Isosorbide POE Fatty Acid Esters for Protein Stabilization

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Solution Overview

Problem

Polysorbates, commonly used surfactants in biopharmaceutical protein formulations, are susceptible to degradation pathways such as chemical hydrolysis and oxidation, leading to the oxidation of amino acid residues and potential negative impacts on protein biological activity, necessitating a more efficient excipient.

Innovation Solution

A liquid formulation comprising a polypeptide and a surfactant where at least 70% of the surfactant is isosorbide polyoxyethylene (POE) fatty acid esters, providing enhanced stability and protective effects for proteins by minimizing surfactant usage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If polysorbates are used as surfactants in protein formulations, then protective effects for proteins are provided, but degradation occurs leading to oxidation of amino acid residues and loss of biological activity

Engineering Contradiction:

Improveprotective effect for proteinsVSAvoidsurfactant stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the chemical structure parameters of the surfactant by using isosorbide (a cyclic ether) instead of sorbitan (a polyol), and by controlling the ethoxylate chain length (at least 20 units). This structural modification makes the surfactant resistant to both chemical and enzymatic degradation while maintaining its protective function for proteins.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite surfactant molecule combining the isosorbide core with polyoxyethylene chains and fatty acid esters. This composite structure provides both the protective surfactant function and resistance to degradation pathways that affect conventional polysorbates.

Inventive Principle:

Principle #40Composite materials

2Reliability

If conventional polysorbates are used, then surfactant function is provided, but heterogeneous mixtures lead to unpredictable degradation patterns

Engineering Contradiction:

Improvesurfactant functionVSAvoiddegradation pattern consistency

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies local quality by making the surfactant structure more uniform and controlled. The isosorbide core provides a consistent starting point, and the controlled ethoxylate chain length (at least 20 units) ensures uniformity. This reduces the heterogeneity inherent in conventional polysorbate mixtures and leads to more predictable, consistent degradation behavior.

Inventive Principle:

Principle #3Local quality

3Reliability

If higher surfactant concentrations are used to enhance protective effects, then protein protection is improved, but degradation products increase causing more oxidation

Engineering Contradiction:

Improveprotein protectionVSAvoidoxidation from degradation products

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent effectively creates a surfactant that is resistant to the degradation pathways that produce harmful peroxides. By using isosorbide polyoxyethylene fatty acid esters with at least 20 ethoxylate units, the surfactant avoids the degradation that occurs with conventional polysorbates, allowing for longer shelf life and reduced accumulation of harmful degradation products even at therapeutic concentrations.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 demonstrates increased protein stability with reduced negative impacts from surfactant degradation, allowing for lower surfactant concentrations while maintaining protective effects, thereby preserving protein biological activity.

Implementation Method 1

The degradation of PS can lead to the generation of various peroxides which subsequently oxidize amino acid residues (e.g., methionine) in the protein during long-term storage.

Methodology Applied

Scientific EffectOxidation: Oxidation

Implementation Method 2

Polysorbates (PS), which are commonly used surfactants in biopharmaceutical protein formulations, have been shown to be susceptible to a variety of degradation pathways including: chemical hydrolysis, oxidation, and enzymatic hydrolysis.

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentUS20240123066A1Composition and methods for stabilizing liquid protein formulations

Publication Date: 2024.04.18 GENENTECH INC

AI summary

The present disclosure provides liquid formulations comprising polypeptides and surfactants. In particular, it discloses a liquid formulation comprising a polypeptide and a surfactant, wherein at least about 70% (wt %) of the surfactant are isosorbide polyoxyethylene (POE) fatty acid esters. The invention also provides methods for making such liquid formulations, articles of manufacture comprising such liquid formulations and methods of treating a patient with such liquid formulations.