Ionization-Stabilized Therapeutic Formulations in Aprotic Polar Solvents
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Solution Overview
Problem
Existing methods for preparing stable therapeutic formulations in aprotic polar solvents require drying the therapeutic molecule from a buffered aqueous solution, which is time-consuming and costly, and direct dissolution in these solvents often leads to instability and aggregation of peptides and small molecules.
Innovation Solution
Dissolving therapeutic agents directly in aprotic polar solvents with a specified concentration of ionization stabilizing excipients, such as mineral or organic acids, to establish an optimal ionization profile without the need for a drying step.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If peptides are dissolved directly in aprotic polar solvents, then solubility is enhanced, but stability deteriorates due to aggregation and fibrillation
Solution Approach 1:
The patent introduces a drying step as an intermediary process between dissolution and storage. Peptides are first dissolved in aqueous buffer, then dried to remove water, and finally reconstituted in aprotic polar solvent. This intermediary drying step prevents direct interaction between water and aprotic solvent that causes aggregation, thereby maintaining stability while achieving solubility enhancement.
Solution Approach 2:
The patent changes the solvent parameter from aqueous to aprotic polar by removing water through drying. This parameter change (from hydrated to anhydrous state) transforms the chemical environment to prevent aggregation while maintaining solubility benefits, resolving the contradiction between solubility enhancement and stability preservation.
2Stability of the object's composition
If peptides are dried from buffered aqueous solution before dissolution in aprotic polar solvent, then stability is improved, but manufacturing complexity and time increase
Solution Approach 1:
The patent extracts water from the peptide solution through drying before reconstitution in aprotic polar solvent. By taking out the water component that causes aggregation, the process achieves stability improvement while the drying step becomes a standardized, scalable unit operation that can be integrated into existing manufacturing workflows.
Solution Approach 2:
The drying step is performed as a preliminary action before final formulation in aprotic polar solvent. By preparing the peptide in a dry state first, the subsequent dissolution step becomes simpler and more reliable, reducing overall manufacturing complexity despite adding an initial preparation step.
3Quantity of substance
If acidic or alkaline aqueous solutions are used to solubilize glucagon, then solubility is improved, but degradation increases due to promoted degradation pathways
Solution Approach 1:
The patent changes the pH parameter by avoiding extreme acidic or alkaline conditions. Instead, it uses neutral pH aqueous buffer for initial dissolution, then removes water to prevent pH-driven degradation. This parameter change (from extreme pH to neutral pH with water removal) maintains solubility while eliminating degradation pathways associated with acidic or alkaline environments.
Solution Approach 2:
The patent converts the potential harm of water (which can promote degradation in extreme pH) into a benefit by using mild aqueous buffer at neutral pH for dissolution, then removing the water through drying. This transforms water from a harmful factor into a temporary medium that enables solubility without triggering degradation, which is then eliminated by drying.
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
This approach enhances the stability and solubility of therapeutic agents, reducing manufacturing complexity and costs by eliminating the drying step and minimizing the use of additional stabilizing excipients, while maintaining chemical and physical stability for extended periods.
Implementation Method 1
establish an optimal ionization profile without the need for a drying step
Data Source
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AI summary
Certain embodiments are directed to a formulation of a therapeutic agent, as well as a method of making such a formulation, comprising at least one therapeutic agent dissolved in an aprotic polar solvent system comprising at least one ionization stabilizing excipient in a concentration sufficient to impart physical and chemical stability to the therapeutic agent.