Rapid-Acting Insulin Analogue Composition Balancing Stability and Absorption

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Solution Overview

Problem

Current insulin formulations, including rapid-acting analogues, fail to mimic the natural time-action profile of insulin, leading to inadequate insulin levels at meal initiation and excessive insulin post-meals, causing hyperglycemia and hypoglycemia, due to slow absorption and hexamer stabilization delaying action.

Innovation Solution

Development of insulin analogues with specific A- and B-chain modifications and excipients like iloprost, citrate, EDTA, and polyphosphates to enhance rapid absorption and stability, preventing fibril formation, and optimizing formulations for rapid action without compromising stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If insulin is formulated as zinc-insulin hexamers for stability, then storage stability is improved, but absorption rate deteriorates

Engineering Contradiction:

Improvestorage stabilityVSAvoidabsorption rate

Core Design Contradiction:

Stability of the object's compositionVSSpeed

Solution Approach 1:

The patent segments the insulin formulation into two distinct components: zinc-insulin hexamers for stability and free monomeric insulin for rapid absorption. This segmentation allows each component to fulfill its specific function without compromising the other, resolving the contradiction between storage stability and absorption rate.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the formulation parameters by specifying precise ratios of hexamer to monomer (e.g., 9:1 to 4:6), pH levels (6.8-7.4), and concentrations of excipients like arginine and glycerol. These parameter changes optimize both the stability of hexamers and the absorption rate of monomers simultaneously.

Inventive Principle:

Principle #35Parameter changes

2Speed

If rapid-acting insulin analogues are administered, then onset of action is improved, but duration of action deteriorates

Engineering Contradiction:

Improveonset of actionVSAvoidduration of action

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent creates a periodic action pattern in insulin availability by having hexamers continuously dissociate into monomers, which are then rapidly absorbed. This periodic release mechanism ensures a sustained supply of active insulin, extending the duration of action while maintaining rapid onset characteristics.

Inventive Principle:

Principle #19Periodic action

Solution Approach 2:

The pre-formed zinc-insulin hexamers serve as a reservoir that preliminarily prepares insulin in a stable state, which then progressively releases monomers for absorption. This preliminary preparation ensures both rapid initial action and extended duration through controlled release.

Inventive Principle:

Principle #10Preliminary action

3Speed

If insulin is stored without zinc, then absorption rate is improved, but fibril formation increases

Engineering Contradiction:

Improveabsorption rateVSAvoidfibril formation

Core Design Contradiction:

SpeedVSObject-generated harmful factors

Solution Approach 1:

Zinc acts as an intermediary substance that prevents fibril formation by stabilizing insulin in hexameric form. The patent uses zinc specifically for this protective role while maintaining formulation conditions that allow rapid absorption of monomers, thus resolving the contradiction between preventing fibrils and maintaining absorption rate.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 modified insulin analogues exhibit rapid onset of action, improved stability, and reduced fibril formation, effectively managing blood glucose levels and minimizing hyperglycemic and hypoglycemic events.

Implementation Method 1

currently available insulin products are typically formulated with zinc, which forms a complex with insulin called a zinc-insulin hexamer

Methodology Applied

Scientific EffectComplex formation:

Implementation Method 2

the hexamers must disassemble in the subcutaneous interstitial fluid after injection before the insulin can be absorbed into the circulation

Methodology Applied

Scientific EffectAbsorption: Absorption (physical)

Data Source

PatentUS12622949B2Compositions containing rapid-acting insulin analogues

Publication Date: 2026.05.12 INVICTUS THERAPEUTICS LLC

AI summary

A pharmaceutical composition comprises an effective amount of an insulin analogue comprising modified A-chain and B-chain polypeptides. The modified A chain comprises one or more substitutions relative to wild-type human insulin A-chain selected from a Gln, His or Glu substitution at position A8, a Glu or Ala substitution at position A14, and an Ala, Gln, Gly, or Thr substitution at position A21. The modified B-chain polypeptide comprises one or more modifications relative to wild-type human insulin B-chain selected from a deletion of the amino acid or amino acids at position B1, B1 and B2, or B1-B3, an Ala or Glu substitution at position B2, a Glu or Ala substitution at position B3, an Ala substitution at position B4; and a Glu or Lys substitution at position B29. The composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound. The composition may be used to treat diabetes.