Stable Glucagon Formulation via Aprotic Solvent
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Solution Overview
Problem
Current glucagon formulations are unstable when reconstituted, leading to fibrillation and loss of effectiveness within hours, making chronic administration impractical for treating mild or moderate hypoglycemia and weight management.
Innovation Solution
Development of a stable glucagon formulation using an aprotic polar solvent system with an ionization stabilizing excipient, such as glycine hydrochloride, that maintains stability for extended periods at various temperatures, allowing for chronic administration without the need for drying from a buffered aqueous solution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucagon is reconstituted in aqueous solution for injection, then it becomes absorbable and usable by the body, but it forms amyloid fibrils and becomes unstable within hours
Solution Approach 1:
The patent changes the fundamental parameter of the solvent system from aqueous to aprotic polar (e.g., DMSO, ethyl acetate, NMP). This parameter change prevents the formation of amyloid fibrils while maintaining glucagon solubility and stability for extended periods at room temperature, directly resolving the contradiction between stability and duration of effectiveness
Solution Approach 2:
The patent creates a composite formulation by combining glucagon with aprotic polar solvents and ionization-stabilizing excipients (such as glycine hydrochloride). This composite system provides both the solubility needed for injection and the stability required for chronic administration, eliminating the fibrillation problem that occurs with pure aqueous solutions
2Duration of action of moving object
If glucagon is administered chronically for weight management and hypoglycemia treatment, then therapeutic benefit is achieved, but the need for frequent reconstitution and sterile handling becomes impractical
Solution Approach 1:
The patent performs preliminary stabilization by formulating glucagon in aprotic polar solvents with ionization-stabilizing excipients before administration. This preliminary action ensures the glucagon remains stable without requiring reconstitution at the time of use, making chronic administration practical and eliminating the need for frequent sterile handling
Solution Approach 2:
The patent replaces the disposable vial-reconstitution system with a stable formulation that can be stored in practical containers (such as pens or syringes) without requiring sterile reconstitution each time. This makes the treatment as convenient as other chronic medications
3Reliability
If glucagon is given in standard doses for severe hypoglycemia, then life-saving effect is achieved, but it is not suitable for treating mild or moderate hypoglycemia or for weight management
Solution Approach 1:
The patent segments the glucagon dosing into different levels (low dose for mild/moderate hypoglycemia and weight management, standard dose for severe hypoglycemia). The stable formulation enables this segmentation by allowing precise control of small doses while maintaining stability, which would be difficult with conventional unstable formulations
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The stable glucagon formulation remains effective for at least one week at room temperature and up to three months at 4°C, enabling effective chronic administration for managing hypoglycemia and weight control without the need for frequent reconstitution.
Implementation Method 1
Development of a stable glucagon formulation using an aprotic polar solvent system with an ionization stabilizing excipient, such as glycine hydrochloride
Implementation Method 2
an aprotic polar solvent system with an ionization stabilizing excipient, such as glycine hydrochloride, that maintains stability for extended periods
Data Source
AI summary
The present invention provides methods for controlling or reducing caloric intake in a subject by administering a low dose of a stable glucagon formulation. The present invention further provides methods for treating mild or moderate hypoglycemia in a subject in need thereof subject by administering a low dose of a stable glucagon formulation. Kits for practicing the methods of the invention are also provided.