Recombinant Fusion Protein Formulation Stability
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Solution Overview
Problem
Recombinant fusion proteins, such as IBI302, are prone to instability and aggregation due to their complex structure, making it challenging to develop stable and effective formulations for conditions like wet age-related macular degeneration, especially under high temperature, long-term refrigeration, and repeated freezing and thawing.
Innovation Solution
A liquid formulation comprising a recombinant fusion protein, a buffer salt (citrate or acetate), a stabilizer (arginine and sucrose), and a surfactant (polysorbate 20 or poloxamer 188) in sterile water, with specific concentration ranges to maintain stability and safety, is developed.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If recombinant fusion protein is formulated at high concentration, then therapeutic effectiveness is improved, but protein stability deteriorates and aggregation increases
Solution Approach 1:
The patent introduces multiple formulation excipients as intermediaries to mediate between the protein and the aqueous environment. Specifically, surfactants (polysorbate 20 or poloxamer 188) act as intermediaries to prevent protein-protein interactions that lead to aggregation, while stabilizers (arginine and sucrose) serve as intermediaries to maintain protein conformation and prevent denaturation during storage and handling
Solution Approach 2:
The patent creates a composite formulation system combining the recombinant fusion protein with multiple excipients including buffer salts (citrate or acetate), surfactants, and stabilizers. This composite material approach allows the formulation to achieve both high protein concentration and enhanced stability by leveraging the synergistic effects of different components
2Adaptability or versatility
If protein formulation is stored under repeated freezing and thawing conditions, then clinical flexibility is improved, but protein aggregation increases and stability decreases
Solution Approach 1:
The patent applies beforehand cushioning by incorporating stabilizers (arginine and sucrose) and surfactants into the formulation before storage. These additives provide protective effects that cushion the protein against the damaging effects of freezing and thawing cycles, preventing aggregation and maintaining stability even when storage conditions are not optimally controlled
3Loss of time
If protein is stored at high temperature for accelerated testing, then evaluation time is reduced, but protein deterioration accelerates
Solution Approach 1:
The patent converts the potentially harmful effect of high temperature into a beneficial evaluation tool. By formulating the protein with stabilizers and surfactants, the formulation can withstand accelerated temperature conditions without deteriorating, allowing rapid stability assessment while maintaining protein integrity. The harmful thermal stress is mitigated by the protective formulation components
4Adaptability or versatility
If recombinant fusion protein is produced with complex structure, then therapeutic functionality is improved, but manufacturing complexity increases and stability decreases
Solution Approach 1:
The patent applies parameter changes by optimizing formulation conditions (pH, ionic strength, excipient concentrations) to stabilize the complex protein structure. By adjusting these parameters, the formulation maintains the intricate therapeutic functionality of the recombinant fusion protein while preventing the complexity from leading to aggregation and instability
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 significantly improves the stability and shelf life of the recombinant fusion protein, maintaining its quality and safety under accelerated temperature, refrigeration, and freeze-thaw conditions, enhancing clinical use safety.
Implementation Method 1
the buffer salt is selected from citrate salt, acetate salt or any combination thereof, and the concentration of the salt is 5 to 25 mmol/L
Implementation Method 2
the stabilizer is an amino acid or a combination of a polyol (polyhydric alcohol) and an amino acid, wherein the amino acid is selected from arginine, and the polyol is selected from sucrose
Implementation Method 3
the surfactant is selected from polysorbate 20, polysorbate 80, poloxamer 188, or any combination thereof and the concentration of the surfactant is 0.01-0.08 wt%
Data Source
AI summary
Provided is a liquid formulation that enables the stable storage of recombinant fusion proteins, comprising a recombinant fusion protein, a buffer salt, a stabilizer, and a surfactant.