Development of a Highly Stable, Nonaqueous Glucagon Formulation for Delivery via Infusion Pump Systems

Abstract

SymposiumGlucagon is currently approved for the treatment of severe hypoglycemia.1,2 Because glucagon is not stable in aqueous solutions, these preparations are provided as lyophilized powders for reconstitution. Once reconstituted, these preparations begin to degrade and fibrillate rapidly and must be discarded if not used immediately. While suitable for treatment of severe hypoglycemia, these glucagon preparations are unstable and thus not suitable for development of additional indications including minidosing for mild to moderate hypoglycemia 3 and infusion pump applications. In particular, a stable glucagon suitable for use in infusion pump systems creates an opportunity for treatment of hypoglycemia under different conditions, including as a component of an artificial or "bionic" pancreas system. 4,5Despite a vigorous research effort, to date development of aqueous-based glucagon formulations (without reconstitution) has failed to produce any clinical candidates. We have developed a novel, nonaqueous glucagon formulation based on a biocompatible pharmaceutical solvent, dimethyl sulfoxide, which demonstrates excellent physical and chemical stability (up to 2 years at room temperature) 6 at relatively high concentrations.The solubility and stability of this formulation allow for development of a higher concentration formulation (5 mg/ml vs 1 mg/ml for the currently approved glucagon formulations) to facilitate administration from devices such as autoinjectors, pens, pumps, and so on. Furthermore, this glucagon formulation is in clinical development as a treatment for severe hypoglycemia 6 and moderate hypoglycemia and for management of blood glucose in pump applications.This article presents stability, compatibility, and preclinical data supporting progression of this formulation into clinical development. Background: Despite a vigorous research effort, to date, the development of systems that achieve glucagon stability in aqueous formulations (without reconstitution) has failed to produce any clinical candidates. We have developed a novel, nonaqueous glucagon formulation based on a biocompatible pharmaceutical solvent, dimethyl sulfoxide, which demonstrates excellent physical and chemical stability at relatively high concentrations and at high temperatures.

The challenges of achieving postprandial glucose control using closed‐loop systems in patients with type 1 diabetes

“…However, a regular use of glucagon requires the development of a glucagon formulation that can be stable for multiple days at ambient temperatures. Research efforts are advancing for that matter, with new glucagon formulations and analogs being under development or testing in clinical settings . Conversely, glucagon exerts diverse effects on many organs and systems, raising questions about its potential additional benefits (eg, reducing satiety) but also safety in the context of chronic use .…”

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

“…11 There remains an unmet need for a stable glucagon formulation. Xeris Pharmaceuticals is developing a bodytemperature stable, soluble liquid glucagon formulation, G-Pump™ glucagon, that can be administered with an infusion pump, 12,13 and it has been safely administered to adults with type 1 diabetes via syringes.…”

Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

“…Currently available glucagon formulations start degrading and form fibrils shortly after reconstitution, meaning that glucagon has to be replaced every day to avoid a loss in glucagon efficacy or pump occlusions attributable to fibrils . This has led to the search for stable liquid glucagon formulations not requiring reconstitution . Until now, “in‐use” drug stability and compatibility in an infusion‐pump (G‐Pump) has been shown for dimethylsulfoxid (DMSO) glucagon, which demonstrated sufficient efficacy at all three doses tested (0.3, 1.2 and 2.0 μg/kg) compared with GlucaGen; however, DMSO glucagon was associated with significantly more erythema and pain at the infusion site compared with GlucaGen.…”