Hypotonic Protein Formulation Viscosity Control
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Solution Overview
Problem
Developing concentrated protein formulations above 100 mg/mL is challenging due to solubility, viscosity, and stability issues, particularly for injectable administration, where high concentrations lead to aggregation and manufacturing complications.
Innovation Solution
A low viscosity, hypotonic protein formulation comprising a concentrated protein, a tonicifier (salt and buffer), and a surfactant, with specific concentrations and combinations to achieve a viscosity of 25-60 cP, osmolality below 290 mOs/kg, and pH between 5.4 and 6.4, allowing for stable and manageable administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If protein concentration is increased to greater than 100 mg/mL, then the dosage efficiency and volume for administration is improved, but the viscosity increases making administration difficult
Solution Approach 1:
The patent applies parameter changes by carefully controlling pH (5.0-6.5), ionic strength (through salt and buffer combinations), temperature, and the presence of surfactants to maintain low viscosity at high protein concentrations greater than 100 mg/mL
Solution Approach 2:
The patent introduces intermediary substances including salts (sodium chloride, sodium acetate), buffers (acetate, citrate), and surfactants (polysorbate 20, polysorbate 80) that mediate between high protein concentration and acceptable viscosity by modifying the physical chemistry environment
2Quantity of substance
If protein concentration is increased to greater than 100 mg/mL, then the dosage efficiency is improved, but aggregation problems occur reducing stability
Solution Approach 1:
The patent introduces stabilizing intermediaries including salts, buffers, and surfactants that prevent protein-protein interactions leading to aggregation, thereby maintaining stability at high concentrations
Solution Approach 2:
The patent controls physical-chemical parameters including pH (5.0-6.5), ionic strength, and temperature to prevent conformational changes and aggregation that would otherwise occur at high protein concentrations
3Reliability
If salt and buffer amounts are increased to achieve isotonicity, then the tonicity is improved, but the viscosity increases
Solution Approach 1:
The patent applies partial action by using sub-isotonic salt and buffer concentrations that provide sufficient tonicity control without reaching full isotonicity, thereby avoiding the viscosity increase that would accompany complete isotonic formulation
Solution Approach 2:
The patent optimizes the balance between salt concentration and pH buffer capacity to achieve adequate tonicity and stability without excessive ionic strength that would increase viscosity
4Quantity of substance
If concentrated protein formulation is prepared for injectable administration, then the dosage efficiency is improved, but the formulation becomes highly viscous creating manufacturing limitations
Solution Approach 1:
The patent controls manufacturing parameters including pH (5.0-6.5), ionic strength, temperature, and mixing conditions to prevent viscosity increase during preparation and filling operations
Solution Approach 2:
The patent introduces surfactants and buffer systems as intermediary substances that reduce interfacial tension and prevent aggregation during manufacturing processes, thereby maintaining manufacturability at high concentrations
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 enables stable, low viscosity, and hypotonic protein delivery, reducing aggregation and manufacturing difficulties, facilitating subcutaneous and parenteral administration with improved manufacturability and safety.
Implementation Method 1
a surfactant, wherein the formulation is hypotonic
Implementation Method 2
a buffer present in a combined amount of from about 110 mM to about 120 mM
Data Source
AI summary
Described are low viscosity, hypotonic formulations containing one or more proteins, e.g., antibodies, at high concentration, uses of the formulations, and articles of manufacture. In particular, the formulations are useful and beneficial for the subcutaneous administration or delivery of a high concentration of a protein drug, such as an antibody, to a subject who is afflicted with a disease or condition that is treatable by the protein drug.