Terlipressin Formulation Stabilization via pH and Buffer Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Terlipressin aqueous solutions are unstable due to structural degradation, particularly at elevated temperatures, and require pH optimization to maintain stability, but existing formulations often rely on high buffer concentrations that can be detrimental to the peptide's stability.
Innovation Solution
An aqueous solution composition of terlipressin with a pH range of 4.0 to 6.0, containing low or minimal buffer concentrations (0-5 mM) and optionally an amino acid or tonicity modifier, which helps stabilize the peptide by minimizing buffer impact and enhancing stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If high buffer concentrations are used to maintain pH stability, then pH control is improved, but peptide stability deteriorates due to buffer-induced degradation
Solution Approach 1:
The patent changes the pH parameter from conventional ranges (pH 6-8) to an acidic range (pH 3.5-5.5), which fundamentally alters the stability profile of terlipressin. This parameter change allows the use of low buffer concentrations (0-5 mM) while maintaining pH stability, thereby resolving the contradiction between pH control and peptide stability.
2Reliability
If buffer concentrations are reduced to improve peptide stability, then peptide stability is improved, but pH control capability deteriorates
Solution Approach 1:
The patent introduces specific excipients (amino acids such as arginine, lysine, or histidine; and surfactants such as polysorbates) that act as intermediaries to maintain pH control capability even at low buffer concentrations. These additives mediate between the reduced buffer system and the peptide, ensuring both peptide stability and adequate pH control.
3Duration of action of stationary object
If terlipressin is formulated for stability at elevated temperatures, then shelf-life is improved, but structural degradation increases at these temperatures
Solution Approach 1:
The patent applies parameter changes in multiple dimensions: pH (to acidic range), buffer concentration (to low levels), and temperature stability (enabling storage at 25-30°C). This combination of parameter changes creates a formulation that maintains structural integrity and minimizes degradation even at elevated storage temperatures, thereby extending shelf-life.
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 composition maintains stability at elevated temperatures, reducing impurity formation and extending shelf-life, with formulations showing improved stability and lower impurity levels compared to traditional high-buffer formulations.
Implementation Method 1
pH optimization is a key step in formulation development. It is thought to be important to ensure that the pH is maintained at the selected range and pH fluctuations are minimized. Therefore, it has been understood that a certain degree of buffering capacity is needed in the formulation.
Implementation Method 2
The structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomerization or oxidation.
Implementation Method 3
The structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomerization or oxidation.
Implementation Method 4
In some cases, the degradation can be physical in nature (e.g. aggregation or gel formation), although these processes are relatively less common in peptides than in the case of larger proteins.
Implementation Method 5
In some cases, the degradation can be physical in nature (e.g. aggregation or gel formation), although these processes are relatively less common in peptides than in the case of larger proteins.
Implementation Method 6
The structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomerization or oxidation.
Implementation Method 7
The structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomerization or oxidation.
Data Source
AI summary
The invention provides inter alia an aqueous solution composition of pH in the range 4.0-6.0 comprising: —terlipressin or a salt thereof; —optionally one or more buffers being substances having at least one ionisable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition; —optionally an amino acid; and—optionally a tonicity modifier wherein the buffers are present in the composition at a total concentration of 0-5 mM.