Lyophilized Disodium Methylene-THF Composition for Oxidation Stability
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Solution Overview
Problem
Existing formulations of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF) are susceptible to oxidation and chemical degradation, particularly in aqueous solutions and amorphous forms, leading to high impurity levels and unsatisfactory stability, solubility, and content issues, limiting their pharmaceutical use.
Innovation Solution
A lyophilized composition comprising the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF*Na2) combined with citrate and an alkali metal sulfate, prepared without additional reducing agents or antioxidants, which enhances stability and solubility, allowing for high content formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If 5,10-CH2-(6R)-THF is formulated in aqueous solution or amorphous form, then solubility and bioavailability are improved, but oxidation susceptibility and chemical degradation increase
Solution Approach 1:
The patent changes the chemical form of 5,10-CH2-(6R)-THF from the free acid to the disodium salt form, which fundamentally alters the solubility and stability parameters. The disodium salt exhibits enhanced water solubility while simultaneously demonstrating improved stability against oxidation and chemical degradation compared to the free acid form, thus resolving the contradiction between solubility and stability.
Solution Approach 2:
The patent creates a composite formulation by combining the disodium salt of 5,10-CH2-(6R)-THF with specific excipients including buffers (phosphate, citrate, acetate), stabilizers (sulfites, bisulfites), and antioxidants. This composite system provides both the required solubility for aqueous formulation and enhanced stability against degradation, resolving the contradiction between ease of operation and reliability.
2Quantity of substance
If high content formulations of 5,10-CH2-(6R)-THF are prepared, then therapeutic effectiveness is improved, but oxidation and degradation rates increase
Solution Approach 1:
By changing from the free acid form to the disodium salt form, the patent enables preparation of high content formulations with improved oxidation resistance. The disodium salt form inherently exhibits lower oxidation susceptibility, allowing higher active ingredient content to be formulated without proportionally increasing degradation rates.
Solution Approach 2:
The patent introduces intermediary substances including buffers (phosphate, citrate, acetate), stabilizers (sulfites, bisulfites), and antioxidants that mediate between the high content requirement and oxidation susceptibility. These intermediaries create a protective environment that allows high concentrations of the active ingredient to be maintained with reduced oxidation and degradation.
3Reliability
If reducing agents and antioxidants are added to stabilize 5,10-CH2-(6R)-THF, then stability is improved, but formulation complexity and additional degradation risks increase
Solution Approach 1:
The patent uses buffers (phosphate, citrate, acetate) and stabilizers (sulfites, bisulfites) as intermediary substances that provide stabilization through pH control and chemical protection mechanisms. These intermediaries create a controlled chemical environment that reduces oxidation susceptibility without requiring multiple antioxidants, thereby improving stability while limiting formulation complexity.
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 achieves high stability and solubility, maintaining purity and reducing impurity formation, enabling effective use in cancer treatment with a high content of 5,10-CH2-(6R)-THF*Na2, even without antioxidants, and supports reconstitution for intramuscular or intravenous administration.
Implementation Method 1
5,10-CH2-(6R)-THF is highly susceptible to oxidation and chemical degradation... The composition achieves high stability and solubility, maintaining purity and reducing impurity formation, enabling effective use in cancer treatment with a high content of 5,10-CH2-(6R)-THF*Na2, even without antioxidants
Implementation Method 2
supports reconstitution for intramuscular or intravenous administration
Data Source
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AI summary
The present invention relates to stable formulations and lyophilizates comprising a high content of the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid, sulfate and citrate.