Reconstitutable Teverelix-TFA Composition for Homogeneous Microcrystals
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Solution Overview
Problem
Existing teverelix-TFA compositions form gels, are not homogeneous, and have a short shelf life due to deamidation, with batch variations in molar ratios affecting bioavailability, making them difficult to inject and administer.
Innovation Solution
A reconstitutable teverelix-TFA composition with a molar ratio below the microcrystal formation threshold, containing 0.3-5% water by weight, is developed, allowing for a stable, prolonged shelf life and adjustable molar ratio during reconstitution to ensure a homogeneous, milky microcrystalline suspension.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If a molar ratio of teverelix to TFA of at least 1:1.6 is used to prevent gel formation, then the suspension becomes fluid, but the suspension is not homogeneous and gel formation still occurs
Solution Approach 1:
The patent applies parameter changes by precisely controlling the molar ratio of teverelix to TFA within the range of 1:1.8 to 1:2.5, and further optimizing it to 1:2.0 to 1:2.5 in the reconstituted solution. This specific parameter range prevents gel formation while ensuring homogeneous suspension, resolving the contradiction between stability and ease of operation.
2Reliability
If teverelix-TFA composition is stored at refrigeration and room temperatures, then the composition is stable during storage, but deamidation occurs reducing shelf life
Solution Approach 1:
The patent applies parameter changes by controlling the water content to 0.3-5% by weight and maintaining the molar ratio of teverelix to TFA at 1:1.8 to 1:2.5. These parameter optimizations reduce deamidation rates while maintaining storage stability at refrigeration and room temperatures, thereby extending shelf life.
3Duration of action of stationary object
If water content is reduced to increase shelf life, then deamidation rate increases due to lower pH-value
Solution Approach 1:
The patent applies parameter changes by optimizing water content to 0.3-5% by weight and controlling the molar ratio of teverelix to TFA at 1:1.8 to 1:2.5. This balanced approach prevents excessive deamidation while maintaining shelf life, avoiding the harmful effect of reduced water content causing lower pH and increased deamidation.
4Manufacturing precision
If batch variations in molar ratio occur during manufacturing, then the desired microcrystalline suspension cannot be consistently obtained, affecting bioavailability
Solution Approach 1:
The patent applies parameter changes by specifying a narrow and precise molar ratio range of teverelix to TFA (1:1.8 to 1:2.5, preferably 1:2.0 to 1:2.5). This precise parameter control ensures consistent microcrystalline suspension formation across batches and maintains reliable bioavailability.
5Ease of operation
If a homogeneous microcrystalline suspension is achieved, then the composition is easy to inject, but gel formation interferes with sustained action
Solution Approach 1:
The patent applies parameter changes by optimizing the molar ratio of teverelix to TFA to 1:2.0 to 1:2.5 in the reconstituted solution. This creates a homogeneous microcrystalline suspension that is easy to inject while preventing gel formation, thereby maintaining the sustained action of the peptide.
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 provides a stable teverelix-TFA formulation with extended shelf life, easier handling, and adjustable release profile, ensuring optimal bioavailability and reduced deamidation, facilitating less frequent administration and improved patient compliance.
Implementation Method 1
a predefined molar ratio of peptide to counter-ion which is below the molar ratio required for microcrystal formation
Implementation Method 2
Since teverelix is deamidated when placed in contact with water and acid, the teverelix-TFA compositions of WO 2003/022243 is not stable during storage
Data Source
AI summary
The present invention relates to a reconstitutable teverelix-TFA composition having a predefined molar ratio of teverelix to trifluoroacetate which is below the molar ratio required for microcrystal formation. Said composition remains stable during storage e.g., at a temperature around 2-8° C. Upon reconstitution a fixed amount of trifluoroacetate can be added to said composition thereby effectively and simply achieving an exact and desired molar ratio in order to obtain a fluid, milky microcrystalline aqueous teverelix-TFA suspension.