Factor VIII Formulation Without Sodium Chloride
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Solution Overview
Problem
Current Factor VIII (FVIII) preparations rely on albumin and von Willebrand factor for stability, making it difficult to characterize FVIII and posing a risk of viral transmission, while attempts to formulate FVIII without these excipients have resulted in instability due to the presence of sodium chloride, which lowers the collapse temperature and compromises product stability during lyophilization.
Innovation Solution
Formulating FVIII compositions without or with trace amounts of sodium chloride, incorporating buffering agents like histidine, antioxidants such as glutathione, and surfactants like TWEEN-80, to achieve stability and reduce lyophilization cycle time, while using methods like dialysis or solvent exchange chromatography to minimize NaCl presence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If albumin and von Willebrand factor are added to stabilize FVIII, then FVIII stability is improved, but it becomes difficult to characterize FVIII and poses a risk of viral transmission
Solution Approach 1:
The invention extracts and removes albumin and von Willebrand factor from the FVIII formulation, replacing them with alternative excipients (sucrose, mannitol, histidine, polysorbate 80) that do not interfere with FVIII characterization while still providing stability. This extraction eliminates the viral transmission risk associated with human-derived albumin.
Solution Approach 2:
The invention changes the formulation parameters by substituting traditional stabilizers (albumin, vWF) with alternative excipients at optimized concentrations. Specifically, sucrose (0.1-10%), mannitol (0.1-10%), histidine (0.01-0.5 M), and polysorbate 80 (0.001-0.5% v/v) are used to achieve stability without the drawbacks of albumin-based formulations.
2Reliability
If sodium chloride is present in the formulation, then ionic strength is maintained, but the collapse temperature is lowered and lyophilization stability is compromised
Solution Approach 1:
The invention removes sodium chloride from the formulation or reduces it to trace amounts (less than 10 mM). Instead, the formulation relies on sucrose, mannitol, and histidine to maintain ionic strength and osmotic balance without compromising lyophilization stability. This extraction of NaCl eliminates the collapse temperature issue while maintaining formulation stability.
Solution Approach 2:
The invention changes the formulation composition by eliminating or minimizing sodium chloride and using alternative excipients (sucrose, mannitol, histidine) to achieve the desired ionic strength and stability profile. This parameter change allows the formulation to maintain stability during lyophilization without the collapse problems associated with NaCl.
3Reliability
If a large molar excess of albumin is added to increase FVIII stability, then FVIII stability is improved, but the complexity of the formulation increases and characterization becomes difficult
Solution Approach 1:
The invention extracts albumin from the formulation entirely, replacing it with alternative stabilizers (sucrose, mannitol, histidine, polysorbate 80) that do not add to the complexity or interfere with characterization. This simplifies the formulation while maintaining FVIII stability.
Solution Approach 2:
The invention changes the formulation strategy by using small molecules (sucrose, mannitol, histidine) instead of large protein excipients (albumin). This parameter change reduces formulation complexity and eliminates interference with FVIII characterization while maintaining stability through optimized concentrations of the alternative excipients.
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 approach results in a stable lyophilized FVIII with increased stability and reduced lyophilization time, avoiding the collapse issues associated with sodium chloride and enhancing the safety of recombinant FVIII preparations by minimizing human-derived excipients.
Implementation Method 1
using methods like dialysis or solvent exchange chromatography to minimize NaCl presence
Implementation Method 2
Dialysis removes sodium chloride from the FVIII solution through diffusion across a semipermeable membrane
Implementation Method 3
using methods like dialysis or solvent exchange chromatography to minimize NaCl presence
Implementation Method 4
attempts to formulate FVIII without these excipients have resulted in instability due to the presence of sodium chloride, which lowers the collapse temperature and compromises product stability during lyophilization
Implementation Method 5
Lyophilization removes water from the FVIII formulation through sublimation, producing a stable lyophilized product
Data Source
AI summary
A Factor VIII (FVIII) composition formulated such that NaCl is not present in the final formulation or is present in trace amounts, which allows for a concomitant reduction in the lyophilization cycle time and increased stability of the lyophilized FVIII.