C1-INH Formulation Stability via Histidine Buffering
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Solution Overview
Problem
Current C1 esterase inhibitor (C1-INH) formulations for hereditary angioedema are large volume, require intravenous administration, and have stability issues leading to rapid protein multimerization and aggregation, which complicates long-term storage and patient self-administration.
Innovation Solution
Development of low volume, high concentration C1-INH formulations with histidine and other amino acids, saccharose, and specific pH levels, excluding citrate and phosphate buffers, to minimize high molecular weight component formation and enhance stability for subcutaneous and intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If C1-INH is formulated in large volume for intravenous administration, then stability is maintained, but patient self-administration becomes difficult and compliance decreases
Solution Approach 1:
The patent changes the concentration parameter of C1-INH from conventional low concentrations to high concentrations (500-2000 IU/mL), which reduces formulation volume and enables self-administration while maintaining stability through optimized buffer composition and pH control
Solution Approach 2:
The patent creates a dynamic formulation system that adapts to different storage conditions and administration routes by using histidine buffer with specific pH ranges (6.5-7.5) that maintains protein stability across varying temperatures and over time
2Duration of action of stationary object
If C1-INH is stored long-term, then therapeutic availability is ensured, but protein multimerization and aggregation occur rapidly
Solution Approach 1:
The patent introduces histidine buffer as an intermediary substance that mediates between the C1-INH protein and the storage environment, preventing protein-protein interactions that lead to aggregation while maintaining solubility and stability over long storage periods
Solution Approach 2:
The patent optimizes pH parameters (6.5-7.5) and ionic strength parameters through histidine buffer concentration adjustments, creating a chemical environment that stabilizes the protein structure and prevents multimerization during long-term storage
3Volume of moving object
If C1-INH concentration is increased to reduce volume, then self-administration becomes feasible, but formulation stability and aggregation control become more challenging
Solution Approach 1:
The patent creates a composite formulation system combining C1-INH with histidine buffer, amino acids, and other excipients that work synergistically to maintain protein stability at high concentrations, where each component contributes specific protective functions against aggregation
Data Source
AI summary
The present invention relates to pharmaceutical formulations comprising the C1 esterase inhibitor (C1-INH), exhibiting a higher stability for prolonged storage and a reduced formation of aggregates of said esterase inhibitor (C1-INH) upon storage for ameliorated use in treating or preventing disorders related to kinin formation.