Biologic Formulation Excipients for High-Concentration Viscosity Control
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Solution Overview
Problem
Highly concentrated biologic formulations face challenges with increased viscosity and stability issues due to protein-protein interactions and self-associations, making them difficult to handle and administer, while current additives often compromise stability for viscosity reduction.
Innovation Solution
Performance-enhancing excipients, such as bis acetyl arginine and propionyl histidine, interact with proteins through hydrophobic and ionic interactions to reduce viscosity and prevent deamidation, enhancing physical and chemical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high concentration formulations are used for subcutaneous administration, then dose volume limitation is met, but viscosity increases making handling and administration difficult
Solution Approach 1:
The patent introduces amino acid derivatives (acetylated and propionylated amino acids) as intermediary substances that mediate between the high concentration requirement and the viscosity problem. These derivatives interact with the biologic protein through hydrophobic and ionic interactions, preventing excessive protein-protein associations while maintaining high product concentration, thus enabling both high concentration formulation and manageable viscosity for subcutaneous injection
Solution Approach 2:
The patent changes the chemical parameters of the formulation by using derivatized amino acids (acetylated and propionylated forms) instead of native amino acids. This parameter change in the excipient structure enhances their ability to reduce viscosity through improved hydrophobic interactions with the biologic, allowing high concentration formulations to maintain lower viscosity and better flow properties
2Ease of operation
If traditional additives (amino acids and salts) are used to reduce viscosity, then viscosity decreases, but stability is compromised
Solution Approach 1:
The patent employs composite excipient systems combining derivatized amino acids (acetylated and propionylated) with other formulation components. This composite approach creates synergistic effects where the derivatized amino acids provide viscosity reduction through hydrophobic interactions while simultaneously stabilizing the biologic structure, preventing both aggregation and deamidation, thus achieving both viscosity reduction and stability enhancement
Solution Approach 2:
The patent modifies the chemical parameters of traditional amino acid excipients by introducing acetyl and propionyl groups. This parameter change transforms simple amino acids into more effective excipients that can reduce viscosity while providing stabilizing effects, preventing the stability compromise that occurs with traditional additives
3Quantity of substance
If protein concentration is increased to meet dosing requirements, then delivery volume is reduced, but protein-protein interactions increase causing aggregation and degradation
Solution Approach 1:
The derivatized amino acids act as intermediary molecules that interfere with direct protein-protein interactions. They bind to hydrophobic regions on the biologic surface through their modified side chains, creating a protective barrier that prevents aggregation and deamidation even at high protein concentrations, thus maintaining compositional stability while enabling high concentration formulation
Solution Approach 2:
The patent extracts or removes the harmful protein-protein interaction networks by introducing excipients that preferentially bind to the biologic surface. The derivatized amino acids are taken into the formulation system and selectively interact with the biologic, extracting it from the destabilizing crowded environment and maintaining its stability at high concentrations
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 excipients effectively reduce viscosity by 10-80% and improve stability by maintaining higher monomer content, lower aggregates, and reduce degradants, while preventing deamidation and other chemical modifications under stress conditions.
Implementation Method 1
The performance-enhancing excipients contain functional groups that interact with proteins by hydrophobic interactions, ionic interaction, and hydrogen bonding, resulting in viscosity reduction and physical and chemical stability enhancement.
Implementation Method 2
The performance-enhancing excipients contain functional groups that interact with proteins by hydrophobic interactions, ionic interaction, and hydrogen bonding, resulting in viscosity reduction and physical and chemical stability enhancement.
Implementation Method 3
The performance-enhancing excipients contain functional groups that interact with proteins by hydrophobic interactions, ionic interaction, and hydrogen bonding, resulting in viscosity reduction and physical and chemical stability enhancement.
Data Source
AI summary
The present invention relates to the viscosity reduction and stability enhancement of biotherapeutics in biomanufacturing and formulation. The method of viscosity reduction and stability enhancement comprises combining a biotherapeutic with a performance-enhancing excipient chosen from bis acetyl arginine, bis acetyl lysine, bis acetyl histidine, bis acetyl serine, bis acetyl proline, bis acetyl tryptophan, propionyl arginine, propionyl lysine, propionyl histidine, propionyl serine, propionyl proline, propionyl tryptophan, and mixtures thereof.