Trabectedin Lyophilized Composition for Stability and Fast Reconstitution
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Solution Overview
Problem
Trabectedin formulations face challenges due to limited aqueous solubility and thermal stability, leading to degradation issues and unsuitable formulations for medical use, particularly affecting diabetic patients and requiring long reconstitution times.
Innovation Solution
A composition comprising trabectedin and specific amino acids, such as L-arginine, with a weight ratio of 1:10 to 1:250, along with buffering agents like citric acid and phosphoric acid, stabilizes the formulation and allows for a lyophilized form that maintains stability for at least 3 months at 2-8°C, preventing degradation products and facilitating easy reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If trabectedin is formulated with high amounts of amino acid (e.g., L-arginine in 1:400 ratio), then stability is improved, but solution volume increases leading to longer drying cycles and higher production costs
Solution Approach 1:
The patent changes the concentration parameter of amino acid from the conventional 1:400 ratio to a range of 1:10 to 1:250, optimizing the balance between stability and processing efficiency. This parameter modification reduces solution volume and drying time while maintaining formulation stability.
Solution Approach 2:
Instead of using excessive amounts of amino acid (1:400 ratio), the patent applies partial action by reducing the amino acid concentration to the optimal range of 1:10 to 1:250, achieving sufficient stability without the negative effects of high concentrations.
2Reliability
If trabectedin is formulated with high amounts of auxiliary additives, then stability is improved, but negative impacts on patients increase
Solution Approach 1:
The patent modifies the concentration parameter of auxiliary additives by reducing amino acid content from 1:400 to 1:10-1:250 ratio, thereby minimizing potential harmful effects on patients while preserving formulation stability through optimized concentration levels.
3Device complexity
If trabectedin is formulated without sufficient stabilizing agents, then formulation simplicity is improved, but thermal stability and aqueous solubility deteriorate
Solution Approach 1:
The patent optimizes the concentration parameters of stabilizing agents (amino acids in 1:10 to 1:250 ratio) to achieve the minimum effective amount needed for thermal stability and aqueous solubility, avoiding both under-stabilization and over-complexification.
Solution Approach 2:
The patent employs readily available amino acids (L-arginine, L-histidine, L-lysine, etc.) as stabilizing agents, using simple, well-characterized substances that provide effective stabilization without requiring complex or expensive additives.
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 ensures stability and suitability for medical use, avoiding degradation products and enabling long-term storage, with improved handling and reconstitution, suitable for treating various cancers including sarcoma and ovarian cancer.
Implementation Method 1
A composition comprising trabectedin and specific amino acids, such as L-arginine, with a weight ratio of 1:10 to 1:250, along with buffering agents like citric acid and phosphoric acid, stabilizes the formulation
Implementation Method 2
allows for a lyophilized form that maintains stability for at least 3 months at 2-8°C, preventing degradation products
Data Source
AI summary
The present invention relates to a stable pharmaceutical composition comprising trabectedin. The present invention also provides a lyophilized formulation and an intravenous injection solution comprising trabectedin and an amino acid.