Building block type 18F-FDG synthesis module device

Abstract

The utility model relates to a building block type 18F-FDG synthesis module device which comprises a base module, a valve group module and a reagent group module, and the base module is a first building block type module used for installing a reaction tube and providing positioning for the valve group module; the valve group module is a second building block type module which integrates a plurality of control valves, pipelines, QMA columns and solid-phase extraction columns required by 18F-FDG synthesis, and the second building block type module is directly arranged at the mounting position of the first building block type module; the reagent group module is a third building block type module which integrates a plurality of injectors for storing prodrugs and reagents required by the synthesis process and a product purification column, and the third building block type module is directly inserted into the second building block type module. According to the utility model, one 18F-FDG synthesis unit can be formed by simply splicing and combining the three building block type modules, so that the preparation work of 18F-FDG synthesis can be quickly completed, and a plurality of independently running 18F-FDG synthesis units can be placed in one protection box through the combination of a plurality of building block type bases.

Description

Technical Field

[0001] The utility model relates to a radiopharmaceutical synthesis device using fluorine-18 labeling, specifically a building block type 18 F-FDG synthesis module device can be completed once or multiple times through simple combination 18 F-FDG synthesis. Background Art

[0002] 18 F-FDG is a positron-emitting radioactive drug that is currently required for PET / CT examinations, accounting for approximately 90% of the current PET / CT examination dosage. 18 F-FDG is a radioactive drug with two characteristics: first, it has no shelf life and needs to be produced only when it is used every day; second, 18 After the annihilation of F's beta rays, high-energy rays of 511Kev are generated. High-energy rays are harmful to the human body and cannot be operated manually. They need to be automatically synthesized in a lead protective box under computer control, and each module can only be installed with reagents once a day. 18 The demand for F-FDG is high, and it needs to be synthesized once or multiple times a day. 18 F-FDG automated synthesis module has put forward very high requirements. 18 The reagents for the F-FDG module are all prepared before synthesis on the same day, which requires a lot of preparation work and does not meet the requirements of pharmaceutical GMP operation. It is necessary to improve the integration of reagents to facilitate one-click preparation.

[0003] 18 The technology used in F-FDG synthesis is still the traditional method. In terms of reagent transfer, positive pressure or negative pressure transfer is adopted. This method has many control points and requires a control point for each reagent, and cannot achieve quantitative transfer. After the reaction is completed, the hydrolysis of the intermediate adopts acid hydrolysis or alkaline hydrolysis. Acid hydrolysis is eliminated due to the high hydrolysis temperature and long time. There are two methods of alkaline hydrolysis. One is liquid phase alkaline hydrolysis, which is characterized by room temperature and low concentration of alkali. However, since the boiling point of the solvent acetonitrile is the same as the volatilization temperature of the intermediate at 82°C, it cannot completely remove acetonitrile, so the acetonitrile content in the product often exceeds the standard (400PPM). The other is solid phase hydrolysis, that is, the intermediate is adsorbed on a reverse phase C-18 column, and then concentrated alkali is added to the C-18 column at room temperature. The C-18 column is rinsed with a large amount of water to reduce the acetonitrile content to a very low concentration. The commonly used C-18 column is based on silica gel [Si(CH3)2C 18 H 37] reverse phase C-18 extraction column, the pH tolerance range of silica gel bonded C-18 is 2-8. When the pH increases to 9, the Si-O bond becomes extremely unstable and easily broken. Strong alkali causes the silane to fall off and produce trimethylsilane. This compound has certain toxicity and needs to be controlled within a certain range [Study on the unknown impurity trimethylsilanol in fluoro[(18)F]deoxyglucose injection, Isotope, 2023, Issue 2]; People use Light tC-18 instead of conventional C-18, and even treat C-18 with alkali first and then adsorb it to reduce the content of trimethylsilane. However, there is still no effective method to control the content of trimethylsilane in the solid phase alkaline hydrolysis synthesis process. In addition, the silica gel bonded C-18 column, due to its surface hydrophobicity, the hydrophobic functional group will curl up, so it needs to be activated with ethanol before use. The ethanol content is also the product. 18 One of the F-FDG quality controls. Utility Model Content

[0004] The purpose of this utility model is to provide a building block type 18 F-FDG synthesis module device can be quickly completed through simple combination 18 Preparation of F-FDG synthesis and realization of multiple 18 Simultaneous operation of the F-FDG synthesis module.

[0005] The technical solution of the utility model is as follows: a building block type 18 The F-FDG synthesis module device includes a base module, a valve group module and a reagent group module, wherein the base module is a first building block module for installing the reaction tube and providing positioning for the valve group module; the valve group module is a 18 The second building block module integrates several control valves, pipelines, QMA columns (anion capture columns) and solid-phase extraction columns required for F-FDG synthesis. The second building block module can be directly installed in the installation position of the first building block module, and the pipeline outlet is connected to the reaction tube set on the first building block module; the reagent group module is a third building block module that integrates several syringes for storing drug precursors and reagents required for the synthesis process and a product purification column. The third building block module is directly plugged into the second building block module, so that each syringe and product purification column is connected to the corresponding valve pipeline.

[0006] Furthermore, the building block 18 F-FDG synthesis module device, wherein the first building block module, the second building block module and the third building block module constitute a 18 F-FDG synthesis unit, multiple units can be set up in one protective box 18 F-FDG synthesis unit.

[0007] Further, as a specific embodiment, the building block 18 The F-FDG synthesis module device is provided with several positioning columns at the installation position of the first building block module (base module), and the second building block module (valve group module) is provided with positioning holes corresponding to each positioning column. When the second building block module is placed at the installation position of the first building block module, the positioning columns are inserted into the corresponding positioning holes to achieve positioning.

[0008] Furthermore, corresponding female snap-in slots and male snap-in slots are respectively provided on the first building block module and the second building block module, and the female snap-in slots and the male snap-in slots are engaged with each other to fix the second building block module to the first building block module.

[0009] Further, as a specific embodiment, the building block 18 The F-FDG synthesis module device, the third building block module (reagent group module) is provided with several connectors connected to each syringe and product purification column, the second building block module (valve group module) is provided with several pipe columns connected to the corresponding valve pipelines, and the connectors are inserted into the corresponding pipe columns to realize the combined connection of the third building block module and the second building block module.

[0010] Further, as a specific embodiment, the building block 18 The F-FDG synthesis module device is further provided with a peristaltic pump connected to a water supply device on the third building block module.

[0011] Further, as a specific embodiment, the building block 18 The F-FDG synthesis module device is provided with a positioning point for limiting the position of the syringe pressure rod, and the positioning point is used to limit the downward pressing position of the syringe pressure rod.

[0012] Further, as a specific embodiment, the building block 18 In the F-FDG synthesis module device, the reaction tube is placed in the groove of the first building block module, and a heating element is provided in the groove.

[0013] Further, as a specific embodiment, the building block 18 In the F-FDG synthesis module device, the solid phase extraction column provided on the second building block module is an HLB column.

[0014] Further, as a specific embodiment, the building block 18 The F-FDG synthesis module device, the product purification columns arranged on the third building block module include IC-H hydrogen ion exchange column, Al2O3 column and C-18 column in sequence.

[0015] The beneficial effects of the utility model are as follows:

[0016] 1) The utility model designs the base module, valve group module and reagent group module into building block modules, which can be formed into a 18 F-FDG synthesis unit, thus quickly completing 18 Preparation for F-FDG synthesis.

[0017] 2) Through the combination of multiple building block bases, multiple 18 F-FDG synthesis unit. Even if one unit fails, it can ensure that the remaining units can operate independently without affecting 18 Production of F-FDG.

[0018] 3) By combining positive pressure with the syringe positioning point, nitrogen is injected into the syringe inlet. The syringe is provided with a positioning point to control the position of the pressure rod, and the injected nitrogen is used as the power to press out the liquid in the syringe. If the volume of the injected nitrogen is controlled, the liquid in the syringe can be transferred in batches and in a quantitative manner.

[0019] 4) The utility model adopts an HLB column to replace the adsorption intermediate of the reversed-phase C-18 column and hydrolyzes it, thereby preventing the generation of trimethylsilanol on the reversed-phase C-18 column; at the same time, there is no need to activate the HLB column with ethanol, and the final product does not contain ethanol. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 In the specific implementation of the utility model, the building block 18 Schematic diagram of the exploded structure of the F-FDG synthesis module device;

[0021] Figure 2 This is a structural diagram of the second building block module (valve group module) in a specific embodiment of the present utility model;

[0022] Figure 3 2 is a schematic structural diagram of the third building block module (reagent set module) in a specific embodiment of the present invention. DETAILED DESCRIPTION

[0023] The present invention will be described in detail below with reference to the accompanying drawings and embodiments.

[0024] Currently commercialized 18F-FDG is available in two types. One is a single-shot synthesis module, requiring only one reagent installation and one run. This module boasts high stability, but occupies a single hot cell and can only be run once a day. The other is a multiple-shot synthesis module, requiring only one reagent installation and two or four runs. This module can perform multiple syntheses per day within a single hot cell, but utilizes a single control system. A single system failure renders the module inoperable for the day. Furthermore, the reagents in most FDG kits are stored in 10mL ampoules, which are then transferred to syringes or reaction vials upon use. This requires extensive preparation and increases the workload.

[0025] The utility model provides a building block type 18 F-FDG synthesis module device can achieve 18 F-FDG synthesis unit can be quickly assembled and installed, and multiple units can be placed in one protective box. 18 F-FDG synthesis unit, each unit operates independently without affecting each other.

[0026] In this embodiment, the building block 18 The structure of the F-FDG synthesis module device is as follows Figure 1 As shown, it consists of three building block modules, the first building block module is the base module A, the second building block module is the valve group module B, and the third building block module is the reagent group module C. When synthesized, a simple combination of A+B+C is formed. 18 F-FDG synthesis unit and completed the preparation work.

[0027] Specifically, the base module A is used to house the reaction tubes and provide a location for the valve assembly module B. In this embodiment, the base module A has an L-shaped longitudinal cross-section, with a mounting position defined between the sidewalls and the bottom, into which the valve assembly module B can be directly placed. A recess 9 is designed at the bottom of the base module A, into which the reaction tubes are placed. A heating element is located within this recess for heating during the drug synthesis process.

[0028] In this embodiment, the valve group module B is in a plate shape. Figure 2 As shown, 18 Several control valves, pipelines, QMA columns (anion capture columns), and solid-phase extraction columns (HLB columns are used in this embodiment) required for F-FDG synthesis are integrated on the plate body. The valve group module B can be directly placed on the installation position of the base module A like a building block, and the pipeline outlet is connected to the reaction tube set on the base module A.

[0029] Specifically, four positioning posts 7 are provided on the sidewalls of the base module A, and positioning holes 8 corresponding to each post are provided on the valve assembly module B. When the valve assembly module B is placed in the mounting position of the base module A, the positioning posts 7 are inserted into the corresponding positioning holes 8 to achieve positioning. Furthermore, the base module A and the valve assembly module B are each provided with multiple sets of corresponding female and male bayonet holes 10 and 11. These bayonet holes 10 and 11 engage with each other to secure the valve assembly module B to the base module A. The above is only one optional fixed connection method; those skilled in the art can design other combinations in combination with conventional structures.

[0030] In this embodiment, the longitudinal cross-section of the reagent set module C is L-shaped. Figure 3 As shown, the lower edge width corresponds to the plate width of the valve group module B. Reagent group module C integrates several syringes and product purification columns for storing drug precursors and reagents required for the synthesis process. Reagent group module C can be directly plugged into the upper end of valve group module B so that each syringe and product purification column are connected to the corresponding valve pipeline. In the present embodiment, the reagent group module C is respectively provided with a syringe (position 1) for storing K222 eluent, a syringe (position 2) for storing acetonitrile, a syringe (position 3) for storing drug precursors, and a syringe (position 6) for storing NaOH solution. At the same time, a peristaltic pump connected to a water supply device is provided at position 4, and a product purification column is provided at position 5. The product purification column includes an IC-H hydrogen ion exchange column, an Al2O3 column, and a C-18 column in sequence.

[0031] Specifically, the reagent assembly module C is equipped with several connectors 13 that connect to the syringes, peristaltic pumps, and product purification columns. The valve assembly module B is equipped with several tubing columns 12 that connect to the corresponding valve pipelines. The connectors 13 are inserted into the corresponding tubing columns 12 to achieve the combined connection between the reagent assembly module C and the valve assembly module B. That is, the connectors in positions 1-6 on the reagent assembly module C correspond to the tubing columns in positions 1-6 on the valve assembly module B. After insertion, the syringes, peristaltic pumps, and product purification columns on the reagent assembly module C are connected to the corresponding valve pipelines.

[0032] The building block type 18 The F-FDG synthesis module device stores all the reagents required for synthesis in a syringe. The liquid transfer method on the syringe is achieved by ventilation, the limit of the syringe pressure rod, and then the automatic transfer method powered by the compressed gas. Specifically, see Figure 1 、 Figure 3Each syringe is equipped with a positioning point G. By combining positive pressure with the syringe positioning point G, nitrogen is injected into the syringe inlet. The syringe is equipped with a positioning point to control the position of the pressure rod, and the liquid in the syringe is pressed out by the injected nitrogen. If the volume of the injected nitrogen is controlled, the liquid in the syringe can be transferred in batches and in a quantitative manner.

[0033] Using the building block type of this embodiment 18 F-FDG synthesis module device 18 The process for synthesizing F-FDG comprises the following steps:

[0034] (1) Combine the three building block modules (base module A, valve group module B, reagent group module C) to form a 18 F-FDG synthesis unit;

[0035] (2) Transferring fluorine-18 ions from the accelerator to the QMA column on valve block module B;

[0036] (3) Using ventilation, limiting, and then automatic transfer, the K222 eluent in the syringe at position 1 of the reagent group module C is injected into the QMA column on the valve group module B, and the fluorine-18 ions are transferred to the reaction tube on the base module A, and heated to remove water;

[0037] (4) Using the method of step (3), transfer the acetonitrile in the syringe at position 2 of reagent module C to the reaction tube and heat it to remove water;

[0038] (5) Using the method of step (3), move the drug precursor in the syringe at position 3 of the reagent set module C to the reaction tube for reaction;

[0039] (6) 10 mL of water is added to the reaction tube through the peristaltic pump at position 4 of the reagent group module C to dilute it. The diluted reaction solution is then transferred to the HLB column on the valve group module B through the pump body. The product is adsorbed on the HLB column.

[0040] (7) Wash the HLB column three times with 10 mL of water using the peristaltic pump in position 4 of the reagent module C;

[0041] (8) Using the method of step (3), add 1 mL of 2N NaOH from the syringe in position 6 of reagent module C to the HLB column;

[0042] (9) The product was eluted from the HLB column with 10 mL of water through the peristaltic pump at position 4 of the reagent module C and then flowed out through the product purification column at position 5 of the reagent module C; the product was filtered through a sterile filter membrane to obtain a product suitable for intravenous injection. 18 F-FDG.

[0043] It will be apparent to those skilled in the art that the structure of the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the present invention is defined by the appended claims, not the foregoing description, and it is intended that all variations within the meaning and range of equivalents of the claims be encompassed within the present invention. Any reference signs in the claims should not be construed as limiting the claim to which they relate.

[0044] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A building block type 18 The F-FDG synthesis module device includes a base module, a valve group module and a reagent group module, characterized in that: The base module is a first building block module used to install the reaction tube and provide positioning for the valve group module; the valve group module is 18 The second building block module integrates several control valves, pipelines, QMA columns and solid phase extraction columns required for F-FDG synthesis. The second building block module can be directly installed in the installation position of the first building block module, and the pipeline outlet is connected to the reaction tube set on the first building block module; the reagent group module is a third building block module that integrates several syringes for storing drug precursors and reagents required for the synthesis process and a product purification column. The third building block module is directly plugged into the second building block module, so that each syringe and product purification column is connected to the corresponding valve pipeline.

2. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The first building block module, the second building block module and the third building block module constitute a 18 F-FDG synthesis unit, multiple units can be set up in one protective box 18 F-FDG synthesis unit.

3. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: A plurality of positioning posts are provided at the installation position of the first building block module, and positioning holes corresponding to the positioning posts are provided on the second building block module. When the second building block module is placed at the installation position of the first building block module, the positioning posts are inserted into the corresponding positioning holes to achieve positioning.

4. The building block type as claimed in claim 3 18 The F-FDG synthesis module device is characterized in that: The first building block module and the second building block module are respectively provided with corresponding female snap-fits and male snap-fits, which are engaged with each other to fix the second building block module to the first building block module.

5. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The third building block module is provided with several connectors connected to each syringe and product purification column, and the second building block module is provided with several pipe columns connected to the corresponding valve pipelines. The connectors are inserted into the corresponding pipe columns to realize the combined connection of the third building block module and the second building block module.

6. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: A peristaltic pump connected to the water supply device is also provided on the third building block module.

7. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The syringe is provided with a positioning point for limiting the position of the syringe pressure rod, and the positioning point is used to limit the downward pressing position of the syringe pressure rod.

8. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The reaction tube is placed in a groove of the first modular module, and a heating element is provided in the groove.

9. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The solid phase extraction column provided on the second building block module is an HLB column.

10. The building block type as claimed in claim 1 18 The F-FDG synthesis module device is characterized in that: The product purification columns arranged on the third building block module include an IC-H hydrogen ion exchange column, an Al2O3 column and a C-18 column in sequence.

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