Disodium Levofolinate Composition With Low-Impurity Stability
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Solution Overview
Problem
Existing compositions of disodium levofolinate suffer from stability issues due to high impurity levels, which affect their shelf-life and efficacy in medical treatments.
Innovation Solution
The development of compositions comprising disodium levofolinate with controlled impurity levels, specifically not more than 1% mole fraction of certain components, and a lyophilization process at temperatures below 18°C, along with the inclusion of mannitol, to enhance stability and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compositions of disodium levofolinate are used, then they can be administered for medical treatment, but they suffer from stability issues due to high impurity levels
Solution Approach 1:
The patent applies parameter changes by controlling the pH of the composition to be between 6.0 and 8.0, and by specifying precise concentration ranges for disodium levofolinate (40-60 mg/mL) and mannitol (10-30 mg/mL). These parameter adjustments optimize stability while managing impurity formation during storage and lyophilization processes.
Solution Approach 2:
The patent creates a composite composition by combining disodium levofolinate with mannitol as a stabilizing excipient. This composite formulation enhances the overall stability of the active ingredient while the controlled impurity profile ensures compliance with pharmacopoeial standards. The composite approach allows the composition to maintain efficacy throughout its shelf life.
2Duration of action of stationary object
If lyophilization process is used to improve stability, then shelf-life is extended, but process complexity increases
Solution Approach 1:
The lyophilization process parameters are precisely controlled: freezing temperature between -20°C and -40°C, drying temperature between -10°C and 0°C, and pressure between 0.01 and 0.1 mbar. These parameter specifications extend shelf-life to at least 24 months while managing process complexity through defined operational ranges that can be implemented with standard lyophilization equipment.
3Reliability
If impurity levels are reduced to enhance purity, then stability is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent establishes specific concentration ranges and purity thresholds: disodium levofolinate (40-60 mg/mL), mannitol (10-30 mg/mL), pH (6.0-8.0), and impurity limits (individual impurities ≤0.1%, total impurities ≤1.0%). These parameter specifications enable stability enhancement while providing clear manufacturing targets that balance purity requirements with practical production capabilities.
Solution Approach 2:
The patent implements quality control feedback by specifying impurity thresholds that trigger process adjustments. During manufacturing and quality testing, impurity levels are monitored against the defined limits (0.1% individual, 1.0% total), and process parameters such as pH and concentration are adjusted accordingly to maintain compliance and optimize stability throughout the product lifecycle.
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 improved compositions exhibit enhanced stability and purity, maintaining effective biological activity over time, suitable for medical treatments such as cancer therapy and methotrexate toxicity rescue.
Implementation Method 1
The glass transition of disodium levofolinate occurred at −17.88° C. The glass transition of disodium levofolinate and 10 mg/mL mannitol showed a glass transition occurring at −24.10° C.
Data Source
AI summary
Provided herein are compositions comprising disodium levofolinate. Also provided are processes for preparing compositions comprising disodium levofolinate. Also provided are compositions comprising disodium levofolinate prepared by the processes provided herein. Also provided are methods of treating folic acid deficiency in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering 5-fluorouracil and a composition provided herein to the subject. Also provided are methods of reducing the immediate toxic effects of methotrexate overdose in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering high-dose methotrexate and a composition provided herein to the subject. Also provided are methods of treating megaloblastic anemia in a subject in need thereof, comprising administering a composition provided herein to the subject.