Glucagon Kits: GlucaPen Aims To Improve Our Emergency Arsenal


As a child with diabetes, one of the most frightening reminders of the danger of the disease was the emergency glucagon kit. Not only was it a symbol of the terrifying risk of severe hypoglycemia, it also had a giant needle.  And as I look at the kit today, which I found after digging through some drawers, I have to agree with my childhood self; that’s one big needle!

Glucagon kits are part of the emergency arsenal for diabetics; Novo Nordisk and Eli Lilly each manufacture the kits, which come in bright red or orange cases and contain a disposable syringe pre-filled with liquid and a vial with 1 milligram of glucagon powder. The glucagon powder has the same chemical formulation as human glucagon, but has been preserved through lyophilization (freeze-drying).

Glucagon kits are not designed for quotidian lows, but for severe hypoglycemic incidents, in which a diabetic’s blood sugar gets so low that she becomes unconscious or has a seizure. In the event of severe hypoglycemia, a friend, family member, or emergency responder would remove the syringe and glucagon vial from the case. The responder would then remove the cap from the needle, remove the cap from the vial, and inject the liquid contained in the syringe into the glucagon vial. The liquid and freeze-dried glucagon would have to be mixed within the vial and subsequently drawn back up into the syringe. Finally, the responder would inject the newly mixed solution into the diabetic’s leg or abdomen.

Why is the procedure so complex, and the needle so threatening? Glucagon, like insulin, is an unstable protein when dissolved in solution. At a moment’s notice, glucagon forms amyloid fibrils, or tightly woven chains of proteins made up of the individual glucagon peptides. And, as soon as glucagon begins to fibrilize, it becomes useless when injected, as the glucagon cannot be absorbed and used in the body.

This amyloid fibril formation can happen very quickly, and within a few days, glucagon in solution becomes noticeably viscous [1]. Clearly, this would be a problem for anything designed to be used in emergencies; can you imagine having to replace your glucagon kit every week, or, pulling out a glucagon kit from your purse in an emergency and discovering that after only a few days of jostling around it had become cloudy and useless?

Without the invention of a chemical formulation of glucagon that is more stable, the available alternative is to freeze-dry the glucagon peptide. This prevents the protein molecules from changing form, and therefore allows glucagon to be kept on hand and stored at room temperature for about two years [2]. So despite the complexity of assembling the glucagon kit in an emergency, the user and the patient can at least be confident that the solution will still be potent and effective at the moment it is needed.

As to the length of the needle, it is important to know that glucagon can be injected intravenously, intramuscularly, or subcutaneously, however, the three types of injection do not all achieve the same results. Intravenous injections work the most quickly, but require an IV and trained personnel to administer. Having to wait for emergency medical teams before using glucagon could delay the treatment, and would defeat the purpose of having a kit for immediate response from home.

Friends and family would be able to administer either subcutaneous or intramuscular injections, and of the two, intramuscular injections work more rapidly, achieving maximum effect in less than 30 minutes, while subcutaneous injections can take 30 – 45 minutes [2,3]. The length of the needle, then, serves to ensure that any untrained person is able to inject the diabetic patient with glucagon, and to get far enough into the patient’s tissue that the glucagon begins to take effect within a short period of time.

Despite these complexities, it is surprising that there is not a more user-friendly glucagon kit available. It is crucial for the unconscious diabetic that the response be immediate and effective, but the difficulties inherent in the glucagon kit make such a response harder for untrained friends and family. The more steps required before the glucagon is circulating in the patient’s blood stream, the more opportunity there is for error and failure.

So why isn’t there something better, easier, faster, and simpler? Well, fortunately, there may be soon. Enject, Inc., a Washington-based biotech start-up, has announced that they’ve completed prototypes of – and are moving forward with – a novel way to inject glucagon in emergencies: the GlucaPen.

The GlucaPen is designed to be the entire glucagon kit, rolled into a single pen-needle. The pen cartridge contains both the freeze-dried glucagon powder and the liquid for mixing. In an emergency, users would rotate the base of the pen to engage an integration process within the pen that automatically mixes the two elements. Then the user need only uncap the needle, and inject the solution into the diabetic patient.

This simplified injection process seems a good way to improve the success rates of emergency treatment for hypoglycemia, but there are many open questions, especially given the fact that the product is still in an early stage of development. I was happy to be able to ask Dick Rylander, CEO of Enject, some of my questions directly, and to get some promising answers:

Why is glucagon necessary in the treatment of diabetics?

It’s necessary if and when their blood sugar drops low enough, fast enough, that they lose consciousness and can slip into a diabetic coma, have seizures, suffer brain damage or die. This degree of hypoglycemia is defined as severe because it requires the assistance of another. Because the patient is unconscious, oral sugar/glucose is not an option. The injected glucagon signals the liver to release its stored glucose into the blood thereby returning the patient to consciousness where additional measures can be taken.

What is wrong with current glucagon kit systems?

They are cumbersome, require numerous steps (12-15 depending on who’s counting), are prone to damaged needles, risk of secondary needle sticks, loss of liquid due to handling, dropping, etc. Caregivers are under stress, agitated, prone to making mistakes, and frequently fear seeing the needle and the act of giving the injection (despite the fact that the patient is unconscious, and assuming they make no errors).

How is the GlucaPen™ better than the current kits?


  • Twist the base to automatically mix, rotate the needle cover which automatically engages the needle, primes and extends the needle shield, and then press against a muscle until a click is felt and heard. You can see the mixing and injection completion in the side windows of the pen
  • No dose choices: GlucaPen™ will deliver 1mg and GlucaPen Jr™ 0.5mg
  • Needle shield locks after use so it is safe and simple to dispose of
  • No exposed needle and thus no potential for secondary needle sticks
  • Invisible needle and thus not intimidating
  • Better portability and just simpler to use


Is there any evidence, other than anecdotal, that shows that the difficulty of using the current glucagon kits has led to a significant number of botched responses to hypoglycemic incidents?
Not that we are aware of. One senior executive at one of the existing manufacturers suggested a failure rate of as high as 25%, but this is also anecdotal. Most reports of failure come from the community (patients and caregivers). More importantly, the perceived difficulty and risks of the current kits that reduce the likelihood of the kit being prescribed, purchased, readily available and used when needed.


From the outside, the GlucaPen™ seems simple to use– twist the base to mix, twist off the cap to open, and insert. What’s happening inside the pen that makes this possible?

There is a special glass cartridge (see graphic) that is divided into two chambers. In the forward (top) chamber is the lyophilized (freeze-dried) glucagon and in the rear (bottom) chamber is the diluent. There is a glass channel just above the middle stopper that allows the liquid to pass around the forward stopper when mixed.

  • When the base of the pen is twisted a spring releases a rod that pushes the rear stopper upward
  • The pressure of the liquid causes the forward stopper to slide toward the top of the cartridge
  • The liquid flows through the channel where it dissolves the glucagon
  • Removing the needle cover causes the base of the needle to puncture the top of the cartridge, followed by automated priming, which releases about 1ml of air and a tiny squirt of liquid. (The cartridge has 1.1ml so a small loss is of no consequence.)
  • Pressing and holding the end of the pen firmly against the skin (the needle is always hidden inside the needle shield) triggers the injection to occur automatically, and can be seen visibly through the observation windows.
  • As the pen is removed after the injection, the spring-loaded shield extends over the needle and locks thus preventing secondary needle sticks and reuse.


Aside from the mechanics and injection process, is anything different about the glucagon in the GlucaPen™ and the current glucagon kits? Are the glucagon powder and mixing solution different in any way from the currently used sets?

Yes there are differences:

  • We will use synthetic glucagon rather than the human recombinant glucagon used by both of the existing products (each company has their own process for manufacturing glucagon)
  • The reduced potential for contamination in the manufacturing process makes the synthetic preferable and easier to make
  • Our freeze-dried glucagon has a proprietary formulation (for both the glucagon and the diluent) specially designed for rapid dissolution.


Three of the four members of Enject’s management team share a history at DiObex, Inc., a biotechnology company that was engaged in clinical trials of a number of diabetes-focused drugs, including a low-dose glucagon called DIO-901. DIO-901 showed promise as a compliment to insulin treatment and as a means of preventing hypoglycemia in type 1 diabetics, but all news of DIO-901 stopped after DiObex was shut down by investors in 2009. What happened to DIO-901, and, given the backgrounds of the members, does Enject have any plans beyond the GlucaPen™ for novel glucagon formulations and implementations?
We’re not in a position to comment about the status of any DiObex projects. Enject is entirely focused on getting GlucaPen™ to market at this time.


How do the manufacturing costs for the GlucaPen™ compare to those of the current glucagon kits? Will any change in manufacturing costs be passed on the consumer?
The costs of components for GlucaPen™ are understandably higher than the old vial/syringe system, and then of course there are the investments in development, which as you can imagine are substantial. Pricing decisions will be made closer to the time of launch.


Does Enject hold any patents related to the GlucaPen™?

We have global exclusive agreements with the manufacturers of both the cartridge and pen components. Through these agreements we accrue the protection afforded by their extensive intellectual property, know-how, and decades of experience. We of course are also beneficiaries of their installed capacity and have no need to invest in any additional manufacturing capability.


Who is the intended audience of the GlucaPen™? Do you think the easier injection format will create new markets for glucagon in institutions that do not currently purchase the product?

  • Patients (insulin using diabetics) and their caregivers
  • School nurses and teachers
  • Fire departments (EMS)
  • Hospitals and clinics


How often do diabetic patients replace glucagon kits now, and how would this change with the GlucaPen™?

There are no data. The prescriptions are written to be refilled annually but anecdotal reports suggest that some do yearly, some every two years and some never seem to remember to replace expired kits.We believe GlucaPen™ uptake and use will be very similar to the EpiPen® model (which was preceded by epinephrine ampoules and syringes).Because of their simplicity and ease of use, insulin using diabetics will be more likely to purchase multiple GlucaPens™, to keep in multiple locations where the need may arise and are likely to replace them more diligently upon expiration.The simplicity may drive increased use which would reduce EMT responses, ambulance transfers and hospital admissions. This could save the healthcare system tens of millions or more.


How does the shelf-life of the GlucaPen™ compare to that of current glucagon kits?

The existing kits have an approved life of 24 months. We expect GlucaPen™ will have the same.


What stage of development is the GlucaPen™ currently in, and what is required in terms of funding, scientific development, manufacturing processes, and FDA approval to bring the pen to market? What is the current timeline of these processes?

We have completed the pen development and it is fully functional. The cartridge is done. The formulation is done. We are now preparing to initiate commercial scaling, perform extensive reliability testing of the pen and conduct a human factors study.The regulatory pathway is well defined, with established precedent. In a nutshell we will demonstrate equivalence to marketed glucagons with a modest program of animal and human studies. Our goal is to submit the IND [Investigational New Drug Application] next Spring followed rapidly by the NDA [New Drug Application]. We will also apply for “fast track” status once our IND is open.


Who is funding Enject? Will the current funding be sufficient to carry the GlucaPen™ to completion, or will further funding be sought as the product nears the market?

To date the company has been funded by Angel investors, experienced and knowledgeable in the biopharmaceutical space. We are in the process of determining whether to commercialize independently or in partnership with a larger company. Depending on that decision, we will either raise an institutional venture round, or our development will be completed with partner support.

So will there be alternatives to the current emergency glucagon kits in the near future? Potentially, if Enject has its way; and eventually there may even be new formulations of glucagon itself, allowing an even broader set of uses and injection mechanisms. In the meantime, though, all of this has made me realize that my glucagon kit is expiring soon, so I’d better get a new one, complicated and scary as it is.

[1] Gratzer W.B., Bailey E., Beaven G.H. Conformational states of glucagon (1967) Biochemical and Biophysical Research Communications, 28 (6), pp. 914-919.

[3] GlucaGen [glucagon (rDNA origin) for injection]

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Scott S
12 years ago

You mentioned amyloid fibrils, which is interesting because on July 9, 2010, the medical journal Endocrinology reported (see for details) that inhaled insulin forms toxic pulmonary amyloid aggregates in the lungs, and yet the drug industry is trying to promote this as better for people with diabetes due to its speed of action.  Sounds suspect to me.  As for the issues with glucagon, there are several companies including Biodel, Inc. and Marcadia Biotech, Inc. (based in Carmel, IN, but has signed a deal with Eli Lilly & Co., as the company was started by some former Lilly researchers) who are… Read more »

GlucaPen and GlucaPen Jr
GlucaPen and GlucaPen Jr
12 years ago
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