Antibody Formulation Viscosity Reduction via pH and Buffer Control
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Solution Overview
Problem
High concentration protein formulations in therapeutic drugs often lead to aggregation, increased viscosity, and reduced bioavailability due to the formation of high molecular weight species, posing challenges for drug stability and administration.
Innovation Solution
Development of isotonic liquid compositions containing monoclonal antibodies at concentrations above 100 mg/mL, formulated with arginine glutamate or proline, and a surfactant, maintaining a pH of 4.5 to 5.5, which reduces viscosity and aggregation, and is stable for extended storage periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the concentration of therapeutic protein is increased in drug formulations, then the dosage efficiency is improved, but aggregation occurs resulting in the formation of high molecular weight species
Solution Approach 1:
The patent changes the pH parameter to an acidic range (4.5-5.5) and modifies the buffer composition to reduce aggregation. This parameter change allows high concentration formulations to maintain stability by preventing the formation of high molecular weight species through optimized acid buffer conditions
Solution Approach 2:
The patent introduces acid buffers (acetate, citrate, succinate, or tartaric acid) as intermediary substances that mediate between the high concentration antibody and the aggregation tendency. These buffers act as protective intermediaries that stabilize the protein at high concentrations without causing aggregation
2Quantity of substance
If the concentration of therapeutic protein is increased in drug formulations, then the dosage efficiency is improved, but viscosity is elevated that can adversely impact drug product filling and administration
Solution Approach 1:
The patent changes the pH parameter to an acidic range (4.5-5.5) which fundamentally alters the protein's charge state and intermolecular interactions. This parameter change reduces viscosity at high concentrations by minimizing electrostatic attractions between protein molecules, thereby improving ease of filling and administration
3Quantity of substance
If the concentration of therapeutic protein is increased in drug formulations, then the dosage efficiency is improved, but subcutaneous bioavailability is affected and pharmacokinetics are altered
Solution Approach 1:
The patent changes the pH parameter to an acidic range (4.5-5.5) and optimizes buffer composition to ensure reliable pharmacokinetics. This parameter change prevents aggregation and maintains proper protein conformation, ensuring consistent subcutaneous bioavailability and predictable pharmacokinetic behavior even at high concentrations
4Quantity of substance
If the concentration of therapeutic protein is increased in drug formulations, then the dosage efficiency is improved, but bioactivity is lost and immunogenicity increases
Solution Approach 1:
The patent changes the pH parameter to an acidic range (4.5-5.5) and optimizes buffer composition to preserve bioactivity and reduce immunogenicity. This parameter change maintains proper protein folding and prevents aggregation, ensuring that high concentration formulations retain full bioactivity while minimizing immune response
Data Source
AI summary
Provided herein are liquid compositions comprising a high concentration of a monoclonal antibody, e.g., greater than about 100 mg/mL, which demonstrate storage-stability and reduced viscosity. In exemplary embodiments, the liquid composition comprises about less than about 400 mM arginine glutamate, and, in alternative exemplary embodiments, the liquid composition comprises proline and a buffer.