Fosfomycin Aqueous Formulation pH Stabilization
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Solution Overview
Problem
Current fosfomycin formulations for parenteral administration face challenges such as complex production processes, supply bottlenecks, and risky handling steps, which can lead to contamination and incorrect dosages, and are limited by the instability of fosfomycin in solution, requiring it to be used as a powder that must be dissolved shortly before administration.
Innovation Solution
A closed container containing an aqueous solution of a pharmaceutically acceptable salt of fosfomycin and succinic acid, with a mass ratio between 30:1 and 50:1, ready for parenteral administration, eliminating the need for on-site mixing and ensuring stability for extended periods, including after autoclaving and storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If fosfomycin is prepared as a dry powder mixture with succinic acid, then the formulation can be stored for extended periods, but the production process becomes complex and requires sophisticated mixing technology
Solution Approach 1:
The patent applies preliminary action by pre-dissolving succinic acid in water during the manufacturing process to create a homogeneous aqueous solution containing both fosfomycin and succinic acid. This solution is then filled into containers under sterile conditions and sealed. By performing the dissolution and mixing steps during manufacturing rather than requiring complex sterile mixing technology at the point of use, the patent achieves both long-term storage stability and simplified production processes that can be implemented with standard pharmaceutical manufacturing equipment
2Stability of the object's composition
If fosfomycin is prepared as a dry powder that must be dissolved before administration, then storage stability is improved, but the risk of contamination and incorrect dosage increases due to additional processing steps
Solution Approach 1:
The patent eliminates the need for on-site dissolution by performing the dissolution of fosfomycin and succinic acid during the manufacturing process. The resulting homogeneous aqueous solution is filled into sterile containers and sealed. This preliminary preparation ensures that the formulation is ready for immediate administration without requiring additional processing steps that could introduce contamination or dosing errors, thereby improving both stability and administrative safety
Solution Approach 2:
The patent employs disposable sterile single-dose containers that are pre-filled with the fosfomycin-succinic acid solution during manufacturing. Each container is hermetically sealed and intended for single use only. This approach eliminates the need for repeated handling, opening, and closing of containers, thereby minimizing the risk of contamination and dosing errors while maintaining formulation stability throughout the product's shelf life
3Stability of the object's composition
If fosfomycin solution is prepared with high pH to maintain stability, then the antibiotic remains effective, but the solution becomes incompatible with parenteral administration
Solution Approach 1:
The patent introduces succinic acid as an intermediary substance that mediates between fosfomycin and the physiological environment. Succinic acid acts as a buffering agent that reacts with excess hydroxide ions in the fosfomycin solution to lower and stabilize the pH within the physiological range (pH 6-8). This buffering action maintains fosfomycin stability while rendering the solution compatible with parenteral administration, eliminating both precipitation and tissue irritation
Solution Approach 2:
The patent applies parameter changes by systematically adjusting the pH of the fosfomycin solution through the addition of succinic acid. The process involves adding succinic acid to lower the pH from the initially high value (pH 10-12) to the physiological range (pH 6-8). This parameter change is achieved by controlling the amount of succinic acid added and monitoring the pH during the adjustment process, thereby transforming the solution from an unstable, incompatible form to a stable, parenterally compatible formulation
4Ease of operation
If fosfomycin is provided as a ready-to-use aqueous solution, then administration is simplified and safety is improved, but the formulation requires advanced sterile processing technology
Solution Approach 1:
The patent performs all dissolution, mixing, and sterile filtration operations during the manufacturing process rather than requiring them at the point of use. The fosfomycin and succinic acid are dissolved in water, the solution is filtered through sterile filters, and the clarified solution is filled into sterile containers under controlled conditions. By completing these complex sterile processing steps during manufacturing, the product is delivered as a ready-to-use solution that can be administered immediately without requiring sophisticated sterile processing equipment or expertise at the administration site
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 solution provides a stable, ready-to-use fosfomycin formulation that is easier to produce and administer, reducing the risk of contamination and incorrect dosages, and maintaining antimicrobial activity for at least three months, thus overcoming the limitations of previous formulations.
Implementation Method 1
In order to achieve a tissue-compatible or vein-compatible pH value, succinic acid is added to fosfomycin formulations for parenteral administration in currently available preparations
Data Source
Figure 1A~1B
Figure 1C~1D
AI summary
The invention relates to fosfomycin formulations for parenteral administration, in particular intravenous administration. Formulations in the prior art provide fosfomycin as a powder to be diluted directly prior to the administration. The aim of the invention is to provide a fosfomycin formulation for parenteral administration which is easier to produce and administer or which lowers the risk of stabbing injuries for healthcare professionals and the health risks for the patients (for example due to contamination or incorrect dosages) by preventing additional administration steps. During the course of the invention, it was surprisingly shown that fosfomycin is much more stable in an aqueous solution than what is commonly assumed. The invention therefore provides a closed container which contains an aqueous solution for parenteral administration. At least one pharmaceutically acceptable salt of fosfomycin, in particular fosfomycin disodium salt, and a pharmaceutically acceptable acid, in particular succinic acid, are dissolved in the solution. Preferred containers are breakable ampoules made of plastic or glass, puncturable vials, infusion bags, or prefilled syringes.