Glucagon Solution Stabilization via Acidic pH and Polyol
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current glucagon formulations for treating hypoglycemia are not liquid, ready-to-use, non-gelling, chemically stable, pump-able, fast-acting, and safe for long-term use, particularly in bi-hormonal pumps, which are essential for effective glucose regulation in Type-1 diabetes patients.
Innovation Solution
A glucagon solution composition comprising an anti-gelling polyol, an injectable acid, a stabilizing-salt, an antioxidant, and water, with a pH between 2 and 5, which prevents gelation and chemical degradation, making it suitable for injection and use in insulin pumps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If glucagon is dissolved in water at physiological pH, then it is initially soluble, but it aggregates to form a gel within hours
Solution Approach 1:
The patent applies parameter changes by adjusting the pH to acidic conditions (pH 2.0-3.5) and incorporating specific excipients (glycerin, hydrochloric acid) to prevent gelation. This chemical parameter modification maintains glucagon in a soluble, non-gelled state suitable for injection while preserving its therapeutic activity.
2Stability of the object's composition
If glucagon is stored in acidic solution, then it remains soluble, but it degrades rapidly into numerous degradation products
Solution Approach 1:
The patent employs a composite formulation comprising glucagon hydrochloride, glycerin, hydrochloric acid, and water. This composite system leverages the stabilizing effects of glycerin and the solubilizing effects of hydrochloric acid to create a formulation that maintains chemical stability while preventing degradation, resolving the contradiction between solubility and stability.
3Stability of the object's composition
If glucagon is provided as a dry lyophilized cake, then it remains chemically stable, but it requires a multiple-step reconstitution procedure
Solution Approach 1:
The patent applies preliminary action by pre-dissolving glucagon in an acidic glycerin solution during manufacturing to create a ready-to-use liquid formulation. This eliminates the need for reconstitution at the point of administration, allowing for immediate injection while maintaining chemical stability through the acidic environment and glycerin stabilization.
4Ease of operation
If a ready-to-inject glucagon solution is developed, then administration is simplified, but it must be used immediately due to instability
Solution Approach 1:
The patent utilizes parameter changes by maintaining the solution at acidic pH (2.0-3.5) with glycerin as a stabilizing excipient. These parameter modifications extend the shelf life of the ready-to-inject solution while preserving its liquid, ready-to-use characteristics, allowing storage without precipitation or gelation.
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 solution is a clear, stable, and fast-acting glucagon formulation that maintains glucagon activity for extended periods, ensuring effective glucose regulation and safety for chronic use in bi-hormonal pumps.
Implementation Method 1
The gelled glucagon consists predominantly of β-sheets or fibrils that are induced by the molecule's hydrophobicity and the inter- and intra-chain hydrogen bond forming potential of the peptide
Implementation Method 2
an antioxidant
Implementation Method 3
Glucagon has an isoelectric point of 7.1 and is insoluble in water at a physiological pH (pH 4-8). At pH 3 or lower, it is initially soluble
Data Source
Figure 1
Figure 2
Figure 3
AI summary
This invention relates to ready-to-use and safe solution compositions of glucagon suitable for administration by manual injection or by an insulin pump or other injection device to treat hypoglycemia. Said compositions comprise glucagon, an acid, anti-gelling polyol, a stabilizing-salt, viscosity reducer and an antioxidant, have a final pH between about 2 and 5, and is gel-free, chemically-stable, and pump-able.