Melphalan Liquid Formulation Stability and Reconstitution
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Solution Overview
Problem
The existing formulations of Melphalan, such as Alkeran®, are clinically inconvenient due to the time-consuming and expensive lyophilization process, and the reconstitution of the lyophilized product is not practical for immediate use.
Innovation Solution
A ready-to-use liquid parenteral formulation of Melphalan is developed, comprising Melphalan Hydrochloride, solvents like dimethylacetamide, polyethylene glycol, and ethanol, along with anti-oxidants like monothioglycerol, which are combined and stirred to form a clear solution, then filtered and filled into vials, providing a stable and convenient alternative.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If lyophilized formulation is used, then Melphalan can be stored stably, but reconstitution is time-consuming and clinically inconvenient
Solution Approach 1:
The patent applies preliminary action by pre-dissolving Melphalan hydrochloride in the liquid formulation before storage. The active ingredient is already in dissolved form in the vial, eliminating the need for time-consuming reconstitution at the point of use. This resolves the contradiction by maintaining stability during storage while enabling immediate use without time loss.
2Stability of the object's composition
If lyophilized formulation is used, then Melphalan can be stored stably, but the process is expensive
Solution Approach 1:
The patent applies parameter changes by transitioning from solid lyophilized form to liquid dissolved form. This parameter change in physical state eliminates the need for expensive lyophilization equipment and complex drying processes, reducing manufacturing costs while maintaining stability through appropriate solvent selection and pH control.
3Loss of time
If liquid formulation is used, then reconstitution is immediate, but stability over time may be compromised
Solution Approach 1:
The patent applies the intermediary principle by introducing specific components as mediators: cyclodextrin derivatives as stabilizing agents, anti-oxidants to prevent degradation, and controlled pH levels. These intermediaries protect the Melphalan in the liquid formulation from degradation over time, enabling immediate use while maintaining stability.
Solution Approach 2:
The patent uses composite materials by combining Melphalan hydrochloride with specific excipients including cyclodextrin derivatives, anti-oxidants, and buffering agents in a coordinated formulation. This composite approach creates a stable liquid system that maintains integrity over time while providing immediate usability.
4Reliability
If dilution is performed to achieve desired concentration, then administration is safe, but effectiveness may be reduced
Solution Approach 1:
The patent applies preliminary action by pre-dissolving Melphalan at controlled concentrations in the liquid formulation during manufacturing. The formulation is prepared with appropriate concentration levels that maintain effectiveness, and the stability of this pre-dissolved state is ensured through protective agents, allowing safe administration without significant dilution while maintaining therapeutic effectiveness.
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 new formulation is stable at 2-8° C and 25° C/60% RH for six months, shows improved stability compared to reference products, and maintains effectiveness when diluted, overcoming the disadvantages of prior art.
Implementation Method 1
comprising Melphalan Hydrochloride, one or more solvents selected from the group comprising of dimethylacetamide, polyethylene glycol, ethanol, propylene glycol and glycerine
Implementation Method 2
anti-oxidants selected from monothioglycerol, L-cysteine, ascorbic acid
Data Source
AI summary
The present invention relates to stable, liquid parenteral formulations of Melphalan or pharmaceutically acceptable salts thereof. Further this invention also describes process of preparing such formulations.