Lyophilized Degarelix Composition for Predictable Depot Formation
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Solution Overview
Problem
Degarelix, a synthetic decapeptide used for prostate cancer treatment, tends to self-associate and form gels in aqueous solutions, leading to depot formation and unpredictable sustained release properties, which complicates its administration and bioavailability.
Innovation Solution
A lyophilized degarelix drug product is produced by dissolving degarelix in a mannitol-containing solution, followed by lyophilization, with controlled acetic acid concentration and temperature conditions to achieve a viscosity range of 2 to 12 mPas upon reconstitution, ensuring consistent depot formation and sustained release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If degarelix is dissolved in aqueous solution for administration, then it can be administered to patients, but it self-associates and forms gels leading to unpredictable sustained release properties
Solution Approach 1:
The patent controls the acetic acid concentration at 4.5 to 10.0% (w/w) and water content at 10% (w/w) or less in the lyophilized degarelix drug substance. These parameter controls prevent gel formation upon reconstitution while maintaining sustained release properties, resolving the contradiction between administerability and predictability of release
Solution Approach 2:
The patent creates a composite lyophilized drug product comprising degarelix mixed with mannitol as an excipient. This composite formulation prevents self-association and gel formation of degarelix in aqueous solution while maintaining controlled sustained release properties, thereby improving both ease of operation and reliability
2Duration of action of moving object
If degarelix forms gels in aqueous solution, then depot formation occurs, but the sustained release properties become unpredictable
Solution Approach 1:
The patent specifies precise parameter ranges: acetic acid concentration of 4.5 to 10.0% (w/w) and water content of 10% (w/w) or less. These controlled parameters ensure consistent physical properties upon reconstitution, leading to predictable and consistent sustained release profiles while maintaining adequate duration of action
Solution Approach 2:
The patent uses mannitol as an intermediary substance mixed with degarelix in the lyophilized formulation. This intermediary prevents direct self-association of degarelix molecules that would lead to uncontrolled gel formation, thereby ensuring manufacturing precision and consistent release profiles while maintaining sustained release duration
3Manufacturing precision
If acetic acid concentration is increased to control viscosity, then viscosity control improves, but drug substance stability may be affected
Solution Approach 1:
The patent optimizes acetic acid concentration to a specific range of 4.5 to 10.0% (w/w), which is sufficient to control viscosity within 2 to 12 mPas upon reconstitution while maintaining drug substance stability. This balanced parameter selection resolves the contradiction between manufacturing precision and stability
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 method controls the viscosity of the reconstituted degarelix solution, providing a consistent and controlled depot formation and sustained release, enhancing bioavailability and administration stability.
Implementation Method 1
dissolving degarelix in a mannitol-containing solution
Implementation Method 2
lyophilising the de-aggregated degarelix to provide the lyophilised degarelix drug substance
Data Source
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AI summary
The present invention provides methods for producing a lyophilized degarelix product which, upon reconstitution with water for injection in an amount of 20 mg/ml, shows a viscosity of up to 15 mPas. The present invention also provides a lyophilized degarelix drug substance which shows, upon dissolution in water in an amount of 20 mg/ml, a viscosity of up to 3.2 mPas, and processes for providing this lyophilized degarelix drug substance.