Amylin Derivatives with Proline Substitutions for Fibrillation Control

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Solution Overview

Problem

Human amylin derivatives used in treating diabetes face challenges such as fibrillation and instability at physiologic pH, leading to ineffective formulations that require frequent injections.

Innovation Solution

Amylin derivatives with specific amino acid modifications, particularly replacing the amino acid at position 17 with His, Ser, Gly, or Pro, exhibit reduced fibrillation and improved stability at acidic pH, extending pharmacokinetic profiles and maintaining pharmacodynamic properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If human amylin is formulated at physiologic pH, then it should be stable and effective, but it tends to fibrillate and precipitate

Engineering Contradiction:

ImprovestabilityVSAvoidfibrillation tendency

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent modifies the amino acid sequence of human amylin by substituting residues at positions 25, 28, and 29 with proline, and optionally at position 17 with histidine or arginine. These parameter changes in the molecular structure reduce the fibrillation tendency while maintaining stability at physiologic pH, resolving the contradiction between stability and fibrillation risk

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a modified amylin derivative that combines the beneficial properties of reduced fibrillation (through proline substitutions) with improved stability (through histidine or arginine at position 17). This composite molecular structure integrates multiple modifications to simultaneously address both stability and reliability concerns

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If amylin derivatives are formulated in acidic solution, then solubility is improved, but fibrillation still occurs and pharmacokinetic properties are suboptimal

Engineering Contradiction:

ImprovesolubilityVSAvoidfibrillation tendency

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies parameter changes by substituting amino acids at positions 25, 28, and 29 with proline, and at position 17 with histidine or arginine. These modifications enable the derivative to maintain solubility in acidic solution while significantly reducing fibrillation tendency and improving pharmacokinetic properties, resolving the contradiction between solubility and reliability

Inventive Principle:

Principle #35Parameter changes

3Reliability

If traditional insulin is used to treat diabetes, then blood glucose control is effective, but body weight increases and frequent injections are required

Engineering Contradiction:

Improveblood glucose controlVSAvoidinjection frequency

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the amylin molecule by substituting residues at positions 25, 28, and 29 with proline and position 17 with histidine or arginine. These parameter changes create a derivative with prolonged duration of action and improved pharmacokinetic properties, allowing for less frequent administration compared to traditional insulin, while maintaining effective blood glucose control

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP2340261B1Amylin derivatives

Publication Date: 2017.12.20 NOVO NORDISK AS

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AI summary

The present invention relates to novel amylin derivatives, pharmaceutical compositions containing such derivatives and to methods of treating diabetes and hyperglycaemia using the amylin derivatives of the invention.