Baclofen Formulation pH Adjustment for Sterilization Stability
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Solution Overview
Problem
Current baclofen formulations for intrathecal administration are limited by solubility issues, leading to particulate formation and increased degradation products when attempting higher concentrations, which are desirable to reduce infusion device refilling frequency and maintain stability and sterility.
Innovation Solution
Baclofen solutions with concentrations greater than 2 mg/mL are stabilized by adjusting the pH to between 5.0 and 6.2 and steam sterilizing, using sulfate or phosphate to prevent particulate formation and minimize 4-(4-chlorophenyl)-2-pyrrolidinone (4-CPP) degradation, maintaining stability and sterility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If baclofen concentration is increased to reduce refilling frequency, then productivity is improved, but baclofen may not entirely dissolve in aqueous solution and may precipitate during storage
Solution Approach 1:
The patent changes the chemical parameters of the solution by introducing specific buffers (phosphate buffer at pH 6.0-7.0 or sulfate buffer at pH 5.0-6.5) and adjusting ionic strength with NaCl to achieve optimal solubility and stability of high-concentration baclofen solutions without precipitation
Solution Approach 2:
The patent creates a composite aqueous solution system combining baclofen with specific buffer systems (phosphate or sulfate) and electrolytes (NaCl), where the interaction between components enhances overall solubility and stability beyond what individual components could achieve alone
2Reliability
If heat sterilization is used to ensure sterility, then reliability is improved, but degradation products increase
Solution Approach 1:
The patent performs preliminary pH adjustment to 6.0-7.0 or 5.0-6.5 and addition of buffer systems before sterilization to create a protective chemical environment that prevents degradation during the subsequent heat sterilization process
Solution Approach 2:
The patent introduces buffer systems and electrolytes in advance to cushion against the harmful effects of heat sterilization, creating a chemically stable environment that protects baclofen from degrading into 4-CPP during the sterilization process
3Quantity of substance
If baclofen is dissolved in hot water and cooled to achieve higher concentrations, then concentration is improved, but particulate formation occurs during storage
Solution Approach 1:
The patent changes the temperature and pH parameters during the dissolution and storage process, specifically dissolving baclofen in hot water adjusted to pH 6.0-7.0 or 5.0-6.5, then cooling to room temperature while maintaining these parameters to prevent particulate formation during storage
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 method allows for stable, high-concentration baclofen solutions that remain free of detectable particulates and minimize 4-CPP formation, ensuring effective and long-term stability and sterility, suitable for infusion devices.
Implementation Method 1
steam sterilizing, using sulfate or phosphate to prevent particulate formation and minimize 4-(4-chlorophenyl)-2-pyrrolidinone (4-CPP) degradation
Data Source
AI summary
Methods for preparing sterilized baclofen solutions include adjusting the pH to below a desired pH, and steam sterilizing the solution with adjusted pH, which results in the solution having the desired pH. Such solutions may also have low concentrations of 4-CPP. Injectable baclofen solutions having greater than 2 mg/mL baclofen include between 5 mM and 25 mM of a phosphate or sulfate species. The solution has an ionic strength equivalent of about 1.5 M NaCl. The present application also provides baclofen formulations for use in treating spasticity, brain injury, cerebral palsy, spinal cord injury, cervical injury, multiple sclerosis, thoracic injury, or withdrawal symptoms.