Dual GLP-1 Peptide Formulation pH Optimization

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Solution Overview

Problem

Formulating dual GLP-1/glucagon receptor agonist peptides into stable liquid pharmaceutical formulations for subcutaneous, intramuscular, and intraperitoneal administration is challenging due to sub-optimal solubility and stability issues at specific pH values, particularly at pH 5.0-6.5 and 7.0-8.5, which affects their therapeutic efficacy and safety.

Innovation Solution

A pharmaceutical formulation comprising a dual GLP-1/glucagon receptor agonist peptide with a specific amino acid sequence, chemically modified with a C14-C24 fatty acid linker and amidated C-terminal amino acid, buffered at pH 7.8-9.0, including a tonicity agent and antioxidant to prevent fibrillation and oxidation, ensuring stability and solubility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If the peptide is formulated at lower pH values (5.0-6.5), then the formulation is more stable, but the solubility becomes sub-optimal

Engineering Contradiction:
Improvepeptide stabilityVSAvoidpeptide solubility
Core Design Contradiction:
Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by optimizing the pH to a specific range of 7.0-8.5, which resolves the contradiction between stability and solubility. This pH range was determined through experimental evaluation to provide both adequate solubility and stability for the dual GLP-1/glucagon receptor agonist peptide, avoiding the sub-optimal solubility at lower pH values while preventing degradation at higher pH values.

Inventive Principle:
Principle #35Parameter changes

2Quantity of substance

If the peptide is formulated at higher pH values (7.0-8.5), then the solubility is improved, but the stability becomes sub-optimal

Engineering Contradiction:
Improvepeptide solubilityVSAvoidpeptide stability
Core Design Contradiction:
Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent resolves this contradiction by establishing an optimal pH window of 7.0-8.5 through systematic parameter optimization. Experimental data showed that peptides at pH values above 8.5 exhibited reduced stability, so the formulation specifies pH 7.0-8.5 to maintain both solubility and stability, representing a balanced parameter setting that avoids both extremes.

Inventive Principle:
Principle #35Parameter changes

3Quantity of substance

If the peptide concentration is increased for effective dosing, then the therapeutic efficacy is improved, but the risk of fibrillation and aggregation increases

Engineering Contradiction:
Improvepeptide concentrationVSAvoidfibrillation and aggregation
Core Design Contradiction:
Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent employs intermediary substances including antioxidants and surfactants in the formulation to prevent fibrillation and aggregation at therapeutic peptide concentrations. These additives act as mediators that protect the peptide from harmful interactions while maintaining the required concentration for efficacy, thereby resolving the contradiction between dosing requirements and physical stability.

Inventive Principle:
Principle #24Intermediary (Mediator)

4Ease of operation

If the peptide is formulated as a liquid for self-administration, then the ease of operation is improved, but the manufacturing precision and stability control become more difficult

Engineering Contradiction:
Improveself-administration convenienceVSAvoidformulation stability control
Core Design Contradiction:
Ease of operationVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by specifying precise formulation parameters including pH 7.0-8.5, buffer composition, and excipient concentrations to ensure liquid formulation stability. These controlled parameters enable both liquid state for easy self-administration and manufacturing reproducibility, resolving the contradiction between ease of operation and manufacturing precision.

Inventive Principle:
Principle #35Parameter changes

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 maintains the functional characteristics of the peptide, enhancing its stability and solubility, reducing fibrillation and oxidation risks, thereby ensuring therapeutic efficacy and safety for self-administration.

Implementation Method 1

buffered at pH 7.8-9.0

Methodology Applied
Scientific EffectpH buffering:

Implementation Method 2

antioxidant to prevent fibrillation and oxidation

Methodology Applied
Scientific EffectOxidation prevention: Oxidation

Implementation Method 3

reducing fibrillation and oxidation risks

Methodology Applied
Scientific EffectFibrillation prevention:

Data Source

PatentUS20240299499A1Therapeutic Peptide Formulations
Publication Date: 2024.09.12 ELI LILLY & CO
  • US20240299499A1 patent drawing
  • US20240299499A1 patent drawing
  • US20240299499A1 patent drawing

AI summary

Stable pharmaceutical formulations for therapeutic dual GLP-1 receptor/glucagon receptor agonists and methods of using such stable pharmaceutical formulations.