Sustained-Release Bupivacaine Composition for Impurity Control
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Solution Overview
Problem
There is a need for improved drug delivery systems with enhanced storage stability and safety, particularly in reducing impurities such as 2,6-dimethylaniline, bupivacaine N-oxide, water, peroxide, benzyl acetate, and benzyl isobutyrate, and metal content, to provide sustained release and reduced opioid consumption.
Innovation Solution
A method involving the use of a bupivacaine composition comprising bupivacaine free base or salt, optionally with sucrose acetate isobutyrate and benzyl alcohol, stored at 15° C. to 30° C., administered in a single dose through a 16-gauge or larger needle into the subacromial space, using a clear glass vial protected by a carton, to achieve prolonged analgesia without additional local anesthetics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional drug delivery systems are used, then drug delivery is achieved, but storage stability and safety are compromised due to impurity accumulation
Solution Approach 1:
The patent extracts and removes harmful impurities (2,6-dimethylaniline, bupivacaine N-oxide, peroxides, benzyl esters, and metal particles) from the drug delivery system through purification processes, thereby improving storage stability while maintaining drug delivery functionality
Solution Approach 2:
The patent changes critical parameters including reducing water content to less than 0.5%, controlling impurity levels (2,6-dimethylaniline less than 500 ppm, bupivacaine N-oxide less than 1%), and optimizing storage conditions (15-30°C) to enhance stability and safety
2Duration of action of moving object
If sustained release delivery systems are implemented, then prolonged analgesia is achieved, but impurity accumulation occurs during storage
Solution Approach 1:
The patent performs preliminary purification actions during manufacturing to prevent impurity formation and accumulation during sustained release storage, ensuring low impurity levels are maintained throughout the extended duration of action
Solution Approach 2:
The patent uses inert storage conditions and stabilizers to create a protected environment that prevents oxidation and degradation reactions during sustained release, thereby maintaining low impurity levels over extended periods
3Duration of action of moving object
If high concentration bupivacaine composition is administered, then prolonged analgesia is achieved, but safety is compromised due to potential toxicity
Solution Approach 1:
The patent employs single-use sterile containers and disposal protocols to prevent contamination and degradation that could increase toxicity, ensuring safety while maintaining high concentration for prolonged effect
Solution Approach 2:
The patent optimizes the concentration parameters and purity specifications to achieve the highest safe concentration of bupivacaine with controlled impurity levels, balancing prolonged analgesia duration with safety margins
Data Source
AI summary
The present disclosure provides for methods of producing analgesia in a subject. In some cases, methods produce analgesia in a subject undergoing arthroscopic subacromial decompression surgery. The present disclosure also relates to improved sustained release drug delivery systems. In some cases, a composition comprises an active pharmaceutical agent; at least one of sucrose acetate isobutyrate and a polyorthoester; an organic solvent; and 2,6-dimethylaniline, wherein the 2,6-dimethylaniline is present at a level less than 500 ppm. In some cases, a composition comprises bupivacaine N-oxide at a level less than 1 wt %, based on weight of the composition. In some cases, a composition comprises metal present at a level less than 5 ppm. Dosage forms and methods are also provided.