Insulin Formulation Using Controlled Zinc Binding for Fast Stable Action
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Solution Overview
Problem
Existing insulin formulations with EDTA for zinc chelation provide rapid action but compromise stability, necessitating a balance between speed and stability in insulin formulations for diabetes treatment.
Innovation Solution
An aqueous liquid formulation comprising insulin, ionic zinc, a zinc binding species with a log K of 4.5-12.3, and a non-ionic surfactant like alkyl glycoside, while avoiding EDTA and other strong zinc binders, to achieve rapid action with improved stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If EDTA is used to chelate zinc ions in hexameric insulin, then the speed of onset of action is improved, but the physical and chemical stability is greatly reduced
Solution Approach 1:
The patent introduces a zinc binding species as an intermediary substance that mediates between zinc ions and insulin. This species binds zinc ions with controlled affinity (log K between 4.5-12.3) to facilitate rapid insulin action while preventing the destabilizing effects of strong zinc chelation. The zinc binding species acts as a buffer that regulates zinc ion availability without forming unstable complexes like EDTA does.
Solution Approach 2:
The patent changes the binding strength parameter of zinc chelators by selecting species with specific log K values (4.5-12.3) rather than using strong binders like EDTA (log K > 12.3). This parameter optimization allows the formulation to achieve rapid action through moderate zinc binding while maintaining stability by avoiding excessive binding strength that would destabilize the insulin structure.
2Quantity of substance
If higher concentration of insulin compound is provided, then the dosage efficiency is improved, but the speed of onset of action may be compromised
Solution Approach 1:
The zinc binding species serves as a mediator that decouples the relationship between insulin concentration and onset speed. By regulating free zinc ion concentration through controlled binding, the system maintains rapid action even at higher insulin concentrations, as the zinc binding species ensures adequate zinc availability for hexamer formation without being limited by fixed concentration ratios.
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 provides rapid or ultra-rapid acting insulin with enhanced physical and chemical stability, suitable for diabetes treatment, particularly Type 1 diabetes, maintaining insulin efficacy and minimizing destabilizing effects.
Implementation Method 1
a zinc binding species at a concentration of 1 mM or more selected from species having a log K with respect to zinc ion binding in the range 4.5-12.3 at 25° C.
Implementation Method 2
a non-ionic surfactant which is an alkyl glycoside
Data Source
AI summary
There is provided inter alia an aqueous liquid pharmaceutical formulation comprising (i) an insulin compound, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a log K with respect to zinc ion binding in the range 4.5-12.3 at 25° C., and (iv) a non-ionic surfactant which is an alkyl glycoside; and wherein the formulation is substantially free of EDTA and any other zinc binding species having a log K with respect to zinc ion binding of more than 12.3 at 25° C.