Glucagon Formulation in Aprotic Polar Solvents for Stability
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Solution Overview
Problem
Current glucagon formulations for treating hypoglycemia face challenges due to poor solubility and stability in water, leading to time-consuming preparation and potential instability, limiting their use beyond severe hypoglycemia rescue.
Innovation Solution
Development of a storage stable sustained release (SR) glucagon formulation using an aprotic polar solvent system with a divalent zinc-containing compound as a sustained release modifier, stabilizing glucagon in solution to create a depot that gradually releases glucagon upon administration, maintaining stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If glucagon is formulated in aqueous-based solutions, then it can be easily administered, but it suffers from poor stability due to hydrolysis, deamidation, and aspartic acid isomerization
Solution Approach 1:
The patent changes the fundamental parameter of the solvent system from aqueous to aprotic polar (e.g., DMSO, NMP, DMA). This parameter change eliminates water-mediated degradation pathways while maintaining the ability to dissolve and administer glucagon, thereby resolving the contradiction between ease of administration and stability.
Solution Approach 2:
The patent creates a composite formulation system combining aprotic polar solvent with stabilizing agents (such as amino acids, peptides, or proteins) and sustained release modifiers. This composite approach enhances both stability and administrability by leveraging the complementary properties of each component.
2Stability of the object's composition
If glucagon is formulated as immediate-release in aprotic polar solvent, then storage stability is improved, but it cannot provide sustained therapeutic levels without repeated dosing
Solution Approach 1:
The patent introduces sustained release modifiers (such as polymers, lipids, or particulate materials) as intermediary components that mediate between the stable aprotic polar formulation and the therapeutic target. These modifiers enable controlled release of glucagon over extended periods while maintaining the stability benefits of the aprotic polar solvent system.
Solution Approach 2:
The patent incorporates sustained release modifiers into the formulation beforehand, creating a pre-engineered system that automatically provides extended release upon administration. This preliminary action eliminates the need for repeated dosing while preserving the storage stability achieved through the aprotic polar solvent.
3Quantity of substance
If glucagon is dissolved in water, then it remains soluble, but it undergoes rapid degradation through hydrolysis and other water-mediated pathways
Solution Approach 1:
The patent changes the solvent parameter from water to aprotic polar solvents (DMSO, NMP, DMA), which fundamentally alters the chemical environment. This parameter change maintains glucagon solubility through the polar nature of these solvents while eliminating hydrolysis and other water-mediated degradation pathways, thereby resolving the contradiction between solubility and chemical stability.
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 SR formulation provides extended therapeutic levels of glucagon in the bloodstream, improving management of hypoglycemia and potentially treating other conditions like hypoglycemia unawareness and nocturnal hypoglycemia with reduced symptoms and calorie consumption.
Implementation Method 1
These pathways, including hydrolysis, deamidation and aspartic acid isomerization, are known to be largely responsible for peptide and protein instability in aqueous-based formulations
Implementation Method 2
comprising glucagon at therapeutic levels in an aprotic polar solvent system (dimethylsulfoxide (DMSO))
Implementation Method 3
at least one sustained release modifier, in an aprotic polar solvent system
Data Source
AI summary
The present invention relates to the use of aprotic polar solvents and an ionization stabilizing agent to prepare storage stable sustained release therapeutic formulations by dissolving a therapeutic agent (active ingredient) in an aprotic polar solvent system that can then be administered to patients suffering from or predisposed to a variety of physical conditions or disorders, notably hypoglycemia. In certain embodiments, the invention is directed to formulations comprising one or more therapeutic agents, as well as methods of making such formulations, comprising at least one therapeutic agent dissolved in an aprotic polar solvent such as DMSO, comprising at least one ionization stabilizing excipient (suitably, a mineral acid) and at least one sustained release modifier (suitably, a divalent cation-donating compound such as a zinc salt and/or a polymer such as a PLGA) in concentrations sufficient to impart physical and chemical stability to the therapeutic agent and to produce a formulation that results in a sustained release of the therapeutic agent into the bloodstream of an animal to which the formulation has been administered. The invention also relates to methods of producing such storage stable sustained release therapeutic formulations and to methods of treating, preventing and diagnosing certain physical conditions and disorders, notably hypoglycemia, by administering such storage stable sustained release therapeutic formulations to a patient.