Stable, ready-to-administer aqueous formulations of dalbavancin
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Solution Overview
Problem
Dalbavancin, a second-generation lipoglycopeptide antibiotic, is unstable in aqueous solutions, leading to degradation issues and requiring reconstitution before use, which limits its storage stability and availability in areas without cold storage facilities.
Innovation Solution
Aqueous pharmaceutical compositions of dalbavancin stabilized with pharmaceutically acceptable buffers and divalent salts or cyclodextrins, maintaining stability at various temperatures, including above 25°C, for extended periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If dalbavancin is formulated as a lyophilized powder requiring reconstitution, then storage stability is improved, but ease of operation deteriorates due to additional preparation steps and time constraints
Solution Approach 1:
The patent changes the physical state parameter from lyophilized powder to ready-to-use aqueous solution, and adjusts pH parameters (using buffers at pH 4.0-8.0) to achieve both stability and ease of administration. This resolves the contradiction by eliminating the need for reconstitution while maintaining stability through controlled pH conditions.
2Ease of operation
If dalbavancin is stored in aqueous solution, then ease of operation is improved, but stability of the object's composition deteriorates due to degradation and formation of Mannosyl Aglycone
Solution Approach 1:
The patent applies parameter changes by controlling pH (4.0-8.0 buffer systems) and temperature (storage at 2-8°C or 20-25°C) to prevent degradation. The buffer systems maintain optimal pH conditions that minimize hydrolysis of the glycosidic linkage, thereby preventing Mannosyl Aglycone formation while keeping the drug in stable aqueous solution for easy administration.
Solution Approach 2:
The patent introduces buffer systems (acetate, phosphate, citrate buffers) as intermediary substances that mediate between the dalbavancin molecule and the aqueous environment. These buffers act as protective intermediaries that maintain pH conditions preventing degradation, allowing the drug to remain stable in ready-to-use aqueous formulation.
3Stability of the object's composition
If dalbavancin requires refrigerated storage, then stability of the object's composition is improved, but adaptability deteriorates due to lack of cold storage facilities in many areas
Solution Approach 1:
The patent employs parameter changes by using buffer systems and controlling pH conditions that enable stability across a broader temperature range. The formulations demonstrate stability at both refrigerated temperatures (2-8°C) and controlled room temperatures (20-25°C), providing adaptability to different storage environments while maintaining chemical stability through optimized pH conditions.
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 retain at least 90% of dalbavancin concentration for several months at 5°C and up to a year at room temperature, significantly improving storage stability and usability.
Implementation Method 1
aqueous pharmaceutical compositions for intravenous administration that include dalbavancin or pharmaceutically acceptable salts thereof and one or more of metal cations and/or cyclodextrin in an aqueous buffer. The formulations exhibit improved stability at standard and accelerated storage conditions
Implementation Method 2
aqueous pharmaceutical compositions for intravenous administration that include dalbavancin or pharmaceutically acceptable salts thereof and one or more of metal cations and/or cyclodextrin in an aqueous buffer
Implementation Method 3
aqueous pharmaceutical compositions for intravenous administration that include dalbavancin or pharmaceutically acceptable salts thereof and one or more of metal cations and/or cyclodextrin
Data Source
AI summary
An aqueous pharmaceutical composition for intravenous administration that includes dalbavancin or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable buffer having a pH of from about 4.0 to about 8.0. The aqueous composition further includes either or both of a pharmaceutically acceptable divalent salt wherein the divalent salt is distinct from the buffer and/or a pharmaceutically acceptable cyclodextrin. The formulation demonstrates improved long-term stability for storage at room or elevated temperatures. Methods of using the aqueous pharmaceutical composition of dalbavancin to treat skin infections.