Preparation system for preparing multi-nuclide medicine

Abstract

The invention provides a preparation system for preparing a multi-nuclide drug, which comprises four groups of three-way valves connected in series, each group of three-way valves comprises five three-way valves connected in series, the upper end of the first three-way valve of the first group of three-way valves is connected with a cleaning gas branch, and the last three-way valve of the fourth group of three-way valves is connected with a waste liquid bottle. The waste liquid bottle is further connected with a vacuum generator, the upper end of each three-way valve is connected with an external reaction part, and the preparation system further comprises a controller for controlling each three-way valve. The preparation system for preparing the multi-nuclide medicine is suitable for fully automatically collecting, purifying and reacting liquid and gaseous substances in a closed state to generate different nuclide medicines; different synthesis processes can be adapted by utilizing different numbers and rotation modes of the three-way valves.

Description

Technical Field

[0001] The invention belongs to the field of medicine, in particular to the technology of preparing nuclide medicines; in particular, it relates to a preparation system for preparing multi-nuclide medicines. Background Art

[0002] Nuclear medicine refers to medicines containing radioactive isotopes. Using nuclear medicine for the diagnosis and treatment of diseases can comprehensively reflect the genetic, molecular, metabolic and functional status of the disease, and provide earlier insights into the molecular level of the disease, thereby achieving early diagnosis and precise treatment. However, the most important feature of nuclear medicine is that it contains radioactive isotopes that can emit radioactivity of different energies. Artificially synthesized nuclear medicines will be damaged by radiation, so the development of radioactive automated synthesizers is crucial.

[0003] In actual use, 18F-FDG (fluorodeoxyglucose) is used in more than 90% of cases, but because it is a broad-spectrum imaging agent, it is not accurate enough for diagnosing certain cancers. 177 Lu-PSMA-617 (English name Pluvicto) can be used to treat prostate cancer. 68 Ca-DOTATATE (Netspot) can diagnose neuroendocrine tumors. These drug targets are clear and are the focus of current research, but most of the synthetic modules on the market are single-nuclides and single-drug modules with fixed processes, making it difficult to synthesize new drugs. Therefore, developing a module that automatically synthesizes multiple drugs can better meet clinical needs. Summary of the invention

[0004] In order to overcome the defects of the prior art, the present invention discloses a preparation system for preparing multi-nuclide medicines.

[0005] The preparation system for preparing multi-nuclide drugs of the present invention comprises four groups of three-way valves connected in series, each group of three-way valves comprises five three-way valves connected in series, the upper end of the first three-way valve of the first group of three-way valves is connected to a cleaning gas branch, the last three-way valve of the fourth group of three-way valves is connected to a waste liquid bottle, the waste liquid bottle is also connected to a vacuum generator, the upper end of each three-way valve is connected to an external reaction component, and the preparation system also comprises a controller for controlling each three-way valve.

[0006] Preferably, the three-way valves are connected in series via a Luer connector.

[0007] Preferably, the waste liquid bottle is connected to a waste discharge pump.

[0008] Preferably, the cleaning gas branch adopts nitrogen as the cleaning gas, and includes a nitrogen gas source, a pressure reducing valve connected to the nitrogen gas source, and a gas flow meter connected to the pressure reducing valve.

[0009] Preferably, the first group of three-way valves are the first to fifth three-way valves in sequence, the left end of the first three-way valve is connected to the reaction bottle P1, and the upper ends of the second to fifth three-way valves are respectively connected to different raw material bottles; The second group of three-way valves are the sixth to thirteenth-way valves in sequence, wherein the upper end of the sixth three-way valve is connected to the oxygen water recovery bottle, the upper ends of the seventh and eighth three-way valves are connected to the solid phase extraction column, and the upper ends of the ninth and thirteenth three-way valves are connected to the target water transfer bottle and the precursor bottle respectively; The third group of three-way valves are the eleventh to fifteenth three-way valves, wherein the upper ends of the eleventh, twelfth and thirteenth three-way valves are connected to the first syringe, the reaction bottle and the second syringe respectively; the first C-18 column is connected between the upper ends of the fourteenth and fifteenth three-way valves; The fourth group of three-way valves are the sixteenth to twenty-third valves, among which the IC-H column, the neutral aluminum column and the second C-18 column are connected in series between the upper ends of the sixteenth and seventeenth three-way valves, and the upper ends of the eighteenth, nineteenth and twentieth three-way valves are connected to the product bottle, the reaction bottle and the oxygen and water recovery bottle respectively.

[0010] Preferably, the first group of three-way valves are the first to fifth three-way valves, the second group of three-way valves are the sixth to thirteenth three-way valves, and the third group of three-way valves are the eleventh to fifteenth three-way valves; The left end of the first three-way valve is connected to the reaction bottle, the upper end of the second three-way valve is connected to the target water transfer bottle, the upper end of the third three-way valve is closed, and the upper ends of the fourth and fifth three-way valves are respectively connected to different raw material bottles; A solid phase extraction column is connected between the fifth three-way valve and the sixth three-way valve, the upper ends of the sixth and thirteenth three-way valves are connected to the oxygen and water recovery bottle and the reaction bottle respectively, and the upper ends of the seventh to ninth three-way valves are connected to different raw material bottles respectively; the upper ends of the eleventh, fourteenth and fifteenth three-way valves are connected to the third syringe, the product bottle and the reaction bottle respectively, the upper end of the fifteenth three-way valve is also connected to the oxygen and water recovery bottle, and a third C-18 column is connected between the twelfth and thirteenth three-way valves.

[0011] The present invention also discloses a method for preparing 18F-FDG, which adopts the preparation system and comprises the following steps: The reagents are installed as follows before synthesis: the raw material bottle connected to the second three-way valve contains eluent, the raw material bottle connected to the third three-way valve contains acetonitrile, the raw material bottle connected to the fourth three-way valve contains sterile water for injection, and the raw material bottle connected to the fifth three-way valve contains sterile water for injection; The precursor bottle connected to the thirteenth-way valve stores the precursor, the first syringe connected to the eleventh three-way valve contains sterile water for injection, and the second syringe connected to the thirteenth three-way valve contains sodium hydroxide solution; The connection status of each three-way valve during the preparation process is defined as follows: State 1 is the upper left connected state: the upper and left valves are connected, and the right valve is closed; State 2 is the upper and right connected state: the upper and right valves are connected, and the left valve is closed; State 3 is the left-right connection state: the left and right valves are connected, and the upper valve is closed; The status of each three-way valve is assumed to be status 3 unless otherwise described. The specific synthesis method comprises the following steps: S1: Pour the target water into the target water transfer bottle connected to the ninth three-way valve, and turn on the controller to adjust the status of each three-way valve, specifically: The sixth three-way valve is in state 1, the seventh three-way valve is in state 2, the eighth three-way valve is in state 1, the ninth three-way valve is in state 2, and the twenty-third three-way valve is in state 2; the vacuum generator is turned on to provide negative pressure for the oxygen water recovery bottle, and the negative pressure is used as a driving force to make the target water pass through the solid phase extraction column connected to the seventh three-way valve to the oxygen water recovery bottle; S2: Adjust the states of the three-way valves so that the second three-way valve connects the eluent in the raw material bottle to enter the reaction system. The valve states are: the second three-way valve state 2, the seventh three-way valve state 2, the eighth three-way valve state 1, the twelfth three-way valve state 1, and the nineteenth three-way valve state 2. Turn on the vacuum generator to provide negative pressure for the reaction bottle, and the eluent elutes the solid phase extraction column into the reaction bottle; S3: Turn on the heating device of the reaction bottle to remove the remaining acetonitrile in the reaction bottle and the water in the mixed solution; adjust the three-way valve state to: the first three-way valve state 2, the twelfth three-way valve state 1, and the nineteenth three-way valve state 2; Open the cleaning gas branch, and after the cleaning gas enters the reaction bottle through the first three-way valve, the acetonitrile vapor in the bottle is blown into the waste liquid bottle through the corresponding pipeline through the nineteenth three-way valve. This step ends when there is no residual solution in the reaction bottle; S4: The three-way valve states are adjusted to: the third three-way valve state 2, the twelfth three-way valve state 1, the nineteenth three-way valve state 2; the acetonitrile in the raw material bottle connected to the third three-way valve enters the reaction bottle; S5: Turn on the heating device of the reaction bottle to remove the remaining water in the reaction bottle; adjust the three-way valve state to: first three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; adjust the cleaning gas to enter the reaction bottle through the first three-way valve, and then blow the acetonitrile vapor in the bottle through the corresponding pipeline through the nineteenth three-way valve into the waste liquid bottle; when there is no residual solution in the reaction bottle, this step ends; S6: The three-way valve states are adjusted to: 13th-way valve state 1, 12th-way valve state 1, 19th-way valve state 2; the precursor stored in the precursor bottle P7 connected to the 13th-way valve enters the reaction system through the 12th three-way valve, the 19th three-way valve provides a negative pressure state, and the precursor enters the reaction bottle under negative pressure to perform a nucleophilic reaction; S7: The three-way valve states are adjusted to: first three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; Turn on the heating device of the reaction bottle, adjust the cleaning gas to enter the reaction bottle through the first three-way valve, and then blow the acetonitrile vapor in the bottle into the waste liquid bottle through the corresponding pipeline; Then adjust the state of the first three-way valve to state 3, and adjust the state of the fourth three-way valve to state 2, so that the fourth three-way valve is connected to the sterile water for injection stored in the raw material bottle and added to the reaction bottle for dilution.

[0012] S8: The three-way valve states are adjusted to: first three-way valve state 1, twelfth three-way valve state 2, fourteenth three-way valve state 1, fifteenth three-way valve state 2; The liquid in the reaction bottle passes through the first C-18 column to the waste liquid bottle through the fourteenth three-way valve and the fifteenth three-way valve under the pressure of the cleaning gas; S9: the three-way valve states are adjusted to: the thirteenth three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2; The sodium hydroxide solution is introduced into the C-18 column through the syringe connected to the thirteenth three-way valve through the fourteenth and fifteenth three-way valves to perform solid phase alkaline hydrolysis; S10: the three-way valve states are adjusted to: the eleventh three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2, the sixteenth three-way valve state 1, the seventeenth three-way valve state 2, the eighteenth three-way valve state 1; The eleventh three-way valve is connected to the sterile water for injection in the syringe to enter the pipeline, and passes through the twelfth to seventeenth three-way valves, wherein three purification columns in series are connected between the sixteenth and seventeenth three-way valves, which are IC-H column, neutral aluminum column and second C-18 column respectively; finally, it enters the product bottle through the eighteenth three-way valve to obtain 18F-FDG.

[0013] The preparation system for preparing multi-nuclide drugs of the present invention is suitable for fully automatically collecting, purifying and reacting liquid and gaseous substances in a closed state to generate different nuclide drugs; different numbers and rotation modes of three-way valves can be used to adapt to different synthesis processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 A schematic diagram of a specific embodiment of the preparation system of the present invention; Figure 2 It is a schematic diagram of another specific embodiment of the preparation system of the present invention; The reference numerals in the figures are: V1, first three-way valve; V2, second three-way valve; V3, third three-way valve; V4, fourth three-way valve; V5, fifth three-way valve; V6, sixth three-way valve; V7, seventh three-way valve; V8, eighth three-way valve; V9, ninth three-way valve; V10, thirteenth three-way valve; V11, eleventh three-way valve; V12, twelfth three-way valve; V13, thirteenth three-way valve; V14, fourteenth three-way valve; V15, fifteenth three-way valve; V16, sixteenth three-way valve; V17, seventeenth three-way valve; V18, eighteenth three-way valve; V19, nineteenth three-way valve; V20, twenty-third three-way valve; P1, reaction bottle; P2, target water transfer bottle; P3, first syringe; P4, second syringe; P5, first C-18 column; P6, solid phase extraction column; P7, precursor bottle; P8, product bottle; P9, waste liquid bottle; P10, oxygen and water recovery bottle; P11, IC-H column; P12, neutral aluminum column; P13, second C-18 column; P14, third syringe; P15, third C-18 column. DETAILED DESCRIPTION

[0015] The specific implementation modes of the present invention are further described in detail below.

[0016] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely explained below in combination with the specific implementation methods of the present invention and the corresponding drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] The preparation system for preparing multi-nuclide drugs described in the present invention includes four groups of three-way valves connected in series, each group of three-way valves includes five three-way valves connected in series, the upper end of the first three-way valve of the first group is connected to a cleaning gas branch, the last three-way valve of the fourth group of three-way valves is connected to a waste liquid bottle P9, and the waste liquid bottle is also connected to a vacuum generator. The upper end of each three-way valve is connected to an external reaction component, and the external reaction component includes a reaction container, a product container, a reaction raw material storage bottle, a syringe, a reaction column and other reaction components required in the drug preparation process. The preparation system also includes a controller for controlling each three-way valve.

[0018] The three-way valves can be connected in series via Luer connectors, and the waste liquid bottle can be connected to a waste pump to achieve autonomous transfer of waste liquid. Figure 1 In the specific embodiment shown, the cleaning gas branch uses nitrogen as the cleaning gas, including a nitrogen gas source, a pressure reducing valve connected to the nitrogen gas source, and a gas flow meter connected to the pressure reducing valve; the high-pressure nitrogen stored in the nitrogen gas source is reduced in pressure by the pressure reducing valve and then connected to the first three-way valve as the cleaning gas for the entire pipeline system.

[0019] like Figure 1 The figure shows a specific embodiment of the preparation system of the present invention, which is used to prepare 18F-FDG, which is the most commonly used PET imaging agent. It tracks glucose uptake by a single scan to reflect the glucose accumulation level in primary tumor tissue and metastatic lesions. The metabolic parameters obtained are useful indicators of tumor load. Therefore, it is a basic requirement to synthesize 18F-FDG with a multifunctional synthesis module.

[0020] Figure 1 In the specific embodiment shown, the preparation system includes four groups of three-way valves connected in series, each group of three-way valves includes five three-way valves connected in series, the first group of three-way valves are the first to fifth three-way valves in sequence, wherein the upper end of the first three-way valve is connected to a cleaning gas branch, and the left end is connected to the reaction bottle P1, and the upper ends of the second to fifth three-way valves are respectively connected to different raw material bottles; The second group of three-way valves are the sixth to thirteenth-way valves, wherein the upper end of the sixth three-way valve is connected to the oxygen water recovery bottle P10, the upper ends of the seventh and eighth three-way valves are connected to the solid phase extraction column P6, and the upper ends of the ninth and thirteenth three-way valves are connected to the target water transfer bottle P2 and the precursor bottle P7 respectively; The third group of three-way valves are the eleventh to fifteenth three-way valves, wherein the upper ends of the eleventh, twelfth and thirteenth three-way valves are connected to the first syringe P3, the reaction bottle P1 and the second syringe P4 respectively; the first C-18 column P5 is connected between the upper ends of the fourteenth and fifteenth three-way valves; The fourth group of three-way valves includes the sixteenth to twenty-third way valves, wherein the IC-H column P11, the neutral aluminum column P12 and the second C-18 column P13 are connected in series between the upper ends of the sixteenth and seventeenth three-way valves, the upper ends of the eighteenth, nineteenth and twentieth three-way valves are connected to the product bottle P8, the reaction bottle P1 and the oxygen and water recovery bottle P10 respectively, and the right end of the twenty-third way valve is also connected to a waste liquid bottle, and the waste liquid bottle is also connected to a vacuum generator.

[0021] Figure 1 The specific implementation shown is a process diagram for synthesizing 18F-FDG using the preparation system of the present invention. For ease of understanding and description, the connection status of each three-way valve in the following steps is defined as follows: State 1 is the upper left connected state: the upper and left valves are connected, and the right valve is closed; State 2 is the upper and right connected state: the upper and right valves are connected, and the left valve is closed; State 3 is the left-right connection state: the left and right valves are connected, and the upper valve is closed; Unless otherwise described, the status of each three-way valve defaults to status 3, and the status of each three-way valve is controlled by the controller.

[0022] The reagents are installed as follows before synthesis: the raw material bottle connected to the second three-way valve contains 2 ml of eluent, specifically a mixed solution of cryptand potassium carbonate, the raw material bottle connected to the third three-way valve contains 2.4 ml of acetonitrile, the raw material bottle connected to the fourth three-way valve contains 8 ml of sterile water for injection, and the raw material bottle connected to the fifth three-way valve contains 8 ml of sterile water for injection; The precursor bottle P7 connected to the thirteenth-way valve contains 1.6 ml of acetonitrile solution of trifluoromannose as a precursor, the first syringe P3 connected to the eleventh three-way valve contains 12 ml of sterile water for injection, and the second syringe P4 connected to the thirteenth three-way valve contains 1.5 ml of 2 mol / L sodium hydroxide solution.

[0023] The specific synthesis method comprises the following steps: S1: Transfer the target water produced by the medical cyclotron to the target water transfer bottle connected to the ninth three-way valve. Start the automatic synthesis program and adjust the status of each three-way valve, specifically: The sixth three-way valve state 1, the seventh three-way valve state 2, the eighth three-way valve state 1, the ninth three-way valve state 2, the twenty-third valve state 2; turn on the vacuum generator to provide negative pressure for the oxygen and water recovery bottle, and use the negative pressure as a driving force to make the target water pass through the solid phase extraction column QMA connected to the seventh three-way valve to the oxygen and water recovery bottle.

[0024] S2: Adjust the status of each three-way valve so that the second three-way valve connects the eluent in the raw material bottle to enter the reaction system. Valve status: second three-way valve state 2, seventh three-way valve state 2, eighth three-way valve state 1, twelfth three-way valve state 1, nineteenth three-way valve state 2. Turn on the vacuum generator to provide negative pressure for the reaction bottle, and the eluent elutes the solid phase extraction column and enters the reaction system.

[0025] S3: Turn on the heating device of the reaction bottle, which is usually a solid heating device such as an electric heating wire, so that the acetonitrile that may remain in the reaction bottle from the previous reaction is azeotropically removed with the water in the mixed solution; the three-way valve state is adjusted to: the first three-way valve state 2, the twelfth three-way valve state 1, the nineteenth three-way valve state 2; after the nitrogen enters the reaction bottle through the first three-way valve, the acetonitrile vapor in the bottle is blown into the waste liquid bottle through the corresponding pipeline through the nineteenth three-way valve. When there is no residual solution in the reaction bottle, this step ends.

[0026] S4: The three-way valve states are adjusted to: third three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; the acetonitrile in the raw material bottle connected to the third three-way valve enters the reaction bottle.

[0027] S5: Turn on the heating device of the reaction bottle, so that the acetonitrile that may remain in the reaction bottle is azeotropically removed with the water in the mixed solution; the three-way valve state is adjusted to: the first three-way valve state 2, the twelfth three-way valve state 1, the nineteenth three-way valve state 2; after adjusting the nitrogen to enter the reaction bottle through the first three-way valve, the acetonitrile vapor in the bottle is blown into the waste liquid bottle through the corresponding pipeline through the nineteenth three-way valve. After there is no residual solution in the reaction bottle, this step ends. After adding acetonitrile in S4, it is miscible with water and increases the volatilization rate. The water is blown out again, which can achieve further removal of residual water and avoid residual water affecting the nucleophilic reaction.

[0028] S6: The three-way valve states are adjusted to: thirteenth-way valve state 1, twelfth three-way valve state 1, nineteenth three-way valve state 2; the precursor stored in the precursor bottle P7 connected to the thirteenth-way valve enters the reaction system through the twelfth three-way valve, and the nineteenth three-way valve provides a negative pressure state, and the precursor enters the reaction bottle under negative pressure for nucleophilic reaction.

[0029] S7: The three-way valve states are adjusted to: first three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; Turn on the heating device of the reaction bottle, adjust the nitrogen to enter the reaction bottle through the first three-way valve, and then blow the acetonitrile vapor in the bottle into the waste liquid bottle through the corresponding pipeline. Then adjust the state of the fourth three-way valve to state 2, so that the fourth three-way valve is connected to the sterile water for injection stored in the raw material bottle and added to the reaction bottle for dilution.

[0030] S8: The three-way valve states are adjusted to: first three-way valve state 1, twelfth three-way valve state 2, fourteenth three-way valve state 1, fifteenth three-way valve state 2; After the nucleophilic reaction, the reaction bottle contains fat-soluble intermediates, water-soluble precursor trifluoromannose, cryptand and other components; under positive and negative pressure, the liquid in the reaction bottle passes through the fourteenth three-way valve and the fifteenth three-way valve under the pressure of the cleaning gas through the first C-18 column to the waste liquid bottle. The C-18 column is a reverse hydrophobic column that can effectively capture the intermediates.

[0031] S9: the three-way valve states are adjusted to: the thirteenth three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2; The sodium hydroxide solution is introduced into the C-18 column through the syringe connected to the thirteenth three-way valve through the fourteenth and fifteenth three-way valves for solid phase alkaline hydrolysis.

[0032] S10: the three-way valve states are adjusted to: the eleventh three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2, the sixteenth three-way valve state 1, the seventeenth three-way valve state 2, the eighteenth three-way valve state 1; The eleventh three-way valve is connected to the sterile water for injection in the syringe and enters the pipeline, and passes through the twelfth to seventeenth three-way valves, wherein three purification columns are connected in series between the sixteenth and seventeenth three-way valves, which are the ion exchange column IC-H column for neutralizing the Ph value, the neutral aluminum column for adsorbing free fluoride ions, and the second C-18 column for adsorbing intermediates; finally, it enters the product bottle through the eighteenth three-way valve to obtain 18F-FDG. like Figure 2 The preparation system of the present invention is shown in FIG. 18 A specific implementation of F-PSMA-11, at this time, all three-way valves in the fourth three-way valve group are in state 3, that is, a straight-through pipeline is formed. Figure 2 The three-way valve inside the fourth three-way valve is not specifically drawn.

[0034] As shown in Figure 2, the left end and the upper end of the first three-way valve are respectively connected to the reaction bottle P1 and the cleaning gas branch, the upper end of the second three-way valve is connected to the target water transfer bottle P2, the upper end of the third three-way valve is closed, the upper ends of the fourth and fifth three-way valves are respectively connected to different raw material bottles, a solid phase extraction column P6 is connected between the fifth three-way valve and the sixth three-way valve, the upper ends of the sixth and thirteenth three-way valves are respectively connected to the oxygen and water recovery bottle P10 and the reaction bottle, and the upper ends of the seventh to ninth three-way valves are respectively connected to different raw material bottles; the upper ends of the eleventh, fourteenth and fifteenth three-way valves are respectively connected to the third syringe P14, the product bottle P8 and the reaction bottle P1, the upper end of the fifteenth three-way valve is also connected to the oxygen and water recovery bottle P10, and the third C-18 column P15 is connected between the twelfth and thirteenth three-way valves.

[0035] Before synthesis, the reagents in each raw material bottle and syringe were installed as follows: the raw material bottle connected to the fourth three-way valve was 8 ml of sterile water for injection, the raw material bottle connected to the fifth three-way valve was 1.8 ml of acetic acid buffer as eluent, the raw material bottle connected to the seventh three-way valve was 0.8 ml of PSMA-11 ethanol solution, the raw material bottle connected to the eighth three-way valve was 8 ml of sterile water for injection, the raw material bottle connected to the ninth three-way valve was 8 ml of sterile water for injection, and the third syringe connected to the eleventh three-way valve contained 2 ml of 50% ethanol solution.

[0036] The preparation process can be briefly described as: S21. The reaction bottle is pre-filled with 10 μL of aluminum chloride solution, the product bottle is pre-filled with 9 mL of physiological saline, the vacuum generator is turned on, the target water is filled into the target water transfer bottle P2, and the target water is connected to the second three-way valve. The 18F- in the target water is captured by the solid phase extraction column (QMA) P6; S22. Using the injection water in the raw material bottle connected to the fourth three-way valve to clean the metal ions in the solid phase extraction column; S23. The fluorine-18 isotope captured on the solid phase extraction column is eluted into the reaction bottle using the eluent in the raw material bottle connected to the fifth three-way valve, and incubated with 10 μl of aluminum chloride solution pre-filled in the reaction bottle at room temperature for 3 minutes; S24. Add the precursor solution in the raw material bottle connected to the seventh three-way valve to the reaction bottle and incubate at room temperature for 10 minutes; S25. After adding sterile water for injection from the raw material bottle connected to the eighth three-way valve into the reaction bottle for dilution, the liquid in the raw material bottle was transferred to the third C-18 column; S26. Wash the reaction flask and the third C-18 column using the washing water in the raw material bottle connected to the eighth three-way valve; S27. The liquid in the third C-18 column is transferred to a product bottle pre-filled with 9 mL of saline solution using a third syringe P11 connected to the eleventh three-way valve. Since the ethanol injection limit for human body cannot exceed 10%, this step needs to ensure that the ethanol content is not higher than 10%, and Al is prepared. 18 F-PSMA-11.

[0037] The technical principle in the above preparation process is the preparation of Al 18 In the prior art of F-PSMA-11, the control method of each three-way valve refers to the specific embodiment 1, and the state of the three-way valve is adjusted to implement steps S21 to S27.

[0038] The preparation system for preparing multi-nuclide drugs of the present invention is suitable for collecting, purifying and reacting liquid and gaseous substances in a closed state in a fully automated manner to generate different nuclide drugs; different numbers of three-way valves and different rotation modes can be used to adapt to different synthesis processes; and disposable connectors and ferrules can be used to achieve one-time replacement during synthesis to avoid cross-contamination of synthesized drugs.

[0039] The foregoing describes various preferred embodiments of the present invention. Unless the preferred implementation modes in various preferred embodiments are obviously self-contradictory or based on a certain preferred implementation mode, various preferred implementation modes can be arbitrarily superimposed and used in combination. The embodiments and specific parameters in the embodiments are only for clearly describing the invention verification process of the inventor, and are not used to limit the patent protection scope of the present invention. The patent protection scope of the present invention shall still be based on its claims. All equivalent structural changes made using the contents of the description and drawings of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation system for preparing a multi-nuclide drug, characterized in that: The invention comprises four groups of three-way valves connected in series, each group of three-way valves comprises five three-way valves connected in series, the upper end of the first three-way valve of the first group of three-way valves is connected to a cleaning gas branch, the last three-way valve of the fourth group of three-way valves is connected to a waste liquid bottle, the waste liquid bottle is also connected to a vacuum generator, the upper end of each three-way valve is connected to an external reaction component, and the preparation system also comprises a controller for controlling each three-way valve.

2. The preparation system according to claim 1, characterized in that: The three-way valves are connected in series via a Luer connector.

3. The preparation system according to claim 1, characterized in that: The waste liquid bottle is connected with a waste discharge pump.

4. The preparation system according to claim 1, characterized in that: The cleaning gas branch adopts nitrogen as the cleaning gas, and comprises a nitrogen gas source, a pressure reducing valve connected to the nitrogen gas source, and a gas flow meter connected to the pressure reducing valve.

5. The preparation system according to any one of claims 1 to 4, characterized in that: The first group of three-way valves are the first to fifth three-way valves in sequence, the left end of the first three-way valve is connected to the reaction bottle P1, and the upper ends of the second to fifth three-way valves are connected to different raw material bottles respectively; The second group of three-way valves are the sixth to thirteenth-way valves, wherein the upper end of the sixth three-way valve is connected to the oxygen water recovery bottle (P10), the upper ends of the seventh and eighth three-way valves are connected to the solid phase extraction column (P6), and the upper ends of the ninth and thirteenth three-way valves are connected to the target water transfer bottle (P2) and the precursor bottle (P7), respectively. The third group of three-way valves are the eleventh to fifteenth three-way valves, wherein the upper ends of the eleventh, twelfth and thirteenth three-way valves are respectively connected to the first syringe (P3), the reaction bottle (P1) and the second syringe (P4); the first C-18 column (P5) is connected between the upper ends of the fourteenth and fifteenth three-way valves; The fourth group of three-way valves includes the sixteenth to twenty-third way valves, wherein the upper ends of the sixteenth and seventeenth three-way valves are connected in series with an IC-H column (P11), a neutral aluminum column (P12) and a second C-18 column (P13), and the upper ends of the eighteenth, nineteenth and twentieth three-way valves are connected to a product bottle (P8), a reaction bottle (P1) and an oxygen and water recovery bottle (P10), respectively.

6. The preparation system according to any one of claims 1 to 4, characterized in that: The first group of three-way valves are the first to fifth three-way valves, the second group of three-way valves are the sixth to thirteenth three-way valves, and the third group of three-way valves are the eleventh to fifteenth three-way valves; The left end of the first three-way valve is connected to the reaction bottle (P1), the upper end of the second three-way valve is connected to the target water transfer bottle (P2), the upper end of the third three-way valve is closed, and the upper ends of the fourth and fifth three-way valves are respectively connected to different raw material bottles; A solid phase extraction column (P6) is connected between the fifth three-way valve and the sixth three-way valve; the upper ends of the sixth and thirteenth three-way valves are respectively connected to an oxygen and water recovery bottle (P10) and a reaction bottle (P1); the upper ends of the seventh to ninth three-way valves are respectively connected to different raw material bottles; the upper ends of the eleventh, fourteenth and fifteenth three-way valves are respectively connected to a third syringe (P14), a product bottle (P8) and a reaction bottle (P1); the upper end of the fifteenth three-way valve is also connected to the oxygen and water recovery bottle (P10); and a third C-18 column (P15) is connected between the twelfth and thirteenth three-way valves.

7. A method for preparing 18F-FDG, characterized in that: The preparation system as claimed in claim 5 comprises the following steps: The reagents are installed as follows before synthesis: the raw material bottle connected to the second three-way valve contains eluent, the raw material bottle connected to the third three-way valve contains acetonitrile, the raw material bottle connected to the fourth three-way valve contains sterile water for injection, and the raw material bottle connected to the fifth three-way valve contains sterile water for injection; The precursor bottle connected to the thirteenth-way valve stores the precursor, the first syringe connected to the eleventh three-way valve contains sterile water for injection, and the second syringe connected to the thirteenth three-way valve contains sodium hydroxide solution; The connection status of each three-way valve during the preparation process is defined as follows: State 1 is the upper left connected state: the upper and left valves are connected, and the right valve is closed; State 2 is the upper and right connected state: the upper and right valves are connected, and the left valve is closed; State 3 is the left-right connection state: the left and right valves are connected, and the upper valve is closed; The status of each three-way valve is assumed to be status 3 unless otherwise described. The specific synthesis method comprises the following steps: S1: Pour the target water into the target water transfer bottle connected to the ninth three-way valve, and turn on the controller to adjust the status of each three-way valve, specifically: The sixth three-way valve is in state 1, the seventh three-way valve is in state 2, the eighth three-way valve is in state 1, the ninth three-way valve is in state 2, and the twenty-third three-way valve is in state 2; the vacuum generator is turned on to provide negative pressure for the oxygen water recovery bottle, and the negative pressure is used as a driving force to make the target water pass through the solid phase extraction column connected to the seventh three-way valve to the oxygen water recovery bottle; S2: Adjust the states of the three-way valves so that the second three-way valve connects the eluent in the raw material bottle to enter the reaction system. The valve states are: the second three-way valve state 2, the seventh three-way valve state 2, the eighth three-way valve state 1, the twelfth three-way valve state 1, and the nineteenth three-way valve state 2. Turn on the vacuum generator to provide negative pressure for the reaction bottle, and the eluent elutes the solid phase extraction column and enters the reaction bottle; S3: Turn on the heating device of the reaction bottle to remove the remaining acetonitrile in the reaction bottle and the water in the mixed solution; adjust the three-way valve state to: the first three-way valve state 2, the twelfth three-way valve state 1, and the nineteenth three-way valve state 2; Open the cleaning gas branch, and after the cleaning gas enters the reaction bottle through the first three-way valve, the acetonitrile vapor in the bottle is blown into the waste liquid bottle through the corresponding pipeline through the nineteenth three-way valve. This step ends when there is no residual solution in the reaction bottle; S4: The three-way valve states are adjusted to: the third three-way valve state 2, the twelfth three-way valve state 1, the nineteenth three-way valve state 2; the acetonitrile in the raw material bottle connected to the third three-way valve enters the reaction bottle; S5: Turn on the heating device of the reaction bottle to remove the remaining water in the reaction bottle; adjust the three-way valve state to: first three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; adjust the cleaning gas to enter the reaction bottle through the first three-way valve, and then blow the acetonitrile vapor in the bottle through the corresponding pipeline through the nineteenth three-way valve into the waste liquid bottle; when there is no residual solution in the reaction bottle, this step ends; S6: The three-way valve states are adjusted to: 13th-way valve state 1, 12th-way valve state 1, 19th-way valve state 2; the precursor stored in the precursor bottle P7 connected to the 13th-way valve enters the reaction system through the 12th three-way valve, the 19th three-way valve provides a negative pressure state, and the precursor enters the reaction bottle under negative pressure to perform a nucleophilic reaction; S7: The three-way valve states are adjusted to: first three-way valve state 2, twelfth three-way valve state 1, nineteenth three-way valve state 2; Turn on the heating device of the reaction bottle, adjust the cleaning gas to enter the reaction bottle through the first three-way valve, and then blow the acetonitrile vapor in the bottle into the waste liquid bottle through the corresponding pipeline; Then adjust the state of the first three-way valve to state 3, and the state of the fourth three-way valve to state 2, so that the fourth three-way valve is connected to the sterile injection water stored in the raw material bottle and added to the reaction bottle for dilution; S8: The three-way valve states are adjusted to: first three-way valve state 1, twelfth three-way valve state 2, fourteenth three-way valve state 1, fifteenth three-way valve state 2; The liquid in the reaction bottle passes through the first C-18 column to the waste liquid bottle through the fourteenth three-way valve and the fifteenth three-way valve under the pressure of the cleaning gas; S9: the three-way valve states are adjusted to: the thirteenth three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2; The sodium hydroxide solution is introduced into the C-18 column through the syringe connected to the thirteenth three-way valve through the fourteenth and fifteenth three-way valves to perform solid phase alkaline hydrolysis; S10: the three-way valve states are adjusted to: the eleventh three-way valve state 2, the fourteenth three-way valve state 1, the fifteenth three-way valve state 2, the sixteenth three-way valve state 1, the seventeenth three-way valve state 2, the eighteenth three-way valve state 1; The eleventh three-way valve is connected to the sterile water for injection in the syringe to enter the pipeline, and passes through the twelfth to seventeenth three-way valves, wherein three purification columns in series are connected between the sixteenth and seventeenth three-way valves, which are IC-H column, neutral aluminum column and second C-18 column respectively; finally, it enters the product bottle through the eighteenth three-way valve to obtain 18F-FDG.

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