Glucagon Formulation Using Aprotic Polar Solvent for Stability
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Solution Overview
Problem
Current glucagon rescue medications for severe hypoglycemia are not user-friendly, requiring complex reconstitution and are not stable at non-refrigerated temperatures, making them unsuitable for continuous carry and emergency use.
Innovation Solution
A stable glucagon formulation using an aprotic polar solvent like DMSO, which maintains the peptide's ionization profile upon reconstitution, allowing for long-term storage at room temperature and simple administration without reconstitution, suitable for parenteral or transdermal delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucagon is formulated in aqueous solution, then it is soluble and administrable, but it becomes unstable at non-refrigerated temperatures and requires complex reconstitution procedures
Solution Approach 1:
The patent changes the solvent parameter from aqueous to aprotic polar (DMSO, NMP, ethyl acetate), which fundamentally alters the stability profile of glucagon. This parameter change enables the formulation to maintain stability at room temperature without requiring refrigeration, while still allowing for simple administration without complex reconstitution procedures.
Solution Approach 2:
The formulation uses a composite approach by combining glucagon peptide with specific aprotic polar solvents and optional stabilizing excipients (sugars, starches, sugar alcohols). This composite formulation achieves both stability and ease of administration by leveraging the complementary properties of each component.
2Reliability
If glucagon is dried from aqueous solution, then stability improves, but the ionization profile changes and complicates reconstitution
Solution Approach 1:
The patent changes the drying parameter by using aprotic polar solvents instead of aqueous solutions. This prevents the ionization profile changes that occur during aqueous drying, as the aprotic polar environment maintains the peptide's ionization state. The result is a formulation that is stable in dried form but requires no reconstitution, eliminating the complexity entirely.
Solution Approach 2:
The patent extracts water from the formulation by using aprotic polar solvents and drying processes that remove aqueous components. This extraction of water prevents hydrolysis and degradation, improving stability, while the resulting anhydrous or low-moisture formulation requires no reconstitution, simplifying administration.
3Reliability
If current glucagon kits are used, then treatment of severe hypoglycemia is effective, but the procedures are complex and not suitable for continuous carry
Solution Approach 1:
The patent merges the peptide and solvent into a single stable formulation that can be stored as-is without separate vials or reconstitution steps. This combining of components into one stable preparation maintains effectiveness while dramatically improving user-friendliness, making the medication suitable for continuous carry by diabetics and caregivers.
Solution Approach 2:
The patent performs preliminary stabilization by formulating glucagon in aprotic polar solvents and drying it under controlled conditions before use. This preliminary action creates a formulation that is pre-stabilized and ready for immediate administration, eliminating the need for complex reconstitution procedures at the time of emergency use.
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 user-friendly glucagon rescue medication that remains effective over a range of temperatures, ensuring prolonged stability and ease of use in emergency situations.
Implementation Method 1
a stable formulation for parenteral injection comprising: a peptide or a salt thereof that has been previously dried from an aqueous composition to a dried peptide powder having an ionization profile that corresponds to a peptide ionization profile in an aqueous solution wherein a pH of the aqueous solution is about equal to a pH of optimal stability and solubility for the peptide; and an aprotic polar solvent, wherein the dried peptide powder is reconstituted into the aprotic polar solvent and has an ionization profile that is about equal to the peptide ionization profile in the aqueous solution
Data Source
Figure 1
AI summary
Disclosed is a stable formulation for parenteral injection, as well as methods for its use and preparation, that includes a peptide or a salt thereof that has been previously dried from an aqueous composition comprising a partially volatile buffer, a volatile buffer, a strong acid, or a strong base, or any combination thereof, wherein the dried peptide or salt thereof has a first ionization profile that corresponds to the peptide's optimal stability and solubility, and an aprotic polar solvent, wherein the dried peptide or salt thereof is reconstituted into an aprotic polar solvent and has a second ionization profile in the aprotic polar solvent, wherein the first and second ionization profiles are substantially the same, such as within 1 pH unit of one another.