Daptomycin Liquid Formulation pH Stability
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Solution Overview
Problem
Daptomycin exhibits premature degradation upon reconstitution, leading to increased impurities and instability in liquid form, making it unsuitable for long-term storage.
Innovation Solution
Daptomycin-containing compositions with a buffer having an acidic functional group, a pH of 6.0 to 7.0, and a tonicifying agent, which maintain stability and reduce impurities to less than 10% over 18 months, allowing for long-term storage and use without the need for lyophilized powder.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If daptomycin is reconstituted into liquid form for administration, then ease of operation is improved, but stability deteriorates due to premature degradation and impurity formation
Solution Approach 1:
The patent applies parameter changes by optimizing the pH of the liquid composition to a specific range (6.0-7.0) and controlling daptomycin concentration (less than or equal to 25 mg/ml). These parameter adjustments stabilize the drug in liquid form, preventing degradation while maintaining ease of administration. The buffered composition at controlled pH prevents the premature degradation that occurs in conventional liquid formulations.
2Stability of the object's composition
If daptomycin is stored as lyophilized powder, then stability is improved, but ease of operation deteriorates due to reconstitution requirements
Solution Approach 1:
The patent inverts the conventional approach by formulating daptomycin as a stable liquid composition rather than converting it to powder form for storage. This inversion eliminates the need for reconstitution while maintaining stability through controlled pH (6.0-7.0) and buffer systems. The liquid form is typically associated with instability, but the patent reverses this expectation by achieving stability in liquid form through specific compositional controls.
3Productivity
If daptomycin is stored in liquid form for long term, then productivity is improved by eliminating reconstitution steps, but reliability deteriorates due to degradation and impurity formation
Solution Approach 1:
The patent applies parameter changes by controlling pH (6.0-7.0), daptomycin concentration (≤25 mg/ml), and incorporating buffer systems to maintain these parameters during long-term storage. These controlled parameters prevent degradation and impurity formation, ensuring reliability and drug efficacy is maintained while allowing long-term storage in liquid form without reconstitution, thus improving productivity.
4Stability of the object's composition
If buffer concentration is increased to maintain pH stability, then stability is improved, but manufacturing precision deteriorates due to concentration control requirements
Solution Approach 1:
The patent applies parameter changes by optimizing the pH to a specific range (6.0-7.0) and controlling daptomycin concentration (less than or equal to 25 mg/ml). These parameter adjustments stabilize the drug in liquid form, preventing degradation while maintaining ease of administration. The buffered composition at controlled pH prevents the premature degradation that occurs in conventional liquid formulations.
Data Source
AI summary
Long term storage stable daptomycin-containing compositions are disclosed. The compositions include daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL, a buffer having an acidic functional group and have a pH of from about 6.0 to about 7. The formulations are surprisingly free of degradation products such as the hydrolysis product of daptomycin and the β-isomer of daptomycin after storage periods of at least about 18 months.