Microfluidics-based radiopharmaceutical labeling automation device and method

Abstract

The invention relates to the technical field of radiopharmaceutical labeling, and provides a microfluidics-based radiopharmaceutical labeling automation device and method, and the microfluidics-based radiopharmaceutical labeling automation device comprises a plurality of reactant sample injectors; the micro-channel reactor is connected with the plurality of reactant sample injectors; the purification column is connected with the micro-channel reactor; the plurality of leacheate sample injectors are connected with the purification column; the effluent liquid storage tank is connected with the purification column; the leacheate storage tank is connected with the purification column; the two-way valve is arranged on the pipeline between the microchannel reactor and the purification column and is used for switching the flow direction of the flow path; the intermediate product liquid storage tank is connected with one outlet of the two-way valve; the control system is electrically connected with the reactant sample injector, the leacheate sample injector, the two-way valve, the intermediate product driving pump and the micro-channel reactor. Liquid is accurately controlled through the control system, physical isolation of radioactive operation and personnel operation is achieved, efficient diffusion mixing is achieved through the micro-flow control technology, and the reaction rate is increased.

Description

Technical Field

[0001] This application relates to the field of radiopharmaceutical labeling technology, and more specifically, to an automated device and method for radiopharmaceutical labeling based on microfluidics. Background Technology

[0002] Currently, traditional radiopharmaceutical labeling processes are typically performed manually in sterile chambers using batch reactors. This presents two major technical challenges: first, ensuring sterility and pyrogen-free operation relies on manual operation and complex environmental control, making personnel intervention highly susceptible to contamination and cumbersome; second, batch reactors suffer from low mass and heat transfer efficiency, resulting in uneven reactant mixing and poor temperature control precision, leading to lengthy labeling reactions. During this process, operators must handle highly active radionuclides at close range, significantly increasing their radiation exposure risk. To mitigate this risk, heavy lead shielding and intermittent operation are often employed, severely limiting labeling efficiency and consistency, and failing to meet the requirements of short-half-life radiopharmaceuticals for efficient, automated, and intrinsically safe labeling processes. Summary of the Invention

[0003] This application aims to at least address the technical problems in the related art, where traditional radiopharmaceutical labeling processes are usually operated manually in sterile rooms using batch reactors, resulting in inaccurate control during preparation, slow reaction rates, and the risk of damage to operators from radioactive rays generated during the decay of radionuclides.

[0004] To solve the above-mentioned technical problems, this application is implemented as follows:

[0005] In a first aspect, this application provides an automated radiopharmaceutical labeling device based on microfluidics, comprising: multiple reactant injectors for storing and delivering reactants; a microchannel reactor, the inlet of which is connected to the outlet of the multiple reactant injectors via tubing, for mixing multiple reactants therein and performing a labeling reaction; a purification column, the inlet of which is connected to the outlet of the microchannel reactor via tubing, for separating and purifying the mixture after the reaction; multiple eluent injectors, the outlets of which are connected to the inlet of the purification column via tubing, for delivering eluent; an effluent reservoir, the inlet of which is connected to the outlet of the purification column via tubing, for collecting the effluent; and eluent. The system includes: a reservoir for collecting the target product eluted from the purification column; a two-way valve for switching the flow path between the microchannel reactor and the purification column; an intermediate product reservoir for temporarily storing intermediate products in the multi-step reaction; and a control system for controlling the flow rates of the reactants and eluent, switching the flow path, and controlling the reaction temperature of the microchannel reactor. The reservoir is connected to one outlet of the two-way valve via a pipeline.

[0006] The automated radiopharmaceutical labeling device based on microfluidics provided in this application, through the collaborative design of an integrated microfluidic module and a remote control system, features multiple reactant injectors connected in parallel at the inlet of a microchannel reactor and multiple eluent injectors connected in parallel at the inlet of a purification column. This allows all fluids to achieve efficient diffusion mixing within the micron-level channels through laminar flow, resulting in an order-of-magnitude improvement in mass transfer efficiency and completely solving the problem of uneven mixing in traditional batch reactors. Furthermore, the automated radiopharmaceutical labeling device integrates a bidirectional valve and an intermediate product storage tank. By switching the valve position, the fluid path can be flexibly configured to achieve automated continuous execution of one-step, non-sequential or multi-step sequential reactions. Additionally, the microchannel reactor integrates a precision temperature control component, whose ultra-large specific surface area improves the device's thermal response speed and ensures high temperature control accuracy. Moreover, all liquid path drive components, flow path switching components, and reaction components can be housed within a shielded enclosure, connected to the external control system only via electrical signals, achieving physical isolation between radioactive operation and human operation. This device eliminates the pollution risks and radiation exposure problems caused by human operation in traditional processes, and solves the problems of low efficiency, poor flexibility and insufficient safety in radiopharmaceutical labeling.

[0007] Secondly, this application proposes an automated method for radiopharmaceutical labeling based on microfluidics, employing the automated microfluidic radiopharmaceutical labeling device described above. The automated method includes: adding reactants and eluent to a reactant reservoir and an eluent reservoir, respectively; setting the flow rate of the reactant-driven pump and the reaction temperature of the microchannel reactor through a control system; when there is no specific reaction sequence requirement for the reactants, controlling a two-way valve to direct the flow path to the purification column, starting the reactant-driven pumps of multiple reactant injectors, delivering multiple reactants to the microchannel reactor for mixing and reaction to generate a labeled compound, and then... The mixture is transported to the purification column for separation and purification. When the reaction sequence of reactants is required, the two-way valve is controlled to direct the flow path to the intermediate product reservoir. The reactant drive pump of the preceding reactant injector is started to transport the reactants to the microchannel reactor for reaction. The generated intermediate product is temporarily stored in the intermediate product reservoir. The reactant drive pump of the subsequent reactant injector and the intermediate product drive pump are started to transport the intermediate product and subsequent reactants to the microchannel reactor for the next reaction. After the final reaction is completed, the two-way valve is controlled to switch the flow direction so that the final product enters the purification column for separation and purification. The purification column is eluted by starting the eluent drive pump of the eluent injector.

[0008] The automated radiopharmaceutical labeling method based on microfluidics provided in this application has all the beneficial effects of the automated radiopharmaceutical labeling device based on microfluidics in the above technical solution, and will not be repeated here.

[0009] Additional aspects and advantages of this application will become apparent in the following description or may be learned by practice of this application. Attached Figure Description

[0010] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0011] Figure 1 This is a schematic diagram of the structure of an automated radiopharmaceutical labeling device based on microfluidics according to an embodiment of this application;

[0012] Figure 2 This is a flowchart of an embodiment of the automated radiopharmaceutical labeling method based on microfluidics according to this application.

[0013] in, Figure 1 The correspondence between the reference numerals and component names in the attached drawings is as follows:

[0014] 100 Microfluidic automated radiopharmaceutical labeling device, 110 Reactant injector, 112 Reactant reservoir, 114 Reactant drive pump, 116 Reactant tubing, 120 Microchannel reactor, 122 Microreaction channel, 124 Microreactor inlet, 126 Temperature control component, 130 Purification column, 140 Eluent injector, 142 Eluent reservoir, 144 Eluent drive pump, 146 Eluent tubing, 150 Effluent reservoir, 160 Eluent reservoir, 170 Two-way valve, 180 Intermediate product reservoir, 182 Intermediate product drive pump, 190 Control system. Detailed Implementation

[0015] To better understand the above-mentioned objectives, features, and advantages of this application, the application will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be combined with each other.

[0016] Many specific details are set forth in the following description in order to provide a full understanding of this application. However, this application may also be implemented in other ways different from those described herein. Therefore, the scope of protection of this application is not limited to the specific embodiments disclosed below.

[0017] The following reference Figure 1 and Figure 2 This application describes a microfluidic-based automated radiopharmaceutical labeling apparatus 100 and a microfluidic-based automated radiopharmaceutical labeling method provided according to some embodiments of the present application.

[0018] like Figure 1 and Figure 2 As shown, Figure 1 This is a schematic diagram of the structure of an automated radiopharmaceutical labeling device 100 based on microfluidics according to an embodiment of this application; Figure 2 This is a flowchart of an embodiment of the automated radiopharmaceutical labeling method based on microfluidics according to this application.

[0019] According to the first aspect of this application, Figure 1As shown, one embodiment of this application provides an automated radiopharmaceutical labeling device 100 based on microfluidics, comprising: multiple reactant injectors 110 for storing and transporting reactants; a microchannel reactor 120, the inlet of which is connected to the outlet of the multiple reactant injectors 110 via a pipeline, for mixing multiple reactants therein and performing a labeling reaction; a purification column 130, the inlet of which is connected to the outlet of the microchannel reactor 120 via a pipeline, for separating and purifying the mixture after the reaction; multiple eluent injectors 140, the outlet of which is connected to the inlet of the purification column 130 via a pipeline, for transporting eluent; an effluent reservoir 150, the inlet of which is connected to the outlet of the purification column 130 via a pipeline, for collecting effluent; and an eluent reservoir 160, for collecting eluent. The inlet of the washing solution reservoir 160 is connected to the outlet of the purification column 130 via a pipeline, and is used to collect the target product eluted from the purification column 130; the two-way valve 170 is located on the pipeline between the microchannel reactor 120 and the purification column 130, and is used to switch the flow direction; the intermediate product reservoir 180 and the intermediate product drive pump 182 are located on the pipeline between the outlet of the intermediate product reservoir 180 and the microchannel reactor 120; the control system 190 is electrically connected to the reactant injector 110, the eluent injector 140, the two-way valve 170, the intermediate product drive pump 182, and the microchannel reactor 120, and is used to control the flow rate of the reactants and eluent, the switching of the flow path, and the reaction temperature of the microchannel reactor 120.

[0020] Specifically, such as Figure 1As shown, the microfluidic-based automated radiopharmaceutical labeling device 100 includes multiple reactant injectors 110, a microchannel reactor 120, a purification column 130, multiple eluent injectors 140, an effluent reservoir 150, an eluent reservoir 160, a two-way valve 170, an intermediate product reservoir 180, an intermediate product drive pump 182, and a control system 190. Multiple reactant injectors 110 are used to store and transport reactants. The inlet of the microchannel reactor 120 is connected to the outlet of the multiple reactant injectors 110 via a pipeline, allowing multiple reactants to be mixed and labeled in the microchannel reactor 120. The inlet of the purification column 130 is connected to the outlet of the microchannel reactor 120 via a pipeline, used to separate and purify the mixture after the reaction. The outlets of multiple eluent injectors 140 are connected to the inlet of the purification column 130 via a pipeline, used to supply eluent to the purification column 130. The inlet of the effluent reservoir 150 is connected to the outlet of the purification column 130 via a pipeline, used to collect the effluent. The inlet of the eluent reservoir 160 is connected to the outlet of the purification column 130 via a pipeline. The system has an end connection for collecting the target product eluted from the purification column 130. A two-way valve 170 is installed on the pipeline between the microchannel reactor 120 and the purification column 130 to switch the flow direction. The inlet of the intermediate product reservoir 180 is connected to one outlet of the two-way valve 170 through a pipeline to temporarily store intermediate products in the multi-step reaction. An intermediate product drive pump 182 is installed on the pipeline between the outlet of the intermediate product reservoir 180 and the microchannel reactor 120. The control system 190 is electrically connected to the reactant injector 110, the eluent injector 140, the two-way valve 170, the intermediate product reservoir 180, and the microchannel reactor 120 to control the flow rate of the reactants and eluent, the switching of the flow path, and the reaction temperature of the microchannel reactor 120.

[0021] Specifically, for example, such as Figure 1 As shown, there are multiple reactant injectors 110, which can be specifically set to 1 to N, such as reactant injectors 1 to reactant injectors N, used to store different reactants. There are multiple eluent injectors 140, which can be specifically set to 1 to N, such as eluent injectors 1 to eluent injectors N, used to store different eluents.

[0022] When there are N reactants and no specific reaction order is required, the control system 190 switches the two-way valve 170 to allow the reaction mixture to flow to the purification column 130. The N reactants are added to the reactant reservoirs 112 in reactant injectors 1 to N, respectively. The control system 190 opens each reactant drive pump 114 in the multiple reactant injectors 110, allowing the N reactants to mix in the microchannel reactor 120 through the reactant pipeline 116. The control system 190 adjusts the flow rate of each reactant drive pump 114 and the reaction temperature of the microchannel reactor 120, so that the various reactants react in the microchannel reactor 120 at a certain speed and temperature. The radiolabeled compound formed after the reaction is completed is sent to the purification column 130, where the free radionuclides and the labeled radiopharmaceuticals are separated.

[0023] When the N reactants react sequentially, the bidirectional valve 170 is switched via the control system 190 to return the reaction mixture to the microreactor inlet 124. The first X reactant injectors 110 are opened via the control system 190. After the reaction is complete, the first X reaction products enter the intermediate product storage tank 180. The pump 182 for the next Y reactants and intermediate products is opened via the control system 190 to complete the second stage reaction. This process is repeated for N reactions with different reaction sequences. When the final product reaction is underway, the bidirectional valve 170 is opened to allow the final product to enter the purification column 130 for purification.

[0024] When the purification column 130 adsorbs labeled free radionuclides, the labeled product passes through the purification column 130 and enters the effluent reservoir 150, completing the purification of the radiolabeled drug. Specifically, the eluent drive pump 144 of the eluent injector 140 is turned on by the control system 190, and the free radionuclides on the purification column 130 are eluted with eluent to complete the recovery of the radionuclides. When the purification column 130 adsorbs labeled radiopharmaceuticals, the radiopharmaceuticals are adsorbed on the purification column 130, and the unlabeled free radionuclides pass through the purification column 130 and enter the effluent reservoir 150 for recovery. The eluent drive pump 144 of the eluent injector 140 is turned on by the control system 190, and the radiopharmaceuticals on the purification column 130 are eluted into the eluent reservoir 160 using reagents such as ethanol.

[0025] When there are N types of eluents, the different eluents are loaded into eluent injectors 1 to N in sequence. The eluent drive pump 144 of eluent injector 1 is turned on to eluent the purification column 130. After the rinsing is completed, the eluent drive pump 144 of the subsequent eluent injectors 140 is turned on in sequence to complete the rinsing of N types of eluents.

[0026] Compared with existing technologies, the automated radiopharmaceutical labeling device 100 based on microfluidics provided in this application has the following advantages: It uses a microchannel reactor 120 instead of a traditional batch reactor, allowing for continuous flow and reaction of the solution within the microchannel reactor 120, increasing the automation level of the device. Furthermore, reactants and labeled substances can be mixed more uniformly in the microchannels, resulting in a higher reaction rate at the microscale. The micro-reaction channels 122 of the microchannel reactor 120 have a temperature control system, i.e., a temperature control component 126, which has faster heat transfer efficiency compared to a batch reactor, allowing for more precise temperature control. In addition, the automated radiopharmaceutical labeling device 100 based on microfluidics has a wide range of applications, suitable for process systems involving single or multiple reactants and single or multiple purified eluents in drug labeling. Moreover, the automated radiopharmaceutical labeling device 100 based on microfluidics is mainly driven by pumps, and the control of all pumps can be externally connected to the control system 190, achieving isolation between operation and the reaction system, effectively reducing the dose to personnel. The automated radiopharmaceutical labeling device 100 based on microfluidics provided in this application introduces microfluidics technology into radiopharmaceutical labeling, enabling the labeling process to take place in a microchannel reactor 120. This device allows for automated continuous flow reactions, and the control system 190 can be isolated from the operating system, thereby avoiding bacterial contamination and reducing the radiation dose to personnel during the radiopharmaceutical labeling process.

[0027] Specifically, drug labeling currently refers to the identification and tracking of drugs using specific markers or technologies for research, monitoring, and use. Drug labeling includes radionuclide labeling, fluorescent tracer labeling, and biotin labeling. Radiolabeled compounds are products obtained by replacing one or more atoms or chemical groups in a compound with their easily identifiable radioisotopes or other easily identifiable radionuclides. In medicine, radionuclides can only be used directly for diagnosis, treatment, or research in a few cases; in most cases, radionuclides must be converted into labeled compounds before they can be used as radiopharmaceuticals or tracers. The process of radiopharmaceutical labeling typically includes solution preparation, radionuclide labeling reaction, and marker purification. Because radiopharmaceuticals generally require sterility and pyrogen-free conditions during preparation, storage, and transportation, the standard operating procedure involves preparing various solutions in a sterile room, then mixing them for reaction and purification. There are two main challenges in the preparation of such radiopharmaceuticals: First, to ensure that the radiopharmaceutical products are sterile and pyrogen-free, the environmental conditions and personnel operation requirements during the preparation process are very high; second, the reaction rate is slow, requiring frequent and long-term operations, and the radioactive rays produced during the decay of radionuclides can cause damage to the operators.

[0028] To address the shortcomings of existing technologies, such as Figure 1As shown, the automated radiopharmaceutical labeling device 100 based on microfluidics provided in this application includes multiple reactant injectors 110, a microchannel reactor 120, a purification column 130, multiple eluent injectors 140, an effluent reservoir 150, an eluent reservoir 160, a two-way valve 170, an intermediate product reservoir 180, and a control system 190. The main function of the automated radiopharmaceutical labeling device 100 is to inject reactant samples into the microchannel reactor 120 via the reactant injectors 110, complete the reaction within the microchannel reactor 120, and then remove unlabeled radionuclides through the purification column 130, ultimately obtaining a purified radiopharmaceutical product. The device can operate automatically and continuously based on the reactant injectors 110, performing strong mixing within the micro-reaction channel 122 to shorten the reaction time. The control system 190 is isolated from the reaction system, ensuring sterility and pyrogen-free product production and reducing personnel radiation exposure. Microfluidic technology can effectively solve the above difficulties. First, microfluidic technology can precisely control the liquid through an external control system 190. Isolating the control system 190 from the solution reaction system can avoid bacterial contamination caused by human operation and reduce the radiation dose to personnel. Second, at the microscale, the solution flow reaction has a higher reaction rate. When the diameter of the circular tube is reduced, the mass transfer coefficient increases and the reaction rate can increase by orders of magnitude.

[0029] In some embodiments, optionally, such as Figure 1 As shown, the reactant injector 110 includes: a reactant reservoir 112 for storing reactants; a reactant drive pump 114 connected to the reactant reservoir 112 for driving reactants into the microchannel reactor 120; and a reactant pipeline 116 connected between the reactant reservoir 112 and the reactant drive pump 114 for transporting reactants.

[0030] Specifically, such as Figure 1 As shown, the reactant injector 110 includes a reactant reservoir 112, a reactant drive pump 114, and a reactant pipeline 116. The reactant reservoir 112 stores reactants. The reactant drive pump 114 is connected to the reactant reservoir 112 and drives the reactants into the microchannel reactor 120. The reactant pipeline 116 connects the reactant reservoir 112 and the reactant drive pump 114 and delivers the reactants. Multiple reactant injectors 110 are connected in parallel on the inlet side of the microchannel reactor 120 to provide different reactants to the microchannel reactor 120.

[0031] In some embodiments, optionally, such as Figure 1As shown, the eluent injector 140 includes: an eluent reservoir 142 for storing eluent; an eluent drive pump 144 connected to the eluent reservoir 142 for driving the eluent into the purification column 130; and an eluent line 146 connected between the eluent reservoir 142 and the eluent drive pump 144 for delivering the eluent.

[0032] Specifically, such as Figure 1 As shown, the eluent injector 140 includes an eluent reservoir 142, an eluent drive pump 144, and an eluent line 146. The eluent reservoir 142 stores the eluent. The eluent drive pump 144 is connected to the eluent reservoir 142 and drives the eluent into the purification column 130. The eluent line 146 connects the eluent reservoir 142 and the eluent drive pump 144 to deliver the eluent. Multiple eluent injectors 140 are connected in parallel to the inlet side of the purification column 130 to provide different eluents to the purification column 130.

[0033] In some embodiments, optionally, such as Figure 1 As shown, the microchannel reactor 120 includes: a microreaction channel 122 for mixing and labeling multiple reactants within the microreaction channel 122; and a microreactor inlet 124 connected to an intermediate product storage tank 180 via a pipeline.

[0034] Specifically, such as Figure 1 As shown, the microchannel reactor 120 includes a microreaction channel 122 and a microreactor inlet 124. The microreaction channel 122 is used to mix and label multiple reactants within the channel, serving as the space for the reaction. The microreactor inlet 124 is connected to an intermediate product reservoir 180 via a pipeline. When a specific reaction sequence is required, the control system 190 controls a two-way valve 170 to direct the flow to the intermediate product reservoir 180. Thus, the intermediate product generated from the reactants in the preceding reactant injector 110 is temporarily stored in the intermediate product reservoir 180. Subsequent reactants from the following injectors 110 are then transported to the microchannel reactor 120 along with the intermediate product through the microreactor inlet 124 for the next reaction. After the final reaction is complete, the control system 190 controls the two-way valve 170 to switch the flow direction, allowing the final product to enter the purification column 130 for separation and purification.

[0035] In some embodiments, optionally, such as Figure 1 As shown, the microchannel reactor 120 includes a temperature control component 126, which is electrically connected to the control system 190 and is used to control the reaction temperature inside the microchannel reactor 120. The temperature control component 126 has a temperature control range of -5℃ to 200℃.

[0036] Specifically, such as Figure 1 As shown, the microchannel reactor 120 includes a temperature control component 126. The temperature control component 126 is electrically connected to the control system 190 and is used to control the reaction temperature within the microchannel reactor 120. The temperature control range of the temperature control component 126 is -5℃ to 200℃. This improves the thermal response speed, provides high temperature control accuracy, and increases the overall reaction rate.

[0037] In specific applications, the temperature control component 126 can be specifically configured as a temperature control system to control the temperature of the micro-reaction channel 122 in the microchannel reactor 120. The specific temperature control temperature is -5℃, 0℃, 20℃, 50℃, 100℃ and 200℃, which can be set according to the specific situation, and will not be elaborated here.

[0038] In some embodiments, optionally, such as Figure 1 As shown, the intermediate product drive pump 182 is installed on the pipeline between the microreactor inlet 124 and the intermediate product storage tank 180.

[0039] Specifically, the microfluidic-based automated radiopharmaceutical labeling device 100 also includes an intermediate product driving pump 182. The intermediate product driving pump 182 is located on the pipeline between the microreactor inlet 124 and the intermediate product storage tank 180, and is used to transport the intermediate products generated from the reactants to the microchannel reactor 120, improving the stability of the pipeline transport.

[0040] In some embodiments, the flow rate control range of the reactant-driven pump 114 and the eluent-driven pump 144 is optionally 0 ml / min to 1000 ml / min.

[0041] Specifically, by setting the flow rate control range of the reactant-driven pump 114 and the eluent-driven pump 144 to 0 ml / min to 1000 ml / min, the flow rates of the reactant-driven pump 114 and the eluent-driven pump 144 can be adjusted by the control system 190, and the reaction temperature of the microchannel reactor 120 can be adjusted in conjunction with this adjustment, so that various reactants can react in the microchannel reactor 120 at a certain rate and temperature, thereby improving the reaction rate of the reactants.

[0042] In specific applications, the flow rate control range of reactant-driven pump 114 and eluent-driven pump 144 is 0 ml / min, 100 ml / min, 300 ml / min, 500 ml / min, 800 ml / min and 1000 ml / min, which can be set according to specific circumstances, and will not be elaborated here.

[0043] In some embodiments, optionally, the number of reactant injectors 110 is 2 to 5, and the inner diameter of the micro-reaction channel 122 of the microchannel reactor 120 is 10 μm to 10 mm.

[0044] Specifically, by setting the number of reactant injectors 110 to 2 to 5, and the inner diameter of the micro-reaction channel 122 of the microchannel reactor 120 to 10 μm to 10 mm, various reactants can react in the microchannel reactor 120, thereby increasing the reaction rate of the reactants.

[0045] In specific applications, the number of reactant injectors 110 can be set to 2, 3, 4 and 5, and the inner diameter of the micro-reaction channel 122 of the microchannel reactor 120 can be set to 10μm to 10mm. Preferably, the inner diameter of the micro-reaction channel 122 of the microchannel mixer is 100μm to 2000μm, which can be set according to specific circumstances, and will not be elaborated here.

[0046] According to the second aspect of this application, such as Figure 2 As shown, embodiments of this application also propose an automated method for radiopharmaceutical labeling based on microfluidics. Employing the automated radiopharmaceutical labeling device based on microfluidics described in the above embodiments, the automated method for radiopharmaceutical labeling based on microfluidics includes:

[0047] Step 202: Add reactants and eluent to the reactant storage tank and the eluent storage tank, respectively;

[0048] Step 204: Set the flow rate of the reactant-driven pump and the reaction temperature of the microchannel reactor through the control system.

[0049] Step 206: When there is no reaction order requirement for the reactants, control the two-way valve to direct the flow path to the purification column, start the reactant drive pump of multiple reactant injectors, deliver multiple reactants to the microchannel reactor for mixing and reaction, generate labeled compounds, and deliver the mixture after reaction to the purification column for separation and purification.

[0050] When there is a required reaction sequence for the reactants, the bidirectional valve is controlled to direct the flow path to the intermediate product reservoir. The reactant drive pump of the preceding reactant injector is started to deliver the reactants to the microchannel reactor for reaction. The generated intermediate product is temporarily stored in the intermediate product reservoir. The reactant drive pump of the subsequent reactant injector and the intermediate product drive pump are started to deliver the intermediate product and subsequent reactants to the microchannel reactor for the next reaction. After the final reaction is completed, the bidirectional valve is controlled to switch the flow direction so that the final product enters the purification column for separation and purification.

[0051] Step 208: The purification column is eluted by starting the eluent drive pump of the eluent injector.

[0052] Specifically, the microfluidic-based automated radiopharmaceutical labeling method achieves fully automated and closed-loop operation of the radiopharmaceutical labeling process through the coordinated control of the drive pump, bidirectional valve, and microchannel reactor. Its technical principle lies in: utilizing the large specific surface area of ​​the microchannel reactor to achieve efficient mass transfer and instantaneous mixing of reactants; precisely controlling the reaction temperature through integrated temperature control components; flexibly supporting single-step disordered reactions or multi-step sequential reactions by using bidirectional valves to switch flow paths and combining the temporary storage function of the intermediate product reservoir; and efficiently separating free radionuclides from labeled drugs and recovering target products by using the online separation and purification function of the purification column and switching different eluents through the eluent injector. This method achieves the technical effects of increased reaction rate, significantly reduced personnel radiation dose, elimination of microbial contamination, and adaptability to various labeling processes.

[0053] In some embodiments, optionally, the purification column is used to adsorb unlabeled free radionuclides, and the labeled radiopharmaceutical is collected as effluent in an effluent reservoir; or, the purification column is used to adsorb labeled radiopharmaceuticals, and the unlabeled free radionuclides are collected as effluent in an effluent reservoir, and eluent is delivered to the purification column through an eluent injector to elute the adsorbed radiopharmaceuticals and collect them in an eluent reservoir.

[0054] Specifically, when the packing material adsorbs free radionuclides, the product drug flows directly through, achieving rapid product collection and purification. When the packing material adsorbs the target drug, impurities are allowed to flow through first, and then the elution conditions, such as pH, ionic strength, and organic phase ratio, are changed by switching the eluent to elute the high-purity product. This design, through automatic switching of the flow path and elution program by the control system, directly achieves efficient and high-purity separation and recovery of various radiolabeled compounds, improving product purity and yield while reducing the generation of radioactive waste liquid.

[0055] For example, 68 Ga-labeled drugs 68 An example of Ga-PSMA-11 is as follows: Figure 1 As shown,

[0056] Preliminary preparation: Dissolve a certain amount of the drug prodrug PSMA-11 in a certain volume of buffer solution, and add the mixture to the reactant reservoir in reactant injector 1; [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 68 Ga 3+HCl eluent is added to the reactant reservoir in reactant injector 2; a certain concentration of ethanol aqueous solution is added to the eluent reservoir in eluent injector 11; physiological saline is added to the eluent reservoir in eluent injector 12; a pre-activated or pre-activated purification column is loaded, and the temperature in the microchannel reactor is set using the control system. After reaching the specified temperature, the reactant drive pumps of reactant injector 1 and reactant injector 2, and the two-way valve are turned on, controlling the flow rate of the two pumps so that the two solutions enter the micro-reaction channel in the microchannel reactor at a certain volume ratio for labeling reaction, and then enter the purification column through the two-way valve for separation. At this time, the labeled radiopharmaceutical is adsorbed by the purification column, and the unlabeled free nuclide enters the effluent reservoir through the two-way valve. The eluent drive pump of eluent injector 12 is turned on using the control system so that a certain amount of physiological saline washes the residual free nuclide on the purification column into the effluent reservoir. Using the control system to switch the two-way valve and open the eluent drive pump of eluent injector 11, a certain amount of ethanol-water solution is used to elute the radiopharmaceutical on the purification column into the eluent reservoir. Using the control system to open the eluent drive pump of eluent injector 12, a certain amount of physiological saline is used to wash the residual radiopharmaceutical on the purification column into the effluent reservoir, and the ethanol content in the radiopharmaceutical is adjusted to below the pharmacopoeia-specified value, ultimately obtaining... 68 Ga-PSMA-11 product.

[0057] For example, 177 Lu-labeled drugs 177 An example of Lu-PSMA-617 is as follows: Figure 1 As shown,

[0058] Preliminary preparation: Dissolve a certain amount of the drug prodrug PSMA-617 in a certain volume of buffer solution, and add the mixture to the reactant reservoir in reactant injector 1; [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 177 Lu 3+HCl eluent is added to the reactant reservoir in reactant injector 2; a certain concentration of ethanol aqueous solution is added to the eluent reservoir in eluent injector 11; physiological saline is added to the eluent reservoir in eluent injector 12; and a pre-activated or pre-activated purification column is loaded. The temperature in the microchannel reactor is set using the control system. Once the specified temperature is reached, the reactant drive pumps of reactant injector 1 and 2, and the two-way valve are opened, controlling the flow rate of both pumps to allow the two solutions to enter the micro-reaction channels in the microchannel reactor at a certain volume ratio for labeling reaction. The solutions then enter the purification column through the two-way valve for separation. At this point, the labeled radiopharmaceutical is adsorbed by the purification column, while the unlabeled free nuclide enters the effluent reservoir through the two-way valve. The eluent drive pump of eluent injector 12 is opened using the control system, allowing a certain amount of physiological saline to wash the residual free nuclide on the purification column into the effluent reservoir. Using the control system to switch the two-way valve and open the eluent drive pump of eluent injector 11, a certain amount of ethanol-water solution is used to elute the radiopharmaceutical on the purification column into the eluent reservoir. Using the control system to open the eluent drive pump of eluent injector 12, a certain amount of physiological saline is used to wash the residual radiopharmaceutical on the purification column into the effluent reservoir, and the ethanol content in the radiopharmaceutical is adjusted to below the pharmacopoeia-specified value, ultimately obtaining... 177 Lu-PSMA-617 product.

[0059] For example, 161 Tb-labeled drugs 161 The following is an example of Tb-PSMA-I&T: (e.g., ...) Figure 1 As shown,

[0060] Preliminary preparation: Dissolve a certain amount of the drug prodrug PSMA-I&T in a certain volume of buffer solution, and add the mixture to the reactant reservoir in reactant injector 1; [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 161 Tb 3+HCl eluent is added to the reactant reservoir in reactant injector 2; a certain concentration of ethanol aqueous solution is added to the eluent reservoir in eluent injector 11; physiological saline is added to the eluent reservoir in eluent injector 12; and a pre-activated or pre-activated purification column is loaded. The temperature in the microchannel reactor is set using the control system. Once the specified temperature is reached, the reactant drive pumps of reactant injector 1 and 2, and the two-way valve are opened, controlling the flow rate of both pumps to allow the two solutions to enter the micro-reaction channels in the microchannel reactor at a certain volume ratio for labeling reaction. The solutions then enter the purification column through the two-way valve for separation. At this point, the labeled radiopharmaceutical is adsorbed by the purification column, while the unlabeled free nuclide enters the effluent reservoir through the two-way valve. The eluent drive pump of eluent injector 12 is opened using the control system, allowing a certain amount of physiological saline to wash the residual free nuclide on the purification column into the effluent reservoir. Using the control system to switch the two-way valve and open the eluent drive pump of eluent injector 11, a certain amount of ethanol-water solution is used to elute the radiopharmaceutical on the purification column into the eluent reservoir. Using the control system to open the eluent drive pump of eluent injector 12, a certain amount of physiological saline is used to wash the residual radiopharmaceutical on the purification column into the effluent reservoir, and the ethanol content in the radiopharmaceutical is adjusted to below the pharmacopoeia-specified value, ultimately obtaining... 161 Tb-PSMA-I&T products.

[0061] In the description of this application, the term "multiple" refers to two or more. Unless otherwise expressly defined, the terms "upper," "lower," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this application. The terms "connection," "installation," "fixing," etc., should be interpreted broadly. For example, "connection" can be a fixed connection, a detachable connection, or an integral connection; it can be a direct connection or an indirect connection through an intermediate medium. For those skilled in the art, the specific meaning of the above terms in this application can be understood according to the specific circumstances.

[0062] In the description of this specification, the terms "one embodiment," "some embodiments," "specific embodiment," etc., refer to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0063] The above are merely preferred embodiments of this application and are not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. An automated device for labeling radiopharmaceuticals based on microfluidics, characterized in that, include: Multiple reactant injectors are used to store and deliver reactants; A microchannel reactor, wherein the inlet end of the microchannel reactor is connected to the outlet end of a plurality of reactant injectors via a pipeline, for mixing and labeling multiple reactants therein; A purification column, the inlet of which is connected to the outlet of the microchannel reactor via a pipeline, is used to separate and purify the mixture after the reaction is completed; Multiple eluent injectors are provided, and the outlet ends of the multiple eluent injectors are connected to the inlet end of the purification column via pipelines for delivering eluent. An effluent storage tank, the inlet of which is connected to the outlet of the purification column via a pipeline, is used to collect the effluent. The eluent storage tank has its inlet connected to the outlet of the purification column via a pipeline, and is used to collect the target product eluted from the purification column. A two-way valve is installed on the pipeline between the microchannel reactor and the purification column to switch the flow direction. An intermediate product storage tank and an intermediate product driving pump are provided. The inlet of the intermediate product storage tank is connected to one outlet of the two-way valve via a pipeline for temporarily storing intermediate products in a multi-step reaction. The intermediate product driving pump is located on the pipeline between the outlet of the intermediate product storage tank and the microchannel reactor. The control system is electrically connected to the reactant injector, the eluent injector, the two-way valve, the intermediate product drive pump, and the microchannel reactor, and is used to control the flow rate of the reactants and eluent, the switching of the flow path, and the reaction temperature of the microchannel reactor.

2. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The reactant injector includes: Reactant storage tank, used to store reactants; A reactant-driven pump, connected to the reactant reservoir, is used to drive the reactants into the microchannel reactor; A reactant pipeline is connected between the reactant storage tank and the reactant drive pump for transporting the reactants.

3. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The eluent injector includes: A rinsing solution storage tank is used to store rinsing solution; An eluent drive pump, connected to the eluent storage tank, is used to drive the eluent into the purification column; The rinsing fluid pipeline is connected between the rinsing fluid storage tank and the rinsing fluid drive pump, and is used to transport the rinsing fluid.

4. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The microchannel reactor includes: Microreaction channels are used to mix and label multiple reactants within the microreaction channels. The microreactor inlet is connected to the intermediate product storage tank via a pipeline.

5. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The microchannel reactor includes: A temperature control component, electrically connected to the control system, is used to control the reaction temperature inside the microchannel reactor. The temperature control component has a temperature control range of -5℃ to 200℃.

6. The automated radiopharmaceutical labeling device based on microfluidics according to claim 4, characterized in that, The intermediate product drive pump is located on the pipeline between the microreactor inlet and the intermediate product storage tank.

7. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The flow rate control range of the reactant-driven pump and the eluent-driven pump is 0 ml / min to 1000 ml / min.

8. The automated radiopharmaceutical labeling device based on microfluidics according to claim 1, characterized in that, The number of reactant injectors is 2 to 5, and the inner diameter of the micro-reaction channel of the microchannel reactor is 10 μm to 10 mm.

9. An automated method for labeling radiopharmaceuticals based on microfluidics, characterized in that, The automated radiopharmaceutical labeling method based on microfluidics, using any one of claims 1 to 8, comprises: Add reactants and eluents to the reactant storage tank and the eluent storage tank respectively; The flow rate of the reactant-driven pump and the reaction temperature of the microchannel reactor are set by the control system. When there is no requirement for the reaction sequence of reactants, the two-way valve is controlled to direct the flow path to the purification column, and the reactant drive pump of multiple reactant injectors is started to deliver multiple reactants to the microchannel reactor for mixing and reaction, generating labeled compounds, and the mixture after reaction is delivered to the purification column for separation and purification. When there is a required reaction sequence for the reactants, the bidirectional valve is controlled to direct the flow path to the intermediate product reservoir. The reactant drive pump of the preceding reactant injector is started to deliver the reactants to the microchannel reactor for reaction. The generated intermediate product is temporarily stored in the intermediate product reservoir. The reactant drive pump of the subsequent reactant injector and the intermediate product drive pump are started to deliver the intermediate product and subsequent reactants to the microchannel reactor for the next reaction. After the final reaction is completed, the bidirectional valve is controlled to switch the flow direction so that the final product enters the purification column for separation and purification. The purification column is eluted by starting the eluent drive pump of the eluent injector.

10. The automated method for radiopharmaceutical labeling based on microfluidics according to claim 9, characterized in that, The purification column is used to adsorb unlabeled free radionuclides, and the labeled radiopharmaceutical is collected as effluent in an effluent reservoir; or, The purification column is used to adsorb labeled radiopharmaceuticals. Unlabeled free radionuclides are collected as effluent in an effluent reservoir. Eluent is delivered to the purification column through an eluent injector to wash off the adsorbed radiopharmaceuticals and collect them in the eluent reservoir.

Images