Insulin Formulation with pH Memory and Aprotic Solvent
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Solution Overview
Problem
Current insulin formulations for parenteral administration, particularly for diabetes treatment, face challenges in replicating the natural physiological insulin spike due to the slow absorption of insulin analogs, leading to inadequate blood glucose control and adverse effects like hyperglycemia and hypoglycemia, and are prone to instability and aggregation issues.
Innovation Solution
A formulation of insulin dried in a buffer to maintain a specific pH memory, reconstituted in an aprotic polar solvent with low water content, resulting in stable monomeric and dimeric forms that enhance absorption and reduce aggregation, allowing for both native and modified insulin use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If insulin is formulated as stabilized zinc-bound hexamers in aqueous solution, then stability is improved, but absorption rate deteriorates
Solution Approach 1:
The patent changes the solvent parameter from aqueous to aprotic polar (DMSO, DMF, NMP), which fundamentally alters insulin's association state from hexamers to monomers/dimers. This parameter change enables simultaneous achievement of stability (through pH memory effect) and rapid absorption (through monomeric/dimeric forms)
Solution Approach 2:
The patent utilizes phase transition during lyophilization (freezing-drying) to convert insulin from solution state to solid state with preserved pH memory, then upon reconstitution in aprotic polar solvent, transitions to monomeric/dimeric forms that are both stable and rapidly absorbable
2Speed
If insulin is formulated as monomeric forms in aqueous solution, then absorption rate is improved, but stability deteriorates
Solution Approach 1:
The patent changes the pH parameter through the pH memory effect during lyophilization, establishing optimal pH (2-4 or 6-8) that stabilizes monomeric insulin. The aprotic polar solvent parameter prevents water-mediated degradation pathways while maintaining monomeric/dimeric association state
Solution Approach 2:
The patent introduces aprotic polar solvent as an intermediary medium that replaces water's role in solubilization without providing the degradation pathways present in aqueous environments. This intermediary enables monomeric stability that cannot be achieved in water
3Speed
If rapid-acting insulin analogs are used, then absorption rate is improved, but physiological mimicry deteriorates
Solution Approach 1:
The patent changes the formulation parameters (aprotic polar solvent, pH memory, low water content) to achieve rapid absorption of native or analogue insulin while maintaining pharmacokinetic profiles that better mimic physiological insulin release, avoiding the excessive peak levels and prolonged duration of current rapid-acting analogs
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
This approach enables rapid absorption of insulin, improving blood glucose control by mimicking natural insulin spikes, reducing the volume of administration, and maintaining stability and bioavailability, thus addressing the limitations of existing insulin formulations.
Implementation Method 1
insulin that comprises a pH memory between 1 to 4 or between 6 to 8 and has been previously dried from a non-volatile buffer
Implementation Method 2
the insulin is solubilized in the aprotic polar solvent
Implementation Method 3
the rate-limiting factors for absorption of soluble insulin are (i) interstitial transport to the capillaries by diffusion
Implementation Method 4
the majority of the solubilized insulin comprises stable monomeric or dimeric forms of insulin or mixtures thereof
Data Source
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AI summary
Disclosed is a formulation for parenteral administration comprising insulin that comprises a pH memory between 1 to 4 or between 6 to 8 and an aprotic polar solvent, wherein the insulin is solubilized in the aprotic polar solvent, wherein the solubilized insulin comprises stable monomeric or dimeric forms of insulin or mixtures thereof, and wherein the water content of the formulation is equal to or less than 15% w/v.