Lyophilized Romiplostim Composition Stabilization
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Solution Overview
Problem
The bioavailability of commercially available protein therapeutics like Romiplostim is limited by their short plasma half-life and susceptibility to protease degradation, leading to suboptimal clinical potency and short shelf life of lyophilized formulations.
Innovation Solution
A novel lyophilized pharmaceutical composition of Romiplostim is developed, incorporating citro-phosphate as a buffer, sucrose or trehalose as bulking agents, and polysorbate 20 as a surfactant, maintained at a pH range of 4.0-6.0, to enhance stability and shelf life, preventing protein denaturation and aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If proteins are formulated in aqueous solutions, then they maintain biological activity, but they undergo denaturation and aggregation leading to short shelf life
Solution Approach 1:
The patent changes the physical state of the formulation from aqueous liquid to lyophilized solid form, and optimizes pH parameters (4.0-6.0 range) to stabilize the protein structure. This parameter change prevents denaturation and aggregation while maintaining biological activity upon reconstitution
Solution Approach 2:
The patent creates a composite lyophilized formulation containing the Fc-peptide fusion protein combined with excipients including buffer (citro-phosphate), bulking agents (sucrose or trehalose), and surfactant (polysorbate 20). This composite structure provides structural support and protection during storage, preventing protein degradation while extending shelf life
2Duration of action of stationary object
If lyophilization is used to extend shelf life, then storage stability improves, but reconstitution complexity increases
Solution Approach 1:
The patent optimizes the local composition within the lyophilized cake by strategically placing excipients in specific concentrations and combinations. The buffer maintains pH, bulking agents provide structural matrix, and surfactant prevents surface denaturation. This localized optimization ensures simple reconstitution with minimal steps while maintaining stability
Solution Approach 2:
The patent introduces excipients as intermediary substances that facilitate the transition from lyophilized state to aqueous formulation. The buffer, bulking agents, and surfactant act as mediators that protect the protein during freezing and drying, and enable simple reconstitution by maintaining solubility and structural integrity
3Stability of the object's composition
If conventional buffers are used in lyophilized formulations, then pH stability is maintained, but buffer salts precipitate during freezing causing pH changes
Solution Approach 1:
The patent changes the buffer system parameters by selecting citro-phosphate buffer and optimizing its concentration and pH range (4.0-6.0). This parameter optimization prevents salt precipitation during freezing while maintaining pH stability throughout the lyophilization process and upon reconstitution
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 achieves extended shelf life and maintains biological activity and purity at elevated temperatures, ensuring operational simplicity and effective therapeutic use.
Implementation Method 1
therapeutic protein products are made more stable via lyophilization (freeze-drying)
Implementation Method 2
incorporating citro-phosphate as a buffer, sucrose or trehalose as bulking agents, and polysorbate 20 as a surfactant, maintained at a pH range of 4.0-6.0
Implementation Method 3
polysorbate 20 as a surfactant, maintained at a pH range of 4.0-6.0, to enhance stability and shelf life, preventing protein denaturation and aggregation
Data Source
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AI summary
The present invention relates to novel and thermostable lyophilized pharmaceutical composition of Romiplostim (Fc-peptide fusion protein) along with buffer, bulking agent, stabilizer, and surfactant at pH range of 4.0-6.0.