Antibody Formulation Stabilization via Cyclodextrin and Methionine
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Solution Overview
Problem
Liquid formulations of antibodies face challenges in stability due to aggregation and precipitation, especially in subcutaneous administration, where high protein concentrations lead to injection site issues and reduced efficacy.
Innovation Solution
A novel liquid formulation combining an antibody or antigen-binding fragment with cyclodextrin and methionine, where cyclodextrin concentrations range from 7.5 mM to 250 mM and methionine from 7.5 mM to 200 mM, providing a synergistic stabilizing effect to reduce aggregation and precipitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If liquid formulations of antibodies are used for ease of administration, then ease of operation is improved, but stability of the antibody composition deteriorates due to aggregation and precipitation
Solution Approach 1:
The patent introduces cyclodextrin as an intermediary substance that forms inclusion complexes with hydrophobic regions of antibodies. This mediator prevents direct protein-protein interactions that lead to aggregation, while maintaining the liquid formulation's ease of administration. The cyclodextrin acts as a protective intermediary between antibody molecules.
Solution Approach 2:
The patent creates a composite stabilization system combining cyclodextrin and methionine together. This composite approach leverages the hydrophobic binding capability of cyclodextrin and the antioxidant properties of methionine to provide comprehensive stability protection in liquid formulations, addressing multiple degradation pathways simultaneously.
2Productivity
If high concentration of antibodies is used in liquid formulations, then productivity is improved, but stability deteriorates due to increased aggregation and precipitation
Solution Approach 1:
Cyclodextrin serves as a molecular intermediary that binds to hydrophobic patches on antibody surfaces through its cavity structure. This prevents high-concentration antibody molecules from interacting directly and forming aggregates, enabling the formulation to maintain high productivity through elevated antibody concentrations without sacrificing stability.
Solution Approach 2:
The patent alters the chemical environment parameters by introducing cyclodextrin and methionine, which change the solvation dynamics and molecular interaction parameters. This allows the system to sustain higher antibody concentrations by modifying the physical-chemical parameters of the formulation matrix.
3Stability of the object's composition
If stabilizers are added to prevent aggregation, then stability is improved, but device complexity increases due to additional formulation components
Solution Approach 1:
The patent employs a composite stabilization strategy using cyclodextrin and methionine together. This composite approach provides multi-faceted protection (hydrophobic interaction prevention and antioxidant activity) using relatively simple, well-characterized excipients, avoiding the need for complex polymer-based stabilizers or multiple additive systems.
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 combination of cyclodextrin and methionine significantly reduces the rate of antibody precipitation, enhancing the stability and bioavailability of antibodies in liquid formulations, thereby minimizing injection site reactions and maintaining therapeutic effectiveness.
Implementation Method 1
The hydrophobic cavity provides an environment into which non-polar compounds, e.g. non-polar amino acids can be included and form complexes.
Implementation Method 2
Typical chemical instability may result in deamidation, hydrolysis, oxidation, beta-elimination or disulfide exchanges.
Data Source
AI summary
The invention relates to a liquid pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof, cyclodextrin and methionine. In addition, it relates to a method for reducing precipitation of an antibody or an antigen-bindmg fragment thereof in a liquid pharmaceutical formulation through addition of methionine and cyclodextrin. In particular, the liquid pharmaceutical formulations comprises an anti-sclerostin antibody, hydroxypropyl-gamma cyclodextrin and methionine and may be used in the treatment of a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength, and especially for treating osteoporosis. Furthermore, the invention relates to a method of reducing inflammation at injection site in a mammalian subject comprising administering a therapeutically effective amount of a liquid pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof, cyclo dextrin and methionine.