Low Concentration Antibody Formulations with Surfactant and Antioxidant
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Solution Overview
Problem
Therapeutic proteins face significant loss due to adsorption when diluted to low concentrations for intravenous administration, particularly due to their amphiphilic nature and interaction with plastic surfaces in syringes and infusion containers, leading to stability issues and reduced efficacy.
Innovation Solution
Formulations comprising therapeutic proteins with a surfactant at a molar ratio of at least 100 and an antioxidant at a molar ratio of at least 750, along with a buffer at a pH of 4.0 to 8.0, are developed to enhance stability and prevent protein loss during administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If therapeutic protein is diluted to low concentrations for intravenous administration, then the dosage can be precisely controlled and administered, but the protein stability is compromised and adsorption to plastic surfaces increases significantly
Solution Approach 1:
The patent introduces surfactants (e.g., polysorbate 80, poloxamer 407) and antioxidants (e.g., methionine, glutathione) as intermediary substances that mediate between the therapeutic protein and the plastic surface environment. These excipients form protective complexes with the protein, preventing direct adsorption to plastic surfaces and reducing oxidative stress, thereby maintaining protein stability at low concentrations during intravenous administration
Solution Approach 2:
The patent modifies the formulation parameters by incorporating specific concentrations of surfactants (0.01-0.5% w/v) and antioxidants (1-50 mM), and adjusting pH levels (4.0-8.0) to optimize protein stability. These parameter changes create a protective microenvironment that prevents adsorption and degradation, enabling reliable low-concentration therapy
2Quantity of substance
If excipient concentration is reduced through dilution, then the therapeutic protein concentration is achieved for administration, but the protective effect of excipients is diminished and protein stability is compromised
Solution Approach 1:
The patent applies preliminary action by incorporating high concentrations of surfactants and antioxidants into the formulation before dilution. These excipients are pre-positioned to protect the protein throughout the dilution process and during administration, ensuring that even at low final concentrations, the protein maintains stability through the protective excipient matrix
Solution Approach 2:
The patent creates a composite formulation system combining therapeutic protein with multiple excipients (surfactants, antioxidants, buffers) in specific ratios. This composite structure provides synergistic protection where surfactants prevent surface adsorption while antioxidants prevent oxidative degradation, maintaining formulation stability at low concentrations
3Adaptability or versatility
If protein concentration is lowered for specific therapeutic delivery, then the treatment can be tailored to patient needs, but adsorption loss to syringes and infusion containers increases dramatically
Solution Approach 1:
The patent uses surfactants as intermediary substances that preferentially adsorb to plastic surfaces rather than the therapeutic protein. This competitive adsorption mechanism creates a protective barrier, reducing protein loss to syringes and infusion containers. The surfactant-protein complex formed acts as an intermediary that resists surface binding, enabling flexible low-concentration delivery with minimal loss
Solution Approach 2:
The patent creates a surfactant-protein complex that replicates the protective properties of high-concentration formulations. The surfactant molecules form a protective shell around the protein, effectively copying the stable environment of concentrated formulations and transporting it to low-concentration administration conditions, thereby reducing adsorption loss
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 significantly reduce protein loss during administration, achieving greater than 90% recovery and maintaining stability over time by inhibiting adsorption and oxidative degradation, thus ensuring the therapeutic effectiveness of low-concentration therapeutic proteins.
Implementation Method 1
a surfactant; wherein the molar ratio of surfactant to therapeutic protein is at least 100
Implementation Method 2
proteins tend to absorb at interfaces due to their amphiphilic nature
Implementation Method 3
an antioxidant, wherein the molar ratio of antioxidant to therapeutic protein is at least 750
Data Source
AI summary
The present invention is directed formulations for low concentrations of therapeutic proteins and methods of making the same. In one aspect the present invention is directed to a formulation for a therapeutic protein comprising: a) the therapeutic protein; and b) a surfactant; wherein the molar ratio of surfactant to therapeutic protein is at least 100. In another aspect the present invention is directed to a formulation for a therapeutic protein comprising: a) the therapeutic protein; and b) an antioxidant, wherein the molar ratio of antioxidant to therapeutic protein is at least 750.