Device for continuously preparing biological macromolecular micro-nano particles by liquid nitrogen

Abstract

The invention discloses a device for continuously preparing biological macromolecular micro-nano particles by liquid nitrogen. The device comprises a supporting platform, a freezing flat plate positioned on the supporting platform, a movable spraying frame, a movable scraping plate and a control panel, a liquid nitrogen containing cavity is formed in the freezing flat plate, and the containing cavity is filled with liquid nitrogen; a spraying device is arranged on the movable spraying frame and is used for spraying materials on the surface of the freezing flat plate; the movable spraying frame and the movable scraping plate are arranged at the two opposite ends of the freezing flat plate respectively and electrically connected with the control panel, and the control panel can control the movable spraying frame and the movable scraping plate to move oppositely or reversely in the extending direction of the freezing flat plate; the method has the advantages that continuous production can be achieved, the biological activity of the medicine is reserved, and energy consumption is reduced.

Description

Technical Field

[0001] This application relates to the technical field of liquid nitrogen spray freeze drying (SFD), and more specifically, to an apparatus for the continuous preparation of micro / nano particles of biomacromolecules using liquid nitrogen. Background Technology

[0002] Biomolecular micro / nanoparticles refer to particulate systems with sizes ranging from micrometers to nanometers, constructed from or based on biomolecular macromolecules (such as proteins and nucleic acids). These systems combine the physicochemical properties of micro / nanomaterials with the biocompatibility and functional specificity of biomolecular macromolecules, showing broad application prospects in fields such as drug delivery, diagnostics, and environmental science. Currently, there are still some shortcomings in the devices used to prepare micro and nano particles of biological macromolecules: (i) Import dependence and technology premium: The core components of high-end micro and nano particle preparation equipment (such as high-efficiency atomization systems and ultra-low temperature continuous freeze dryers) are heavily dependent on imports, and the equipment procurement and maintenance costs are extremely high (for example, the price of imported nano spray dryers is 600,000 to 700,000 yuan), which restricts the independent development of my country's inhaled preparation industry; (ii) Non-continuous process and low efficiency: Although traditional spray freeze drying technology can achieve continuous operation in the atomization stage, its core freezing and drying stages are mostly intermittent batch processing; the materials need to be freeze-dried in a closed chamber for a long time (the cycle is about 15-30 hours), which cannot achieve true continuous production, resulting in low production efficiency, high energy consumption and difficulty in large-scale production; (iii) Difficulty in ensuring drug activity: The traditional freeze drying process has low heat transfer efficiency and long cycle, which may have an adverse effect on the activity of heat-sensitive biological macromolecular drugs. Intermittent operation also increases the difficulty of process control and product quality uniformity: (iv) Low equipment integration and automation level: Existing laboratory or pilot equipment often separates atomization, freezing, drying and other units, which is complicated to operate and makes it difficult to achieve precise linkage control and online monitoring of process parameters, which does not conform to the trend of modern pharmaceutical "quality by design" (QbD) and continuous production. Summary of the Invention

[0003] This application addresses the aforementioned shortcomings of the prior art by providing a device for the continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen, which enables continuous production, preserves the bioactivity of drugs, and reduces energy consumption.

[0004] To solve the above-mentioned technical problems, the technical solution adopted in this application is as follows: an apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen. The apparatus includes a support platform, a freezing plate, a movable spray rack, a movable scraper, and a control panel located on the support platform. The freezing plate is provided with a liquid nitrogen containment cavity, which is filled with liquid nitrogen. The movable spray rack is provided with a spraying device for spraying material onto the surface of the freezing plate. The movable spray rack and the movable scraper are respectively located at opposite ends of the freezing plate and are electrically connected to the control panel. The control panel can control the movable spray rack and the movable scraper to move relative to or in opposite directions along the extension direction of the freezing plate.

[0005] Using the above structure, this application, by setting up a freezing plate, a movable spray rack, and a movable scraper, allows the raw materials for the biomacromolecule micro / nano particles to be produced to be sprayed onto the surface of the freezing plate via a spray device on the movable spray rack. Since liquid nitrogen is contained within the freezing plate, the raw materials are thoroughly frozen. The frozen material is then scraped off the surface of the freezing plate and collected by the movable scraper. In this process, both the movable spray rack and the movable scraper can be automatically moved via a control panel electrically connected to them, performing spraying, freezing, and scraping / collection. The entire process involves continuous conveying and transfer, achieving continuous controllability of the freezing preparation process and increasing the consistency of particle parameters and performance in batch production. This transforms the traditional intermittent, batch processing mode into an integrated continuous production mode. Furthermore, the direct spraying onto the surface of the freezing plate containing liquid nitrogen enhances the process design and control of online, instantaneous deep freezing with liquid nitrogen, ensuring rapid freezing.

[0006] Furthermore, the freezing plate includes a freezing preparation plate and a liquid nitrogen storage plate; the freezing preparation plate is located above the liquid nitrogen storage plate, and the upper surface of the freezing preparation plate is used to receive the material sprayed from the spraying device; the liquid nitrogen containment cavity is disposed within the liquid nitrogen storage plate, and the freezing preparation plate is provided with a liquid nitrogen filling port and a liquid nitrogen exhaust port communicating with the liquid nitrogen containment cavity; with this structure, the material can quickly and directly contact the freezing preparation plate, and the liquid nitrogen in the liquid nitrogen storage plate can be continuously introduced and flowed in real time, ensuring that the cooling effect of the liquid nitrogen is not reduced.

[0007] Furthermore, the liquid nitrogen containment chamber is equipped with multiple parallel baffles. Each baffle has one end connected to the interior of the chamber, and the other end has a gap between it and the interior of the chamber to allow liquid nitrogen to pass through. The gaps and connections between adjacent baffles are alternated. This structure allows liquid nitrogen to flow sequentially from the first baffle to the last baffle, thus allowing the liquid nitrogen to remain in the chamber for a longer time and improving the freezing effect. Furthermore, the spraying device comprises at least three units, arranged sequentially along the length of the movable spraying frame, and the length of the arrangement of the at least three spraying devices is adapted to the width of the frozen preparation plate to be sprayed. This structure allows for simultaneous spraying of materials from at least three spraying devices, improving spraying efficiency and yield. Furthermore, the matching length of the spraying devices to the width of the frozen preparation plate ensures full utilization of the plate's surface without wasting space, thus improving production efficiency and freezing effect.

[0008] Furthermore, the movable spray frame is connected to the spray drive sliding assembly, which can drive the movable spray frame to move back and forth along the length of the track. With the above structure, the spray device can be moved back and forth along one direction of the frozen preparation plate, thereby spraying the material to cover the entire frozen preparation plate.

[0009] Furthermore, the first moving guide rail includes a first moving block connected to the screw (lead screw) of the first drive motor, and a first moving guide rail that slides with the first moving block. The movable spray frame is fixedly connected to the first moving block. With this structure, when the spray device needs to be moved back and forth, the first motor is started, and the output shaft of the first motor drives the screw to rotate, thereby driving the first moving block on it to slide back and forth along the length direction of the first moving guide rail. This allows the spray device on the movable spray frame to move back and forth, so that the material can be sprayed to cover the entire frozen preparation plate.

[0010] Furthermore, the movable scraper includes a movable scraper frame, a blade, a blade adjustment device, and a second moving guide rail. Both the blade and the blade adjustment device are mounted on the movable scraper frame. The blade adjustment device is connected to the blade and can adjust its height. The second moving guide rail is mounted on a support platform. Support frames are provided at both ends of the movable scraper frame along its length. These support frames are connected to a sliding drive mechanism, allowing them to move back and forth along the second moving guide rail. Using this structure, after the material sprayed onto the freezing preparation plate is frozen, the blade is adjusted to a suitable height using the blade adjustment device. Then, the sliding drive mechanism is activated, causing the movable scraper frame to drive the blade to scrape off the material on the freezing preparation plate for collection. This structure can effectively adjust the blade height to a suitable position according to the thickness of the material and allows the blade to slide back and forth to automatically scrape off the frozen material.

[0011] Furthermore, the blade adjustment device includes a second drive motor, a lead screw (screw) connected to the output shaft of the second drive motor, a blade connected to one end of the lead screw, and second moving blocks connected to both ends of the blade along its length. The second moving blocks are connected to a third moving block, which is slidably fitted onto a second moving guide rail mounted on a movable scraper frame. A support plate is also provided between the blade and the movable scraper frame. The support plate is connected to the lead screw, and a guide rod is provided between the support plate and the movable scraper frame. With this structure, when the height of the blade needs to be adjusted, the second drive motor is started, and the motor drives the lead screw to rotate, causing the blade connected to the lead screw to slide back and forth along the second moving guide rail to achieve height adjustment. The support plate is connected to the lead screw and can also move back and forth along the length of the lead screw according to its rotation, maintaining the smooth operation of the entire structure.

[0012] Furthermore, the sliding drive mechanism is disposed on the lower surface of the support platform. The sliding drive mechanism includes a fourth moving block fixedly connected to the support frame, and the fourth moving block is slidably connected to the third moving guide rail. The fourth moving block is connected to the first transmission belt, and the two ends of the first transmission belt are engaged with the transmission wheel. The transmission wheel is driven to rotate by a second transmission belt and a third drive motor. With this structure, when the third drive motor is started, it drives the transmission wheel to rotate through the second transmission belt. The transmission wheel can then drive the first transmission belt to rotate. During the rotation, the fourth moving block connected to it can move together, thereby realizing the back-and-forth movement of the support frame within the second moving guide rail, and thus realizing the back-and-forth movement of the blade along the frozen preparation plate to scrape off the frozen material on it.

[0013] Furthermore, a collection groove is provided at one end of the liquid nitrogen storage plate along the blade's moving direction, and the collection groove is connected to the edge of the freezing preparation plate. With this structure, when the blade scrapes the frozen material along the extension direction of the freezing preparation plate to the edge of the freezing preparation plate, it can fall into the collection groove for collection, which is convenient for operation.

[0014] Furthermore, the collection tank and the liquid nitrogen storage plate are slidably fitted together, and a force-applying handle is provided at one end of the collection tank. With this structure, when the collection tank is full of material, the collection tank can be pulled out by the force-applying handle, and a new collection tank can be added or the collection tank can be inserted again after it is emptied.

[0015] Furthermore, the bottom surface of the support platform is provided with multiple support legs, which can be raised and lowered; this structure allows for easy adjustment of the height of the entire support platform to accommodate the height requirements of different heights or usage environments. Attached Figure Description

[0016] Figure 1 This application presents a schematic diagram of the first view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen.

[0017] Figure 2 This application presents a second view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen.

[0018] Figure 3 This application presents a third view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen.

[0019] Figure 4 The fourth view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen is a structural schematic diagram.

[0020] Figure 5 The fifth view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen is a structural schematic diagram.

[0021] Figure 6 The sixth view of the apparatus for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen is a structural schematic diagram.

[0022] Figure 7 This application presents a schematic diagram of the first view of the blade adjustment device.

[0023] Figure 8 This application presents a schematic diagram of the blade adjustment device from its second view.

[0024] Figure 9 This application presents a structural diagram of a movable spray rack.

[0025] Figure 10 This application presents a schematic diagram of the structure of a freezing plate.

[0026] Figure 11 This application presents a structural schematic diagram of a frozen plate assembly.

[0027] As shown in the attached diagram: S. Liquid nitrogen containment chamber; 1. Support platform; 2. Freezing plate; 201. Freezing preparation plate; 202. Liquid nitrogen storage plate; 203. Liquid nitrogen filling port; 204. Liquid nitrogen exhaust port; 205. Partition; 3. Movable spray frame; 4. Movable scraper; 401. Movable scraper frame; 402. Blade; 403. Blade adjustment device; 4031. Second drive motor; 4032. Second moving block; 4033. Third moving block; 4034. Third moving guide rail; 404. Second moving guide rail (support platform) On the platform), 405. Support frame, 406. Support plate, 407. Guide rod, 5. Control panel, 6. Spraying device, 7. Spray drive sliding assembly, 701. First drive motor, 702. First moving block, 703. First moving guide rail, 8. Sliding drive mechanism, 801. Fourth moving block, 802. Fourth moving guide rail, 803. First transmission belt, 804. Transmission wheel, 805. Second transmission belt, 806. Third drive motor, 9. Collection tank, 10. Force application handle, 11. Track, 12. Motor control system. Detailed Implementation

[0028] The technical solutions in the embodiments of this application will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are merely preferred embodiments, and not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this invention. Furthermore, it should be noted that when a component is referred to as being "fixed to" another component, it can be directly on the other component or it may be fixed via another intermediate component. When a component is considered to be "connected to" another component, it can be directly connected to the other component or it may be fixed via another intermediate component. When a component is considered to be "set on" another component, it can be set directly on the other component or it may be fixed via another intermediate component. The terms "vertical," "horizontal," "left," "right," and similar expressions used herein are for illustrative purposes only; unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0029] As attached Figure 1-9 The diagram illustrates an apparatus for the continuous preparation of micro / nano particles of biomacromolecules using liquid nitrogen, as per this application. The apparatus comprises a support platform 1, a freezing plate 2, a movable spray rack 3, a movable scraper 4, and a control panel 5, all situated on the support platform 1. The freezing plate 2 contains a liquid nitrogen reservoir S filled with liquid nitrogen. The movable spray rack 3 is equipped with a spraying device 6, which sprays the material onto the surface of the freezing plate 2. The movable spray rack 3 and the movable scraper 4 are positioned at opposite ends of the freezing plate 2 and are electrically connected to the control panel 5. The control panel 5 controls the movable spray rack 3 and the movable scraper 4 to move along the surface of the freezing plate 2. The extension direction can be relative to or opposite to the direction of movement; specifically, this application sets a freezing plate filled with liquid nitrogen on the support platform, and sprays the material onto its surface for freezing through a spraying device. The spraying device can move back and forth relative to the freezing plate, such as sliding back and forth along the length of the plate, so that the material can be sprayed onto the entire surface; after exiting, a movable scraper can be moved to scrape off the frozen material from the freezing plate for collection; the movable spraying frame 3 and the movable scraper 4 are respectively set at opposite ends in the length or width direction of the freezing plate 2, spraying first and then scraping off; the back and forth movement of the movable spraying frame 3 and the movable scraper 4 can be operated through the control panel, with a high degree of automation and stable operation.

[0030] Using the above structure, this application, by setting up a freezing plate, a movable spray rack, and a movable scraper, allows the raw materials for the biomacromolecule micro / nano particles to be produced to be sprayed onto the surface of the freezing plate via a spray device on the movable spray rack. Since liquid nitrogen is contained within the freezing plate, the raw materials are thoroughly frozen. The frozen material is then scraped off the surface of the freezing plate and collected by the movable scraper. In this process, both the movable spray rack and the movable scraper can be automatically moved via a control panel electrically connected to them, performing spraying, freezing, and scraping / collection. The entire process involves continuous conveying and transfer, achieving continuous controllability of the freezing preparation process and increasing the consistency of particle parameters and performance in batch production. This transforms the traditional intermittent, batch processing mode into an integrated continuous production mode. Furthermore, the direct spraying onto the surface of the freezing plate containing liquid nitrogen enhances the process design and control of online, instantaneous deep freezing with liquid nitrogen, ensuring rapid freezing.

[0031] As attached Figure 1-2 , Figure 10-11As shown, the freezing plate 2 includes a freezing preparation plate 201 and a liquid nitrogen storage plate 202. The freezing preparation plate 201 is located above the liquid nitrogen storage plate 202, and the upper surface of the freezing preparation plate 201 is used to receive the material sprayed from the spraying device 6. The liquid nitrogen accommodating cavity S is disposed in the liquid nitrogen storage plate 202, and the freezing preparation plate 201 is provided with a liquid nitrogen filling port 203 and a liquid nitrogen exhaust port 204 communicating with the liquid nitrogen accommodating cavity S. That is, liquid nitrogen can enter from the inlet and exit from the outlet in real time, which allows the material to quickly and directly contact the freezing preparation plate, and the liquid nitrogen in the liquid nitrogen storage plate can be continuously introduced to ensure that the cooling effect of liquid nitrogen is not reduced.

[0032] More specifically, as shown in the appendix Figure 11 As shown, the liquid nitrogen containment cavity S is provided with multiple parallel baffles 205. Each baffle has one end connected to the inside of the cavity and the other end has a gap between it and the inside of the cavity to allow liquid nitrogen to pass through. Furthermore, the gap and connection end of two adjacent baffles are alternate (i.e., two adjacent baffles have the same length at one end, one is connected to the inside of the cavity and the other has a gap between it and the inner wall of the cavity). This allows the liquid nitrogen to flow sequentially from the first baffle to the last baffle, thus allowing the liquid nitrogen to stay in the cavity for a longer time and improving the freezing effect.

[0033] As attached Figure 1-2 and Figure 9 As shown, the spraying device 6 described in this application comprises at least three units, which are arranged sequentially along the length of the movable spraying frame 3. The length of the arrangement of the at least three spraying devices 6 is adapted to the extension width of the cryogenic preparation plate 201 to be sprayed. Specifically, the spray decoration here can be a spray drying device commonly used in the industry. The material is stored in the spray drying device, and then the spray nozzles are set on the movable spraying frame to spray the material onto the cryogenic preparation plate 201. With this structure, the material can be sprayed simultaneously from at least three spraying devices, which can improve spraying efficiency and yield. Moreover, the length of the arrangement of the spraying devices is adapted to the extension width of the cryogenic preparation plate to be sprayed, which can make full use of the surface of the cryogenic preparation plate without causing area waste, thereby improving production efficiency and freezing effect.

[0034] As attached Figure 1-2 and Figure 9As shown, the movable spray frame 3 described in this application is connected to the spray drive sliding assembly 7. The spray drive sliding assembly 7 can drive the movable spray frame 3 to move back and forth along the length of the track. Specifically, a first moving guide rail 703 is fixed on the support platform 1. The movable spray frame 3 is driven to move back and forth along the length of the guide rail by the drive mechanism, so that the spray device can move from one end of the frozen preparation plate to the other end and evenly spray the material on its surface. This structure can realize the ability to move the spray device back and forth along one direction of the frozen preparation plate, thereby spraying the material to cover the entire frozen preparation plate.

[0035] As attached Figure 1-2 and Figure 9 As shown, the spray-driven sliding assembly 7 described in this application includes a first moving block 702 connected to the screw (lead screw, such as a ball screw or trapezoidal lead screw on the market) of the first drive motor 701, a first moving guide rail 703 slidably engaged with the first moving block 702, and the movable spray frame 3 fixedly connected to the first moving block 702. Specifically, when it is necessary to move the spray device back and forth, the first drive motor is started, such as by using a stepper motor to drive the lead screw to rotate, thereby causing the first moving block to slide back and forth along the first moving guide rail, which in turn drives the spray device on the movable spray frame to move back and forth, so that the material can be sprayed to cover the entire frozen preparation plate.

[0036] As attached Figure 1-2 As shown, both the movable spray frame 3 and the movable scraper 4 described in this application are connected to a track 11 below. Specifically, two tracks are provided, one connected to the movable spray frame 3 and the other connected to the movable scraper. The two tracks are symmetrically arranged along the width direction of the movable scraper (i.e., the direction perpendicular to the moving direction of the scraper or spraying device). This structure allows the movable spray frame and the movable scraper to move more smoothly and accurately on their respective sliding tracks.

[0037] As attached Figure 4-6 As shown, a motor control system 12 is provided on the lower surface of the support platform 1 described in this application. The motor control system is used for electrical connection with the control panel. Specifically, the motor control system can be configured as follows: Figure 4 The two electrical control box structures shown are used to control the movable spray frame 3 to move back and forth along its track so that the spray device can spray and freeze the material; the other is used to control the movable scraper 4 so that the blades scrape off and collect the material prepared on the freezing platform.

[0038] As attached Figure 1-8As shown, the movable scraper 4 described in this application includes a movable scraper frame 401, a blade 402, a blade adjustment device 403, and a second moving guide rail 404. The blade 402 and the blade adjustment device 403 are both mounted on the movable scraper frame 401. The blade adjustment device 403 is connected to the blade 402 and can adjust the height of the blade 402. The second moving guide rail 404 is mounted on a support platform 1 (i.e., two sets of symmetrical through-slot structures are provided in the length or width directions of the support platform). Support frames 405 are provided at both ends of the movable scraper frame 401 along its length direction. The support frames 405 are connected to a sliding drive mechanism. The support frame 405 is connected to the second moving guide rail 404 and moves back and forth. Specifically, the support frame 405 extends downward perpendicular to the surface of the support platform and passes through the second moving guide rail to the bottom side of the support platform, where it is connected to the sliding drive mechanism 8. With the above structure, after the material sprayed on the freezing preparation plate is frozen, the blade is adjusted to a suitable height by the blade adjustment device, and then the sliding drive mechanism is activated to make the movable scraper frame drive the blade to scrape off the material on the freezing preparation plate for collection. This structure can effectively adjust the height of the blade to a suitable position according to the thickness of the material, and can also make the blade slide back and forth to automatically scrape off the frozen material.

[0039] As attached Figure 1-8 As shown, the blade adjustment device 403 described in this application includes a second drive motor 4031, a lead screw (screw) connected to the output shaft of the second drive motor 4031, a blade 402 connected to one end of the lead screw, and second moving blocks 4032 connected to both ends of the blade 402 along its length. The second moving blocks 4032 are connected to a third moving block 4033, and the third moving block 4033 is slidably fitted onto a third moving guide rail 4034 mounted on a movable scraper frame 401 (specifically, two support plates extend vertically downward from the movable scraper frame, and the third moving guide rail 4034 is fixed on the support plates); a [further details about the device are missing from the original text]. A support plate 406 (extending laterally and parallel to the movable scraper frame 401) is connected to a lead screw, and a guide rod 407 (two guide rods, perpendicular to the support platform 1, used for sliding guidance between the support plate 406 and the movable scraper frame 401, and limiting the support plate 406 from rotating) is provided between the support plate 406 and the movable scraper frame 401. With the above structure, when it is necessary to adjust the height of the blade, the second drive motor is started, and the motor drives the lead screw to rotate, so that the blade connected to the lead screw slides back and forth along the second moving guide rail to achieve height adjustment. The support plate is connected to the lead screw and can also move back and forth along the length of the lead screw according to the rotation of the lead screw, keeping the operation of the entire structure stable.

[0040] As attached Figure 1-8 As shown, the sliding drive mechanism 8 described in this application is disposed on the lower surface of the support platform 1. The sliding drive mechanism 8 includes a fourth moving block 801 fixedly connected to the support frame 405. The fourth moving block 801 is slidably connected to the fourth moving guide rail 802. The fourth moving block 801 is also connected to the first transmission belt 803. Both ends of the first transmission belt 803 are engaged with the transmission wheel 804. The transmission wheel 804 is driven to rotate by a transmission connection between the second transmission belt 805 and the third drive motor 806. Specifically, the transmission wheels located at both ends of the first transmission belt are connected to the support platform and can rotate relative to it, wherein one end of the transmission wheel is the active drive wheel. The first drive wheel is a driven wheel, and the other end is a driven wheel. The sliding drive mechanism of this application is provided with two sets of parallel and symmetrically arranged at both ends of the length direction of the movable scraper frame. Among them, two of the driving wheels in the two sets and another transmission wheel connected to the transmission wheel on the output shaft of the third drive motor through the second conveyor belt are coaxially arranged. In this way, when the third drive motor is started, it drives the transmission wheel to rotate through the second transmission belt. The transmission wheel can drive the first transmission belt to rotate. During the rotation, the fourth moving block connected to it can move together, thereby realizing the back-and-forth movement of the support frame within the second moving guide rail, thereby realizing the blade moving back and forth along the frozen preparation plate to scrape off the frozen material on it.

[0041] As attached Figure 1 and Figure 10-11 As shown, the liquid nitrogen storage plate 202 described in this application is provided with a collection groove 9 at one end along the moving direction of the blade 402. The collection groove 9 is connected to the edge of the freezing preparation plate 201. That is, the height of the collection groove is lower than the height of the freezing preparation plate, so the material coming down from the freezing preparation plate can fall directly into the collection groove. With this structure, when the blade scrapes the frozen material along the extension direction of the freezing preparation plate to the edge of the freezing preparation plate, it can fall into the collection groove for collection, which is convenient for operation.

[0042] As attached Figure 11 As shown, the collection tank 9 and the liquid nitrogen storage plate 202 described in this application are slidably fitted together. A force-applying handle 10 is provided at one end of the collection tank 9. Specifically, a groove is provided along the width direction at one end of the liquid nitrogen storage plate, and the collection tank is slidably fitted directly or indirectly in the groove. The length extension direction of the groove should be perpendicular to the running direction of the blade. With this structure, when the collection tank is full of material, the collection tank can be pulled out by the force-applying handle, and a new collection tank can be added or the collection tank can be inserted again after it is emptied.

[0043] As attached Figure 1-6As shown, the support platform 1 described in this application has multiple support feet 101 on its lower surface, which can be raised and lowered. Specifically, these support feet can be configured with double tubes, with the outer tube fixedly connected to the support platform and the inner tube having an external thread corresponding to the inner thread of the outer tube. The outer tube and the inner tube are connected by threads, and the position of the inner tube relative to the outer tube can be adjusted by turning the threads, thereby adjusting the height according to the change in position. This structure allows for convenient adjustment of the height of the entire support platform to meet the height requirements of different heights or usage environments.

[0044] The motor control system 12, control panel 5, and the drive motors (such as stepper motors) of the two moving components involved in this application can be controlled using industry-standard technologies such as PLC control, depending on specific operational needs. The PLC uses a ladder diagram program to implement the logic. A start signal (such as a button press) triggers a rising edge detection, sets the output relay, and self-locks, starting the motor. When the button is pressed again, the rising edge signal resets the self-locking, the output disconnects, and the motor stops. The buttons (start / stop) on the control panel serve as input devices, connected to the input port of the control system via wires. The signal transmission path includes: the start signal is input from the control panel to the control unit (such as a relay coil or PLC input point); the control unit processes the signal and drives the actuator (such as a contactor coil); the contactor's main contacts actuate to control the main circuit's on / off state, thereby achieving motor start and stop. This is industry-standard electrical control technology and does not require detailed explanation.

[0045] The working principle and operation process of this structural product are as follows: (1) Feeding and atomization: The solution containing biomolecular drugs and excipients is atomized by the spray device and sprayed onto the surface of the freezing plate through the nozzle, where it is dispersed into tiny droplets with uniform particle size; (2) Instant freezing with liquid nitrogen: The atomized droplets are rapidly frozen into solid micro ice particles in a very short time (millisecond level), forming a porous precursor structure and preserving the bioactivity of the drug; (3) Continuous conveying and transfer: The frozen particles are smoothly and continuously scraped off the surface of the plate by the blades on the movable scraper and stored in the collection tank at the edge of the liquid nitrogen storage plate; (4) Full-process control: The control system electrically connected to the control panel can monitor the key parameters of each link in real time to ensure process stability and product repeatability.

[0046] Compared with existing devices, the technical solution of this application has the following innovations: 1. Process mode: It transforms the traditional intermittent and batch processing mode into an integrated continuous production mode; 2. System integration: It adds a continuous conveying and transfer system, realizing the continuous controllability of the freezing preparation process and increasing the consistency of particle parameters and performance in batch production; 3. Freezing method: It strengthens the process design and control of online liquid nitrogen and instantaneous deep freezing to ensure rapid freezing; The technical solution of this application realizes the device layout and connection method for continuous integrated spraying and liquid nitrogen freezing processes; The continuous conveying method of this application can adopt various forms such as conveyor belts and vibrating discs; The scale of the device of this application can be modularly scaled to adapt to different scale needs of laboratories, pilot plants and production; The liquid nitrogen refrigeration method of this application can be direct spraying, immersion or low-temperature nitrogen atmosphere, etc.

Claims

1. A device for the continuous preparation of micro / nano particles of biological macromolecules using liquid nitrogen, characterized in that: The device comprises a support platform, a freezing plate on the support platform, a movable spray rack, a movable scraper, and a control panel. The freezing plate contains a liquid nitrogen chamber filled with liquid nitrogen. The movable spray rack is equipped with a spraying device for spraying material onto the surface of the freezing plate. The movable spray rack and the movable scraper are located at opposite ends of the freezing plate and are electrically connected to the control panel. The control panel can control the movable spray rack and the movable scraper to move relative to or in opposite directions along the extension direction of the freezing plate.

2. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 1, characterized in that: The freezing plate includes a freezing preparation plate and a liquid nitrogen storage plate; the freezing preparation plate is located above the liquid nitrogen storage plate, and the upper surface of the freezing preparation plate is used to receive the material sprayed from the spraying device; the liquid nitrogen containment cavity is disposed inside the liquid nitrogen storage plate, and the freezing preparation plate is provided with a liquid nitrogen filling port and a liquid ammonia exhaust port communicating with the liquid nitrogen containment cavity.

3. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 2, characterized in that: The liquid nitrogen containment cavity is provided with multiple partitions arranged in parallel to each other. Each partition has one end connected to the inside of the cavity and the other end has a gap between it and the inside of the cavity to allow liquid nitrogen to pass through. Furthermore, the spacing and connection ends of two adjacent partitions are alternately arranged.

4. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 1, characterized in that: The spraying device is provided in at least three parts, which are arranged sequentially along the length of the movable spraying frame, and the length of the arrangement of the at least three spraying devices is adapted to the width of the frozen preparation plate to be sprayed; the movable spraying frame is connected to a first moving guide rail, which can drive the movable spraying frame to move back and forth along the length of the track.

5. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 4, characterized in that: The first moving guide rail includes a first moving block connected to a screw of a first drive motor, a first moving guide rail slidably engaged with the first moving block, and the movable spray frame is fixedly connected to the first moving block.

6. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 1, characterized in that: The movable scraper includes a movable scraper frame, a blade, a blade adjustment device, and a second moving guide rail. The blade and the blade adjustment device are both mounted on the movable scraper frame. The blade adjustment device is connected to the blade and can adjust the height of the blade. The second moving guide rail is mounted on a support platform. Support frames are provided at both ends of the movable scraper frame along its length. The support frames are connected to a sliding drive mechanism, which allows the support frames to move back and forth along the second moving guide rail.

7. The apparatus for continuous preparation of biomacromolecule micro / nanoparticles using liquid nitrogen according to claim 6, characterized in that: The blade adjustment device includes a second drive motor, a lead screw connected to the output shaft of the second drive motor, a blade connected to one end of the lead screw, and second moving blocks connected to both ends of the blade along its length. The second moving blocks are connected to a third moving block, and the third moving block is slidably fitted onto a second moving guide rail mounted on a movable scraper frame. A support plate is also provided between the blade and the movable scraper frame. The support plate is connected to the lead screw, and a guide rod is provided between the support plate and the movable scraper frame.

8. The apparatus for continuous preparation of biomacromolecule micro / nanoparticles using liquid nitrogen according to claim 7, characterized in that: The sliding drive mechanism is disposed on the lower surface of the support platform. The sliding drive mechanism includes a fourth moving block fixedly connected to the support frame and slidably connected to a third moving guide rail. The fourth moving block is connected to a first transmission belt, and the two ends of the first transmission belt are engaged with a transmission wheel. The transmission wheel is driven to rotate by a third drive motor through a second transmission belt.

9. The apparatus for continuous preparation of biomacromolecule micro / nano particles using liquid nitrogen according to claim 1, characterized in that: The liquid nitrogen storage plate is provided with a collection groove at one end along the blade movement direction, and the collection groove is connected to the edge of the cryogenic preparation plate; the bottom surface of the support platform is provided with multiple support legs, which can be raised and lowered.

10. The apparatus for continuous preparation of biomacromolecule micro / nanoparticles using liquid nitrogen according to claim 9, characterized in that: The collection tank and the liquid nitrogen storage plate are in sliding fit, and a force-applying handle is provided at one end of the collection tank.

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