Thrombin Stabilization via Sucrose and Preservatives
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Solution Overview
Problem
Pharmaceutical proteins like thrombin are prone to degradation and instability, especially during storage and reconstitution, due to unpredictable responses to solution conditions, and existing stabilization methods are costly and limited in extending in-use handling time.
Innovation Solution
A pharmaceutical composition comprising thrombin, a bacteriostatically effective amount of preservatives such as benzyl alcohol or chlorobutanol, and 0.10% to 5.0% sucrose in an aqueous solution, along with optional buffers, salts, and polyols, which stabilizes thrombin against degradation and maintains stability during storage and reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If lyophilization is used to stabilize thrombin, then stability during storage is improved, but processing time and cost increase
Solution Approach 1:
The invention changes the physical state parameter of thrombin from lyophilized (solid) to aqueous solution (liquid) form, while maintaining stability through optimized formulation parameters including preservative concentration (0.5-2% benzyl alcohol or 0.25-1% chlorobutanol), sucrose concentration (0.1-5%), and pH control (5.7-7.4). This parameter optimization allows liquid thrombin to achieve stability comparable to lyophilized forms without the time-consuming lyophilization process.
2Stability of the object's composition
If lyophilization is used to stabilize thrombin, then stability during storage is improved, but cost increases
Solution Approach 1:
The invention optimizes formulation parameters to enable stable liquid thrombin storage, eliminating the need for lyophilization equipment and processing. The specific parameter ranges (preservative 0.5-2%, sucrose 0.1-5%, pH 5.7-7.4) are designed to prevent degradation pathways, providing a cost-effective alternative to expensive lyophilization manufacturing while maintaining thrombin stability.
3Duration of action of stationary object
If preservatives are added to extend in-use handling time, then stability is improved, but protein denaturation may occur
Solution Approach 1:
The invention optimizes preservative concentration parameters to achieve bacteriostatic effectiveness while minimizing protein denaturation. The specified ranges (0.5-2% benzyl alcohol or 0.25-1% chlorobutanol) are carefully balanced to provide sufficient microbial protection during extended in-use handling (up to 28 days) while maintaining thrombin structural integrity through controlled preservative levels.
Solution Approach 2:
The invention uses a composite formulation combining multiple stabilizing components: preservatives (benzyl alcohol or chlorobutanol), carbohydrates (sucrose 0.1-5%), buffers (phosphate, citrate, Tris, histidine, or acetate at pH 5.7-7.4), and optional surfactants or polyols. This composite approach provides synergistic protection, where each component contributes to overall stability, allowing extended in-use handling while preventing protein denaturation through the combined effect of all formulation elements.
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 composition ensures stability of thrombin solutions for extended periods, preventing degradation and maintaining effectiveness, with solutions remaining stable for up to thirteen weeks at refrigerator temperatures and allowing extended in-use handling without compromising sterility.
Implementation Method 1
0.10% to 5.0% (w/v) sucrose in aqueous solution... which stabilizes thrombin against degradation
Implementation Method 2
a bacteriostatically effective amount of a preservative selected from the group consisting of benzyl alcohol and chlorobutanol
Data Source
AI summary
Stabilized thrombin compositions, processes for preparing them, and kits comprising them are disclosed. The compositions comprise thrombin, a bacteriostatically effective amount of benzyl alcohol or chlorobutanol, and 0.10%-5.0% (w/v) sucrose in aqueous solution. The compositions are stable when stored at 2° C.-8° C. for four weeks or more.