Contrast agent macro preparation system, contrast agent macro preparation method and controller

Abstract

The invention discloses a contrast agent macro preparation system, a contrast agent macro preparation method and a controller. The system comprises a synthesis module and a purification module, the synthesis module comprises an activation unit, at least one reaction unit and at least one swelling unit, the activation unit is used for modifying the surface of a carrier microsphere to obtain a modified carrier microsphere, the reaction unit is used for synthesizing a first intermediate product, and the swelling unit is used for swelling the first intermediate product; the swelling unit is used for mixing and reacting the modified carrier microspheres and the first intermediate product in a swelling agent and then adding a shrinking agent to obtain a contrast agent crude product; the purification module comprises a chromatographic column and is used for separating and purifying the contrast agent crude product to obtain a contrast agent target product. By automatically controlling the synthesis module and the purification module, the whole reaction process is controllable, contrast agents containing different types of elements can be rapidly, efficiently and accurately prepared in a large scale, and the requirement for macro preparation of different contrast agents is met.

Description

Technical Field

[0001] The present invention relates to the field of biomedical engineering technology, and in particular to a system, method and controller for preparing a contrast agent in large quantities. Background Art

[0002] Magnetic resonance imaging (MRI) is a multi-sequence, multi-parameter and multi-contrast imaging technology. Its images can reflect the morphology, function and metabolic information of macroscopic and microscopic structures, and can comprehensively and detailedly evaluate the functional status and early lesions of tissues and organs. Magnetic resonance contrast agents (MRA) are a necessary condition for MRI. They change the relaxation time of water protons in tissues and enhance image signals, thereby improving the resolution and contrast of images, providing more accurate information for disease detection and diagnosis.

[0003] However, the synthesis and preparation of existing magnetic resonance contrast agents is mainly based on small-dose synthesis in the laboratory, which has a cumbersome process, a long production cycle, high production costs, low synthesis efficiency, and poor stability of the contrast agent products; and the process is difficult to scale up and is not suitable for industrialization. Summary of the invention

[0004] In view of this, the purpose of the embodiments of the present invention is to provide a system, method and controller for macro-production of contrast agents, which can automatically produce contrast agents in batches, have simple preparation, short production cycle and high stability of the target product.

[0005] In a first aspect, an embodiment of the present invention provides a system for macro-preparation of a contrast agent, comprising a synthesis module and a purification module; the synthesis module comprises an activation unit, at least one reaction unit and at least one swelling unit, the activation unit being used to modify the surface of carrier microspheres to obtain modified carrier microspheres, the reaction unit being used to synthesize a first intermediate product, the swelling unit being used to mix and react the modified carrier microspheres and the first intermediate product in a swelling agent and then adding a shrinking agent to obtain a crude contrast agent product; the purification module comprises a chromatographic column for separating and purifying the crude contrast agent product to obtain a contrast agent target product.

[0006] In some optional embodiments, the system further comprises a feeding module, and the feeding module is used to input the carrier microspheres and reaction raw materials into the synthesis module.

[0007] In some optional embodiments, the system further comprises a characterization module, which is connected to a test characterization instrument and is used to determine the properties of the contrast agent target after being processed by the purification module.

[0008] In some optional embodiments, the feeding module includes a first storage bottle, the first storage bottle is provided with a first plunger and a first plunger push rod, the first plunger push rod is used to push the first plunger, a first one-way valve is provided on the input pipe of the first storage bottle, and the output pipe of the first storage bottle is connected to the activation unit through a second one-way valve and an air pump which are arranged in sequence.

[0009] In some optional embodiments, the activation unit and the reaction unit include a fixing bottle and a reaction bottle, the fixing bottle is used for quantitatively storing the reaction raw materials, and the reaction bottle is used for receiving the reaction raw materials and / or the carrier microspheres and then performing the reaction.

[0010] In some optional embodiments, the synthesis module further includes a first washing unit, which is used to wash the modified carrier microspheres with a first solvent and then transport them to the swelling unit.

[0011] In some optional embodiments, the synthesis module further includes a second washing unit, and the second washing unit is used to wash the crude contrast agent product with a second solvent and then transport it to the purification module.

[0012] In some optional embodiments, the first washing unit and the second washing unit have the same structure, both including a washing bottle and a second storage bottle, the washing bottle is provided with a second plunger and a second plunger push rod, the second plunger push rod is used to push the second plunger, and the second storage bottle is used to transport the first solvent or the second solvent to the washing bottle.

[0013] In some optional embodiments, the reaction bottle is provided with a plurality of liquid inlets and a plurality of liquid outlets, the liquid inlets are used to input the reaction raw materials, and the liquid outlets are used to perform at least one of the following operations:

[0014] In some optional embodiments, the modified carrier microspheres are transported to the swelling unit via the liquid outlet; or, the first intermediate product is transported to the swelling unit via the liquid outlet; or, the unreacted reaction raw materials are discharged via the liquid outlet; or, the modified carrier microspheres are distributed into multiple portions through different liquid outlets and enter different swelling units.

[0015] In some optional embodiments, the swelling unit includes a swelling bottle and a third storage bottle, the swelling bottle is used to input the modified carrier microspheres and the first intermediate product, and after inputting a third solvent through the third storage bottle, the modified carrier microspheres are swelled and then contracted, so that the first intermediate product is encapsulated in the modified carrier microspheres.

[0016] In some optional embodiments, the purification module further comprises a dialysis unit, the dialysis unit comprising a dialysis container and a dialysis membrane, the dialysis membrane being used to separate the crude contrast agent product in the dialysis container from the reaction raw materials and / or excess first intermediate product and / or excess modified carrier microspheres.

[0017] In some optional embodiments, the reaction unit is configured with a temperature monitoring sensor and a pH monitoring sensor, the temperature monitoring sensor is used to monitor the temperature in the reaction bottle, and the pH monitoring sensor is used to monitor the pH in the reaction bottle.

[0018] In some optional embodiments, the reaction unit, the activation unit and the swelling unit are further configured with a heating element and a stirring element.

[0019] In a second aspect, the present invention provides a contrast agent macro-production method, which is applied to a contrast agent macro-production system. The contrast agent macro-production system comprises a synthesis module and a purification module, wherein the synthesis module comprises an activation unit, at least one reaction unit and at least one swelling unit; the contrast agent macro-production method comprises:

[0020] The carrier microspheres are transported to the activation unit for surface modification to obtain modified carrier microspheres;

[0021] The reaction raw materials are transported to the reaction unit for chemical reaction to generate a first intermediate product;

[0022] delivering the modified carrier microspheres and the first intermediate product to the swelling unit;

[0023] The modified carrier microspheres are swollen and shrunk by the swelling unit, so that the first intermediate product enters the modified carrier microspheres for encapsulation to obtain a crude contrast agent product;

[0024] The crude contrast agent product is transported to the purification module for separation and purification to obtain a contrast agent target product.

[0025] In a third aspect, an embodiment of the present invention provides a controller, comprising: a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein the processor implements the above method when executing the computer program.

[0026] In a fourth aspect, an embodiment of the present invention provides a computer storage medium, wherein the computer storage medium stores computer executable instructions, and the computer executable instructions are used to execute the above-mentioned macro-preparation method of contrast agent.

[0027] The contrast agent macro-preparation system according to the embodiment of the present invention has at least the following beneficial effects: through the automated control of the synthesis module and the purification module, the entire reaction process is controllable, and contrast agents containing different types of elements can be prepared quickly, efficiently, accurately and in large quantities, meeting the needs for macro-preparation of different contrast agents, and realizing automatic batch production of contrast agents, with a simple preparation process, a short production cycle, low production costs, and high product batch stability.

[0028] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a structural schematic diagram of a contrast agent macro-preparation system provided by an embodiment of the present invention;

[0030] Figure 2 It is a schematic diagram of some modules or units of a contrast agent macro-system provided by an embodiment of the present invention;

[0031] Figure 3 The present invention provides a flow chart for macro-production of contrast agents.

[0032] Reference numerals: feed module 1 ; activation unit 2 ; reaction unit 3 ; swelling unit 4 ; purification module 5 ; controller 6 . DETAILED DESCRIPTION

[0033] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. 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.

[0034] In the embodiments of the present invention, words such as "exemplary" or "for example" are used to indicate examples, illustrations or explanations. Any embodiment or design described as "exemplary" or "for example" in the embodiments of the present invention should not be interpreted as being more preferred or more advantageous than other embodiments or designs. Specifically, the use of words such as "exemplary" or "for example" is intended to present related concepts in a specific way.

[0035] In the following, the terms "first" and "second" are used for descriptive purposes only and are not to be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the embodiments of the present invention, unless otherwise specified, "plurality" means two or more.

[0036] In the context of the present application, the term "contrast agent" is also referred to as contrast agent in some scenarios. Common small molecule contrast agents include gadopentetate dimeglumine (GD-DTPA), gadodiamide (GD-DTPA-BMA) and gadolinium-tetraazacyclodo (decanetetraacetic acid, GD-DOTA). This type of substance is a substance used to enhance the visibility of magnetic resonance imaging images of certain tissues or pathological conditions. Contrast agents improve the contrast of magnetic resonance images by changing the response of tissues to magnetic fields, thereby clearly observing abnormalities in internal structures.

[0037] The term "macro-amount" in the context of the present application generally refers to the ability to produce at least one kilogram of the target product at a time, for example, in the embodiments of the present invention, it refers to the ability to produce more than 1 kilogram of contrast agent.

[0038] In the first aspect, referring to Figure 1-2 The embodiment of the present invention provides a macro-production system of contrast agent, including a synthesis module and a purification module 5; the synthesis module includes an activation unit 2, at least one reaction unit 3 and at least one swelling unit 4. The activation unit 2 is mainly used to modify the surface of the carrier microsphere to obtain the modified carrier microsphere, the reaction unit 3 is used to synthesize the first intermediate product, and the swelling unit 4 is used to mix the modified carrier microsphere and the first intermediate product in a swelling agent and then add a shrinking agent to obtain a crude contrast agent product; the purification module 5 includes a chromatographic column, which is used to separate and purify the crude contrast agent product to obtain a contrast agent target product.

[0039] Specifically, the activation unit 2 and the swelling unit 4 and the reaction unit 3 and the swelling unit 4 are connected through an input pipe and an output pipe, or through a liquid inlet and a liquid outlet, and the activation unit 2 and the swelling unit 4 can be selectively connected. It can be understood that, for example, for gadolinium-based (Gd-based) contrast agents, mainly based on gadolinium salt as a gadolinium source, gadolinium salt and ligands such as DPTA, DOTA, polypeptides, etc. form a chelate. At this time, the activation unit 2 and the reaction unit 3 are connected in parallel to the swelling unit 4. It can be understood that in this case, the activation unit 2 and the reaction unit 3 react alone before entering the swelling unit 4 for the next step of processing. For example, in some cases, for example, the carrier microspheres and the first intermediate product may also be bonded. In this case, the activation unit 2, the reaction unit 3 and the swelling unit 4 can be connected in sequence, and the swelling unit 4 can act as a washing unit. It is understandable that each of the units can selectively work independently or in coordination with other units, and the reaction conditions and processes are mainly controlled by the controller 6 mentioned below.

[0040] It should be noted that the "carrier microspheres" mentioned here are preferably polystyrene microspheres. Since polystyrene microspheres have insufficient biocompatibility, they are modified by the activation unit 2, for example, carboxyl groups are connected to the surface of the polystyrene microspheres to make their surface carboxylated to form carboxylated polystyrene microspheres. It is understandable that other carrier microspheres that meet the requirements, such as liposomes, etc., can also be selected.

[0041] Further, in reaction unit 3, taking GD-DPTA as an example, DPTA is used as a multidentate ligand to bind Gd3 + ions form a stable chelate structure, thereby reducing Gd3 + The free state of ions. Therefore, in reaction unit 3, Gd3 + The coordination reaction between ions and DPTA, it can be understood that the first intermediate product at this time refers to the Gd-DPTA chelate. For example, it can also be a peptide substance that can form a coordination complex with the gadolinium ion through its nitrogen atom and certain side chains (such as carboxyl or other functional groups), which is not specifically limited here.

[0042] It is understandable that in the activation unit 2, in addition to the reaction raw materials, other reagents such as solvents or other reagents for optimizing the reaction may be added. For example, the carboxylation reaction of polystyrene microspheres and maleic anhydride may also require a catalyst, etc. Therefore, in addition to being connected to the upstream material module, the activation unit 2 is also provided with multiple liquid inlets for auxiliary standby.

[0043] In addition, during the operation of the activation unit 2, the reaction unit 3 and the swelling unit 4, the temperature and pH of the reaction system may need to be monitored according to the different parameters and conditions set in the controller 6 below. Therefore, a temperature monitoring sensor and a pH monitoring sensor are configured to monitor the temperature changes and pH changes of the reaction system.

[0044] It is understandable that, for example, for the coordination reaction between metal ions and ligands, heating and stirring may be required to increase the reaction efficiency, and different reactions may have slightly different reaction conditions, so heating elements and stirring elements are auxiliaryly configured.

[0045] Further, in the swelling unit 4, the first intermediate product obtained from the reaction unit 3 is mainly loaded or coated in the modified carrier microspheres, such as carboxylated polystyrene microspheres, and the first intermediate product is prevented from leaking through the swelling and shrinking strategy, which is convenient for long-term storage. In specific applications, the contrast agent can be quantitatively released from the modified carrier microspheres by controlling the contrast agent. In some optional embodiments, the condensing agent is a mixture of any one of N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole and a reaction solvent, and the reaction solvent is any one of dichloromethane, dimethylformamide, chloroform and tetrahydrofuran. It is understandable that the swelling agent and the shrinking agent are not limited here.

[0046] The condensing agent is specifically a mixture of N,N'-dicyclohexylcarbodiimide (DCC) and chloroform, or a mixture of N,N'-diisopropylcarbodiimide (DIC) and tetrahydrofuran, or a mixture of 1-hydroxybenzotriazole (HOBt) and dimethylformamide; more preferably, a mixture of 1-hydroxybenzotriazole and chloroform.

[0047] It is understandable that the crude contrast agent product obtained by the swelling unit 4 may contain unreacted raw materials, the first intermediate product that has not been swelled and shrunk, and modified carrier microspheres that are not coated with the first intermediate product. Therefore, the crude contrast agent product needs to be purified, for example, by a matching purification system with a chromatographic column, to obtain the contrast agent target product.

[0048] In the purification module 5, in some embodiments, a dialysis unit is also included. The dialysis unit includes a dialysis container and a dialysis membrane. The dialysis membrane is used to separate the crude contrast agent product in the dialysis container from the reaction raw materials and / or excess first intermediate products and / or excess modified carrier microspheres.

[0049] Specifically, the first intermediate product containing impurities such as solvents and unreacted raw materials is transported to a dialysis container. The dialysis membrane in the dialysis container allows small molecules (such as salts, unreacted raw materials, etc.) to pass through, thereby blocking large molecules (synthesized contrast agents) to obtain a decontaminated contrast agent.

[0050] For example, desalination technology uses a semipermeable membrane to separate solutes and solvents in a solution. High pressure is used to drive the solvent through the semipermeable membrane, while ions and impurities in the solute and solvent are retained on the membrane, which can effectively remove salt and other solutes in the solution.

[0051] It is understandable that the contrast agent target product obtained by the above process needs to be tested and characterized for different batches to determine whether its yield and purity meet the requirements, the pure contrast agent is weighed to determine the specific yield, and the ICP MS (inductively coupled plasma mass spectrometry) of the pure contrast agent is obtained to determine the yield, and the purity is determined by liquid chromatography of the pure contrast agent. In the automatic mode, after process debugging, optimization and adjustment, the yield of the chromatographic device is more than 90%, the purity is more than 99.8%, and the production and pilot test results are basically consistent.

[0052] It should be noted that the characterization module here is an open module. For example, relevant equipment and instruments such as nuclear magnetic resonance characterization and morphology characterization can be introduced into the characterization module as needed. That is, the characterization module can be connected to various test characterization instruments, such as scanning electron microscope, nuclear magnetic resonance, etc., so as to display the test data of specific test characterization instruments through the characterization module.

[0053] In some optional embodiments, the synthesis module further includes a first washing unit, which is used to wash the modified carrier microspheres with a first solvent and then transport them to the swelling unit 4.

[0054] Specifically, the first washing unit is arranged between the activation unit 2 and the swelling unit 4. The modified carrier microspheres are washed by the first washing unit to remove excess unreacted compounds and impurities, and the modified carrier microspheres after washing are transported to the swelling unit 4, thereby reducing impurities entering the swelling unit 4 and preventing impurities from affecting subsequent processes.

[0055] In some optional embodiments, the synthesis module further includes a second washing unit, and the second washing unit is used to wash the first intermediate product with a second solvent and then transport it to the purification module 5.

[0056] Specifically, the second washing unit is arranged between the swelling unit 4 and the dialysis unit. The first intermediate product is washed by the second washing unit to remove impurities such as excess unreacted compounds and by-products, and the first intermediate product after washing is transported to the dialysis unit, thereby reducing impurities entering the dialysis unit and preventing impurities from affecting the dialysis quality of the dialysis unit.

[0057] In some optional embodiments, the synthesis module further includes a feed module 1, which is used to input the carrier microspheres and the reaction raw materials into the activation unit 2. The feed module 1 includes a first storage bottle, in which a first plunger and a first plunger push rod are arranged, the first plunger push rod is used to push the first plunger, the output pipeline of the first storage bottle is connected to the activation unit 2 through a first one-way valve and an air pump arranged in sequence, and a second one-way valve is arranged on the input pipeline of the first storage bottle.

[0058] Specifically, the first storage bottle is a quantitative storage container of polystyrene microspheres (i.e., carrier microspheres), and the input pipeline and the output pipeline are connected to the first storage bottle. The first storage bottle is also connected to a larger material reserve container, and the raw material (polystyrene microspheres) can be quantitatively transferred from the material reserve container to the first storage bottle via the input pipeline according to the weight of the contrast agent to be mass-produced, and then the flow of the raw material is controlled in the first storage bottle via the first plunger and the first plunger rod, the first one-way pump, and the air pump. The movement of the plunger in the storage bottle can change the volume of the internal liquid, thereby generating pressure, and pushing the liquid to be transported to the downstream equipment or reactor through the output pipeline. The movement of the plunger is a key component for realizing the quantitative delivery of liquid. The plunger push rod is a mechanism connecting the plunger and the external drive system, providing mechanical force so that the plunger can move up and down or reciprocate. By controlling the moving distance and speed of the plunger, the flow rate and pressure of the liquid can be accurately adjusted to meet the specific application requirements. A first one-way valve is provided on the output pipeline and a second one-way valve on the input pipeline can prevent the liquid from flowing back when there is no drive, ensuring the stability and safety of the system. The plunger can also be used to mix gas and liquid in the storage bottle to promote chemical reactions or other processes. The air pump is used to create negative or positive pressure to further promote the flow of liquid or extract liquid, which complements the plunger. The polystyrene microspheres can be dispersed in a suitable solvent for the next step.

[0059] In some optional embodiments, the feed module 1 also stores other chemical solvents, and the generation of contrast agents is completed by conveying different chemical solvents to different reaction devices. The specific chemical solvents are set according to the specific contrast agents and requirements and are not limited here.

[0060] In some optional embodiments, the activation unit 2 includes a fixed bottle and a reaction bottle, the fixed bottle is used to store the reaction raw materials, and the reaction bottle is used to receive the reaction raw materials and carrier microspheres and then perform a carboxylation reaction to obtain carboxylated carrier microspheres, that is, modified carrier microspheres.

[0061] Specifically, activation unit 2 is mainly used for the carboxylation reaction of carrier microspheres such as polystyrene. Activation unit 2 includes a fixed bottle connected to the output pipeline of feed module 1, that is, feed module 1 is also provided with a device for storing reaction raw materials, and is communicated with the fixed bottle, so that the reaction raw materials are transported to the fixed bottle. Activation unit 2 also includes a first constant flow pump connected to the fixed bottle, a reaction bottle connected to the output pipeline of the first constant flow pump, and an air pump connected to the reaction bottle, and the reaction bottle is provided with a plurality of liquid inlets and liquid outlets. The fixed bottle is used to store the reagent (reaction raw materials) of polystyrene carboxylation, and the first constant flow pump is used to transport the liquid in the fixed bottle to the reaction bottle at a constant flow rate (i.e., the specific flow rate is controlled by the first constant flow pump). The constant flow pump can accurately control the flow rate, which helps to maintain the consistency of the reaction conditions and improve the reaction efficiency and repeatability. The reaction bottle is the main container for the carboxylation reaction, and the carboxylated polystyrene microspheres (carboxylated carrier microspheres) are obtained after the reaction is completed.

[0062] In some optional embodiments, the reaction bottle is provided with a plurality of liquid inlets and liquid outlets, the liquid inlets are used for inputting the reaction raw materials, and the liquid outlets are used for transporting the modified carrier microspheres and / or unreacted reaction raw materials and solid carriers to a swelling unit 4 or a plurality of different swelling units 4, and different swelling units 4 are input with different coordination compounds.

[0063] Specifically, the reaction flask is provided with a plurality of liquid inlets and liquid outlets, which are convenient for the simultaneous input of multiple raw materials and the output of reaction products. The liquid inlet is used to flow the reaction raw materials (such as carboxylation reagent) into the reaction flask, and a plurality of liquid inlets are provided to facilitate the simultaneous addition of different chemical substances. The liquid outlet is used to discharge the product generated by the reaction or the unreacted raw materials from the reaction flask. The carboxylation reaction of polystyrene not only requires the use of polystyrene microspheres and carboxylation reagents (maleic anhydride, etc.), but also may use catalysts according to specific needs, so multiple liquid inlets are standby for convenient addition of reagents, in addition, the carboxylation of polystyrene microspheres (after activation) requires the use of appropriate solvents to clean the reactants, to remove the unnecessary unreacted compounds and impurities, so the liquid inlet can also be used for the entry of solvents. The liquid outlet is used to flow the activated product carboxylated polystyrene microspheres into the swelling unit 4 through the liquid outlet to participate in the reaction. The carboxylated polystyrene microspheres can also be divided into several portions through different liquid outlets. Each portion of carboxylated polystyrene microspheres reacts with different coordination compounds to generate different types of contrast agents, so as to realize the development of multi-element contrast agents. There can also be multiple liquid outlets, some of which are connected to the swelling unit 4 for the next step of reaction, and the remaining liquid outlets can be connected to external devices to discharge excess materials that have not participated in the reaction or waste liquid after washing.

[0064] In some optional embodiments, the swelling unit 4 includes a swelling bottle and a third storage bottle, the swelling bottle is used to input the modified carrier microspheres and the first intermediate product, and the modified carrier microspheres are swelled after the third solvent is input through the third storage bottle, so that the modified carrier microspheres swell and absorb the first intermediate product to obtain a crude contrast agent product.

[0065] Specifically, the swelling unit 4 pumps the carboxylated carrier microspheres (modified carrier microspheres) and the coordination compound (the first intermediate product) into the swelling bottle through the third constant flow pump, and the swelling bottle is provided with a third plunger and a third plunger push rod, and the third plunger is connected to the third plunger push rod, and the swelling bottle is provided with a liquid inlet and a liquid outlet, and the liquid outlet is connected to the input pipeline of the second washing unit input port. The swelling unit 4 is for loading the coordination compound of the reaction unit 3 into the carboxylated polystyrene microspheres, and the carboxylated polystyrene microspheres are swollen after the third solvent is input through the third storage bottle, and the carboxylated polystyrene microspheres are swollen after swelling, and the coordination compound can enter the micropores, thereby entering the inside of the carboxylated polystyrene microspheres, and then the micropores are closed by a condensing agent. For example, the carboxylated polystyrene microspheres are first swollen in a suitable solvent (such as acetonitrile, ethanol, etc.). The ligand compound generated by the gadolinium salt and the ligand solution is added to the swollen carboxylated polystyrene microspheres, and the ligand compound is adsorbed into the interior of the carboxylated polystyrene microspheres by utilizing the micropores of the carboxylated polystyrene microspheres.

[0066] In some optional embodiments, the first washing unit and the second washing unit have the same structure, both including a washing bottle and a second storage bottle, the washing bottle is provided with a second plunger and a second plunger push rod, the second plunger push rod is used to push the second plunger, and the second storage bottle is used to deliver the first solvent or the second solvent to the washing bottle.

[0067] Specifically, the second constant flow pump of the first washing unit is connected to the liquid outlet of the reaction bottle, and outputs the carboxylated polystyrene microspheres in the reaction bottle to the washing bottle of the first washing unit. The second storage bottle of the first washing unit conveys the first solvent to the washing bottle of the first washing unit, washes the carboxylated polystyrene microspheres with the first solvent, thereby washing away the excess unreacted materials in the polystyrene microspheres and removing the waste liquid, and conveys the washed carboxylated polystyrene microspheres to the swelling unit 4 to participate in the next step of the reaction. The second constant flow pump of the second washing unit is connected to the liquid outlet of the swelling bottle of the swelling unit 4, and outputs the crude contrast agent product of the swelling bottle to the washing bottle of the second washing unit. The second storage bottle of the second washing unit conveys the second solvent to the washing bottle of the second washing unit, washes the crude contrast agent product with the second solvent, thereby washing away the excess unreacted materials in the crude contrast agent product and removing the waste liquid, and conveys the washed crude contrast agent product to the dialysis unit to participate in the next step of the reaction.

[0068] In some optional embodiments, the reaction unit 3 is used for the coordination reaction of the metal salt and the ligand. The reaction unit 3 includes a third storage bottle, a coordination reaction bottle, a plunger, a plunger rod, a liquid inlet and a liquid outlet, a stirring device, a temperature sensor, a pH sensor, a safety valve and other structures. The metal salt, such as a 1mol / L gadolinium chloride solution, and the ligand, such as DPTA or a polypeptide substance, are reacted to form a coordination compound or a composition. Gadolinium chloride or other gadolinium compounds are used as the source of gadolinium ions. It is dissolved in a suitable solvent. The synthesized ligand is mixed with the gadolinium salt and reacted at a suitable temperature and conditions, usually under acid-base conditions to ensure the completeness of the reaction. The specific time of the reaction depends on the reaction activity and the ligand structure. The third storage bottle is used to place the metal salt and / or the ligand, and the coordination reaction bottle transports the generated coordination compound to the swelling bottle of the swelling unit 4 for reaction.

[0069] In some optional embodiments, the input ports of the first constant flow pump, the second constant flow pump and the third constant flow pump and each input pipeline are respectively provided with a flow controller to complete the flow control. The flow controller includes an injection pump or a regulating valve. The material of the constant flow pump is polytetrafluoroethylene.

[0070] In some optional embodiments, the first storage bottle, the second storage bottle, the third storage bottle, the reaction bottle, the swelling bottle, the washing bottle, the receiving bottle and the dialysis container are all polytetrafluoroethylene bottles.

[0071] In some optional embodiments, the constant flow pump adopts a plunger type, piston type or peristaltic constant flow pump.

[0072] In some optional embodiments, the input pipeline has the same pushing frequency as the first plunger push rod, the first plunger, the second plunger push rod, the second plunger, the third plunger push rod, and the third plunger.

[0073] In some optional embodiments, the driving flow rates of each constant flow pump are the same.

[0074] In some optional embodiments, the first one-way valve and the second one-way valve are opened and closed synchronously.

[0075] Second, refer to Figure 3 The embodiment of the present invention provides a contrast agent macro-preparation method, which is applied to a contrast agent macro-preparation system. The contrast agent macro-preparation system includes a synthesis module and a purification module 5. The synthesis module includes an activation unit 2, a reaction unit 3 and a swelling unit 4. The contrast agent macro-preparation method includes:

[0076] S200, transporting the carrier microspheres to the activation unit 2 for surface modification to obtain modified carrier microspheres;

[0077] S210, transporting the reaction raw materials to the reaction unit 3 for chemical reaction to generate a first intermediate product;

[0078] S220, transporting the modified carrier microspheres and the first intermediate product to the swelling unit 4;

[0079] S230, swelling and shrinking the modified carrier microspheres through the swelling unit 4, so that the first intermediate product enters the modified carrier microspheres for encapsulation to obtain a crude contrast agent product;

[0080] S240, conveying the crude contrast agent product to the purification module 5 for separation and purification to obtain a contrast agent target product.

[0081] It can be seen that the contents of the above-mentioned contrast agent macro-preparation system embodiment are all applicable to the present method embodiment, the functions specifically implemented by the present method embodiment are the same as those of the above-mentioned contrast agent macro-preparation system embodiment, and the beneficial effects achieved are also the same as those achieved by the above-mentioned contrast agent macro-preparation system embodiment.

[0082] The system of the above embodiments can be used to prepare lanthanum-based contrast agents, gadolinium-based contrast agents, cerium-based contrast agents, zinc-based contrast agents, gadolinium-lanthanum-based contrast agents, gadolinium-lanthanum-zinc-based contrast agents, gadolinium-lanthanum-cerium-based contrast agents, gadolinium-lanthanum-cerium-zinc-based contrast agents, iron-based contrast agents, manganese-based contrast agents, etc.

[0083] For example, the structure of the ligand in the embodiment of the present invention can be as follows:

[0084]

[0085] For example, the structure of the first intermediate product in the context of an embodiment of the present invention may be as follows:

[0086]

[0087]

[0088] wait.

[0089] In a third aspect, an embodiment of the present invention provides a controller, comprising: a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein the above method is implemented when the processor executes the computer program.

[0090] It can be seen that the contents of the above-mentioned contrast agent macro-preparation method embodiment are all applicable to the present controller embodiment, the functions specifically implemented by the present controller embodiment are the same as those of the above-mentioned contrast agent macro-preparation method embodiment, and the beneficial effects achieved are also the same as those achieved by the above-mentioned contrast agent macro-preparation method embodiment.

[0091] In a fourth aspect, an embodiment of the present invention provides a computer storage medium, wherein the computer storage medium stores computer executable instructions, and the computer executable instructions are used to execute the above-mentioned macro-preparation method of contrast agent.

[0092] It can be seen that the contents of the above-mentioned contrast agent macro-preparation method embodiment are all applicable to the present storage medium embodiment, the functions specifically implemented by the present storage medium embodiment are the same as those of the above-mentioned contrast agent macro-preparation method embodiment, and the beneficial effects achieved are also the same as those achieved by the above-mentioned contrast agent macro-preparation method embodiment.

[0093] It is understood that all or some steps and systems in the disclosed method above can be implemented as software, firmware, hardware and appropriate combinations thereof. Some physical components or all physical components can be implemented as processors, such as software executed by a central processing unit, a digital information processor or a microprocessor, or implemented as hardware, or implemented as an integrated circuit, such as an application-specific integrated circuit. Such software can be distributed on a computer-readable medium, and the computer-readable medium can include a computer storage medium (or a non-transitory medium) and a communication medium (or a temporary medium). As known to those of ordinary skill in the art, the term computer storage medium includes volatile and non-volatile, removable and non-removable media implemented in any method or technology for storing information (such as computer-readable instructions, data structures, program modules or other data). Computer storage media include, but are not limited to, RAM, ROM, EEPROM, flash memory or other memory technologies, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tapes, disk storage or other magnetic storage devices, or any other medium that can be used to store desired information and can be accessed by a computer. Furthermore, it is well known to those skilled in the art that communication media generally contain computer readable instructions, data structures, program modules, or other data in modulated data information such as carrier waves or other transport mechanisms, and may include any information delivery media.

[0094] The embodiments of the present invention are described in detail above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of ordinary technicians in the technical field without departing from the purpose of the present invention.

Claims

1. A contrast agent macro-preparation system, characterized in that: It includes a synthesis module and a purification module; The synthesis module comprises an activation unit, at least one reaction unit and at least one swelling unit, wherein the activation unit is used to modify the surface of the carrier microspheres to obtain modified carrier microspheres, the reaction unit is used to synthesize a first intermediate product, and the swelling unit is used to mix the modified carrier microspheres and the first intermediate product in a swelling agent for reaction and then add a shrinking agent to obtain a crude contrast agent product; The purification module comprises a chromatographic column, which is used to separate and purify the crude contrast agent product to obtain a contrast agent target product.

2. The contrast agent macro-preparation system according to claim 1, characterized in that: The system further comprises a feeding module, which is used to input the carrier microspheres and reaction raw materials into the synthesis module.

3. The contrast agent macro-preparation system according to claim 1, characterized in that: The system further comprises a characterization module, which is connected to a test characterization instrument and is used to determine the properties of the contrast agent target after being processed by the purification module.

4. The contrast agent macro-preparation system according to claim 2, characterized in that: The feeding module includes a first storage bottle, in which a first plunger and a first plunger push rod are provided, the first plunger push rod is used to push the first plunger, a first one-way valve is provided on the input pipe of the first storage bottle, and the output pipe of the first storage bottle is connected to the activation unit through a second one-way valve and an air pump which are arranged in sequence.

5. The contrast agent macro-preparation system according to claim 2, characterized in that: The activation unit and the reaction unit include a fixing bottle and a reaction bottle. The fixing bottle is used for quantitatively storing the reaction raw materials, and the reaction bottle is used for receiving the reaction raw materials and / or the carrier microspheres and then performing the reaction.

6. The contrast agent macro-preparation system according to claim 1, characterized in that: The synthesis module further comprises a first washing unit, which is used to wash the modified carrier microspheres with a first solvent and then transport them to the swelling unit.

7. The contrast agent macro-preparation system according to claim 6, characterized in that: The synthesis module further includes a second washing unit, which is used to wash the crude contrast agent product with a second solvent and then transport it to the purification module.

8. The contrast agent macro-preparation system according to claim 7, characterized in that: The first washing unit and the second washing unit have the same structure, and both include a washing bottle and a second storage bottle. The washing bottle is provided with a second plunger and a second plunger push rod. The second plunger push rod is used to push the second plunger. The second storage bottle is used to transport the first solvent or the second solvent to the washing bottle.

9. The contrast agent macro-preparation system according to claim 5, characterized in that: The reaction bottle is provided with a plurality of liquid inlets and a plurality of liquid outlets, wherein the liquid inlets are used to input the reaction raw materials, and the liquid outlets are used to perform at least one of the following operations: transporting the modified carrier microspheres to the swelling unit via the liquid outlet; or delivering the first intermediate product to the swelling unit via the liquid outlet; or discharging the unreacted reaction raw materials through the liquid outlet; or The modified carrier microspheres are distributed into multiple portions through different liquid outlets and enter different swelling units.

10. The contrast agent macro-preparation system according to claim 1, characterized in that: The swelling unit includes a swelling bottle and a third storage bottle, the swelling bottle is used to input the modified carrier microspheres and the first intermediate product, and after inputting a third solvent through the third storage bottle, the modified carrier microspheres are swelled and then shrunk, so that the first intermediate product is encapsulated in the modified carrier microspheres.

11. The contrast agent macro-preparation system according to claim 2, characterized in that: The purification module further comprises a dialysis unit, which comprises a dialysis container and a dialysis membrane, wherein the dialysis membrane is used to separate the crude contrast agent product in the dialysis container from the reaction raw materials and / or excess first intermediate product and / or excess modified carrier microspheres.

12. The contrast agent macro-preparation system according to claim 5, characterized in that: The reaction unit is equipped with a temperature monitoring sensor and a pH monitoring sensor. The temperature monitoring sensor is used to monitor the temperature in the reaction bottle, and the pH monitoring sensor is used to monitor the pH in the reaction bottle.

13. The contrast agent macro-preparation system according to claim 5, characterized in that: The reaction unit, the activation unit and the swelling unit are further provided with a heating element and a stirring element.

14. A method for preparing a contrast agent in large quantities, characterized in that: Applicable to a contrast agent macro-preparation system, the contrast agent macro-preparation system comprises a synthesis module and a purification module, the synthesis module comprises an activation unit, at least one reaction unit and at least one swelling unit; The macro-preparation method of the contrast agent comprises: The carrier microspheres are transported to the activation unit for surface modification to obtain modified carrier microspheres; The reaction raw materials are transported to the reaction unit for chemical reaction to generate a first intermediate product; delivering the modified carrier microspheres and the first intermediate product to the swelling unit; The modified carrier microspheres are swollen and shrunk by the swelling unit, so that the first intermediate product enters the modified carrier microspheres for encapsulation to obtain a crude contrast agent product; The crude contrast agent product is transported to the purification module for separation and purification to obtain a contrast agent target product.

15. A controller, characterized in that: include: A memory, a processor, and a computer program stored in the memory and executable on the processor, wherein the processor implements the method of claim 14 when executing the computer program.

16. A computer storage medium, characterized in that: The computer storage medium stores computer executable instructions for executing the method of claim 14 .

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