Daptomycin Liquid Formulation Stability via Non-Aqueous Solvents
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Daptomycin, a lipopeptide antibiotic, is unstable in aqueous solutions, leading to rapid degradation and impurity formation, making it challenging to develop stable liquid parenteral formulations for intravenous use.
Innovation Solution
Formulating daptomycin in non-aqueous or semi-aqueous solutions with propylene glycol as a solvent and incorporating stabilizers like cysteine and magnesium chloride, along with glycerol, to create stable and pure liquid compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If daptomycin is formulated in aqueous solutions, then it has good solubility, but it degrades rapidly due to instability
Solution Approach 1:
The patent changes the fundamental parameter of the solvent system from aqueous to non-aqueous (using propylene glycol as the primary solvent). This parameter change eliminates the degradation pathways that occur in water (aspartyl transpeptidation, ester hydrolysis, deamidation) while maintaining daptomycin solubility through the cosolvent system of propylene glycol and glycerol.
Solution Approach 2:
The formulation uses a composite solvent system combining propylene glycol (non-aqueous solvent) with glycerol (cosolvent) and stabilizers (cysteine, magnesium chloride). This composite material approach allows the formulation to achieve both solubility (through the cosolvent properties of glycerol) and stability (through the protective non-aqueous environment and stabilizing effects of additives).
2Stability of the object's composition
If non-aqueous solvents are used to improve stability, then degradation is reduced, but solubility becomes poor
Solution Approach 1:
The patent modifies the properties of the non-aqueous solvent system by adjusting the ratio and combination of propylene glycol and glycerol. This parameter optimization ensures that the formulation maintains adequate solubility of daptomycin (achieved through the hydrophilic properties of glycerol) while preserving the stability benefits of the non-aqueous environment.
Solution Approach 2:
Glycerol acts as an intermediary substance between the hydrophobic propylene glycol and the hydrophilic daptomycin molecule. The glycerol component provides cosolvent effects that enhance daptomycin solubility while the overall non-aqueous composition maintains stability, thus mediating between the conflicting requirements of solubility and stability.
3Manufacturing precision
If stabilizers are added to reduce degradation, then purity is improved, but formulation complexity increases
Solution Approach 1:
The patent optimizes the concentrations of stabilizers (cysteine at 1-10 mg/ml, magnesium chloride at 1-10 mg/ml) to achieve maximum purity benefit with minimal formulation complexity. These parameter optimizations ensure that the stabilizers effectively prevent degradation (maintaining >95% purity) while keeping the formulation straightforward and manufacturable.
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 demonstrate extended stability and reduced impurity formation, maintaining high purity and clarity for several months at room temperature and up to a year under refrigerated conditions, with less than 5% anhydrodaptomycin impurity, suitable for long-term storage and administration.
Implementation Method 1
Daptomycin degrades by aspartyl transpeptidation at asp-9 residue in aqueous solutions. Cysteine acts as a stabilizer to prevent this degradation pathway.
Implementation Method 2
Ester hydrolysis, asparginyl deamidation, peptide bond cleavage contribute degradation in aqueous solutions. Magnesium chloride stabilizes against these reactions.
Implementation Method 3
Daptomycin is formulated in non-aqueous or semi-aqueous solutions with propylene glycol as a solvent along with stabilizers like cysteine and magnesium chloride, and glycerol.
Data Source
AI summary
Daptomycin-containing formulations having extended stability are disclosed. The formulations are substantially non-aqueous liquid compositions containing daptomycin, cysteine, magnesium chloride, and propylene glycol. In alternative embodiments, the formulations include glycerol and optionally auxiliary solvents such as ethanol.