Lyophilized Folate Composition for Oxidation-Stable High Solubility
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Solution Overview
Problem
Existing formulations of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF) suffer from high susceptibility to oxidation and chemical degradation, particularly in aqueous solutions and amorphous forms, limiting their pharmaceutical use due to instability and low active ingredient content.
Innovation Solution
A lyophilized composition comprising the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF*Na2) in combination with citrate and an alkali metal sulfate, without additional reducing agents or antioxidants, achieves high stability and solubility, allowing for a concentration of more than 30% w/w of the active ingredient.
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 chemical stability and resistance to oxidation deteriorate
Solution Approach 1:
The patent uses citrate and sulfate as intermediary substances that mediate between the active ingredient and the aqueous environment. These additives form a protective matrix that prevents direct contact between 5,10-CH2-(6R)-THF and oxidizing agents in aqueous solution, thereby maintaining chemical stability while preserving solubility and bioavailability.
Solution Approach 2:
The patent changes the pH parameter of the formulation to an alkaline range (pH 7.5-9.0) where 5,10-CH2-(6R)-THF exhibits improved stability. This parameter change, combined with the use of citrate and sulfate, creates an optimal chemical environment that reduces oxidation susceptibility while maintaining adequate solubility for pharmaceutical use.
2Quantity of substance
If concentration of 5,10-CH2-(6R)-THF is increased to achieve high intracellular levels, then therapeutic effect is improved, but susceptibility to oxidation and degradation increases
Solution Approach 1:
Citrate and sulfate act as protective intermediaries that form a stabilizing matrix around the high concentration of 5,10-CH2-(6R)-THF. This matrix prevents oxidative degradation even at elevated concentrations (20-80% w/w), enabling the formulation to achieve both high therapeutic potency and acceptable stability during storage and administration.
Solution Approach 2:
The patent creates a composite formulation system consisting of 5,10-CH2-(6R)-THF combined with citrate and sulfate in specific ratios. This composite material exhibits synergistic properties where the citrate-sulfate matrix protects the active ingredient from degradation, allowing high concentrations to be maintained without proportionally increasing susceptibility to oxidation.
3Stability of the object's composition
If lyophilizate is prepared to improve storage stability, then resistance to oxidation is improved, but complexity of reconstitution and administration increases
Solution Approach 1:
The citrate-sulfate system serves as a eutectic mixture that acts as an intermediary between the lyophilized state and reconstituted solution. This intermediary system allows the lyophilizate to be easily reconstituted with simple diluents (water, saline, or buffered solutions) without requiring complex procedures, while maintaining high storage stability in the dried state.
Solution Approach 2:
The lyophilization process creates a copied solid-state version of the stable aqueous formulation containing citrate and sulfate. This solid copy preserves the stabilizing effects of the citrate-sulfate system during storage, and upon reconstitution, faithfully reproduces the stable solution characteristics, ensuring consistency between stored and administered formulations.
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 maintains high stability and solubility, ensuring effective storage and administration of 5,10-CH2-(6R)-THF*Na2, suitable for cancer treatment, with enhanced storage stability and minimal degradation products.
Implementation Method 1
5,10-CH2-(6R)-THF is highly susceptible to oxidation and chemical degradation that results in unfavorably high impurity levels
Implementation Method 2
A lyophilized composition comprising the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid
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.