tPA Formulation Stability at Room Temperature
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Solution Overview
Problem
Recombinant tissue-type plasminogen activator (tPA) formulations face challenges with poor long-term stability at room temperature, leading to degradation and instability in liquid form, which complicates storage and administration, especially for catheter use.
Innovation Solution
A novel liquid composition comprising 0.15 to 0.25 units/mL tPA, 1 mM to 10 mM tranexamic acid, 2.5 to 5.0% sucrose, and optional nonionic surfactant and pH buffering agents, with a pH of 6.0 to 8.0, allowing for stable storage and use at room temperature, and an essentially water-free composition by lyophilization for enhanced stability and convenience.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If recombinant tPA is formulated as a liquid solution, then it can be readily administered and used, but it exhibits poor long-term stability and degradation at room temperature
Solution Approach 1:
The patent applies parameter changes by optimizing the pH range (6.0-8.0) and incorporating specific excipients including sucrose (2.5-5.0% w/v), tranexamic acid (1-10 mM), and optional nonionic surfactants at controlled concentrations (0.01-0.1% w/v). These parameter adjustments enable the liquid formulation to maintain stability at room temperature while remaining ready for administration, resolving the contradiction between ease of use and compositional stability.
2Stability of the object's composition
If recombinant tPA is stored in lyophilized form, then it maintains stability at refrigerated temperatures, but it requires reconstitution immediately before use and cannot be stored at room temperature
Solution Approach 1:
The invention changes the physical and chemical parameters of the formulation by incorporating stabilizing excipients (sucrose, tranexamic acid, nonionic surfactants) and maintaining pH between 6.0-8.0, which allows the tPA to remain stable in liquid form at room temperature without requiring lyophilization or refrigeration, thereby eliminating reconstitution steps and storage time losses.
3Reliability
If the concentration of tPA is increased for effective catheter treatment, then clot lysis activity is improved, but stability and handling become more difficult
Solution Approach 1:
The patent creates a composite formulation system combining tPA with multiple stabilizing components: sucrose (2.5-5.0% w/v) as a stabilizer, tranexamic acid (1-10 mM) to prevent fibrinogen degradation, and nonionic surfactants (0.01-0.1% w/v) to prevent aggregation. This composite approach allows higher tPA concentrations to be maintained stably in liquid form, ensuring reliable clot lysis activity while maintaining formulation stability and ease of handling.
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 provides a stable and effective tPA solution for treating occluded catheters, maintaining clot lysis activity and stability during storage and handling, enabling direct instillation into catheters without the need for refrigeration, thus improving handling and storage conditions.
Implementation Method 1
about 2.5 to 5.0% (w/v) sucrose
Implementation Method 2
about 1 mM to 10 mM tranexamic acid
Implementation Method 3
optional nonionic surfactant
Implementation Method 4
pH buffering agents, with a pH of 6.0 to 8.0
Data Source
AI summary
The present disclosure relates to stable formulations of tissue-type plasminogen activator (tPA). In particular, the disclosure relates to specific new formulations, methods of preparing them and methods of using them.