Cetrorelix Ready-to-Use Liquid Formulation
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Solution Overview
Problem
Cetrorelix acetate is thermally labile and unstable in aqueous solutions, leading to aggregation and gel formation, which complicates its formulation and administration, especially requiring reconstitution of lyophilized powders and causing patient discomfort with certain stabilizing agents like lactic acid.
Innovation Solution
Development of ready-to-use stable aqueous compositions of Cetrorelix using amino acids like glycine as stabilizers, acetic acid as an acidifying agent, and isotonicity agents to maintain pH between 3 to 5.5, along with optional cosolvents, to prevent aggregation and extend shelf-life without the need for reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If Cetrorelix is formulated as lyophilized powder for reconstitution, then stability is improved, but ease of operation deteriorates due to requiring reconstitution and handling of powders
Solution Approach 1:
The patent changes the physical state parameter from lyophilized powder to ready-to-use liquid solution, and adjusts pH parameters to 2.8-3.5 using acetic acid, enabling stability without reconstitution. This resolves the contradiction by maintaining stability while eliminating the operational complexity of powder reconstitution.
Solution Approach 2:
The formulation uses a composite system combining Cetrorelix with acetic acid, surfactants, and other excipients in a liquid matrix. This composite approach enables the peptide to remain stable in solution form rather than requiring lyophilization, thus improving ease of operation while maintaining stability.
2Ease of operation
If Cetrorelix is formulated as ready-to-use liquid solution, then ease of operation is improved, but stability deteriorates due to aggregation and gel formation
Solution Approach 1:
The patent optimizes pH to a specific range (2.8-3.5) and controls surfactant concentrations to prevent aggregation and gel formation. By carefully adjusting these parameters, the formulation achieves both ready-to-use liquid form and long-term stability without reconstitution.
Solution Approach 2:
Surfactants are used as intermediary substances that prevent aggregation of Cetrorelix molecules in aqueous solution. These surfactants act as mediators between the peptide and the liquid medium, enabling stability in ready-to-use form by preventing unwanted interactions that would lead to aggregation.
3Stability of the object's composition
If lactic acid is used as stabilizing agent, then stability is improved, but object-affected harmful factors worsen due to irritation and burning sensation at injection site
Solution Approach 1:
The patent extracts or removes lactic acid from the formulation and replaces it with acetic acid as the acidifying agent. This substitution eliminates the harmful effects (irritation and burning sensation) while maintaining the necessary pH control and stability of the formulation.
Solution Approach 2:
The patent substitutes a less harmful acidifying agent (acetic acid) for lactic acid, effectively replacing a problematic component with a milder alternative that achieves the same functional purpose without the adverse effects on patient comfort.
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 solution provides a stable, self-administrable, and cost-effective ready-to-use liquid formulation with reduced impurities and viscosity, suitable for long-term treatments, maintaining potency and stability for at least 24 months, and avoiding gel formation during sterilization.
Implementation Method 1
Development of ready-to-use stable aqueous compositions of Cetrorelix using amino acids like glycine as stabilizers
Implementation Method 2
acetic acid as an acidifying agent, and isotonicity agents to maintain pH between 3 to 5.5
Implementation Method 3
isotonicity agents to maintain pH between 3 to 5.5, along with optional cosolvents, to prevent aggregation
Implementation Method 4
maintaining potency and stability for at least 24 months
Data Source
AI summary
The present invention relates to a stable parenteral composition comprising Cetrorelix or a pharmaceutically acceptable salt thereof, which is ready-to-use and does not require reconstitution prior to administration.