Tocilizumab IgG Aqueous Formulation pH Stabilization
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Solution Overview
Problem
The existing intravenous formulation of Tocilizumab IgG, used to treat IL-6-mediated diseases, is unstable under thermal stress, leading to protein aggregation, which can induce immune responses when administered.
Innovation Solution
An antibody-containing aqueous formulation comprising Tocilizumab IgG, a protein stabilizer such as sucrose or trehalose, a surfactant like polysorbate 80, and a buffer system with a pH range of 4.5 to 6.5, including acetate or histidine buffers, is developed to reduce aggregate formation and enhance stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Tocilizumab IgG is formulated in Actemra intravenous formulation, then the antibody can be administered for treating IL-6-mediated diseases, but the formulation shows instability under thermal stress leading to protein aggregation
Solution Approach 1:
The patent changes the pH parameter of the formulation from 6.5 (Actemra) to a lower range of 4.5-6.5, and modifies the buffer composition to acetate or histidine buffers. These parameter changes result in reduced protein aggregation under thermal stress while maintaining therapeutic efficacy of Tocilizumab IgG
Solution Approach 2:
The patent creates a composite formulation system combining Tocilizumab IgG with specific excipients including protein stabilizers (sucrose, trehalose), surfactants (polysorbate 80, polysorbate 20, poloxamer), and buffer systems (acetate or histidine buffers). This composite formulation provides enhanced stability and suppresses aggregate formation through synergistic interactions among components
2Duration of action of stationary object
If the formulation is stored at elevated temperatures, then the shelf life and storage flexibility are improved, but aggregate formation increases reducing monomer form retention
Solution Approach 1:
The formulation is pre-adjusted to pH 4.5-6.5 with acetate or histidine buffers before storage, and stabilizing excipients are incorporated in advance. This preliminary optimization of formulation conditions prevents aggregate formation during storage at elevated temperatures, maintaining at least 90% monomer form after 3 months at 40°C
Solution Approach 2:
Protein stabilizers (sucrose, trehalose) and surfactants are added to the formulation beforehand to cushion against thermal stress. These excipients form protective interactions with Tocilizumab IgG, preventing denaturation and aggregation during temperature fluctuations and extended storage
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 formulation effectively retains at least 90% of Tocilizumab IgG in its monomer form after storage at 40°C for 3 months, reducing aggregate formation and maintaining stability, thus minimizing immune responses.
Implementation Method 1
The buffer is an acetate buffer or a histidine buffer, and the antibody-containing aqueous formulation falling within a pH of 4.5 to 6.5
Implementation Method 2
a protein stabilizer, and a surfactant... the protein stabilizer is sucrose or trehalose... Tocilizumab IgG formulated in Actemra intravenous formulation is unstable when exposed to thermal stress
Implementation Method 3
the surfactant is polysorbate 80, polysorbate 20 or poloxamer... 0.05% of polysorbate 80
Data Source
AI summary
The present disclosure provides an antibody-containing aqueous formulation, comprising a therapeutically effective amount of an anti-interleukin-6 receptor antibody, a protein stabilizer, a surfactant, and a buffer. The buffer is an acetate buffer or a histidine buffer, and the antibody-containing aqueous formulation has a pH ranging from 4.5 to 6.5.