Developing agent preparation device

Abstract

The utility model relates to a developing agent preparation device which is compact in structure, comprises a reaction bottle, an < 18 > F <-> ion providing module, a first solid-phase extraction column, a high performance liquid chromatography and a preparation module which are sequentially connected in series on a main pipeline, and is simple in structure and free of pipeline intersection; the preparation device is only provided with one reaction bottle, residues are few, products prepared after raw materials react through the modules can be directly injected into a human body, and the preparation efficiency is high; the preparation device is a disposable product, after a reagent is prepared in the early stage, the synthesis process is automatic synthesis, the risks of manual operation errors, pollution and cross contamination are effectively avoided, and it is ensured that the production repeatability and stability of developing agents between batches are high; the kit conforms to the GMP (Good Manufacturing Practice) standard, and the quality and the safety of the prepared developer 18F-AV45 are ensured.

Description

TECHNICAL FIELD

[0001] The utility model belongs to the technical field of preparation for detecting Alzheimer's disease A beta imaging agent, and specifically relates to a preparation device of imaging agent. BACKGROUND

[0002] Alzheimer's disease is mainly characterized by abnormal deposition of beta-amyloid protein (A beta) in the brain. The common means for diagnosing Alzheimer's disease in the past includes nuclear magnetic resonance (MRI) and cerebrospinal fluid analysis. These examination methods can provide information on the structure and biochemistry of the brain, but cannot early diagnose the abnormal deposition of A beta in the brain. With the rapid development of molecular imaging technology, positron emission tomography (PET) has become an important means for early diagnosis of Alzheimer's disease. 18 F-AV45 is the first A beta imaging agent approved by the US FDA for the diagnosis of Alzheimer's disease. It can specifically bind to A beta plaques in the brain, achieving visualization and semi-quantitative evaluation of A beta plaque deposition.

[0003] However, at present 18 The preparation of F-AV45 imaging agent is mostly self-prepared reagent and synthesized by using a multifunctional synthesis module. The operation is complicated, and the production personnel are required to be high. In addition, the self-preparation has a high error rate, and the cleaning effect before and after the use of the multifunctional synthesis module cannot be guaranteed. There is a risk of pollution and cross contamination, which finally affects the quality of the imaging agent and is difficult to meet the GMP standard. SUMMARY

[0004] In view of the deficiencies in the prior art, the utility model provides a preparation device of imaging agent.

[0005] The technical scheme of the utility model comprises:

[0006] A preparation device of imaging agent comprises:

[0007] A reaction bottle;

[0008] 18 An F-ion providing module is used for providing F-ion solution into the reaction bottle. 18 An F-ion solution;

[0009] A solution providing module is used for providing reaction solution into the reaction bottle, and the reaction solution reacts with the F-ion solution to generate product liquid. 18 An F-ion solution;

[0010] A first solid-phase extraction column is used for extracting crude product from the product liquid.

[0011] A high-performance liquid chromatograph is used for purifying the crude product.

[0012] A preparation module, comprising a second solid phase extraction column, for preparing the purified product into an imaging agent.

[0013] Further, the reaction bottle is connected with the main pipeline through a connecting pipe. 18 The F-ion providing module, the solution providing module, the first solid phase extraction column, the high performance liquid chromatography and the preparation module are connected in series on a main pipeline, and the reaction bottle is connected with the main pipeline through a connecting pipe.

[0014] Further, the reaction bottle is connected with the main pipeline through a connecting pipe. 18 The F-ion providing module comprises an eluent bottle, an anion exchange column and a funnel, the anion exchange column is arranged on the main pipeline, the eluent bottle is connected with the main pipeline through the funnel, and the F-ion is eluted from the anion exchange column to the reaction bottle. 18 The F-ion is eluted from the anion exchange column to the reaction bottle.

[0015] Further, the solution providing module comprises a precursor solution bottle, an acetonitrile ampoule, a hydrolysis solution bottle, a neutralization solution bottle, a first eluent bottle and a first cleaning solution bottle, which are connected in series on the main pipeline and arranged in front of the liquid inlet of the first solid phase extraction column.

[0016] Further, the preparation module further comprises a transfer solution bottle, a second eluent bottle, a second cleaning solution bottle and a sodium ascorbate normal saline solution bottle, which are connected in series on the main pipeline and arranged in front of the liquid inlet of the second solid phase extraction column.

[0017] Further, a decompression pipe is arranged in the preparation device and connected with the reaction bottle, for balancing the air pressure in the reaction bottle.

[0018] Further, the preparation device further comprises first and second suction devices, which are connected in series on the main pipeline, the first suction device is arranged in front of the liquid inlet of the first solid phase extraction column, and the second suction device is arranged behind the liquid outlet of the second solid phase extraction column.

[0019] Further, the preparation device further comprises a waste liquid bottle and a gas filter, which are connected in series on the main pipeline, the waste liquid bottle is used for collecting waste liquid from the first and second solid phase extraction columns, and the gas filter is used for filtering gas generated in the reaction.

[0020] Compared with the prior art, the preparation device has at least the following advantages:

[0021] The preparation device for the imaging agent is compact in structure and comprises a reaction bottle, 18The F-ion providing module, the first solid phase extraction column, the high performance liquid chromatography, and the preparation module are connected in sequence on a main pipeline, and the structure is simple and there is no pipeline intersection; the preparation device is provided with only one reaction bottle, residual is small, and the product prepared after raw materials pass through the modules can be directly injected into the human body, so that the preparation efficiency is high; the preparation device is a disposable product, reagents are prepared in advance, the synthesis process is automatic synthesis, human operation errors, pollution and cross contamination risks are effectively avoided, and the production repeatability and stability of the imaging agent between batches are high; the kit meets GMP specifications, and the imaging agent is prepared 18 F-AV45 quality and safety. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to more clearly illustrate the specific embodiment of the present application, the following will briefly introduce the drawings needed to be used in the specific embodiment or prior art description.

[0023] Figure 1 It is a structural schematic view of the present application.

[0024] The reaction bottle 1, the first solid phase extraction column 2, the second solid phase extraction column 3, the acetonitrile solution bottle 4, the precursor solution bottle 5, the first aspirator 6, the hydrolysis solution bottle 7, the neutralization solution bottle 8, the first eluent bottle 9, the second aspirator 10, the reduced pressure pipe 11, the elution liquid bottle 12, the anion exchange column 13, the funnel 14, the first cleaning liquid bottle 15, the transfer liquid bottle 16, the sodium ascorbate normal saline solution bottle 17, the second eluent bottle 18, the second cleaning liquid bottle 19, the gas filter 20, the product bottle connecting pipe 21, the high performance liquid chromatography inlet 22, the high performance liquid chromatography outlet 23, and the main pipeline 24 are illustrated. DETAILED DESCRIPTION

[0025] The following will be further described in detail, and it is necessary to point out that the following specific embodiment is only used for further illustrating the present application, and cannot be understood as limiting the protection scope of the present application, and the person skilled in the art can make some non-essential improvements and adjustments to the present application according to the above application content.

[0026] The present application generally and / or specifically describes the materials used in the experiment and the test method. The test method or test method involved, if no special instructions, is a conventional method; the reagent or instrument used, if no manufacturer is specified, is a conventional product on the market, which is prepared or used by a conventional method.

[0027] Reference Figure 1 It is a structural schematic view of the present application, and a preparation device of an imaging agent comprises a reaction bottle 1, 18F- ion providing module, solution providing module, first solid phase extraction column 2, high performance liquid chromatography, preparation module, in the embodiment, the F- ion providing module, the solution providing module, the first solid phase extraction column 2, the high performance liquid chromatography and the preparation module are connected in series on a main pipeline 24, the reaction bottle 1 is communicated with the main pipeline 24 through a connecting pipe, and the structure is simple and compact, and there is no pipeline intersection. 18 F- ion providing module, solution providing module, first solid phase extraction column 2, high performance liquid chromatography, preparation module, in the embodiment, the F- ion providing module, the solution providing module, the first solid phase extraction column 2, the high performance liquid chromatography and the preparation module are connected in series on a main pipeline 24, the reaction bottle 1 is communicated with the main pipeline 24 through a connecting pipe, and the structure is simple and compact, and there is no pipeline intersection.

[0028] The F- ion providing module is used for providing F- ions into the reaction bottle 1. 18 The F- ion providing module is used for providing F- ions into the reaction bottle 1. 18 The F- ion solution, 18 The F- ion providing module includes a leaching solution bottle 12, an anion exchange column 13 and a funnel 14, the anion exchange column 13 is connected with the main pipeline 24 through a three-way valve, and the leaching solution bottle 12 is connected with the main pipeline 24 through the funnel 14. 18 The F- ions are eluted from the anion exchange column 13 into the reaction bottle 1.

[0029] The solution providing module is used for providing a reaction solution into the reaction bottle 1, and the reaction solution reacts with the F- ion solution to generate a product liquid. 18 The F- ion solution, and the solution providing module includes a precursor solution bottle 5, an acetonitrile solution bottle 4, a hydrolysis solution bottle 7, a neutralization solution bottle 8, a first eluent bottle 9 and a first cleaning liquid bottle 15, in the embodiment, the bottles are all arranged in front of a liquid inlet of the first solid phase extraction column 2, the precursor solution bottle 5 is a 2ml sterile syringe containing a precursor AV105, the acetonitrile solution bottle 4 is a 5mL acetonitrile penicillin bottle, the hydrolysis solution bottle 7 is a 2ml sterile syringe containing 1mL 3M HCL, the neutralization solution bottle 8 is a 2ml sterile syringe containing 1mL 3M NaOH, the first eluent bottle 9 is a 10ml sterile syringe containing 3mL anhydrous ethanol, and the first cleaning liquid bottle 15 contains 500mL sterile water for injection, and the solution bottles are connected with the main pipeline 24 through three-way valves.

[0030] The first solid phase extraction column 2 is used for extracting a crude product from the product liquid.

[0031] The high performance liquid chromatography is used for purifying the crude product, a high performance liquid chromatography liquid inlet 22 and a high performance liquid chromatography liquid outlet 23 are respectively connected with the main pipeline 24 through three-way valves, and in the embodiment, the high performance liquid chromatography liquid inlet 22 is close to a liquid outlet of the first solid phase extraction column 2, the pipeline through which the crude product flows is short, and the residual amount is small.

[0032] The preparation module comprises a second solid phase extraction column 3, the outlet of the second solid phase extraction column 3 is connected with the main pipeline 24 through a tee, a product bottle connecting pipe 21 is further arranged on the main pipeline 24, the product bottle connecting pipe 21 is connected with a product bottle and is used for collecting a final product, and the tee is further connected with a waste liquid bottle; the second solid phase extraction column 3 is used for preparing an imaging agent after purifying a product; since the volume of the product purified through high performance liquid chromatography is large and the ethanol content is high, the product cannot be directly used for human injection, the product is prepared after being purified, the volume of the product can be controlled, and finally, the imaging agent product can be directly injected into the human body; the preparation module further comprises a transfer liquid bottle 16, a second eluent bottle 18, a second cleaning liquid bottle 19 and a sodium ascorbate normal saline solution bottle 17, in the embodiment, the transfer liquid bottle 16, the second eluent bottle 18, the second cleaning liquid bottle 19 and the sodium ascorbate normal saline solution bottle 17 are sequentially connected on the main pipeline 24 through tees and are arranged in front of the inlet of the second solid phase extraction column 3, the transfer liquid bottle 16 is filled with 150 mL of sterilized injection water (containing 0.75 g of sodium ascorbate), the second eluent bottle 18 is a 2ml sterilized syringe filled with 2 mL of 75% ethanol, the second cleaning liquid bottle 19 is a 10ml sterilized syringe filled with 10 mL of sterilized injection water, and the sodium ascorbate normal saline solution bottle 17 is a 10ml sterilized syringe filled with 10 mL of normal saline (containing 50 mg of sodium ascorbate); the product obtained through the preparation module can be directly used for injection.

[0033] The preparation device of the imaging agent further comprises a pressure reducing pipe 11 in communication with the reaction bottle 1 and used for balancing the air pressure in the reaction bottle 1, and the other end of the pressure reducing pipe 11 is connected with the main pipeline 24 through a tee; the preparation device further comprises first and second suction devices, which are sequentially connected on the main pipeline 24; the first suction device 6 is arranged in front of the inlet of the first solid phase extraction column 2, and the second suction device 10 is arranged behind the outlet of the second solid phase extraction column 3; in the embodiment, the first and second suction devices are 30ml sterilized syringes; the structure of using the syringes to transmit the product is simple, the operation is convenient, and the blockage caused by the excessively long pipeline can be avoided; the preparation device of the imaging agent further comprises a waste liquid bottle and a gas filter 20, which are sequentially connected on the main pipeline 24; the waste liquid bottle is used for collecting waste liquid passing through the first and second solid phase extraction columns; and the gas filter 20 is used for filtering the gas generated in the reaction.

[0034] The preparation device of the imaging agent can be used for preparing 18 The F-AV45 imaging agent is prepared by using the preparation device, and the use method is as follows:

[0035] S1. Take out 18 the F-AV45 preparation device, install the F-AV45 preparation device on the synthesis module, and after the preparation work is completed, install the corresponding reagents to the tees as shown in the structure; Figure 1

[0036] ​S2. Accelerator generated 18 F- ions are passed into funnel 14 and through anion exchange column 13, 18 F- ions are adsorbed on the anion exchange column 13;

[0037] S3. Use eluent bottle 12 to elute the F- ions from the anion exchange column 13 into reaction bottle 1; 18 F- ions are eluted from the anion exchange column 13 into reaction bottle 1;

[0038] S4. Open acetonitrile solution bottle 4 three-way valve, add acetonitrile solution to reaction bottle 1, and 18 F- ions are azeotropically distilled to anhydrous state;

[0039] S5. Open precursor solution bottle 5 three-way valve, add precursor solution to reaction bottle 1, and heat to perform nucleophilic substitution reaction;

[0040] S6. After the reaction is completed, open hydrolysis solution bottle 7 three-way valve, add 1 mL of 3M HCl to reaction bottle 1, and heat to perform hydrolysis reaction;

[0041] S7. After the reaction is completed, open neutralization solution bottle 8 three-way valve, add 1 mL of 3M NaOH to reaction bottle 1, and perform neutralization reaction;

[0042] S8. After the reaction is completed, open first aspirator 6 three-way valve, aspirate the reaction liquid in reaction bottle 1, then aspirate 30 mL of sterile water for injection in first washing liquid bottle 15, and finally push it through first solid phase extraction column 2, and the outflowing liquid enters waste liquid bottle;

[0043] S9. Open three-way valve, use first aspirator 6 to aspirate 10 mL of sterile water for injection in first washing liquid bottle 15, add to reaction bottle 1, aspirate the reaction liquid in reaction bottle 1, and push it through first solid phase extraction column 2, and the outflowing liquid enters waste liquid bottle;

[0044] S10. Open three-way valve, use 3 mL of anhydrous ethanol in first eluent bottle 9 to elute the crude product on first solid phase extraction column 2, and inject it into high performance liquid chromatography inlet 22 connected by main pipeline 24 for further purification;

[0045] S11. The product flows out of high performance liquid chromatography outlet 23 and is collected in transfer liquid bottle 16;

[0046] S12. Open three-way valve, pass the liquid in transfer liquid bottle 16 through second solid phase extraction column 3 three-way tube to waste liquid;

[0047] S13. Open three-way valve, pass sterile water for injection in second washing liquid bottle 19 through second solid phase extraction column 3 to waste liquid;

[0048] S14. The three-way valve is opened and the second eluent bottle 18 (2 mL of 75% ethanol) is passed through the second solid phase extraction column 3, through the three-way tube to the second aspirator 10;

[0049] S15. The three-way valve is opened and the liquid in the ascorbic acid sodium salt saline solution bottle 17 is passed through the second solid phase extraction column 3, through the three-way tube to the second aspirator 10;

[0050] S16. The three-way valve is opened and the product bolus in the second aspirator 10 is transferred through the product bottle connection tube 21 to the product bottle, i.e. the desired F-AV45 product is obtained. 18 F-AV45 product.

[0051] The above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some or all of the technical features can be replaced equivalently; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application, and they should be covered in the scope of the claims and the specification of the present application.

Claims

1. An apparatus for preparing an imaging agent, characterized by, It comprises: a reaction bottle (1); 18 F- ion providing module for providing F- ions into the reaction bottle (1) 18 F- ion solution; A solution providing module for providing a reaction solution into the reaction bottle (1), the reaction solution reacting with the 18 F- ion solution reaction product liquid; a first solid phase extraction column (2) for extracting crude product from the product liquid; a high performance liquid chromatography for purifying the crude product; a preparation module comprising a second solid phase extraction column (3) for preparing the purified product into an imaging agent.

2. The apparatus for preparing an imaging agent according to claim 1, wherein The 18 The F-ion providing module, the solution providing module, the first solid phase extraction column (2), the high performance liquid chromatography and the preparation module are connected in series on a main pipeline (24), and the reaction bottle (1) is communicated with the main pipeline (24) through a connecting pipe.

3. The apparatus for preparing an imaging agent according to claim 2, wherein The 18 The F- ion providing module includes a elution bottle (12), an anion exchange column (13), and a funnel (14). The anion exchange column (13) is arranged on a main pipeline (24). The elution bottle (12) is connected to the anion exchange column (13) through the funnel (14). 18 The F- ions are eluted from the anion exchange column (13) to the reaction bottle (1).

4. The apparatus for preparing an imaging agent according to claim 3, wherein The solution providing module comprises a precursor solution bottle (5), an acetonitrile ampoule (4), a hydrolysis solution bottle (7), a neutralization solution bottle (8), a first eluent bottle (9), and a first washing liquid bottle (15), which are connected in series on the main pipeline (24) in front of the liquid inlet of the first solid phase extraction column (2).

5. The apparatus for preparing an imaging agent according to claim 4, wherein The preparation module further comprises a transfer liquid bottle (16), a second eluent bottle (18), a second washing liquid bottle (19), and a sodium ascorbate normal saline solution bottle (17), which are connected in series on the main pipeline (24) in front of the liquid inlet of the second solid phase extraction column (3).

6. A device for the preparation of imaging agents according to any one of claims 1-5, characterized in that, A decompression pipe (11) is further arranged in the preparation device and communicates with the reaction bottle (1) to balance the air pressure in the reaction bottle (1).

7. The apparatus for preparing an imaging agent according to claim 6, wherein The preparation device further comprises a first and a second suction device, which are connected in series on the main pipeline (24), the first suction device (6) is arranged in front of the liquid inlet of the first solid phase extraction column (2), and the second suction device (10) is arranged behind the liquid outlet of the second solid phase extraction column (3).

8. The apparatus according to claim 7, wherein The preparation device further comprises a waste liquid bottle and a gas filter (20), which are connected in series on the main pipeline (24), the waste liquid bottle is used to collect the waste liquid from the first and second solid phase extraction columns, and the gas filter (20) is used to filter the gas generated in the reaction.

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