Fab-PEG Formulation Stability via Lyophilization
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Solution Overview
Problem
Existing pharmaceutical compositions of Fab-PEG or Fab′-PEG molecules face challenges in stability during lyophilization processes and long-term storage, leading to aggregation and prolonged reconstitution times, with no universal protocol available for achieving high concentrations and maintaining molecular integrity.
Innovation Solution
A pharmaceutical composition comprising a Fab-PEG or Fab′-PEG molecule at 50 to 200 mg/mL concentration, buffered between pH 5.0 to 7.0, with 1 to 5% w/v sucrose, 0.5 to 4% w/v glycine, and optionally a surfactant, followed by freeze-drying to create formulations with 50 to 80% w/w Fab-PEG or Fab′-PEG, 3 to 14% w/w buffer, 7 to 30% w/w sucrose, and 3.5 to 24% w/w glycine, ensuring stability and rapid reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If antibodies are stored at high concentration in liquid form, then administration preparation is minimal, but chemical and physical instability increases leading to aggregation and degradation
Solution Approach 1:
The patent applies freeze-drying (lyophilization) to transition the antibody formulation from liquid to solid state, achieving long-term storage stability while maintaining high concentration. The process involves freezing the liquid formulation and then removing water through sublimation under vacuum, creating a stable solid cake that can be stored at elevated temperatures and reconstituted quickly when needed.
2Duration of action of stationary object
If freeze-drying is used for long term storage stabilization, then shelf life is extended and temperature requirements are reduced, but reconstitution time is prolonged
Solution Approach 1:
The patent incorporates stabilizers (sugars, polyols, amino acids, salts, and polymers) into the formulation before freeze-drying to prevent protein denaturation and aggregation during the drying process and storage. This preliminary stabilization action ensures that the antibody maintains its structural integrity throughout storage, enabling rapid reconstitution without loss of stability.
Solution Approach 2:
The patent creates a composite formulation combining the antibody with stabilizing excipients (such as sucrose, trehalose, mannitol, glycine, or polysorbates) that work synergistically to protect the protein structure during freeze-drying and storage. This composite material approach allows the formulation to achieve both long-term stability and rapid reconstitution.
3Stability of the object's composition
If stabilizer concentration is increased to improve stabilization during drying, then protein structure is better preserved, but the formulation may reach a limit of stabilization or become destabilized
Solution Approach 1:
The patent systematically optimizes the concentration and type of stabilizers to achieve the optimal balance between stabilization and formulation reliability. By adjusting parameters such as stabilizer concentration, pH, and buffer composition, the formulation achieves maximum stability during freeze-drying and storage without reaching destabilization thresholds.
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 formulations provide long-term stability and rapid reconstitution, minimizing aggregation and maintaining molecular integrity, with reconstitution times under 20 minutes and stability at 2-25°C, suitable for treating autoimmune, inflammatory, and neurodegenerative diseases.
Implementation Method 1
Freeze-drying (i.e. lyophilisation) may be used for long term storage stabilization of antibodies
Implementation Method 2
The interaction between water and proteins is thought to be important for the conformational stability of the proteins. When water is removed during drying
Implementation Method 3
The stabilizers can form hydrogen bonds with the protein, as water molecules do, which may help to preserve the native protein structure during lyophilization process
Data Source
AI summary
The present invention relates to the field of pharmaceutical compositions. More particularly it is directed to pharmaceutical compositions comprising an antibody molecule, more particularly a Fab-PEG or a Fab′-PEG molecule, e.g., at high concentrations, and to methods of producing such formulations. Pharmaceutical compositions according to the invention can be lyophilised and are stable upon storage at a temperature from about 2 to 25° C. for an appropriate period of time.