Avelumab Formulation Stability Without Methionine
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Solution Overview
Problem
Current aqueous formulations of Avelumab, an anti-PD-L1 antibody, face challenges in stability and concentration, particularly requiring antioxidants and specific pH conditions, which limits their versatility and effectiveness.
Innovation Solution
A novel aqueous pharmaceutical formulation of Avelumab is developed without methionine, using acetate or histidine as buffering agents, D-mannitol or trehalose as stabilizers, and Poloxamer 188 or Polysorbate 20 as surfactants, maintaining stability at pH values as low as 5.2, allowing for higher concentrations and improved stability profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If current aqueous formulations of Avelumab are used, then stability is maintained under specific conditions, but the formulation requires antioxidants and specific pH conditions which limits versatility
Solution Approach 1:
The patent changes the pH parameter range to 5.0-6.0 (preferably 5.2-5.6) and modifies the formulation composition by eliminating methionine while incorporating acetate or histidine buffers, D-mannitol or trehalose stabilizers, and Poloxamer 188 or Polysorbate 20 surfactants. These parameter changes enable the formulation to achieve stability without antioxidants, thereby improving versatility while maintaining stability.
2Quantity of substance
If higher concentrations of Avelumab are formulated, then therapeutic efficacy is improved, but stability and shelf life are compromised
Solution Approach 1:
The patent formulates Avelumab at higher concentrations of 10-30 mg/mL (preferably 15-25 mg/mL, most preferably 20 mg/mL) while maintaining stability through optimized pH (5.0-6.0, preferably 5.2-5.6) and the inclusion of stabilizers (D-mannitol or trehalose at 240-320 mM) and surfactants (Poloxamer 188 or Polysorbate 20 at 0.25-0.75 mg/mL). This resolves the contradiction by enabling high concentration formulation without sacrificing stability.
Solution Approach 2:
The patent creates a composite formulation system combining multiple excipients with specific functions: acetate or histidine as buffering agents, D-mannitol or trehalose as stabilizers, and Poloxamer 188 or Polysorbate 20 as surfactants. This composite approach synergistically maintains antibody stability at high concentrations, resolving the contradiction between concentration and stability.
3Stability of the object's composition
If antioxidants are included in the formulation, then stability is improved, but the formulation complexity and manufacturing constraints increase
Solution Approach 1:
The patent explicitly removes methionine (an antioxidant) from the formulation while achieving stability through alternative means: optimized pH buffering with acetate or histidine, stabilization with D-mannitol or trehalose, and surfactant protection with Poloxamer 188 or Polysorbate 20. This extraction of the antioxidant component simplifies the formulation while maintaining stability.
Solution Approach 2:
The formulation achieves self-stability through the synergistic action of buffering agents (acetate or histidine), stabilizers (D-mannitol or trehalose), and surfactants (Poloxamer 188 or Polysorbate 20), eliminating the need for external antioxidant protection. The system self-regulates stability through its compositional design rather than relying on added antioxidants.
Data Source
AI summary
The present invention relates to a novel anti-PD-L1 antibody formulation. In particular, the invention relates to an aqueous pharmaceutical formulation of the anti-PD-L1 antibody Avelumab.