Highly Concentrated Protein Formulations: Sulfonate Salts for Lower Viscosity
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Solution Overview
Problem
Highly concentrated protein formulations face challenges with increased viscosity, leading to difficulties in processing and administration, particularly for subcutaneous delivery, due to protein aggregation and self-association, which current excipients like NaCl and amino acids do not universally address.
Innovation Solution
Combining proteins with specific excipients such as meglumine, ornithine, benzenesulfonic acid, and sodium p-toluene sulfonic acid in equimolar amounts to reduce viscosity by up to 80% in formulations ranging from 50 mg/ml to 300 mg/ml, stabilizing proteins against aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If high concentration protein formulations are used to reduce injection volume, then patient compliance and healthcare cost improve, but viscosity increases significantly making injection difficult
Solution Approach 1:
The patent introduces sulfonate salts (sodium p-toluenesulfonate, sodium benzenesulfonate, potassium p-toluenesulfonate, or potassium benzenesulfonate) as intermediary substances that mediate between the high concentration protein formulation and the injection process. These excipients act as viscosity-reducing agents that enable easy injection of highly concentrated formulations without requiring dilution, thus maintaining the benefits of low injection volume while solving the injectability problem.
Solution Approach 2:
The patent changes the chemical composition parameters of the formulation by adding specific excipients (sulfonate salts) at optimized concentrations (0.1-1.0 mM). This parameter change fundamentally alters the rheological properties of the formulation, reducing viscosity and improving injectability while maintaining high protein concentration (50-300 mg/ml), thereby resolving the contradiction between concentration and ease of injection.
2Quantity of substance
If high concentration protein formulations are used to achieve therapeutic doses in low volume, then dosage efficiency improves, but protein aggregation and instability increase
Solution Approach 1:
The sulfonate salts serve as protective intermediary substances that prevent direct protein-protein interactions leading to aggregation. These excipients create a molecular environment that stabilizes the protein structure at high concentrations, acting as a buffer against aggregation forces while allowing the maintenance of high therapeutic dose concentrations in low injection volumes.
Solution Approach 2:
The patent creates a composite formulation system combining the therapeutic protein with specific excipients (sulfonate salts) at optimized ratios. This composite material approach allows the formulation to simultaneously achieve high protein concentration for therapeutic efficacy and enhanced stability through the protective effects of the excipient matrix, preventing aggregation even at concentrations up to 300 mg/ml.
3Volume of moving object
If high concentration formulations are prepared to minimize injection volume, then treatment cost and patient burden decrease, but manufacturing and processing become more difficult
Solution Approach 1:
The patent applies preliminary action by incorporating viscosity-reducing excipients (sulfonate salts) into the formulation during the manufacturing process, before the formulation reaches the high-concentration final state. This preliminary inclusion of stabilizing agents prevents viscosity buildup and aggregation during concentration steps such as ultrafiltration and diafiltration, making manufacturing and processing easier while enabling the final low-volume high-concentration product.
Data Source
AI summary
The present invention relates to compositions of highly concentrated protein formulations showing reduced viscosity. The contained proteins in the prepared formulations are stabilized against aggregation and denaturation and are thus sufficiently storage-stable until administration to the patient.