Lefamulin Injectable Formulation pH Buffering
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Solution Overview
Problem
Current formulations for intravenous administration of BC-3781, a pleuromutilin derivative, suffer from injection site intolerance issues such as pain, erythema, and phlebitis, with no effective formulation development outlined in prior art specifically addressing these problems for this compound.
Innovation Solution
Development of injectable formulations of BC-3781 buffered to a pharmaceutically acceptable pH range of 2 to 6, preferably 3 to 5.5, using citrate or phosphate buffers, which reduces or avoids intolerance effects at the injection site, and employing the compound as a pharmaceutically acceptable salt, particularly the acetate salt, in solutions like normal saline or dextrose.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If BC-3781 is administered intravenously in conventional formulations, then systemic delivery of the antibiotic is achieved, but injection site intolerance effects occur including pain, erythema, and phlebitis
Solution Approach 1:
The patent applies parameter changes by adjusting the pH of the formulation to a specific range (pH 3.0-5.5, preferably pH 4.0-5.0) and optimizing the buffer capacity (10-50 mM). These parameter modifications resolve the technical contradiction by reducing injection site intolerance effects while maintaining effective delivery of BC-3781, thereby improving injection site tolerability without compromising the therapeutic function.
2Reliability
If BC-3781 is formulated for intravenous infusion to treat serious infections, then clinical efficacy is achieved, but local intolerance effects increase ranging from mild to severe
Solution Approach 1:
The patent resolves this contradiction by implementing specific parameter changes: adjusting pH to 3.0-5.5 and buffer capacity to 10-50 mM. These changes reduce local intolerance effects (pain, erythema, phlebitis) while preserving the reliable clinical efficacy of BC-3781 for treating serious bacterial infections, allowing both therapeutic effectiveness and patient comfort to be achieved.
Solution Approach 2:
The patent introduces a buffer system (citrate, phosphate, or acetate buffers) as an intermediary substance that mediates between the drug BC-3781 and the biological system. This intermediary buffer capacity-modified formulation reduces the harmful local effects while maintaining the therapeutic action, effectively resolving the contradiction between efficacy and tolerability.
3Device complexity
If conventional intravenous formulations are used without buffer capacity modification, then formulation simplicity is maintained, but hemolysis and precipitation adverse effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the buffer capacity to 10-50 mM and pH to 3.0-5.5, which prevents hemolysis and precipitation adverse effects. While this increases formulation complexity slightly, the changes are straightforward and use common pharmaceutical buffers, achieving a balance between preventing harmful effects and maintaining practical formulation simplicity.
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 buffered formulations significantly improve local tolerability of BC-3781 during intravenous administration, reducing or eliminating adverse effects like hemolysis and irritation, with improved stability and solubility at physiological pH, leading to enhanced clinical efficacy and patient comfort.
Implementation Method 1
buffered to a pharmaceutically acceptable pH range of 2 to 6, preferably 3 to 5.5, using citrate or phosphate buffers
Implementation Method 2
improved stability and solubility at physiological pH
Data Source
AI summary
The present invention relates to an injectable pharmaceutical formulation comprising a compound of formula (I)said formulation being buffered to a pharmaceutically acceptable pH-value, especially a pH-value of from 2 to 6, in particular a pH value of from 3 to 5.5, preferred a pH-value of about 4 to 5, particularly preferred about 5.