Acylated Insulin Zinc Complexes for Prolonged Release
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Solution Overview
Problem
Current insulin compositions for diabetes treatment, particularly long-acting insulin formulations, face issues such as inaccurate dosing, immunogenicity, unpredictable release profiles, and local irritation due to particle size variability and the use of protamine, which can lead to antibody formation and inflammation.
Innovation Solution
A pharmaceutical composition with a high zinc content, specifically comprising more than 4 zinc atoms per 6 molecules of acylated insulin, forming complexes like hexamers and dodecamers to stabilize insulin and control release, while also incorporating surfactants like polysorbate 20 or poloxamer 188 to enhance stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If insulin suspensions are used to achieve prolonged action, then duration of action is improved, but dosing accuracy deteriorates due to particle suspension homogeneity issues
Solution Approach 1:
The patent utilizes phase transition by forming insulin precipitates from acidic solutions that rise to physiological pH upon injection. This phase change from dissolved to precipitated state in the tissue creates the prolonged action profile while the precipitate forms predictable particle sizes that improve dosing accuracy compared to suspensions requiring manual shaking.
2Duration of action of moving object
If protamine is used in insulin compositions, then prolonged action is achieved, but immunogenicity increases leading to antibody formation
Solution Approach 1:
The patent removes protamine from the insulin composition entirely, replacing it with zinc-based complexes and acidic pH mechanisms to achieve prolonged action. This extraction of the immunogenic protamine component eliminates antibody formation while maintaining the desired prolonged action profile through alternative mechanisms.
3Duration of action of moving object
If insulin precipitates are formed in tissue, then prolonged release is achieved, but particle size distribution becomes unpredictable depending on blood flow
Solution Approach 1:
The patent performs preliminary action by forming the insulin precipitate immediately upon injection through the pH rise from acidic to physiological conditions. This controlled in-situ precipitation occurs before blood flow can significantly influence particle formation, resulting in more predictable particle size distribution and release profile compared to formulations where precipitation occurs later in the tissue.
4Duration of action of moving object
If high zinc content is used to stabilize insulin, then prolonged action and reduced immunogenicity are achieved, but manufacturing complexity increases
Solution Approach 1:
The patent utilizes parameter changes by precisely controlling the zinc-to-insulin ratio (more than 4 zinc atoms per 6 insulin molecules) and the pH transition from acidic to physiological. These parameter optimizations enable high zinc content formulations to form stable, predictable precipitates with prolonged action while simplifying manufacturing through well-defined compositional specifications.
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 high zinc content stabilizes insulin, providing a prolonged action profile with reduced immunogenicity and improved bioavailability, minimizing local irritation and ensuring consistent release, thus addressing the limitations of existing long-acting insulin formulations.
Implementation Method 1
comprising more than 4 zinc atoms per 6 molecules of acylated insulin, forming complexes like hexamers and dodecamers to stabilize insulin and control release
Implementation Method 2
incorporating surfactants like polysorbate 20 or poloxamer 188 to enhance stability and bioavailability
Data Source
AI summary
The invention is related to insulin compositions with a high content of zinc atoms per six molecules of acylated insulin. The insulin is an acylated insulin and may be mixed with a further insulin analogue such as the rapid acting insulin Asp B28 human insulin.