Readily soluble and thermostable glucagon formulations and delivery for mini-dosing and closed -loop prophylactic treatment of hypoglycemia

A method of delivering glucagon to a mammalian subject with a release structure comprising a readily soluble and thermostable (ReST) glucagon formulation contained within a pH-sensitive polymer that incorporates or is coated with at least one of glucose oxidase, glucose oxidase derivative, or glucose oxidase analogue and that swells and/or dissolves at a pH of about 6 or greater, the method comprising:

• inserting the release structure in the mammalian subject or applying the release structure to skin of the mammalian subject,
• wherein the at least one of glucose oxidase, glucose oxidase derivative, or glucose oxidase analogue catalyzes production of gluconic acid and hydrogen peroxide in the presence of glucose and oxygen, thereby keeping the pH of the pH-sensitive polymer below 6, in the presence of glucose and preventing release of the ReST glucagon formulation from the release structure, and
• wherein the pH of the pH-sensitive polymer rises above 6 in the absence of glucose, causing the pH-sensitive polymer to swell and/or dissolve, thereby releasing the ReST glucagon formulation from the release structure.

A readily soluble and thermostable glucagon formulation consisting essentially of:

• at least one of glucagon, a glucagon analog, or a glucagon derivative;
• and
• an excipient from the group consisting of benzoic acid, sodium carbonate, meglumine, sodium phosphate tribasic, myristyl sulfobetaine, Kollidon HS 15, dodecylphosphocholine, L-Glutamine, PIPES, or sodium succinate.