Insulin Derivative Formulation Viscosity and Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current long-acting insulin derivatives for basal insulin administration often result in discomfort due to high viscosity and altered oligomerization patterns at the injection site, leading to prolonged residence time and potential instability.
Innovation Solution
A pharmaceutical composition comprising specific long-acting insulin derivatives, such as A14E, B16H, B25H, B29K((Nϵ-Eicosanedioyl-γGlu-[2-(2-{2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl) human insulin, with carefully formulated excipients like glycerol, phenol, m-cresol, and zinc ions, optimized to promote hexamer formation resembling human insulin, reduce viscosity, and enhance stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If high zinc concentration is used to achieve prolonged duration of action, then duration of action is improved, but viscosity increases causing injection discomfort
Solution Approach 1:
The patent optimizes the zinc ion concentration parameter to a specific range (1.5-2.5 moles per six moles of insulin derivative) that balances prolonged duration of action with acceptable viscosity levels, resolving the contradiction between these two parameters
Solution Approach 2:
The formulation combines multiple excipients (phenol, m-cresol, glycerol, zinc ions) with the insulin derivative to create a composite pharmaceutical composition that achieves both prolonged action and reduced viscosity through synergistic interactions
2Stability of the object's composition
If high zinc concentration is used to promote oligomerisation, then stability is improved, but oligomer size increases causing viscosity problems
Solution Approach 1:
The patent carefully controls the zinc ion concentration parameter within a specific range to achieve sufficient oligomerisation for stability while preventing excessive oligomer growth that would cause high viscosity and injection discomfort
3Stability of the object's composition
If phenolic ligands are used to promote R-state hexamer formation, then conformational stability is improved, but upon injection phenol diffuses quickly altering oligomer conformation
Solution Approach 1:
The patent uses phenol and m-cresol as intermediary ligands that facilitate R-state hexamer formation in the formulation, while the controlled zinc ion concentration ensures that the oligomer conformation remains stable after injection when phenol diffuses away
4Duration of action of moving object
If acylated fatty di-acid chain is added to insulin derivative, then duration of action is prolonged, but viscosity increases causing injection discomfort
Solution Approach 1:
The patent optimizes the zinc ion concentration parameter specifically for acylated insulin derivatives to balance the prolonged duration of action provided by the acyl chain with acceptable viscosity levels for comfortable injection
Solution Approach 2:
The formulation combines the acylated insulin derivative with multiple excipients including phenol, m-cresol, glycerol, and zinc ions to create a composite composition where the interactions between components mitigate the viscosity-increasing effect of the acyl chain while maintaining prolonged duration of action
Data Source
AI summary
The present invention is in the field of pharmaceutical compositions for the treatment of medical conditions relating to diabetes. More specifically the invention provides pharmaceutical compositions comprising a long-acting acylated derivative of a human insulin analogue, and to the medical use of such compositions for basal insulin administration therapy.