Stable Polypeptide Formulations Using Divalent Cations

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Solution Overview

Problem

Current protein therapeutic formulations face challenges in maintaining long-term stability due to susceptibility to physical and chemical degradation pathways, such as aggregation and chemical modifications, which can affect potency and safety, necessitating the development of formulations that retain stability under various conditions.

Innovation Solution

A formulation comprising a buffer with a pH between 4.0 and 6.0, a divalent cation like calcium chloride, and an excipient like a sugar or polyol, which stabilizes panitumumab by retaining at least 80% EGFR-binding activity for up to two months in solution.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If proteins are stored in solution for long-term use, then they are susceptible to physical and chemical degradation pathways, but maintaining stability requires minimizing both aggregation and chemical modifications

Engineering Contradiction:

Improveprotein stabilityVSAvoidpotency and safety

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The formulation comprises a buffer having a pH from about 4.0 to less than 6.0, a divalent cation selected from calcium chloride, zinc chloride, manganese chloride or magnesium chloride between about 5-150 mM

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

a divalent cation selected from calcium chloride, zinc chloride, manganese chloride or magnesium chloride between about 5-150 mM

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If proteins are exposed to interfaces through agitation, temperature or pH induced stresses, then adsorption occurs resulting in loss of potency, but avoiding stress conditions limits formulation flexibility

Engineering Contradiction:

ImprovepotencyVSAvoidformulation flexibility

Core Design Contradiction:

Quantity of substanceVSAdaptability or versatility

Solution Approach 1:

Inventive Principle:

Principle #9Preliminary anti-action

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 effectively stabilizes panitumumab, reducing degradation and maintaining biological activity over time, thereby enhancing the safety and efficacy of the therapeutic protein.

Implementation Method 1

a divalent cation selected from calcium chloride, zinc chloride, manganese chloride or magnesium chloride between about 5-150 mM

Methodology Applied

Scientific EffectIonic interactions: Ion Repulsion/Attraction

Implementation Method 2

a buffer having a pH from about 4.0 to less than 6.0

Methodology Applied

Scientific EffectBuffering:

Implementation Method 3

an excipient comprising a sugar or polyol

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentEP2094247B1Stable polypeptide formulations

Publication Date: 2022.06.29 AMGEN INC

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AI summary

The invention provides a formulation including a buffer having a pH less than 6.0, a divalent cation between about 5-200 mM, an excipient comprising a sugar or polyol and an effective amount of a therapeutic polypeptide. Also provided is a method of stabilizing a polypeptide. The method includes contacting a therapeutic polypeptide with a concentration of divalent cation between about 5-150 150 mM in a buffer having a pH less than 6.0 and an excipient comprising a sugar or polyol.