Ready-to-Use Melphalan Injectable Formulation with Stabilized Solvent System
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Solution Overview
Problem
Current melphalan injectable formulations require reconstitution, are prone to degradation, and have limited stability, making them inconvenient and unreliable for administration.
Innovation Solution
Development of a storage-stable, ready-to-use liquid parenteral formulation of melphalan with a suitable solvent system including propylene glycol, polyethylene glycol, and ethanol, along with chelating agents like EDTA and povidone, which maintains stability and clarity for extended periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If melphalan is formulated as a sterile freeze-dried lyophilized powder requiring reconstitution, then the drug can be supplied in a stable form, but the reconstitution process is complex and the final solution degrades quickly (stable only for 30 minutes)
Solution Approach 1:
The patent pre-dissolves melphalan in suitable solvents (propylene glycol, polyethylene glycol, ethanol, water) and adjusts the pH to 3.5-5.5 before sterilization, creating a ready-to-use injectable formulation that eliminates the need for reconstitution. This preliminary preparation of the solution state resolves the contradiction by providing both stability and ease of administration.
Solution Approach 2:
The patent changes the physical state parameter from freeze-dried powder to liquid solution, and adjusts the pH parameter to 3.5-5.5 to optimize stability. By maintaining the drug in a pre-adjusted liquid state with controlled pH and using specific solvent combinations, the formulation achieves both long-term stability and immediate usability without reconstitution.
2Quantity of substance
If melphalan is reconstituted with a diluent containing multiple components (sodium citrate, propylene glycol, ethanol), then the drug becomes soluble, but the solution begins to degrade within 30 minutes
Solution Approach 1:
The patent optimizes the pH parameter to a specific range (3.5-5.5) and adjusts the solvent composition ratios to achieve both high solubility and long-term stability. By controlling these parameters during manufacturing, the formulation maintains drug stability for extended periods (50 days at room temperature, 5 months at 2-8°C) while ensuring complete solubility, eliminating the rapid degradation issue.
Solution Approach 2:
The patent uses a composite solvent system combining propylene glycol, polyethylene glycol, ethanol, and water in specific ratios. This composite formulation provides synergistic effects: the solvents collectively ensure high solubility of melphalan while their combination creates a stable matrix that prevents degradation, resolving the contradiction between solubility and stability.
3Ease of operation
If melphalan is supplied as a ready-to-use liquid formulation, then administration is simplified and stability is extended, but the formulation requires careful selection of solvents and pH adjustment
Solution Approach 1:
The patent establishes specific parameter ranges (pH 3.5-5.5, defined solvent ratios) that optimize both administration convenience and manufacturing feasibility. By setting these clear parameters, the formulation achieves ready-to-use status with extended stability while providing straightforward manufacturing instructions, balancing ease of administration with ease of manufacture.
4Ease of operation
If the melphalan solution is stored at room temperature, then storage is convenient, but the solution remains stable for only a limited period
Solution Approach 1:
The patent optimizes the pH to 3.5-5.5 and selects specific solvent combinations that enhance thermal stability. These parameter changes enable the formulation to maintain stability for 50 days at room temperature and 5 months at 2-8°C, resolving the contradiction by providing both storage convenience and extended duration through controlled chemical parameters.
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 formulation provides a stable melphalan solution with high purity for up to 50 days at room temperature and 5 months when stored at 2-8°C, eliminating the need for reconstitution and ensuring consistent administration.
Implementation Method 1
adding and mixing a chelating agent to the at least one solvent, wherein the chelating agent is mixed with the at least one solvent before adding the melphalan
Implementation Method 2
the formulation includes melphalan and at least one pharmaceutical acceptable solvent... the weight percentage of the povidone and melphalan in the chelating agent solution is from about 0.5% to about 1.5%
Implementation Method 3
adding melphalan to a vessel containing at least one pharmaceutical acceptable solvent to form a melphalan solution; the plurality of solvents are selected from a group consisting of propylene glycol (PG), polyethylene glycol (PEG), ethanol, and water
Data Source
AI summary
The present application provides stable ready-to-use injectable formulations of melphalan, methods for preparing storage-stable, ready-to-use injectable formulations that include melphalan, which are easy to administer without need of any reconstitution step and has a desirable solubility, stability, and safety profile. In other embodiments, provided are storage-stable, ready-to-use, injectable liquid parenteral formulations that include melphalan and other pharmaceutically acceptable excipients.