Liquid Protein Stabilization via Choline Dihydrogen Phosphate
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Protein-based therapeutics are unstable due to their complex three-dimensional structures, leading to denaturation and degradation, making them challenging to store and administer effectively, especially in liquid formulations which are prone to hydrolysis and enzymatic breakdown, increasing manufacturing costs and reducing bioavailability.
Innovation Solution
A parenterally injectable pharmaceutical composition comprising choline dihydrogen phosphate (CDHP), a base, water, and a therapeutic polypeptide, with a specific osmolyte content, formulated to maintain stability and biological activity, potentially eliminating the need for lyophilization and simplifying administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If proteins are formulated in liquid state, then manufacturing cost is reduced and administration is simplified, but protein stability deteriorates due to hydrolysis and enzymatic breakdown
Solution Approach 1:
The patent introduces specific stabilizing agents (osmolytes, surfactants, and other excipients) as intermediary substances that mediate between the protein and the aqueous environment. These agents form protective complexes with the protein, preventing hydrolysis and enzymatic breakdown while allowing the formulation to remain in liquid state, thus resolving the contradiction between ease of manufacture and protein stability.
Solution Approach 2:
The patent systematically optimizes multiple formulation parameters including pH (adjusted to specific ranges), ionic strength, osmolarity, and temperature to create a stable liquid environment for proteins. By changing these physical and chemical parameters within controlled ranges, the formulation maintains protein stability in liquid state without requiring lyophilization, thereby reducing manufacturing cost while preserving stability.
2Stability of the object's composition
If lyophilization is used to maintain protein stability, then protein integrity is improved, but device complexity and processing time increase
Solution Approach 1:
The patent extracts and eliminates the need for complex lyophilization equipment by developing alternative liquid formulations that inherently maintain protein stability. The formulation uses stabilizing agents and optimized conditions to preserve protein integrity without requiring freezing chambers, vacuum pumps, condensers, and other complex lyophilization equipment, thus resolving the contradiction between protein integrity and device complexity.
Solution Approach 2:
The patent employs simple, inexpensive stabilizing agents and excipients that can be easily incorporated into liquid formulations during standard manufacturing processes. These disposable-like simple components replace the need for expensive, complex lyophilization equipment while maintaining adequate protein stability for clinical use.
3Reliability
If lyophilization is used to preserve protein activity, then biological activity is maintained, but loss of time occurs due to reconstitution requirements
Solution Approach 1:
The patent performs preliminary stabilization actions during formulation preparation by incorporating stabilizing agents and adjusting formulation conditions (pH, ionic strength, osmolarity) before administration. This preliminary stabilization ensures that proteins remain biologically active in liquid state without requiring time-consuming reconstitution steps, thus resolving the contradiction between maintaining biological activity and reducing time loss.
4Stability of the object's composition
If stabilizing agents are added to liquid formulations, then protein stability is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent establishes specific parameter ranges (pH 6.0-8.0, osmolarity 200-400 mOsm/kg, temperature 2-8°C) within which protein stability is maintained without requiring extreme precision. By defining acceptable ranges rather than exact target values, the formulation achieves robust stability while accommodating normal manufacturing variations, thus resolving the contradiction between protein stability and manufacturing precision requirements.
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 composition enhances the thermal stability and bioavailability of therapeutic proteins, extending shelf life and reducing manufacturing costs by maintaining protein integrity and activity, even in liquid form, thus improving the delivery and efficacy of protein-based therapeutics.
Implementation Method 1
The composition enhances the thermal stability and bioavailability of therapeutic proteins, extending shelf life and reducing manufacturing costs by maintaining protein integrity and activity
Implementation Method 2
Proteins are very unstable in the gastrointestinal tract, being hydrolyzed and broken down by its acids and enzymes
Implementation Method 3
Factors such as pH, temperature, ionic strength, physical agitations, and cycles of freeze-thaw often result in the destabilization and loss of biological activity of the proteins
Implementation Method 4
The composition enhances the thermal stability and bioavailability of therapeutic proteins, extending shelf life
Data Source
AI summary
The present invention relates to compositions and methods for the preparation, stabilization, and/or storage of active agents, particularly therapeutic proteins and polypeptides such as Interleukin-2.