Thrombin Stabilization via Acetate and Calcium Propionate Buffer
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Solution Overview
Problem
Thrombin-containing compositions for hemostasis applications face challenges in maintaining stability and requiring high initial thrombin activity levels, leading to increased manufacturing costs.
Innovation Solution
Compositions comprising thrombin and collagen in an aqueous buffer solution with specific stabilizers such as sodium acetate, calcium propionate, and sorbitol, which maintain effective thrombin activity over a prolonged shelf-life at reduced initial thrombin levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high initial thrombin activity levels (e.g., 800 IU/ml) are used to maintain effective thrombin activity over shelf-life, then thrombin activity level is improved, but manufacturing cost increases due to excess thrombin
Solution Approach 1:
The patent changes the chemical parameters of the formulation by introducing specific stabilizers (acetate ions, calcium ions, and sugars) that modify the molecular environment of thrombin. This stabilizing effect slows degradation kinetics, allowing lower initial thrombin concentrations (e.g., 400-600 IU/ml) to maintain effective activity levels throughout shelf-life, thereby reducing material costs while preserving reliability
Solution Approach 2:
The patent employs stabilizing agents as intermediary substances that mediate between thrombin and its degradation pathways. These intermediaries (acetate, calcium, sugars) interact with thrombin molecules to prevent unwanted chemical modifications and aggregation, extending the functional lifespan of thrombin without requiring excess initial amounts
2Reliability
If excess thrombin is added to maintain effective activity over shelf-life, then thrombin activity is improved, but manufacturing cost increases
Solution Approach 1:
By modifying the chemical environment through formulation stabilizers, the patent changes the stability parameter of thrombin, reducing its degradation rate. This allows manufacturing at lower thrombin concentrations while maintaining product performance, directly reducing material costs without compromising reliability
Solution Approach 2:
The patent replaces the need for expensive excess thrombin with cheaper stabilizing agents (acetate, calcium salts, sugars) that are inexpensive and can be easily manufactured. These stabilizers act as protective agents during storage, eliminating the need to manufacture and store large excesses of costly thrombin protein
3Ease of manufacture
If thrombin compositions are formulated with traditional stabilizers, then manufacturing is simplified, but stability is insufficient leading to rapid activity loss
Solution Approach 1:
The patent creates a composite stabilization system combining multiple components: acetate ions, calcium ions, and sugar molecules work synergistically to provide comprehensive protection for thrombin. This composite approach addresses multiple degradation mechanisms simultaneously, achieving superior stability while maintaining formulation simplicity through a unified buffer system
Data Source
AI summary
Compositions comprising thrombin and collagen and methods of preparation thereof are disclosed herein. In one embodiment, a composition comprises thrombin and collagen in an aqueous buffer solution, wherein the buffer solution includes at least one of a first compound represented by Formula I: R1—C(O)—O−M+, wherein R1 is —CH3, —CH2CH2C(O)OH, or —CH2CH2C(O)O−M+, and wherein M+ is a monovalent ion; or a second compound represented by Formula II: R2—C(O)—O−M2+−O—C(O)—R2, wherein R2 is —CH3 or —CH2CH3, and wherein M2+ is a divalent ion. In one embodiment, the buffer solution includes sodium acetate, calcium propionate, and sorbitol.