Glucagon Aqueous Composition Using Cationic Surfactant
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Solution Overview
Problem
Current glucagon formulations for injection are unstable in aqueous solutions, leading to aggregation, fibril formation, and deamidation, which complicates their use in emergency hypoglycemia treatment due to solubility issues and pain on injection.
Innovation Solution
A stable aqueous composition of glucagon with a pH between 4 and 7, containing a cationic surfactant such as benzalkonium or benzethonium salts, which maintains solubility and stability, preventing visible precipitation and gel formation during storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If glucagon is formulated in aqueous solution for immediate administration, then convenience and speed of use are improved, but solubility and stability deteriorate leading to aggregation and fibril formation
Solution Approach 1:
A surfactant is introduced as an intermediary substance to mediate between glucagon and the aqueous environment. The surfactant molecules interact with glucagon to prevent aggregation and maintain solubility in aqueous solution, enabling both immediate administration and stability.
Solution Approach 2:
The pH of the aqueous solution is carefully controlled and adjusted to a specific range (pH 2-3) where glucagon exhibits improved solubility and reduced aggregation. This parameter change transforms the unfavorable aqueous environment into a stable formulation condition.
2Quantity of substance
If glucagon is formulated at very low pH to improve solubility, then solubility is improved, but deamidation of glutamine residues increases
Solution Approach 1:
The surfactant acts as a protective intermediary that shields glucagon from pH-induced deamidation while maintaining solubility. This allows the formulation to benefit from low pH solubility enhancement without suffering the full detrimental effects on chemical stability.
3Stability of the object's composition
If glucagon is formulated as lyophilised powder requiring reconstitution, then stability is improved, but time and complexity of administration increase
Solution Approach 1:
The glucagon is pre-formulated and pre-stabilized in aqueous solution with appropriate pH adjustment and surfactant addition during manufacturing. This preliminary action eliminates the need for reconstitution at the point of use, saving time while maintaining stability through the incorporated stabilizing mechanisms.
4Quantity of substance
If conventional surfactants are used to maintain solubility, then solubility is improved, but visible precipitation and gel formation occur during storage
Solution Approach 1:
The pH is precisely controlled within the narrow range of pH 2-3, which optimizes both solubility and physical stability. This specific parameter range prevents the gel formation and precipitation that occur at other pH values while maintaining adequate solubility.
Solution Approach 2:
The formulation uses a composite approach combining glucagon, surfactant, and buffer system in specific proportions. This composite formulation achieves synergistic effects where the combination provides both solubility enhancement and physical stability during storage, overcoming the limitations of individual components.
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 formulation provides a stable and effective glucagon solution that remains clear and non-viscous, reducing deamidation and maintaining glucagon activity, making it suitable for emergency use and long-term storage without the need for reconstitution.
Implementation Method 1
containing a cationic surfactant such as benzalkonium or benzethonium salts, which maintains solubility and stability
Data Source
AI summary
There is provided according to the invention an aqueous composition having pH between 4 and 7 comprising (i) glucagon at a concentration of 0.05% w/v or more and (ii) a cationic surfactant selected from benzalkonium salts and benzethonium salts as solubilizing agent in an amount sufficient to dissolve the glucagon in the composition.