Intranasal Glucagon

Abstract

Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia.

Introduction

Diabetes Mellitus and Hypoglycemia

Today, hundreds of millions of people live with diabetes, and millions of people are on insulin therapy to control their blood glucose levels and to prevent long-term complications of diabetes. Insulin can cause hypoglycemia, a potentially severe, even life-threatening complication that burdens insulin users each and every day. The risk is relevant to all persons with type 1 diabetes and for 30% of patients with type 2 diabetes (persons with T2D who receive insulin). Severe hypoglycemia is defined as an episode of low blood glucose wherein the person with diabetes requires the assistance of a third party to treat the episode. Data generated in a real life cohort of >22 000 persons with T1D as part of the T1D Exchange Patient Registry indicate that severe hypoglycemia occurs frequently. ¹ The fear of another episode often leads to reduced glucose control (ie, allowing blood glucose to remain higher than desired), which, in turn, increases risk of micro- and macrovascular complications. ² It is acknowledged that, if it was not for the barrier of hypoglycemia, people with diabetes could have normal blood glucose levels and thus avoid the complications associated with hyperglycemia. ²

Glucagon, injected by the subcutaneous (SC) or intramuscular (IM), route is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use.

This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia.

Intranasal Administration of Peptide Hormones

Peptide hormones (PHs) are traditionally administered by the parenteral route, be it by SC, IM or intravenous (IV) injection. PHs cannot be administered by the oral route, since they undergo digestion and inactivation in the gastrointestinal tract and a significant first pass metabolism, resulting in complete loss of efficacy. ³ The burden of injective therapies has prompted the search for alternative routes of administration of PHs since the early 1920s, in particular for hormones that require daily and long-life treatments, such as insulin. ⁴ It is now clear that the IN absorption of PHs is inversely related to their dimensions; while short-molecule hormones can be effectively administered by the nasal route, other longer-molecule hormones can not be administered as such, for these hormones do not cross the nasal mucosa, and require promoters. ³

Strategies to improve nasal absorption of molecules have been many, spanning from bile salts to other promoters, nanoparticles, detergents, sodium-tauro 24,25-dihydro-fusidate (STDHF), lysophospholipids, didecanoyl-L-alpha-phosphatidylcholine (DDPC), -cyclodextrins, liposomes, and bioadhesive microspheres. ⁵

During the past decades, nasal administration has become an accepted route for some hormones such as desmopressin, oxytocin, LHRH and its analogues (buserelin, leuprolide, nafarelin),^6,7 salmon calcitonin,^8,9 while intensive efforts have been made but no commercially available formulations have resulted for insulin, GHRH, CRH, GH, human calcitonin, somatostatin, and hexarelin. ⁵ Recently, interest has focused on nasal administration of GLP-1 as a possible treatment for type 2 diabetes mellitus, ¹⁰ and new attempts are under way to deliver insulin by the nasal route. ¹¹ Also, the search for new promoters continues, through the use of phages ¹² and cell-penetrating petides.^13,14

In addition to using the IN route as an alternative to injection for systemic delivery, the IN route has also become a tool to deliver PHs to the brain; for instance, animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity, ¹⁵ and IN insulin has been used to induce insulin sensitivity in lean and obese subjects. ¹⁶ Also, IN insulin has been used to induce immune tolerability in type 1 diabetes mellitus, ¹⁷ and GLP-1 has been administered by the nasal route to modify learning and neuroprotection.^18,19

Challenges With Currently Available Glucagon

As stated before, injected glucagon is the treatment of choice outside of the hospital setting for severe hypoglycemia. Since glucagon is very unstable in the liquid state, it is only available in a kit that consists of glucagon powder in a vial that requires reconstitution immediately prior to injection with diluent provided in a prefilled syringe. For a nonmedical person (a relative, a caregiver) who is confronted with an emergency situation in which a person with diabetes is experiencing a hypoglycemia-related seizure, or is in a hypoglycemic coma, reconstitution and injection of the current injectable form of glucagon is a complex, daunting, and error-prone procedure. This reduces the ready application of current glucagon products by lay people and when used, can result in suboptimal outcomes (eg, through delayed administration, errors in treatment, and delays in receiving medical assistance). In a study in which parents of children and adolescents with type 1 diabetes used a currently available glucagon kit (GlucaGen® HypoKit, Novo Nordisk) in a simulated emergency situation, ²⁰ parents were given an emergency glucagon kit and asked to administer the medication into a wrapped piece of meat to simulate a thigh. Of the 136 parents who participated in the study, all trained on use of glucagon, 69% experienced difficulties in handling the glucagon kit (opening the pack, removing of the needle sheath, mixing the ingredients, and bending needles). On average, the parents who succeeded in completing the procedure required 2 minutes and 30 seconds (range 30 seconds to >12 minutes). Of great concern, 6% aborted the injection entirely and 4% of the participants injected only air or only diluent. ²⁰ These data clearly indicate that the current configuration of glucagon is not optimal for emergency use by non–medical professionals.

Patients also share concerns regarding the current glucagon kits. A telephone survey conducted with 102 patients with type 1 diabetes ascertained their opinions on the currently available glucagon emergency kits. ²¹ Most patients (67%) stated they would prefer an IN administered glucagon were it available, and 82% of these patients believed family members, teachers, and colleagues would prefer to administer emergency therapy by the IN route for treating severe hypoglycemia.

Intranasal Glucagon

Glucagon is different from many other peptide drugs (ie, insulin) for which a precise dose-response is critical to both safety and effectiveness,. Data generated with IV administered glucagon showed that, despite excellent dose proportionality between dose administered and glucagon pharmacokinetics (Cmax and AUC), this was not reflected in the pharmacodynamic (PD) response of glucose (NDA 020928, Eli Lilly). As shown in Table 1, all of the key pharmacokinetic parameters increase with increasing dose following IV dosing. In contrast, the glucose response observed at 2.0 mg IV is essentially the same as that following an IV dose of 0.25 mg. While glucagon levels seen after IV injection far exceed those observed after a SC or IM injection, these results suggest that the maximum glucose PD effect plateaued for glucagon following the lowest dose administered. This effect is further demonstrated in data generated with IN glucagon (see below), demonstrating that it is not necessary to achieve the very high blood glucagon levels obtained with SC or IM injection to achieve a clinically equivalent pharmacodynamic response.

Table 1.

Key Pharmacokinetic and Pharmacodynamic Properties After IV Dosing With Glucagon in Healthy Volunteers (NDA 020928, Eli Lilly).

	Glucagon PK parameters			Glucose PD parameters
Glucagon dose mg, IV	t1/2 (hours)	AUC ng.hr/mL	Cmax ng/mL	BGmax mg/dL	TBGmax hours	AUC mg.hr/dL
0.25	0.128	4.07	37	131	0.34	137
0.5	0.153	8.48	78	138	0.35	137
1.0	0.222	17.9	171	132	0.36	101
2.0	0.299	37.7	368	129	0.35	123

AUC, area under the curve; BGMax, maximum blood glucose; Cmax, maximum concentrations; TBGmax, time to maximum blood glucose; t1/2, elimination half-life;.

In 1983, it was shown for the first time that glucagon, admixed with sodium glycocholate as a promoter, was able to raise blood glucose levels in normal volunteers when administered IN as drops. ²² Studies performed later showed that glucagon solutions and powders were similarly effective, provided a promoter was present (sodium glycocholate, 9-lauryl ether, deoxycholic acid, didecanoyl phosphatidylcholine [DDPC] with alpha-cyclodextrine, sodium caprate, microcrystalline cellulose).^23-26 Eventually, several authors showed the ability of IN glucagon to resolve hypoglycemia in normal volunteers and in diabetic patients, adults, and children.^25-32 These studies, which encompass almost 300 study subjects, demonstrate that glucagon is well-suited for IN administration. Although the bioavailability of IN glucagon is less than that of injected glucagon, resulting in lower peak plasma glucagon concentrations, IN dosing results in a glycemic excursion that is not significantly different from injected glucagon in terms of return to normal glucose levels.^25,28-32 Importantly, reported side effects were limited to short-lived nasal irritation, generally mild, and occasional sneezing. These studies are summarized in Table 2.

Table 2.

Studies Evaluating Intranasal Glucagon.

Author	Glucagon dose (mg)	Subjects	Formulation	Promoter	Efficacy on blood glucose
Pontiroli et al 22	1.0	Healthy volunteers	Drops	Sodium glycocholate	* < IM glucagon
Pontiroli et al 23	1.0	Healthy volunteers	Drops vs spray solution	Sodium glycocholate	Spray > drops * < IM glucagon
Pontiroli et al 24	1.0	Healthy volunteers	Spray solution vs powder	Sodium glycocholate, 9-lauryl ether,	spray = powder
Freychet et al 27	0.28, 0.56, 1.4, 4.2, 7.5	Healthy volunteers, T1DM adults, T1DM adults hypoglycemia	Spray solution	Deoxycholic acid	Dose dependent
Pontiroli et al 28	1.0, 2.0	Healthy volunteers, T1DM adults, T1DM adults hypoglycemia	Spray solution	Glycocholic acid	* = IM glucagon
Slama et al 25	1.0	Healthy volunteers, T1DM adults	Powder	Glycocholic acid	* = SC glucagon
Slama et al 29	1.0	T1DM children	Powder	Glycocholic acid	* = SC glucagon
Rosenfalck et al 30	1.0, 2.0	T1DM adults	Powder	DDPC+ alpha-cyclodextrine	* = IM glucagon
Stenninger and Aman 31	1.0	T1DM children	Powder	DDPC+ alpha-cyclodextrine	* = SC glucagon
Hvidberg et al 32	2.0	T1DM adults	Powder	DDPC + alpha-cyclodextrine	* = IM glucagon
Teshima et al 26	1.0	Healthy volunteers	Spray solution vs powder	sodium glycocholate, sodium caprate, micro-crystalline cellulose

DDPC, didecanoyl-phosphatydilcholine; T1DM, type 1 diabetes mellitus; *, comparison with IM or SC glucagon.

Since the first IN data were generated, extractive porcine glucagon has been replaced with genetically engineered glucagon, which is absolutely identical to the former as to metabolic effects. ³³ Studies are also in progress on chemically stabilized glucagon, ³⁴ chemically modified glucagon, ³⁵ and other approaches to stabilize glucagon in the liquid state.^36,37

Despite promising earlier data, research on IN glucagon appears to have been minimal as no studies have been published, aside from a single case report, published in 2013, in which IN glucagon, without promoters, was reported to be effective in an emergency situation of hypoglycemia. ³⁸ The reasons for which IN glucagon has not been pursued are unknown, but one can speculate that absence of an appropriate administration device, the comparatively limited market size of rescue glucagon compared to insulin and other treatments for diabetes (ie, incretins, SGLT2 inhibitors, etc) with larger commercial potential are such that established companies in diabetes have chosen not to innovate in glucagon delivery.

A Renewed Interest

In recent years, there has been renewed interest in IN glucagon as a potential approach to address the unmet medical need for a glucagon delivery system that is easy for health care providers to teach, easy for patients or caregivers to carry, and easy for nonmedical caregivers to use in treating an episode of severe hypoglycemia. AMG504-1 (Locemia Solutions, Montreal, Canada) is a new IN glucagon product that is being investigated in a series of clinical studies. AMG504-1 is a needle-free, glucagon delivery system that consists of a dry powder glucagon formulation in compact, highly portable, single-use nasal powder dosing device that allows for simple, single step administration. The formulation consists of glucagon with a phospholipid that acts as an absorption enhancing agent and a cyclodextrin as a bulking agent. The formulation is contained within a small nasal dosing device that has been specifically developed for delivering powder into the nasal cavity (Unit Dose Powder, Aptar Pharma, Le Prieure, 27110 Le Neubourg, France). As there is no reconstitution or other steps required prior to use, the caregiver simply inserts the tip of the device into 1 external nare and fully depresses the plunger. This gently expels the powder into the nasal cavity. The product has been designed such that particle size precludes delivery to the lung; therefore, the drug is absorbed through the nasal mucosa without any need for the patient to inhale or to breathe deeply, ensuring effective dosing even in unconscious patients.

This product has been tested in fasted healthy volunteers as part of a 4-way cross-over study to evaluate the safety and PK/PD of 3 dose levels of glucagon administered IN compared to the commercially available 1 mg injected dose. ³⁹ On each of 4 separate dosing days, 16 subjects (ages 20-52 years, 6 female) received 0.5, 1, or 2 mg of glucagon IN or 1 mg of glucagon (Glucagon Emergency Kit for Low Blood Sugar, Eli Lilly, Indianapolis, IN) injected SC. With respect to pharmacokinetics, Figure 1 shows the effects of 3 doses (0.5, 1.0, 2.0 mg) of IN glucagon and of 1.0 mg SC glucagon. As expected from previous studies with IN glucagon, onset of absorption from the nasal mucosa was very rapid with increases in blood glucagon levels occurring within minutes of dosing. Plasma glucagon levels following IN dosing were dose related and SC administration resulted in much higher levels of glucagon that IN dosing. Despite lower bioavailability, dose levels of 1 mg and 2 mg of glucagon administered IN resulted in a substantial glucose response in healthy subjects. The glucose response to a 2 mg IN dose was similar to that observed after a 1 mg SC dose; however, glucagon exposure was significantly less with IN dosing compared to SC dosing.

Figure 1.

Mean (± SE) serum concentrations of glucagon and of glucose after administration of intranasal glucagon (3 doses: 0.5, 1.0, 2.0 mg) and subcutaneous glucagon (1.0 mg).

Data generated in the study suggest AMG504-1 has an acceptable safety profile in that, other than mild to moderate transient signs of nasal and/or ocular irritation in some participants, all dose levels tested were well tolerated. The systemic safety profile of IN glucagon also appears encouraging. In these healthy volunteers, injection of glucagon was followed by nausea in 40% and vomiting in 20% of treated subjects. In contrast, there were no significant gastrointestinal adverse signs after IN dosing at any of the dose levels tested. The results of this early clinical study are encouraging; however, additional research is required to evaluate other important clinical considerations such as the ability of the intended user (ie, caregivers) to use the product, efficacy in treating patients with hypoglycemia, and the effect of nasal congestion on this route of administration.

Conclusions

Treatment of diabetes aims at normal blood glucose levels to prevent long term micro- and macroangiopathic diabetic complications. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. The fear of another episode can lead to nonoptimal glucose control, with an increased risk of diabetic complications. ² Therefore there is a struggle between the well-established clinical benefits of reducing blood glucose levels to the normal range and the increased risk of hypoglycemia that this practice entails.

A unique and critical aspect of glucagon use is the intended user. Unlike insulin, which is routinely injected by the person with diabetes, glucagon is administered by a third party (eg, spouse, child, friend, work colleague, sports coach, etc) who is almost never a trained medical professional. In its current form, administration of glucagon is, in fact, an invasive and relatively complex medical procedure, and therefore it is underprescribed, undertaught, and underused. ²⁰ This leads to suboptimal use of an otherwise effective medication, to unnecessary delays in treatment and costly use of emergency medical systems including ambulance services, emergency room visits, and hospital admissions.

It is hoped that continued research into simple glucagon delivery systems, such as an IN approach, will result in products that make it easier for health care providers to teach people being prescribed insulin therapy, and their caregivers, about the critical importance of hypoglycemia preparedness and, in particular, emergency rescue procedures.