Glucagon Analog Agonists for Stable Aqueous Formulation
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Solution Overview
Problem
Current glucagon therapies for treating hypoglycemia have poor solubility, chemical stability, and physical stability, making them inconvenient for emergency use, and there is a need for alternative therapeutic agents that maintain biological performance under physiological conditions while providing effective glucose control.
Innovation Solution
Development of glucagon analog agonist compounds with specific amino acid sequences, such as HSXGTFTSDYSKYLD(Aib)RRAQX2FVK(4-Pal)LLST, which exhibit improved solubility, stability, and compatibility for use in aqueous solutions, allowing for pre-formulation in pumps and combination with insulin for closed-loop glycemic control.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucagon is formulated in aqueous buffers at or near physiological pH, then it maintains biological performance, but it exhibits poor solubility
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of glucagon (changing specific residues to improve solubility while maintaining biological activity) and adjusting formulation parameters (pH, buffer composition, concentration) to achieve both adequate solubility and preserved biological performance in aqueous buffers
2Quantity of substance
If glucagon is formulated at low or high pH, then solubility may improve, but it demonstrates poor chemical stability and poor physical stability such as gelation and soluble aggregate formation
Solution Approach 1:
The patent optimizes formulation parameters (pH range, buffer type, ionic strength) to find a balance where solubility is adequate without triggering aggregation or gelation, and modifies the amino acid sequence to enhance stability across a broader pH range, preventing chemical degradation and physical instability
Solution Approach 2:
The patent creates composite formulations combining glucagon with specific buffers, excipients, and stabilizing agents that work synergistically to maintain solubility while preventing aggregation and gelation, effectively creating a stable composite system
3Stability of the object's composition
If current commercial glucagon-based therapies are provided as a lyophilized powder, then stability is improved, but reconstituting at the time of administration is burdensome and inconvenient
Solution Approach 1:
The patent applies preliminary action by pre-formulating glucagon in stable aqueous solutions with optimized pH and buffer systems, along with stabilizing excipients, that maintain stability without requiring lyophilization, thereby eliminating the need for reconstitution while preserving stability
Solution Approach 2:
The patent changes the formulation parameters to enable stable aqueous storage, adjusting pH, buffer composition, and adding stabilizing agents that prevent aggregation and degradation, allowing the drug to be stored and administered in ready-to-use liquid form
Data Source
AI summary
Glucagon analog agonist compounds are provided herein that have improved solubility, as well as improved chemical and physical stabilities, when compared to native, human glucagon. Also provided are pharmaceutical compositions including such glucagon analog agonist compounds, as well as methods of using the same for treating hypoglycemia, especially severe hypoglycemia.