Stable, concentrated radionuclide complex solutions
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Solution Overview
Problem
Existing radiopharmaceutical drug products face issues with radiolytic degradation during manufacturing and storage, leading to instability and the need for on-site preparation, which complicates administration and patient comfort, especially when concentrated solutions are required.
Innovation Solution
A process involving the formation of a radionuclide complex with DOTA-TATE using gentisic acid and ascorbic acid as stabilizers, followed by a sequential addition of stabilizers to create a highly concentrated, stable solution with minimal ethanol content, allowing for commercial-scale production and ready-to-use administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the radionuclide complex solution is produced in high concentration, then the infusion volume for patients is reduced and treatment convenience is improved, but the solution becomes more prone to radiolysis and stability deteriorates
Solution Approach 1:
Gentisic acid is introduced as an intermediary substance that mediates between the radionuclide complex and the radiolytic environment. It acts as a stabilizer that protects the radionuclide complex from radiolysis, enabling the solution to maintain high concentration (7.4 GBq in 20-25 mL) while remaining stable during storage and transport.
Solution Approach 2:
The invention changes the chemical composition parameters of the solution by adding gentisic acid and controlling ethanol content below 5% w/w. This parameter modification allows the solution to achieve both high concentration and high stability, resolving the contradiction between concentration and radiolytic stability.
2Reliability
If stabilizers are added to improve stability against radiolysis, then the stability of the drug product is improved, but the stabilizers may have negative impact on complexation or solubility
Solution Approach 1:
The invention optimizes the concentration parameter of gentisic acid and controls the ethanol content parameter to below 5% w/w. These parameter adjustments ensure that the stabilizer effectively protects against radiolysis while maintaining proper complexation and solubility characteristics for pharmaceutical use.
3Reliability
If the drug product is produced in high dilution to avoid radiolysis, then the stability is improved, but large volumes of infusion solution need to be administered causing patient discomfort
Solution Approach 1:
Gentisic acid serves as a protective intermediary that enables the solution to maintain high radionuclide concentration without suffering from radiolytic degradation. This eliminates the need for high dilution, allowing concentrated solutions (7.4 GBq in 20-25 mL) to be administered in small, patient-friendly volumes while maintaining stability.
4Reliability
If freeze-dried kits are used to improve stability, then the shelf-life is extended, but reconstitution and further processing steps are required before administration
Solution Approach 1:
The stabilizer (gentisic acid) is incorporated into the radionuclide complex solution during the manufacturing process itself, before distribution. This preliminary action ensures stability is built-in from the start, allowing the solution to be produced in high concentration and shipped ready-to-use without requiring reconstitution or additional processing at the administration site.
Solution Approach 2:
The invention extracts the need for freeze-drying and reconstitution steps by implementing a different stabilization approach using gentisic acid in the liquid solution. This eliminates the complex preparation steps associated with freeze-dried kits while maintaining stability and 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 solution achieves high chemical and radiochemical stability, enabling a 7.4 GBq dose in a small volume for IV infusion, ensuring stability up to 72 hours at 25°C and 32°C for 12 hours, allowing centralized production and shipment to clinical centers without the need for on-site preparation.
Implementation Method 1
the decay of the radionuclide occurs constantly, e.g. also during the manufacturing and during storage of the drug product, and the released high energy emissions induce the cleavage of the chemical bonds of the molecules which form part of the drug product. This is often referred to as radiolysis or radiolytic degradation.
Implementation Method 2
forming a complex of (i) 177Lu with (ii) DOTA-TATE in the presence of gentisic acid and ascorbic acid as stabilizers
Data Source
AI summary
The present invention relates to radionuclide complex solutions of high concentration and of high chemical stability, that allows their use as drug product for diagnostic and/or therapeutic purposes. The stability of the drug product is achieved by at least one stabilizer against radiolytic degradation. The use of two stabilizers introduced during the manufacturing process at different stages was found to be of particular advantage.