evaluation of errors occurring during the preparation of intravenous medication. CMAJ. 2008;178(1):42–8.CrossRefGoogle Scholar
  15. 15.
    Aronson JK. Medication errors: what they are, how they happen, and how to avoid them. Q J Med. 2009;102:513–21.CrossRefGoogle Scholar
  16. 16.
    Kaufmann J, et al. Medication errors in pediatric emergencies: a systematic analysis. Dtsch Arztebl Int. 2012;109(38):609–16.Google Scholar
  17. 17.
    Merry AF, Anderson BJ. Medication errors-new approaches to prevention. Paediatr Anaesth. 2011;21:743–53.CrossRefGoogle Scholar
  18. 18.
    Motaarefi H, Mahmoudi H, Mohammadi E, Hasanpour-Dehkordi A. Factors associated with needlestick injuries in health care occupations: a systematic review. J Clin Diagn Res. 2016;10(8):IE01–IE042.Google Scholar
  19. 19.
    Sherr JL, Ruedy KJ, Foster NC, Piché CA, Dulude H, Rickels MR, et al. Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care. 2016;39:555–62.Google Scholar
  20. 20.
    Locemia website: [Accessed September 3, 2017] 2017.
  21. 21.
    Reno EF, Normand P, McInally K, Silo S, Stotland P, Triest M, et al. A novel nasal powder formulation of glucagon: toxicology studies in animal models. BMC Pharmacol Toxicol. 2015;16:29.CrossRefGoogle Scholar
  22. 22.
    Pontiroli AI. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia. J Diabetes Sci Technol. 2015;9(1):38–43.CrossRefGoogle Scholar
  23. 23.
    Seaquist ER, Dulude H, Zhang XM, Rabasa-Lhoret R, Tsoukas GM, Conway JR, et al. Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real-world setting. Diabetes Obes Metab. 2018;20:1316–20.CrossRefGoogle Scholar
  24. 24.
    Pontiroli AE, Calderara A, Pozza G. Intranasal drug delivery: potential advantages and limitations from a clinical pharmacokinetic perspective. Clin Pharmacokinet. 1989;17(5):299–307.CrossRefGoogle Scholar
  25. 25.
    Deeb LC, Dulude H, Guzman CB, Zhang S, Reiner BJ, Piché CA, et al. A phase 3 multicenter, open-label, prospective study designed to evaluate the effectiveness and ease of use of nasal glucagon in the treatment of moderate and severe hypoglycemia in children and adolescents with type 1 diabetes in the home or school setting. Pediatr Diabetes. 2018;19:1007–13.CrossRefGoogle Scholar
  26. 26.
    Pontiroli AE, Ceriani V. Intranasal glucagon for hypoglycaemia in diabetic patients. An old dream is becoming reality? Diabetes Obes Metab. 2018;20:1812–6.CrossRefGoogle Scholar
  27. 27.
    Chi A, Curi S, Clayton K, Luciano D, Klauber K, Alexander-Katz A, et al. Rapid reconstitution packages (RRPs) implemented by integration of computational fluid dynamics (CFD) and 3D printed microfluidics. Drug Deliv Transl Res. 2014;4:320–33.CrossRefGoogle Scholar
  28. 28.
    SolidWorks 2013 Dassault Systèmes SolidWorks Corp.Google Scholar
  29. 29.
    ANSYS. Inc Release Notes; 2013. p. V15.Google Scholar
  30. 30.
    Sacha GA, Saffell-Clemmer W, Abram K, Akers MJ. Practical fundamentals of glass, rubber, and plastic sterile packaging systems. Pharm Dev Technol. 2010;15(1):6–34.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2019

Authors and Affiliations

  • Sebastian D’hers
    • 1
  • Agustín N. Abad Vazquez
    • 2
  • Pablo Gurman
    • 2
  • Noel M. Elman
    • 2
    Email author
  1. 1.Department of Mechanical EngineeringInstituto Tecnológico de Buenos Aires (ITBA)Buenos AiresArgentina
  2. 2.GearJump Technologies, LLCBrooklineUSA

Personalised recommendations