Lyophilized Protein Composition With Controlled Moisture Stability
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Solution Overview
Problem
Existing lyophilized therapeutic protein formulations lack long-term stability at room temperature, leading to degradation issues such as aggregation and chemical modifications, which are not adequately addressed by current excipient compositions and processing methods.
Innovation Solution
A lyophilized therapeutic protein formulation with controlled residual moisture levels between 0.5% to 10% and specific excipient ratios, including buffers and stabilizers like histidine, sucrose, trehalose, and polysorbate, combined with an optimized lyophilization process to maintain stability for at least 24 months at room temperature.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If lyophilized protein formulations are stored at room temperature, then distribution and storage accessibility are improved, but protein stability deteriorates due to aggregation and chemical modifications
Solution Approach 1:
The patent changes the moisture content parameter to an optimal range (2-10%) and adjusts excipient concentrations (sucrose 5-20%, trehalose 5-20%, polysorbate 0.01-1%) to achieve both room temperature stability and accessibility. This resolves the contradiction by finding parameter values that work under ambient conditions without requiring refrigeration.
Solution Approach 2:
The patent creates a composite lyophilized formulation combining protein with specific excipients (sucrose, trehalose, polysorbate, histidine) in optimized ratios. This composite structure provides both protective stabilization against degradation and enabling properties for room temperature storage, simultaneously achieving stability and ease of operation.
2Stability of the object's composition
If residual moisture content is reduced to minimize degradation, then protein stability is improved, but formulation manufacturability worsens due to difficulty in achieving low moisture levels
Solution Approach 1:
The patent optimizes the moisture content parameter to a specific range (2-10%) rather than minimizing it completely. This parameter change makes the formulation manufacturable while maintaining sufficient stability, as extremely low moisture levels are difficult to achieve and can compromise formulation quality.
Solution Approach 2:
The patent uses excipients like sucrose and trehalose that form protective glassy matrices similar to natural protein environments. These excipients replicate the stabilizing effect of controlled moisture in a way that is easier to manufacture, providing stability without requiring extremely low moisture content.
3Stability of the object's composition
If excipient concentrations are increased to enhance stability, then protein protection is improved, but formulation complexity increases
Solution Approach 1:
The patent optimizes excipient concentrations to specific ranges (sucrose 5-20%, trehalose 5-20%, polysorbate 0.01-1%) rather than using high concentrations. This parameter optimization achieves sufficient protein protection while maintaining formulation simplicity and avoiding excessive complexity.
Solution Approach 2:
The patent selects excipients that perform multiple functions: sucrose and trehalose provide both stabilization and cryoprotection, polysorbate provides both stabilization and prevents aggregation, and histidine provides both pH buffering and stabilization. This multi-functionality reduces the need for multiple separate excipients, simplifying the formulation.
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 achieves minimal protein degradation, with less than 2% degradation after 24 months at 25°C, maintaining stability through controlled moisture and excipient interactions, preventing aggregate formation and preserving protein integrity.
Implementation Method 1
Lyophilization (freeze drying under controlled conditions) is commonly used for long-term storage of proteins
Implementation Method 2
The container is sufficiently open to allow the outgassing of water vapor. Thermal energy is then added to the sample to permit removal of the water from the sample by sublimation
Implementation Method 3
Plasticizers may also be included to decrease global relaxation time and in some cases may help to preserve the native structure of proteins. Plasticizers include sugar alcohols like sorbitol and glycerol, other polyols, and small amounts of water
Implementation Method 4
Lyoprotectants (a.k.a. stabilizers), such as sucrose and trehalose, are often included in pre-lyophilization formulations to protect the protein against denaturation during the freeze-drying process
Data Source
AI summary
Stable lyophilized therapeutic protein compositions and their methods of manufacture are provided. Specifically, the use of water as a solid cake plasticizer and protein stabilizer is described. Also, the inclusion of a multicomponent stabilizer comprising a larger molecular entity and a smaller molecular entity is described. Also, the inclusion of post-drying annealing under certain conditions improves protein stability. Proteins are predicted to remain stable over 24 months at 25° C.