SDAB Formulations with Lyoprotectants for Storage Stability
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Solution Overview
Problem
There is a need for stable protein formulations, particularly for subcutaneous administration, that can maintain long-term storage and delivery stability, as existing methods face challenges in preserving the conformational integrity and preventing degradation of proteins due to chemical and physical instability pathways.
Innovation Solution
The development of formulations that include single domain antigen binding molecules (SDAB molecules) such as nanobody molecules, combined with lyoprotectants, surfactants, bulking agents, tonicity adjusting agents, stabilizers, and buffers, to create stable formulations that can be administered via injection or inhalation, with specific concentrations and pH ranges to ensure stability and biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If proteins are formulated for long-term storage, then storage stability is improved, but chemical and physical degradation pathways (deamidation, aggregation, oxidation) increase
Solution Approach 1:
The patent employs multiple excipients as intermediary substances that mediate between the protein and the degrading environment. Lyoprotectants (sucrose, trehalose, sorbitol) act as intermediaries during freeze-drying to prevent protein denaturation and aggregation. Surfactants (polysorbate 20, polysorbate 80, poloxamer 188) serve as intermediaries to prevent surface adsorption and aggregation at air-liquid interfaces. These intermediary substances form protective complexes with the protein, reducing direct exposure to harmful conditions during storage and handling.
Solution Approach 2:
The patent systematically optimizes formulation parameters including pH (adjusted to 5.0-7.5 using histidine or Tris buffers), ionic strength, and excipient concentrations to minimize degradation. The specific pH range is chosen to reduce deamidation and aggregation rates. Buffer concentration and excipient ratios are precisely controlled to maintain protein stability while preventing various degradation pathways throughout the storage period.
2Stability of the object's composition
If freeze-drying is used to preserve proteins, then storage stability is improved, but conformational integrity and biological activity may be compromised
Solution Approach 1:
The formulation is designed with protective excipients in place before the freeze-drying process begins. The protein is pre-mixed with lyoprotectants, surfactants, and buffers in optimized concentrations to create a protective environment that will maintain conformational integrity throughout the freeze-drying cycle and subsequent storage. This preliminary protective action prevents denaturation and aggregation before they can occur during the stress of freeze-drying.
Solution Approach 2:
The patent creates a composite formulation system combining the protein with multiple excipients that work synergistically. The composite includes lyoprotectants that form glassy matrices during freeze-drying to physically protect the protein, surfactants that coat the protein surface to prevent aggregation, and buffers that maintain optimal pH. This composite material approach ensures both storage stability and preservation of biological activity by distributing protective functions across multiple components.
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 formulations effectively maintain the integrity and biological activity of SDAB molecules during storage and delivery, reducing chemical and physical instability, and can be administered via various routes, including subcutaneous injection, ensuring effective treatment of TNF-associated disorders.
Implementation Method 1
An excipient may be included in pre-lyophilized formulations to enhance stability during the freeze-drying process
Implementation Method 2
a buffer, such that the pH of the formulation is about 5.0 to 7.5
Implementation Method 3
a surfactant
Data Source
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AI summary
The invention relates to formulations of single domain antigen binding molecules, e.g. nanobody molecules, in particular formulations of TNF-binding nanobody molecules. The single domain antigen binding molecules can include one or more single binding domains that interact with, e.g. bind to, one or more target proteins. The formulations are useful, e.g., as pharmaceutical formulations. Method of preparing, and using the formulations described herein, to treat, e.g., TNF-associated disorders, are also disclosed.