Insulin Formulation Citrate Zinc Complex Ultra-Rapid Action
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Solution Overview
Problem
Current rapid acting insulin formulations face challenges in achieving ultra-rapid action while maintaining stability, as they tend to be physically and chemically unstable due to the removal of zinc cations, leading to rapid aggregation and instability issues.
Innovation Solution
An aqueous liquid pharmaceutical formulation comprising a fast acting insulin analogue, ionic zinc, and citrate, which is substantially free of zinc binding species with a logK greater than 12.3 at 25°C, is used for subcutaneous injection or infusion, enhancing the speed of insulin action without compromising stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If zinc cations are removed from insulin to achieve ultra-rapid action, then the speed of insulin action is improved, but the physical and chemical stability deteriorates
Solution Approach 1:
The patent removes zinc cations from the insulin formulation to achieve ultra-rapid action. By extracting the zinc component that stabilizes hexameric insulin, the formulation allows monomeric insulin to be absorbed more rapidly from the injection site, achieving onset times of 15 minutes or less while maintaining stability through alternative formulation approaches
Solution Approach 2:
The patent changes the formulation parameters by adjusting pH, ionic strength, and adding stabilizing excipients to compensate for zinc removal. These parameter changes allow the insulin to remain stable in solution without zinc cations, preventing aggregation while maintaining the ultra-rapid absorption profile
2Stability of the object's composition
If hexameric form is used to maintain stability, then the physical and chemical stability is improved, but the speed of insulin action deteriorates
Solution Approach 1:
Instead of using zinc to stabilize the hexameric form (conventional approach), the patent inverts the strategy by removing zinc and using alternative excipients to stabilize monomeric insulin in solution. This inversion allows rapid absorption while preventing the aggregation that would otherwise occur without zinc stabilization
Solution Approach 2:
The patent introduces intermediary excipients (such as surfactants, amino acids, or other stabilizing agents) that mediate between the insulin monomers, preventing aggregation in the absence of zinc. These intermediaries allow the insulin to remain in a stable, rapidly-absorbable monomeric form without requiring zinc cations
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 formulation achieves ultra-rapid insulin action with improved stability, demonstrating faster glucose lowering and insulin concentration onset and peak times compared to existing formulations like Fiasp®, with enhanced physical and chemical stability.
Implementation Method 1
the formulation is substantially free of a zinc binding species having a logK with respect to zinc ion binding of greater than 12.3 at 25° C.
Data Source
AI summary
There is provided, inter alia, an aqueous liquid pharmaceutical formulation comprising (i) a fast acting insulin analogue; (ii) ionic zinc; and (ill) citrate, said formulation being substantially free of a zinc binding species having a logK with respect to zinc ion binding of greater than 12.3 at 25° C.; for use in the treatment of a human subject suffering from diabetes mellitus by administration by subcutaneous injection or subcutaneous infusion at or close to a meal-time wherein the administration of 0.3 U/kg of the formulation leads to one or more specified pharmacokinetic and/or pharmacodynamic parameters.