Factor VIII Formulation Stability Without Human Albumin
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Solution Overview
Problem
Current Factor VIII (FVIII) formulations face challenges in stability during lyophilization and storage, often resulting in reduced activity and turbidity issues due to aggregation, and rely on human-derived albumin and von Willebrand factor for stabilization, which complicates characterization and increases the risk of viral transmission.
Innovation Solution
An aqueous composition of FVIII comprising 40 to 195 mM of a sodium salt, histidine, at least 1 mM of a calcium salt, and a surfactant, with specific concentration ratios of histidine to calcium ions, achieving stability and turbidity-free solutions suitable for lyophilization and long-term storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If albumin and vWF are added to stabilize FVIII, then FVIII stability is improved, but characterization difficulty and viral transmission risk increase
Solution Approach 1:
The invention extracts and removes albumin and vWF from the FVIII formulation, stabilizing FVIII through alternative means (pH control, ionic strength optimization, and specific excipients) rather than relying on these human-derived proteins. This eliminates the need for complex characterization of multiple protein components and removes viral transmission risks associated with human plasma derivatives.
2Stability of the object's composition
If albumin is added in large molar excess to stabilize FVIII, then FVIII stability is improved, but characterization precision deteriorates
Solution Approach 1:
The invention removes albumin from the formulation entirely, eliminating the interference it causes in FVIII characterization. FVIII can now be accurately measured and characterized without the confounding presence of large amounts of albumin that would otherwise dominate the protein composition and complicate analytical measurements.
3Stability of the object's composition
If human-derived albumin is added to FVIII preparations, then FVIII stability is improved, but viral transmission risk increases
Solution Approach 1:
The invention extracts and eliminates human-derived albumin from the FVIII formulation, replacing it with synthetic or recombinant stabilizing agents. This removal of human plasma components eliminates the theoretical risk of viral transmission while maintaining FVIII stability through alternative formulation strategies including optimized pH, ionic strength, and excipient selection.
Solution Approach 2:
The invention replaces expensive, potentially hazardous human-derived albumin with safer, synthetic alternatives such as sucrose, glycine, and polysorbate 80. These excipients provide the necessary stabilizing function without the viral transmission risks associated with human plasma products, effectively substituting a hazardous material with safer equivalents.
4Object-affected harmful factors
If FVIII formulations are prepared without albumin or vWF, then viral transmission risk is reduced, but stability during lyophilization and storage deteriorates
Solution Approach 1:
The invention optimizes formulation parameters including pH (maintained at physiological levels), ionic strength (through optimized sodium chloride concentration), and excipient selection (sucrose, glycine, polysorbate 80) to achieve both stability without albumin/vWF and safety. The specific parameter combinations create a stable environment for FVIII during lyophilization and storage while eliminating human-derived proteins.
Solution Approach 2:
The invention creates a composite formulation system combining multiple excipients (sucrose, glycine, polysorbate 80, sodium chloride) that work synergistically to stabilize FVIII in the absence of albumin and vWF. This composite approach provides comprehensive protection against aggregation and degradation during manufacturing and storage while maintaining safety by excluding human plasma derivatives.
Data Source
Figure 1
AI summary
The invention relates to factor VIII compositions and their use.