Bispecific Molecule Composition for High-Concentration Stability
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Solution Overview
Problem
Bispecific antigen-binding molecules, such as BiTE® molecules, are prone to aggregation and require high concentrations for effective dosage, but current formulations struggle to maintain stability at concentrations above 5 mg/mL, posing challenges for manufacturing, storage, and administration.
Innovation Solution
A liquid pharmaceutical composition incorporating Ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentetic acid (DTPA), or citric acid as stabilizing agents at concentrations of 0.005% to 0.25% (w/v) stabilizes bispecific antigen-binding molecules at concentrations ranging from 8 to 35 mg/mL, reducing aggregation and enabling subcutaneous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the concentration of bisspecific antigen-binding molecules is increased to meet dosage requirements, then the volume for administration is reduced, but aggregation and instability occur
Solution Approach 1:
Chelating agents (EDTA, DTPA, or citric acid) are introduced as intermediary substances that bind to metal ions in the formulation, preventing metal-catalyzed oxidation and aggregation of the bispecific antigen-binding molecules. This allows the molecules to remain stable at higher concentrations (8-35 mg/mL) without forming aggregates, thus resolving the contradiction between achieving therapeutic dosage concentration and maintaining molecular stability.
Solution Approach 2:
The formulation parameters are optimized by adjusting pH to ranges (pH 3.0-5.0 or pH 6.0-8.0) and incorporating specific excipients that create a chemical environment preventing aggregation. These parameter changes enable the bispecific antigen-binding molecules to maintain stability at high concentrations, allowing reduced administration volume while preventing the aggregation that would otherwise occur.
2Stability of the object's composition
If chelating agents are added to prevent aggregation, then stability is improved, but formulation complexity increases
Solution Approach 1:
The patent employs simple, inexpensive, and well-characterized chelating agents (EDTA, DTPA, or citric acid) that are routinely used in pharmaceutical formulations. These agents provide effective stabilization without requiring complex formulation strategies, thereby improving stability while minimizing increases in formulation complexity.
3Loss of substance
If higher concentrations are used, then buffer volume and resource consumption are reduced, but aggregation risk increases
Solution Approach 1:
Chelating agents serve as intermediary substances that eliminate the harmful aggregation effect by sequestering metal ions that would otherwise catalyze aggregation reactions. This enables the formulation to achieve higher concentrations with reduced buffer volume and resource consumption without suffering from increased aggregation risk.
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 composition maintains improved product quality and stability of bispecific antigen-binding molecules at higher concentrations, facilitating reduced buffer volume, resource consumption, and enabling stable drug applications through minimized aggregation.
Implementation Method 1
a stabilizing agent selected from Ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentetic acid (DTPA), and citric acid
Data Source
AI summary
The present invention provides provide a pharmaceutical composition comprising a bispecific antigen binding molecule at an increased concentration, wherein the composition comprises at least one buffer agent, at least one saccharide; and at least one stabilizing agent selected from Ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentetic acid (DTP A), and citric acid in order to stabilize the bispecific antigen-binding agent even at higher concentration.