Stable Glucagon Analogues for Liquid Formulations
Solution Overview
Problem
Current glucagon products for treating hypoglycemia have low physical and chemical stability, making them unsuitable for stable liquid formulations, which are necessary for immediate use and storage, especially for individuals who cannot reconstitute them quickly due to acute conditions.
Innovation Solution
Development of stable glucagon analogues with specific amino acid substitutions and deletions that enhance solubility and stability, allowing for a ready-to-use liquid pharmaceutical formulation that can be stored under ambient conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If native glucagon is formulated as a liquid preparation, then it provides immediate usability and convenient storage, but it exhibits low physical and chemical stability leading to aggregation and degradation
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of glucagon at specific positions (2, 3, 4, 9, 10, 15, 16, 17, 20, 21, 24, 28, and/or 29) to create analogues with improved stability. These sequence modifications change the physical and chemical parameters of the peptide, reducing aggregation and degradation while maintaining biological activity, thereby enabling stable liquid formulations for immediate use.
Solution Approach 2:
The patent creates composite structures by incorporating stabilizing amino acid substitutions and deletions into the glucagon sequence. These modifications create a composite peptide structure that combines the pharmacological activity of native glucagon with enhanced stability properties, allowing the molecule to resist aggregation and degradation in liquid formulations.
2Reliability
If freeze-dried solid preparations are used, then storage stability is improved, but reconstitution and injection require additional time and user expertise
Solution Approach 1:
The patent applies preliminary action by pre-modifying the glucagon molecule through amino acid substitutions and deletions to enhance its stability in liquid form. This preliminary structural modification eliminates the need for subsequent reconstitution steps, allowing the medication to be administered directly from liquid formulation while maintaining storage stability.
Solution Approach 2:
The patent extracts the reconstitution step from the administration process by developing stable liquid formulations that can be used directly. The amino acid modifications enable the glucagon analogue to remain stable in liquid form, thereby removing the unnecessary intermediate step of reconstitution and reducing the time required for administration.
3Reliability
If glucagon analogues with amino acid substitutions are developed, then solubility and stability in liquid medium are improved, but molecular structure complexity increases
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions and deletions at specific positions (2, 3, 4, 9, 10, 15, 16, 17, 20, 21, 24, 28, and/or 29) within the glucagon sequence. These localized modifications improve solubility and stability without requiring comprehensive changes to the entire molecular structure, thereby limiting the increase in complexity to specific regions of the molecule.
Data Source
AI summary
The present invention relates to glucagon analogues and their medical use, for example in the treatment of hypoglycaemia. In particular, the present invention relates to stable glucagon analogues suitable for use in a liquid formulation.