Melflufen Formulation Using Glycols to Prevent Degradation
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Solution Overview
Problem
Existing pharmaceutical formulations of melflufen are unstable and form unwanted degradation products, and they require hazardous solvents like dimethylacetamide, which are unsuitable for manufacturing and can damage medical devices.
Innovation Solution
Formulations comprising melflufen or its salts dissolved in propylene glycol or polyethylene glycol, which provide stability and allow for more concentrated solutions without forming unwanted degradation products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline melflufen is dissolved in dimethylacetamide and glucose solution, then dissolution is achieved, but the preparation becomes unstable and forms unwanted melflufen dimers
Solution Approach 1:
The patent changes the solvent parameter from dimethylacetamide to propylene glycol, which fundamentally alters the chemical environment. This parameter change prevents dimer formation while maintaining dissolution, resolving the stability issue without loss of melflufen integrity
Solution Approach 2:
Propylene glycol serves as an intermediary substance that facilitates the dissolution of crystalline melflufen without causing unwanted chemical reactions. It acts as a stable medium that prevents direct interaction between melflufen molecules that would lead to dimer formation
2Stability of the object's composition
If crystalline melflufen is dissolved in highly acidic aqueous solutions, then dissolution is achieved, but the solutions are unsuitable for manufacturing and pharmaceutical purposes
Solution Approach 1:
The patent changes the solvent type from highly acidic aqueous solutions to propylene glycol, which has neutral pH and is suitable for pharmaceutical manufacturing. This parameter change maintains dissolution capability while making the formulation suitable for manufacturing and clinical use
3Stability of the object's composition
If organic solvents like dimethylacetamide are used, then dissolution is achieved, but the solvents can be hazardous to patients and damage medical devices
Solution Approach 1:
The patent replaces hazardous organic solvents with propylene glycol, which is safer and can be disposed of or degraded without harming patients or devices. This substitution eliminates the harmful effects associated with organic solvents while maintaining the formulation's functionality
Solution Approach 2:
The patent converts the potential harm of requiring organic solvents for dissolution into a benefit by using propylene glycol, which is safer for patients and devices. The same dissolution function is achieved through a safer substance, transforming a harmful requirement into a safe solution
4Quantity of substance
If propylene glycol is used as solvent, then melflufen solubility increases and stability improves, but the formulation requires careful storage conditions
Solution Approach 1:
The patent optimizes the propylene glycol formulation by controlling storage temperature parameters. By maintaining appropriate temperature ranges, the formulation achieves high melflufen concentration and stability while preventing degradation, balancing concentration with storage requirements
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 formulations maintain melflufen purity above 95% for over 50 days at 5°C and above 90% at room temperature, enabling stable storage and administration without hazardous solvents.
Implementation Method 1
melflufen and salts thereof, are surprisingly soluble in propylene glycol, such that more concentrated solutions can be prepared than with previously used solvents
Implementation Method 2
when melflufen, or a salt thereof, is stored in the form of a pharmaceutical formulation containing propylene glycol, the melflufen, or salt thereof, is surprisingly stable and does not readily form unwanted degradations products
Data Source
AI summary
The invention provides a pharmaceutical formulation comprising (or consisting essentially of) the following components: i) melflufen, or a salt thereof; ii) propylene glycol; iii) optionally one or more physiologically acceptable aqueous solvent(s); and iv) optionally one or more additional therapeutic agent(s); or a pharmaceutical formulation comprising (or consisting essentially of) the following components: i) melflufen, or a salt thereof; ii) polyethylene glycol; iii) optionally one or more physiologically acceptable aqueous solvent(s); and iv) optionally one or more additional therapeutic agent(s). The invention also provides methods for preparing the pharmaceutical formulations of the invention, kits and uses of the pharmaceutical formulations of the invention.