Pharmaceutical Formulations Stabilizing Proteins with Osmolytes

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Solution Overview

Problem

Pharmaceutically active proteins in aqueous solutions are destabilized by preservatives, leading to degradation, precipitation, and aggregation, which can cause immunogenic responses and reduce the shelf life of multi-dose products.

Innovation Solution

Combining osmolytes with preservatives in specific concentrations to stabilize biologically active proteins in aqueous pharmaceutical formulations, where osmolytes counteract the destabilizing effects of preservatives, maintaining protein stability and extending shelf life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If preservatives are added to multi-dose pharmaceutical formulations to prevent microbial growth, then the reliability of the formulation is improved, but the stability of the protein is worsened due to denaturation, degradation, precipitation and aggregation

Engineering Contradiction:

Improvemicrobial preventionVSAvoidprotein stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Surfactants are introduced as intermediary substances that mediate between the preservative and the protein. The surfactant molecules interact with both the preservative (reducing its denaturing effect) and the protein (maintaining its stability), allowing the preservative to function while minimizing protein degradation and aggregation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the chemical environment parameters by adjusting pH and ionic strength to optimize protein stability in the presence of preservatives. By modifying these parameters, the formulation maintains protein structure while allowing preservative activity against microbes

Inventive Principle:

Principle #35Parameter changes

2Reliability

If preservatives are used at destabilizing concentrations to ensure microbial inhibition, then the reliability is improved, but the protein undergoes denaturation and aggregation

Engineering Contradiction:

Improvemicrobial inhibitionVSAvoidprotein degradation and aggregation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention converts the harmful denaturing effect of preservatives into a beneficial outcome by using surfactants to control the interaction. The preservative's strong antimicrobial activity is maintained while the surfactant prevents harmful protein aggregation, effectively converting the potential harm into a controlled, beneficial preservative effect

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

Surfactants act as protective intermediaries that shield the protein from the harmful effects of high-concentration preservatives, allowing the use of destabilizing preservative levels without causing protein degradation or aggregation

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 formulations with osmolytes and preservatives exhibit improved stability and extended shelf life, maintaining protein activity and preventing aggregation, even at refrigerator temperature for several months.

Implementation Method 1

aqueous pharmaceutical formulations of proteins with destabilizing amounts of preservatives and stabilizing amounts of osmolytes that counteract the destabilization caused by the preservative

Methodology Applied

Scientific EffectOsmolyte stabilization:

Data Source

PatentUS10668154B2Pharmaceutical formulations

Publication Date: 2020.06.02 AMGEN INC

AI summary

A method of stabilizing an aqueous protein or antibody formulation is disclosed herein. Additionally, stable pharmaceutical formulations are contemplated which comprise a biologically active protein, a destabilizing concentration of preservative and a stabilizing concentration of osmolyte.