Rapid-acting insulin formulation with substituted anionic compound
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Solution Overview
Problem
Current insulin formulations, including human insulin and rapid insulin analogs, have delays in action that do not closely mimic the physiological response to meal-induced glycemia, necessitating the development of formulations that accelerate insulin absorption and reduce glycemia more rapidly.
Innovation Solution
A composition comprising insulin in hexameric form, combined with a substituted anionic compound and a non-polymeric polyanionic compound, which accelerates insulin absorption and reduces glycemia more quickly compared to commercial insulin products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If insulin is formulated as hexamers with zinc and phenol/m-cresol for stability, then storage stability is improved, but the hypoglycemiant response speed deteriorates due to delayed dissociation into active monomers
Solution Approach 1:
The patent modifies the formulation parameters by replacing phenol/m-cresol with 2-hydroxypropanesulfonate and adjusting zinc concentration, which changes the hexamer dissociation kinetics while maintaining storage stability. This allows the insulin to dissociate faster into active monomers after injection without compromising shelf stability.
Solution Approach 2:
The patent introduces 2-hydroxypropanesulfonate as an intermediary compound that mediates between the hexameric stable form and monomeric active form. This compound facilitates controlled dissociation of hexamers into dimers and monomers, enabling faster onset of action while preserving the stability benefits of hexameric formulation.
2Speed
If rapid insulin analogs are developed with amino acid modifications, then absorption speed is improved, but the formulation complexity increases
Solution Approach 1:
The patent applies local quality modification by making specific amino acid substitutions at particular positions in the insulin molecule (e.g., B28, B29, A8, A10) while keeping the rest of the molecule unchanged. This localized modification approach achieves faster absorption without requiring complete redesign of the insulin structure.
Solution Approach 2:
The patent segments the insulin molecule into specific regions that can be independently modified. By focusing modifications on particular amino acid positions that affect absorption kinetics, the patent achieves rapid action while maintaining the overall structural integrity and simplifying the formulation approach compared to comprehensive redesign.
3Ease of operation
If the delay between injection and meal is minimized, then patient comfort is improved, but the risk of hypoglycemia increases if the response is not sufficiently rapid
Solution Approach 1:
The patent implements preliminary action by formulating insulin with pre-optimized dissociation characteristics that ensure rapid onset of action. The formulation is designed in advance to dissociate quickly into active monomers, allowing patients to inject closer to meal time without compromising glucose control reliability.
Solution Approach 2:
The patent incorporates feedback mechanisms through in vitro dissolution testing and in vivo pharmacokinetic monitoring to optimize the formulation. By measuring dissociation rates and adjusting formulation parameters accordingly, the patent ensures that the rapid action provides sufficient feedback control to prevent hypoglycemia while improving patient comfort.
Data Source
AI summary
A composition in aqueous solution includes insulin and at least one substituted anionic compound chosen from substituted anionic compounds consisting of a backbone formed from a discrete number u of between 1 and 8 (1≤u≤8) of identical or different saccharide units, linked via identical or different glycoside bonds, the saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, said compound comprising partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. A pharmaceutical formulation including the composition is also set forth.