Protein Formulation Viscosity Reduction Using Creatinine Excipients

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Solution Overview

Problem

Highly concentrated protein solutions exhibit increased viscosity, making them difficult to handle and administer, and are prone to aggregation, which affects stability and immunogenicity.

Innovation Solution

Incorporating creatinine, creatine, or carnitine as excipients in therapeutic protein formulations to reduce viscosity and aggregation, allowing for higher protein concentrations without increased viscosity and improved stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If high concentrations of therapeutic protein are used, then the amount of therapeutic protein delivered per volume is improved, but the viscosity of the formulation increases

Engineering Contradiction:

Improveconcentration of therapeutic proteinVSAvoidviscosity

Core Design Contradiction:

Quantity of substanceVSEase of operation

Solution Approach 1:

The patent introduces creatine or carnitine as intermediary substances that mediate between high protein concentration and viscosity. These excipients interact with the therapeutic protein to prevent excessive viscosity increase while maintaining high concentration, thereby resolving the contradiction between quantity of substance and ease of operation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the chemical composition parameters of the formulation by adding specific excipients (creatine or carnitine) at optimized concentrations. This parameter change allows the system to maintain high protein concentration without the proportional increase in viscosity that would normally occur, thus resolving the technical contradiction

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If high concentrations of therapeutic protein are used, then the amount of therapeutic protein delivered per volume is improved, but aggregation of the protein increases

Engineering Contradiction:

Improveconcentration of therapeutic proteinVSAvoidaggregation

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

Creatine or carnitine acts as an intermediary protective agent that prevents protein-protein interactions leading to aggregation. These excipients surround and stabilize individual protein molecules, preventing them from aggregating even at high concentrations, thus resolving the contradiction between quantity of substance and stability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent applies beforehand cushioning by incorporating stabilizing excipients (creatine or carnitine) into the formulation before protein aggregation can occur. These excipients provide a protective environment that cushions against aggregation stresses, preventing the harmful effect before it manifests

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Quantity of substance

If high concentrations of therapeutic protein are used, then the amount of therapeutic protein delivered per volume is improved, but the stability of the formulation decreases

Engineering Contradiction:

Improveconcentration of therapeutic proteinVSAvoidstability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The excipients creatine or carnitine serve as intermediary stabilizing agents that maintain formulation reliability at high protein concentrations. They interact with the therapeutic protein to preserve its structural integrity and prevent degradation, thus resolving the contradiction between quantity of substance and reliability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The formulation incorporates stabilizing excipients beforehand to cushion against various degradation mechanisms including aggregation, precipitation, and chemical modification. This prior protection ensures the therapeutic protein maintains its stability and reliability even at high concentrations

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Data Source

PatentUS10653781B2Pharmaceutical formulations

Publication Date: 2020.05.19 AMGEN INC

AI summary

A stable pharmaceutical formulation is provided that comprises a biologically active protein and an excipient selected from carnitine, creatine or creatinine.