Industrial-grade nano-drug preparation device and preparation method

Abstract

The invention relates to an industrial-grade nano-drug preparation device and a preparation method, and the industrial-grade nano-drug preparation device comprises a nano-drug preparation assembly, a buffer vehicle assembly, a lipid phase storage assembly, a water phase storage assembly, a dilution phase storage assembly and a harvest phase storage assembly; the buffer vehicle assembly is provided with a lipid phase buffer unit, a water phase buffer unit and a dilution phase buffer unit; the output ends of the storage assemblies are connected with the input ends of the buffer units in a one-to-one correspondence manner; the output ends of the buffer units are connected with the input ends of the nano-drug preparation assemblies in a one-to-one correspondence mode, and the output ends of the nano-drug preparation assemblies are connected with the input end of the harvesting phase storage assembly. A peristaltic pump and a centrifugal pump of the nano-drug preparation assembly are matched to work, and a lipid phase, a water phase and a dilution phase are respectively conveyed to the micro-fluidic chip. The industrial-grade nano-drug preparation device provided by the invention aims to overcome the existing defects, and has the advantages of being convenient to operate, compact in structure, advanced, simple and convenient in process and accurate and stable in operation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to an industrial-grade nano drug preparation device and a preparation method. Background Art

[0002] The industrial-grade nano-drug preparation device is a process that uses microfluidic laminar flow technology to prepare drugs into nano-scale particles. It mainly achieves large-scale preparation of nano-drug particles by optimizing the preparation process and improving the equipment preparation capacity.

[0003] At present, the preparation of industrial-grade nanomedicine generally has problems such as high production cost, complicated process, low automation, barriers to scale-up production, and barriers to quality control, which restrict the development of nanomedicine. There is currently a lack of stable large-scale nanomedicine preparation systems and large-scale nanomedicine preparation equipment. Therefore, an industrial-grade nanomedicine preparation device and preparation method are proposed to address the above problems. Summary of the invention

[0004] The purpose of the present invention is to overcome the existing defects and provide an industrial-grade nano-drug preparation device, which has the advantages of convenient operation, compact structure, advanced and simple process, and precise and stable operation.

[0005] The technical solution to achieve the above object is: an industrial-grade nano drug preparation device, comprising: a nano drug preparation component, a buffer vehicle component, a lipid phase storage component, an aqueous phase storage component, a dilution phase storage component and a harvest phase storage component;

[0006] The buffer vehicle assembly comprises a lipid phase buffer unit, an aqueous phase buffer unit and a dilution phase buffer unit, the output ends of the lipid phase storage assembly, the aqueous phase storage assembly and the dilution phase storage assembly are connected to the input ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit in a one-to-one correspondence; the output ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit are connected to the input end of the nano drug preparation assembly in a one-to-one correspondence, and the output end of the nano drug preparation assembly is connected to the input end of the harvest phase storage assembly;

[0007] Wherein, the nano drug preparation assembly includes a microfluidic chip, a first centrifugal pump, a second centrifugal pump, a third centrifugal pump, a fourth peristaltic pump, a first injection pipeline, a second injection pipeline, a first pipeline, a sixth pipeline and a fluid control unit;

[0008] The first centrifugal pump is connected to the first inlet end of the microfluidic chip through the first sample injection pipeline, the second centrifugal pump is connected to the second inlet end of the microfluidic chip through the second sample injection pipeline, the outlet end of the microfluidic chip is provided with a four-way connector, the first end of the four-way connector is connected to the outlet end of the microfluidic chip, the third centrifugal pump is connected to the second end of the four-way connector through the first pipeline, the fourth peristaltic pump is connected to the third end of the four-way connector through a peristaltic pump tube, and the fourth end of the four-way connector is connected to the sixth pipeline;

[0009] The fluid control unit includes a one-way valve, a pinch valve and a flow sensor which are arranged on the first sample inlet pipeline, the second sample inlet pipeline and the first pipeline.

[0010] Preferably, the first centrifugal pump, the second centrifugal pump and the third centrifugal pump are all magnetic levitation pumps, and the first sample inlet pipeline, the second sample inlet pipeline and the first pipeline are all provided with two one-way valves.

[0011] Preferably, it also includes: a standard liquid storage container and a standard liquid pipeline, the standard liquid pipeline includes a first standard liquid connecting pipeline, a second standard liquid connecting pipeline and a third standard liquid connecting pipeline; one end of the first standard liquid connecting pipeline, the second standard liquid connecting pipeline and the third standard liquid connecting pipeline are all connected to the outlet of the standard liquid storage container, the other end of the first standard liquid connecting pipeline is connected to the third centrifugal pump through a third pump joint connecting pipe, the other end of the second standard liquid connecting pipeline is connected to the second centrifugal pump through a second pump joint connecting pipe, and the other end of the third standard liquid connecting pipeline is connected to the first centrifugal pump through a first pump joint connecting pipe;

[0012] The third standard liquid connecting pipeline, the second standard liquid connecting pipeline and the first standard liquid connecting pipeline are all provided with pipe clamps.

[0013] Preferably, it further comprises a waste liquid collection container and a waste liquid pipeline, the waste liquid pipeline comprises a second pipeline, a third pipeline, a fourth pipeline and a fifth pipeline, the fourth pipeline and the fifth pipeline are arranged in parallel between the waste liquid collection container and the third pipeline, the second pipeline and the fourth peristaltic pump are arranged in parallel between the third pipeline and the third end of the four-way connector;

[0014] The second pipeline is provided with a pinch valve, the fourth pipeline is provided with a mass flow meter, and the fifth pipeline is provided with a pneumatic ball valve.

[0015] Preferably, the fourth pipeline and the fifth pipeline are both provided with a first liquid leakage detection sensor.

[0016] Preferably, the harvest phase storage assembly comprises a second shell, a finished product collection container is arranged in the second shell, an inlet of the finished product collection container is connected to the sixth pipeline, and a tube clamp valve and a tube clamp are arranged on the sixth pipeline.

[0017] The buffer vehicle assembly comprises a third shell, a first weighing sensor, a second weighing sensor and a third weighing sensor are respectively arranged on the top of the third shell, the lower end of the first weighing sensor is connected to a dilution phase buffer bag, the lower end of the second weighing sensor is connected to an aqueous phase buffer bag, and the lower end of the third weighing sensor is connected to a lipid phase buffer bag; a first peristaltic pump, a second peristaltic pump and a third peristaltic pump are respectively arranged on the outer wall of the third shell, the first peristaltic pump is arranged on the lipid phase conveying pipeline, and is used to convey the liquid in the lipid phase storage assembly to the lipid phase buffer bag; the second peristaltic pump is arranged on the aqueous phase conveying pipeline, and is used to convey the liquid in the aqueous phase storage assembly to the aqueous phase buffer bag; the third peristaltic pump is arranged on the dilution phase conveying pipeline, and is used to convey the liquid in the dilution phase storage assembly to the dilution phase buffer bag;

[0018] The outlet of the dilution phase buffer bag is connected to the third centrifugal pump via the third buffer vehicle connecting pipeline and the third pump joint connecting pipe; the outlet of the water phase buffer bag is connected to the second centrifugal pump via the second buffer vehicle connecting pipeline and the second pump joint connecting pipe; the outlet of the lipid phase buffer bag is connected to the first centrifugal pump via the first buffer vehicle connecting pipeline and the first pump joint connecting pipe;

[0019] The third buffer car connecting pipeline, the second buffer car connecting pipeline and the first buffer car connecting pipeline are all provided with pipe clamps.

[0020] The lipid phase storage component comprises a sixth shell, a lipid phase storage bag is arranged in the sixth shell, and an outlet of the lipid phase storage bag is connected to the first peristaltic pump;

[0021] The water phase storage assembly comprises a fourth shell, a water phase storage bag is arranged in the fourth shell, and the outlet of the water phase storage bag is connected to the second peristaltic pump;

[0022] The dilution phase storage assembly comprises a fifth shell, a dilution phase storage bag is arranged in the fifth shell, and an outlet of the dilution phase storage bag is connected to the third peristaltic pump.

[0023] The pump heads of the first centrifugal pump, the second centrifugal pump and the third centrifugal pump, aseptic connectors, clamps, flow sensors, first pipelines, microfluidic chips, four-way connectors, three-way connectors, and peristaltic pump tubes form a disposable consumables kit;

[0024] The inlet of the flow sensor and the outlet of the pump head are fixed together by the clamp, and the three-way connector is used to connect the peristaltic pump tube, the four-way connector and the waste liquid pipeline respectively.

[0025] Preferably, the nano drug preparation assembly further comprises a first shell, a touch screen is arranged above the front end surface of the first shell, a USB interface, a start / stop button, an emergency stop button and a signal indicator light are arranged on one side of the touch screen, and a barcode scanner is arranged on the other side of the touch screen;

[0026] A control system circuit board is provided on the inner side of the first shell, and the USB interface, the start / stop button, the emergency stop button, the signal indicator light, the touch screen, the barcode scanner, and the peristaltic pump, centrifugal pump, one-way valve, pinch valve, flow sensor and mass flow meter arranged on the pipeline are all electrically connected to the control system circuit board.

[0027] Preferably, a leakage collecting tray and a second leakage detection sensor for detecting pipeline leakage are arranged in the first shell.

[0028] A preparation method based on the industrial-grade nano drug preparation device comprises:

[0029] Step S1, loading the buffer vehicle fluid bag;

[0030] Step S2, pre-filling;

[0031] Step S3, flow calibration;

[0032] Step S4, preparing the front-stage waste liquid for discharge;

[0033] Step S5, preparation;

[0034] Step S6, cleaning the mass flow meter.

[0035] The step S1, loading the buffer vehicle fluid bag comprises:

[0036] Step S11, lipid phase liquid bag loading: the control system circuit board issues a lipid phase loading instruction, and the first peristaltic pump on the buffer vehicle works to transfer the liquid in the lipid phase storage bag to the lipid phase buffer bag; when the third weighing sensor detects that the liquid in the lipid phase buffer bag reaches the program-set weight, the first peristaltic pump stops working and the loading is completed;

[0037] Step S12, loading the aqueous phase liquid bag: the control system circuit board issues an aqueous phase loading instruction, and the second peristaltic pump on the buffer vehicle starts working to transfer the liquid in the aqueous phase storage bag to the aqueous phase buffer bag; when the second weighing sensor detects that the liquid in the aqueous phase buffer bag reaches the program-set weight, the second peristaltic pump stops working and the loading is completed;

[0038] Step S13, loading the dilution phase liquid bag: the control system circuit board sends a dilution phase loading instruction, and the third peristaltic pump on the buffer vehicle starts working to transfer the liquid in the dilution phase storage bag to the dilution phase buffer bag; when the first weighing sensor detects that the liquid in the dilution phase buffer bag reaches the program set weight, the third peristaltic pump stops working and the loading is completed.

[0039] The step S2, pre-filling includes:

[0040] Step S21, lipid phase pre-filling: open the first tube clamp, connect the standard solution storage bag to the first pump joint connecting tube through the third standard solution connecting pipeline; the control system circuit board issues a lipid phase pre-filling instruction, opens the fourth peristaltic pump, the pneumatic ball valve and the clamp valve on the lipid phase pre-filling pipeline, and under the action of the fourth peristaltic pump, the standard solution flows from the standard solution storage bag through the first centrifugal pump, the first ultrasonic flow sensor and the fourth one-way valve, and enters the microfluidic chip; after flowing out from the outlet of the microfluidic chip, it enters the waste liquid collection box through the peristaltic pump tube and the fifth pipeline; when the first ultrasonic flow sensor detects the flow of liquid within the set time and detects that there are no bubbles inside the pipeline, the lipid phase pre-filling is completed; at this time, close the corresponding clamp valve, and manually close the first tube clamp to prevent liquid backflow;

[0041] Step S22, water phase pre-filling: open the second tube clamp, connect the standard liquid storage bag to the second pump joint connecting pipe through the second standard liquid connecting pipe; the control system circuit board issues a water phase pre-filling instruction, opens the fourth peristaltic pump, the pneumatic ball valve and the clamp valve on the water phase pre-filling pipe, and under the action of the fourth peristaltic pump, the standard liquid flows from the standard liquid storage bag through the second centrifugal pump, the second ultrasonic flow sensor and the second one-way valve, and enters the microfluidic chip; after flowing out from the outlet of the microfluidic chip, it enters the waste liquid collection box through the peristaltic pump tube and the fifth pipe; when the second ultrasonic flow sensor detects the flow of liquid within the set time; and there are no bubbles in the liquid, the water phase pre-filling is completed; at this time, close the corresponding clamp valve, and manually close the second tube clamp to prevent liquid backflow;

[0042] Step S23, dilution phase pre-filling: open the third tube clamp, connect the standard liquid storage bag to the third pump connector connecting tube through the first standard liquid connecting pipeline; the control system circuit board sends a dilution phase pre-filling instruction, opens the fourth peristaltic pump, the pneumatic ball valve and the clamping valve on the dilution phase pre-filling pipeline, and under the action of the fourth peristaltic pump, the standard liquid flows from the standard liquid storage bag through the third centrifugal pump, the third ultrasonic flow sensor and the sixth one-way valve into the peristaltic pump tube, and after flowing out of the peristaltic pump tube, enters the waste liquid collection box through the fifth pipeline; when the third ultrasonic flow sensor detects the flow of liquid within the set time; and there are no bubbles in the liquid, the dilution phase pre-filling is completed; at this time, close the corresponding clamping valve to prevent the liquid from flowing back.

[0043] Step S3, flow calibration includes:

[0044] Step S31, lipid phase calibration: open the first tube clamp, connect the standard solution storage bag to the first pump joint connection pipe through the third standard solution connection pipe; the control system circuit board sends a lipid phase calibration instruction, turns on the first centrifugal pump, and under the action of the first centrifugal pump, the standard solution flows from the standard solution storage bag through the pump head of the first centrifugal pump, the first ultrasonic flow sensor and the fourth one-way valve, and enters the microfluidic chip; flows out from the outlet of the microfluidic chip, passes through the second pipe, the third pipe, the fourth pipe, and the mass flow meter, and enters the waste liquid collection box; the flow rate of the standard solution detected by the mass flow meter and the flow rate detected by the first ultrasonic flow sensor are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the first ultrasonic flow sensor to calibrate the data of the first ultrasonic flow sensor; after the lipid phase calibration is completed, close the corresponding clamp valve, and manually close the first tube clamp to prevent liquid backflow;

[0045] Step S32, water phase calibration: open the second tube clamp, connect the standard liquid storage bag to the second pump joint connecting pipe through the second standard liquid connecting pipe, the control system circuit board sends a water phase calibration instruction, turn on the second centrifugal pump, and under the action of the second centrifugal pump, the standard liquid flows from the standard liquid storage bag through the pump head of the second centrifugal pump, the second ultrasonic flow sensor and the fifth one-way valve, and enters the microfluidic chip; after flowing out from the outlet of the microfluidic chip, it passes through the second pipeline, the third pipeline, the fourth pipeline, enters the mass flow meter, and enters the waste liquid collection box; the standard liquid flow rate detected by the mass flow meter and the flow rate detected by the second ultrasonic flow sensor are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the second ultrasonic flow sensor to calibrate the data of the second ultrasonic flow sensor; when the water phase calibration is completed, close the corresponding clamp valve, and manually close the second tube clamp to prevent liquid backflow;

[0046] Step S33, dilution phase calibration: open the third tube clamp, connect the standard liquid storage bag to the third pump joint connecting pipe through the first standard liquid connecting pipe; the control system circuit board sends a dilution phase calibration instruction, turns on the third centrifugal pump, and under the action of the third centrifugal pump, the standard liquid flows from the standard liquid storage bag through the pump head of the third centrifugal pump, the third ultrasonic flow sensor, the sixth one-way valve, the second pipeline, the third pipeline, the fourth pipeline, the mass flow meter, and enters the waste liquid collection box; the standard liquid flow rate detected by the mass flow meter and the flow rate detected by the third ultrasonic flow sensor are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the third ultrasonic flow sensor to calibrate the data of the third ultrasonic flow sensor; when the water phase calibration is completed, close the corresponding clamp valve, and manually close the third tube clamp to prevent liquid backflow.

[0047] The step S4, preparing the front-end waste liquid for discharge, comprises:

[0048] Step S41, close the first tube clamp, the second tube clamp and the third tube clamp; first open the fifth tube clamp, the sixth tube clamp and the seventh tube clamp; then open the first tube clamp valve, the second tube clamp valve, the third tube clamp valve and the fifth tube clamp valve; open the pneumatic ball valve; at this time, open the first centrifugal pump, the second centrifugal pump and the third centrifugal pump to drive the liquid to flow through the pipelines of the lipid phase, the aqueous phase and the dilution phase, and after merging at the outlet of the microfluidic chip, enter the waste liquid collection box through the second pipeline, the third pipeline and the fifth pipeline; when the flow rate of the waste liquid in the front stage of the preparation reaches the set value, the discharge of the waste liquid in the front stage of the preparation is completed.

[0049] The step S5, preparation comprises:

[0050] Step S51, after the discharge of the waste liquid in the front stage of the preparation is completed, the first centrifugal pump, the second centrifugal pump, and the third centrifugal pump continue to work; open the fourth tube clamp, close the fifth tube clamp valve, close the pneumatic ball valve, and open the fourth tube clamp valve, so that the preparation liquid flowing out of the outlet of the microfluidic chip enters the finished product collection box from the sixth pipeline; when the first weighing sensor, the second weighing sensor, and the third weighing sensor of the buffer vehicle detect that the liquid in the buffer bag is used up, the preparation is completed; turn off the first centrifugal pump, the second centrifugal pump, and the third centrifugal pump; close the first tube clamp valve, the second tube clamp valve, the third tube clamp valve, and the fourth tube clamp valve.

[0051] The step S6, mass flow meter cleaning comprises:

[0052] Step S61, after the preparation is completed, open the third tube clamp corresponding to the standard solution storage bag; open the third tube clamp valve and the fifth tube clamp valve; start the third centrifugal pump to allow the standard solution to enter the mass flow meter from the dilution phase flow path to clean it; when the cleaning time reaches the set time, the cleaning is completed.

[0053] The beneficial effects of the present invention are as follows: the industrial-grade nano-drug preparation device and preparation method have the advantages of convenient operation, compact structure, advanced and simple process, and precise and stable operation.

[0054] Among them, loading the liquid through the buffer cart assembly can ensure that the pressure of the liquid remains constant when entering the pump head, reduce liquid disturbance, and avoid the liquid level height of the external liquid preparation equipment affecting the flow rate accuracy of the device, thereby improving the stability of the nano-preparation system and enhancing its compatibility in different working environments. The buffer cart assembly is used to set the buffer solution volume in advance, and the stability of the preparation process can be guaranteed regardless of the preparation amount.

[0055] In addition, by using a mass flow meter to calibrate the first ultrasonic flow sensor, the second ultrasonic flow sensor, and the third ultrasonic flow sensor, the accuracy of the flow rate at each stage in the preparation of nanomedicine is ensured, thereby improving the stability of the large-scale production process. At the same time, by setting up a cleaning process for the mass flow meter, its accuracy can be maintained more effectively, thereby ensuring the performance of the mass flow meter.

[0056] Furthermore, the use of standard solution pre-filling in the pre-filling stage effectively reduces the loss of lipids, thereby reducing the cost in the large-scale preparation of nanomedicines.

[0057] On this basis, by optimizing the design of the consumable flow path of the nanomedicine preparation components, the use of disposable consumable kits is not only easy to operate, but also can effectively reduce liquid residue and further reduce production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 It is an overall schematic diagram of the industrial-grade nano-drug preparation device of the present invention;

[0059] Figure 2 This is a front view of the industrial-grade nano-drug preparation device of the present invention;

[0060] Figure 3 is a schematic diagram of the nano drug preparation assembly of the present invention;

[0061] Figure 4 is a schematic diagram of another perspective of the nanomedicine preparation assembly of the present invention;

[0062] Figure 5 is a front view of the buffer car assembly of the present invention;

[0063] Figure 6 is an axonometric view of the buffer car assembly of the present invention;

[0064] Figure 7 This is a detailed diagram of the pipeline connection of the industrial-grade nano-drug preparation device of the present invention;

[0065] Figure 8 It is a structural schematic diagram of the disposable consumable kit of the present invention;

[0066] Fig. 9 is a side view of the disposable consumable kit of the present invention;

[0067] Fig.10 It is a schematic diagram of the preparation method of the industrial-grade nano drug preparation device of the present invention;

[0068] Fig.11 It is a detailed diagram of step S1 of the preparation method of the industrial-grade nano-drug preparation device of the present invention;

[0069] Fig.12 is a detailed diagram of step S2 of the method for preparing an industrial-grade nano-drug preparation device of the present invention;

[0070] Fig.13 is a detailed diagram of step S3 of the preparation method of the industrial-grade nano-drug preparation device of the present invention;

[0071] Fig.14 is a detailed diagram of step S4 of the method for preparing an industrial-grade nano-drug preparation device of the present invention;

[0072] Fig.15 is a detailed diagram of step S5 of the method for preparing an industrial-grade nano-drug preparation device of the present invention;

[0073] Fig.16 It is a detailed diagram of step S6 of the preparation method of the industrial-grade nano-drug preparation device of the present invention.

[0074] In the figure: 1. Nano drug preparation component; 2. Buffer vehicle component; 201. Third shell; 3. Lipid phase storage component; 301. Sixth shell; 4. Water phase storage component; 401. Fourth shell; 5. Dilution phase storage component; 501. Fifth shell; 6. Harvest phase storage component; 601. Second shell; 7. First shell; 8. USB interface; 9. Start / stop button; 10. Emergency stop button; 12. Signal indicator light; 13. Touch screen; 14. Barcode scanner; 48. Standard solution storage bag; 49. First standard solution connecting pipeline; 50. Second standard solution connecting pipeline; 51. Third standard solution connecting pipeline 52, first pipe clamp; 53, second pipe clamp; 541, third pipe clamp; 54, first pump joint connecting pipe; 55, second pump joint connecting pipe; 56, third pump joint connecting pipe; 57, first centrifugal pump; 58, second centrifugal pump; 59, third centrifugal pump; 60, first ultrasonic flow sensor; 61, second ultrasonic flow sensor; 62, third ultrasonic flow sensor; 63, first pinch valve; 64, second pinch valve; 65, third pinch valve; 66, first one-way valve; 67, second one-way valve; 68, third one-way valve; 69, fourth one-way valve; 70, fifth one-way valve; 71, Sixth one-way valve; 72, first pipeline; 73, fourth clamp valve; 74, sixth pipeline; 75, fourth pipe clamp; 76, finished product collection box; 77, fifth clamp valve; 78, fourth peristaltic pump; 79, peristaltic pump tube; 80, second pipeline; 81, third pipeline; 82, mass flow meter; 83, fourth pipeline; 84, pneumatic ball valve; 85, fifth pipeline; 86, waste liquid collection box; 87, first leakage detection sensor; 88, second leakage detection sensor; 89, first buffer car connecting pipeline; 90, second buffer car connecting pipeline; 91, third buffer car connecting pipeline; 92, fifth pipe clamp; 9 3. The sixth tube clamp; 94. The seventh tube clamp; 95. The dilution phase buffer bag; 96. The aqueous phase buffer bag; 97. The lipid phase buffer bag; 98. The first weighing sensor; 99. The second weighing sensor; 100. The third weighing sensor; 101. The first peristaltic pump; 102. The second peristaltic pump; 103. The third peristaltic pump; 104. The lipid phase storage bag; 105. The aqueous phase storage bag; 106. The dilution phase storage bag; 107. The dilution phase delivery pipeline; 108. The aqueous phase delivery pipeline; 109. The lipid phase delivery pipeline; 110. The microfluidic chip; 111. The first injection pipeline; 112. The second injection pipeline. DETAILED DESCRIPTION

[0075] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. In the description of the present invention, it should be noted that the terms "center", "up", "down", "left", "right", "vertical", "horizontal", "inside", "outside" and the like indicate directions or positional relationships based on the directions or positional relationships shown in the accompanying drawings, which are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific direction, be constructed and operated in a specific direction, and therefore cannot be understood as a limitation on the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance.

[0076] The present invention will be further described below in conjunction with the accompanying drawings.

[0077] like Figure 1-7 As shown, an industrial-grade nano drug preparation device comprises: a nano drug preparation component 1, a buffer vehicle component 2, a lipid phase storage component 3, an aqueous phase storage component 4, a dilution phase storage component 5 and a harvest phase storage component 6; the buffer vehicle component 2 comprises a lipid phase buffer unit, an aqueous phase buffer unit and a dilution phase buffer unit, the output ends of the lipid phase storage component 3, the aqueous phase storage component 4 and the dilution phase storage component 5 are connected to the input ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit in a one-to-one correspondence; the output ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit are connected to the input end of the nano drug preparation component 1 in a one-to-one correspondence, and the output end of the nano drug preparation component 1 is connected to the input end of the harvest phase storage component 6; wherein the nano drug preparation component 1 comprises a microfluidic chip 110, a first centrifugal pump 57, a second centrifugal pump 58 , a third centrifugal pump 59, a fourth peristaltic pump 78, a first sampling pipeline 111, a second sampling pipeline 112, a first pipeline 72, a sixth pipeline 74 and a fluid control unit; the first centrifugal pump 57 is connected to the first inlet end of the microfluidic chip 110 through the first sampling pipeline 111, the second centrifugal pump 58 is connected to the second inlet end of the microfluidic chip 110 through the second sampling pipeline 112, the outlet end of the microfluidic chip 110 is provided with a four-way connector, the first end of the four-way connector is connected to the outlet end of the microfluidic chip 110, the third centrifugal pump 59 is connected to the second end of the four-way connector through the first pipeline 72, the fourth peristaltic pump 78 is connected to the third end of the four-way connector through the peristaltic pump tube 79, and the fourth end of the four-way connector is connected to the sixth pipeline 74; the fluid control unit includes a one-way valve, a pinch valve and a flow sensor arranged on the first sampling pipeline 111, the second sampling pipeline 112 and the first pipeline 72.

[0078] Specifically, the microfluidic chip 110 has two inlet ends and one outlet end, one of which is connected to the first inlet line 111 and the other is connected to the second inlet line 112 . The first line 72 is connected to the outlet end of the microfluidic chip 110 via a four-way connector.

[0079] The first sample inlet pipeline 111 , the second sample inlet pipeline 112 and the first pipeline 72 are all provided with a one-way valve, a pinch valve and a flow sensor for controlling the flow of the fluid.

[0080] like Figure 7 As shown, the first sampling pipeline 111 is provided with a fourth one-way valve 69, a first one-way valve 66, a first pinch valve 63 and a first ultrasonic flow sensor 60 from top to bottom; the second sampling pipeline 112 is provided with a fifth one-way valve 70, a second one-way valve 67, a second pinch valve 64 and a second ultrasonic flow sensor 61 from top to bottom; the first pipeline 72 is provided with a sixth one-way valve 71, a third one-way valve 68, a third pinch valve 65 and a third ultrasonic flow sensor 62 from top to bottom. In this embodiment, the first centrifugal pump 57, the second centrifugal pump 58 and the third centrifugal pump 59 are all magnetic levitation pumps. Due to the characteristics of the magnetic levitation pump, there is a situation where the pressure is low and the flow rate is unstable. Therefore, two one-way valves are provided on the first sampling pipeline 111, the second sampling pipeline 112 and the first pipeline 72. By increasing the hydraulic pressure through the two one-way valves, the flow rate uniformity can be controlled within 2%.

[0081] In this embodiment, the flow sensors provided on the first sample inlet pipeline 111, the second sample inlet pipeline 112 and the first pipeline 72 are all ultrasonic flow sensors, which are not only used to detect the uniformity of flow velocity, but also have the function of detecting bubbles.

[0082] like Figure 7 As shown, the pump head of the first centrifugal pump 57 is connected to the first ultrasonic flow sensor 60, the pump head of the second centrifugal pump 58 is connected to the second ultrasonic flow sensor 61, and the pump head of the third centrifugal pump 59 is connected to the third ultrasonic flow sensor 62. The first ultrasonic flow sensor 60, the second ultrasonic flow sensor 61 and the third ultrasonic flow sensor 62 can all detect bubbles in the corresponding pump heads.

[0083] Please continue to refer to Figure 1-2, 5-6, the buffer vehicle component 2 has a lipid phase buffer unit, an aqueous phase buffer unit and a dilution phase buffer unit, each buffer unit has an input end and an output end, the input ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit are connected one-to-one with the output ends of the lipid phase storage component 3, the aqueous phase storage component 4 and the dilution phase storage component 5, the output ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit are connected one-to-one with the input end of the nano drug preparation component 1, and the output end of the nano drug preparation component 1 is connected to the input end of the harvesting phase storage component 6.

[0084] The fluids provided by the lipid phase storage component 3, the water phase storage component 4 and the dilution phase storage component 5 are all delivered to the nano drug preparation component 1 through the buffer unit corresponding to the buffer vehicle component 2. The nano drug preparation component 1 is used to receive and mix the fluid to generate nano particles. The harvest phase storage component 6 is connected to the nano drug preparation component 1 to receive and store nano particles. The setting of the buffer vehicle component 2 enables the industrial-grade nano drug preparation device to be compatible with a variety of preparation amounts. Regardless of whether the preparation amount is large or small, the amount of buffer can be set in advance to ensure the stability of nano drug preparation.

[0085] Please continue to refer to Figure 7 The industrial-grade nano-drug preparation device also includes: a standard liquid storage container 48 and a standard liquid pipeline, the standard liquid pipeline includes a first standard liquid connecting pipeline 49, a second standard liquid connecting pipeline 50 and a third standard liquid connecting pipeline 51; one end of the first standard liquid connecting pipeline 49, the second standard liquid connecting pipeline 50 and the third standard liquid connecting pipeline 51 are all connected to the outlet of the standard liquid storage container 48, the other end of the first standard liquid connecting pipeline 49 is connected to the third centrifugal pump 59 through the third pump joint connecting pipe 56, the other end of the second standard liquid connecting pipeline 50 is connected to the second centrifugal pump 58 through the second pump joint connecting pipe 55, and the other end of the third standard liquid connecting pipeline 51 is connected to the first centrifugal pump 57 through the first pump joint connecting pipe 54;

[0086] A first tube clamp 52 is provided on the third standard liquid connecting pipeline 51 , a second tube clamp 53 is provided on the second standard liquid connecting pipeline 50 , and a third tube clamp 541 is provided on the first standard liquid connecting pipeline 49 .

[0087] Please continue to refer to Figure 7The industrial-grade nano-drug preparation device also includes a waste liquid collection container 86 and a waste liquid pipeline, the waste liquid pipeline includes a second pipeline 80, a third pipeline 81, a fourth pipeline 83 and a fifth pipeline 85, the fourth pipeline 83 and the fifth pipeline 85 are arranged in parallel between the waste liquid collection container 86 and the third pipeline 81, the second pipeline 80 and the fourth peristaltic pump 78 are arranged in parallel between the third pipeline 81 and the third end of the four-way connector; the second pipeline 80 is provided with a fifth clamping valve 77; the fourth pipeline 83 is provided with a mass flowmeter 82, the fifth pipeline 85 is provided with a pneumatic ball valve 84, one end of the second pipeline 80 and the peristaltic pump tube 79 are connected to the third end of the four-way connector, the other end of the second pipeline 80 and the fourth peristaltic pump 78 are connected to the third pipeline 81, and the other ends of the fourth pipeline 83 and the fifth pipeline 85 are connected to the waste liquid collection box 86.

[0088] When the pneumatic ball valve 84 is opened, the waste liquid pipeline is connected; when the pneumatic ball valve 84 is closed, the accuracy of the ultrasonic flow sensor is calibrated through the mass flow meter 82.

[0089] Preferably, the fourth pipeline 83 and the fifth pipeline 85 are both provided with a first liquid leakage detection sensor 87 , and the first liquid leakage detection sensor 87 is integrated with the mass flow meter 82 .

[0090] Please continue to refer to Figure 1-4 The nano drug preparation component 1 also includes a first shell 7, a touch screen 13 is arranged above the front end surface of the first shell 7, a USB interface 8, a start / stop button 9, an emergency stop button 10 and a signal indicator light 12 are arranged on one side of the touch screen 13, and a barcode scanner 14 is arranged on the other side of the touch screen 13; a control system circuit board is arranged on the inner side of the first shell 7, and the USB interface 8, the start / stop button 9, the emergency stop button 10, the signal indicator light 12, the touch screen 13, the barcode scanner 14 and the peristaltic pumps (i.e., the first peristaltic pump 101, the second peristaltic pump 102, the third peristaltic pump 103, the fourth peristaltic pump 78) arranged on the pipeline, the centrifugal pumps (i.e., the first centrifugal pump 57, the second centrifugal pump 58, the third centrifugal pump 59), the one-way valve, the pinch valve, the flow sensor and the mass flow meter are all electrically connected to the control system circuit board.

[0091] In this embodiment, the electrical parts of the nanomedicine preparation component 1, the buffer vehicle component 2, the lipid phase storage component 3, the water phase storage component 4, the dilution phase storage component 5 and the harvest phase storage component 6 are all electrically connected to the control system circuit board to achieve unified control of each component.

[0092] Please continue to refer to Figure 1 and Figure 7The harvest phase storage component 6 includes a second shell 601 , in which a finished product collection container 76 is arranged. The inlet of the finished product collection container 76 is connected to a sixth pipeline 74 , and a fourth pipe clamp valve 73 and a fourth pipe clamp 75 are arranged on the sixth pipeline 74 .

[0093] Please continue to refer to Figure 5-7 The buffer vehicle assembly 2 includes a third housing 201, a first weighing sensor 98, a second weighing sensor 99 and a third weighing sensor 100 are respectively arranged on the top of the third housing 201, the lower end of the first weighing sensor 98 is connected to the dilution phase buffer bag 95, the lower end of the second weighing sensor 99 is connected to the water phase buffer bag 96, and the lower end of the third weighing sensor 100 is connected to the lipid phase buffer bag 97, and the dilution phase buffer bag 95, the water phase buffer bag 96 and the lipid phase buffer bag 97 are all hung on the hooks of the corresponding weighing sensors; the outer wall of the third housing 201 is respectively provided with a first weighing sensor 98, a second weighing sensor 99 and a third weighing sensor 100, the lower end of the first weighing sensor 98 is connected to the dilution phase buffer bag 95, the lower end of the second weighing sensor 99 is connected to the water phase buffer bag 96, and the lower end of the third weighing sensor 100 is connected to the lipid phase buffer bag 97. A first peristaltic pump 101, a second peristaltic pump 102 and a third peristaltic pump 103 are provided, wherein the first peristaltic pump 101 is connected to a lipid phase delivery pipeline 109, and is used to deliver the liquid in the lipid phase storage component 3 to the lipid phase buffer bag 97; the second peristaltic pump 102 is connected to an aqueous phase delivery pipeline 108, and is used to deliver the liquid in the aqueous phase storage component 4 to the aqueous phase buffer bag 96; the third peristaltic pump 103 is connected to a dilution phase delivery pipeline 107, and is used to deliver the liquid in the dilution phase storage component 5 to the dilution phase buffer bag 95;

[0094] The outlet of the dilution phase buffer bag 95 is connected to the third centrifugal pump 59 via the third buffer vehicle connecting pipeline 91 and the third pump joint connecting pipe 56; the outlet of the water phase buffer bag 96 is connected to the second centrifugal pump 58 via the second buffer vehicle connecting pipeline 90 and the second pump joint connecting pipe 55; the outlet of the lipid phase buffer bag 97 is connected to the first centrifugal pump 57 via the first buffer vehicle connecting pipeline 89 and the first pump joint connecting pipe 54;

[0095] The third buffer vehicle connecting pipeline 91 is connected to the seventh pipe clamp 94 ; the second buffer vehicle connecting pipeline 90 is connected to the sixth pipe clamp 93 ; and the first buffer vehicle connecting pipeline 89 is connected to the fifth pipe clamp 92 .

[0096] In this embodiment, the pipe clamp and the pipe pinch valve are both used to control the on-off of the pipeline, wherein the pipe clamp is manually operated and the pipe pinch valve is electrically controlled.

[0097] Preferably, the outlets of the dilution phase buffer bag 95, the water phase buffer bag 96 and the lipid phase buffer bag 97 are all located at the bottom of the bag. The first tube clamp 52, the second tube clamp 53, the third tube clamp 541, the fourth tube clamp 75, the fifth tube clamp 92, the sixth tube clamp 93 and the seventh tube clamp 94 are all Robert clamps.

[0098] Please continue to refer to Figure 1 and Figure 7 The lipid phase storage component 3 includes a sixth shell 301, in which a lipid phase storage bag 104 is arranged, and the outlet of the lipid phase storage bag 104 is connected to the first peristaltic pump 101; the water phase storage component 4 includes a fourth shell 401, in which a water phase storage bag 105 is arranged, and the outlet of the water phase storage bag 105 is connected to the second peristaltic pump 102; the dilution phase storage component 5 includes a fifth shell 501, in which a dilution phase storage bag 106 is arranged, and the outlet of the dilution phase storage bag 106 is connected to the third peristaltic pump 103.

[0099] Please refer to Figure 8 and Fig. 9 The pump heads 38 of the first centrifugal pump 57, the second centrifugal pump 58 and the third centrifugal pump 59, the sterile connector 39, the clamp 40, the first pipeline 72, the microfluidic chip 110, the four-way connector 44, the three-way connector 45, and the peristaltic pump tube 79 form a disposable consumables kit; wherein, the first pipeline 72 is a silicone tube, and the inlets of the flow sensors (i.e., the first ultrasonic flow sensor 60, the second ultrasonic flow sensor 61, and the third ultrasonic flow sensor 62) are connected one by one with the outlets of the pump heads 38 of the three centrifugal pumps and fixed together by the clamp 40; the three-way connector 45 is used to respectively connect the peristaltic pump tube 79, the four-way connector 44 and the waste liquid pipeline.

[0100] Please continue to refer to Figure 1 and Figure 7 A liquid leakage collecting tray 19 and a second liquid leakage detecting sensor 88 for detecting liquid leakage in the pipeline are arranged in the first shell 7. The second liquid leakage detecting sensor 88 is arranged at the position of the liquid leakage collecting tray 19 and detects the liquid in the liquid leakage collecting tray 19 by laser reflection.

[0101] Preferably, the first liquid leakage detection sensor 87 and the second liquid leakage detection sensor 88 are both disposed in the first shell 7 .

[0102] like Figure 10-16 As shown, a preparation method based on an industrial-grade nano drug preparation device comprises the following steps:

[0103] Step S1, loading the buffer vehicle fluid bag;

[0104] Step S2, pre-filling;

[0105] Step S3, flow calibration;

[0106] Step S4, preparing the front-stage waste liquid for discharge;

[0107] Step S5, preparation;

[0108] Step S6, cleaning the mass flow meter.

[0109] Specifically, step S1, the process of loading the buffer vehicle fluid bag includes:

[0110] Step S11, lipid phase liquid bag loading: the control system circuit board issues a lipid phase loading instruction, and the first peristaltic pump 101 on the buffer vehicle starts working to transfer the liquid in the lipid phase storage bag 104 to the lipid phase buffer bag 97; when the third weighing sensor 100 detects that the liquid in the lipid phase buffer bag 97 reaches the program-set weight, the first peristaltic pump 101 stops working and the loading is completed;

[0111] Step S12, loading the aqueous phase liquid bag: the control system circuit board issues an aqueous phase loading instruction, and the second peristaltic pump 102 on the buffer vehicle starts working to transfer the liquid in the aqueous phase storage bag 105 to the aqueous phase buffer bag 96; when the second weighing sensor 99 detects that the liquid in the aqueous phase buffer bag 96 reaches the weight set by the program, the second peristaltic pump 102 stops working and the loading is completed;

[0112] Step S13, loading the dilution phase liquid bag: the control system circuit board sends a dilution phase loading instruction, and the third peristaltic pump 103 on the buffer vehicle starts working to transfer the liquid in the dilution phase storage bag 106 to the dilution phase buffer bag 95; when the first weighing sensor 98 detects that the liquid in the dilution phase buffer bag 95 reaches the program-set weight, the third peristaltic pump 103 stops working and the loading is completed.

[0113] Step S2, the pre-filling process includes:

[0114] Step S21, lipid phase pre-filling: open the first tube clamp 52, connect the standard solution storage bag 48 to the first pump connector connection tube 54 through the third standard solution connecting pipeline 51; the control system circuit board issues a lipid phase pre-filling instruction, opens the fourth peristaltic pump 78, the pneumatic ball valve 84 and the clamp valve on the lipid phase pre-filling pipeline, and under the action of the fourth peristaltic pump 78, the standard solution flows from the standard solution storage bag 48 through the first centrifugal pump 57, the first ultrasonic flow sensor 60 and the fourth one-way valve 69, and enters the microfluidic chip 110; from the microfluidic chip After flowing out of the outlet of the chip 110, it enters the waste liquid collection box 86 through the peristaltic pump tube 79 and the fifth pipeline 85; during the pre-filling process, the standard liquid enters the centrifugal pump head and discharges the bubbles in the pump head; when the first ultrasonic flow sensor 60 detects the flow of liquid within the set time (according to the algorithm, when the sensor collects data that reaches the set range, it is considered that the set time has arrived), and detects that there are no bubbles inside the pipeline, the lipid phase pre-filling is completed; at this time, close the corresponding clamp valve, and manually close the first tube clamp 52 to prevent liquid backflow;

[0115] Step S22, water phase pre-filling: open the second tube clamp 53, connect the standard liquid storage bag 48 to the second pump connector connection tube 55 through the second standard liquid connecting pipeline 50; the control system circuit board issues a water phase pre-filling instruction, opens the fourth peristaltic pump 78, the pneumatic ball valve 84 and the clamp valve on the water phase pre-filling pipeline, and under the action of the fourth peristaltic pump 78, the standard liquid flows from the standard liquid storage bag 48 through the second centrifugal pump 58, the second ultrasonic flow sensor 61 and the second one-way valve 67, and enters the microfluidic chip 110; from the microfluidic chip After flowing out of the outlet 110, it enters the waste liquid collection box 86 through the peristaltic pump tube 79 and the fifth pipeline 85; similarly, during the pre-filling process, the standard liquid enters the centrifugal pump head and discharges the bubbles in the pump head; when the second ultrasonic flow sensor 61 detects the flow of liquid within the set time (according to the algorithm, when the sensor collects data that reaches the set range, it is considered that the set time has been reached), and there are no bubbles in the liquid, the water phase pre-filling is completed; at this time, the corresponding clamp valve is closed, and the second clamp 53 is manually closed to prevent the liquid from flowing back;

[0116] Step S23, dilution phase pre-filling: open the third tube clamp 541, the standard liquid storage bag 48 is connected to the third pump connector connection tube 56 through the first standard liquid connecting pipeline 49; the control system circuit board issues a dilution phase pre-filling instruction, opens the fourth peristaltic pump 78, the pneumatic ball valve 84 and the clamp valve on the dilution phase pre-filling pipeline, and under the action of the fourth peristaltic pump 78, the standard liquid flows from the standard liquid storage bag 48 through the third centrifugal pump 59, the third ultrasonic flow sensor 62 and the sixth one-way valve 71 into the peristaltic pump tube 79, and after flowing out of the peristaltic pump tube 79, it enters the waste liquid collection box 86 through the fifth pipeline 85; similarly, during the pre-filling process, the standard liquid enters the centrifugal pump head and discharges the bubbles in the pump head; when the third ultrasonic flow sensor 62 detects that the liquid flows within the set time (according to the algorithm, when the sensor collects data that reaches the set range, it is considered that the set time has been reached), and there are no bubbles in the liquid, the dilution phase pre-filling ends; at this time, close the corresponding clamp valve to prevent the liquid from flowing back.

[0117] Step S3, the flow calibration process includes:

[0118] Step S31, lipid phase calibration: open the first tube clamp 52, connect the standard solution storage bag 48 to the first pump joint connection pipe 54 through the third standard solution connection pipe 51; the control system circuit board sends a lipid phase calibration instruction, turns on the first centrifugal pump 57, and under the action of the first centrifugal pump 57, the standard solution flows from the standard solution storage bag 48 through the pump head of the first centrifugal pump 57, the first ultrasonic flow sensor 60 and the fourth one-way valve 69, and enters the microfluidic chip 110; flows out from the outlet of the microfluidic chip 110, passes through the second pipe 80, the third pipe 81, the fourth pipe 83, and the mass flow meter 82, and enters the waste liquid collection box 86; the standard solution flow rate detected by the mass flow meter 82 and the flow rate detected by the first ultrasonic flow sensor 60 are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the first ultrasonic flow sensor 60 to calibrate the data of the first ultrasonic flow sensor 60; after the lipid phase calibration is completed, close the corresponding clamp valve, and manually close the first tube clamp 52 to prevent liquid backflow;

[0119] Step S32, water phase calibration: open the second tube clamp 53, connect the standard liquid storage bag 48 to the second pump joint connecting pipe 55 through the second standard liquid connecting pipe 50, and the control system circuit board issues a water phase calibration instruction, and turn on the second centrifugal pump 58. Under the action of the second centrifugal pump 58, the standard liquid flows from the standard liquid storage bag 48 through the pump head of the second centrifugal pump 58, the second ultrasonic flow sensor 61 and the fifth one-way valve 70, and enters the microfluidic chip 110; after flowing out from the outlet of the microfluidic chip 110, it passes through the second pipeline 80, the third pipeline 81, the fourth pipeline 83, enters the mass flow meter 82, and enters the waste liquid collection box 86; the standard liquid flow rate detected by the mass flow meter 82 and the flow rate detected by the second ultrasonic flow sensor 61 are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the second ultrasonic flow sensor 61 to calibrate the data of the second ultrasonic flow sensor 61; when the water phase calibration is completed, close the corresponding clamp valve, and manually close the second tube clamp 53 to prevent liquid backflow;

[0120] Step S33, dilution phase calibration: open the third tube clamp 541, connect the standard liquid storage bag 48 to the third pump joint connecting pipe 56 through the first standard liquid connecting pipe 49; the control system circuit board issues a dilution phase calibration instruction, turns on the third centrifugal pump 59, and under the action of the third centrifugal pump 59, the standard liquid flows from the standard liquid storage bag 48 through the pump head of the third centrifugal pump 59, the third ultrasonic flow sensor 62, the sixth one-way valve 71, the second pipeline 80, the third pipeline 81, the fourth pipeline 83, the mass flow meter 82, and enters the waste liquid collection box 86; the standard liquid flow rate detected by the mass flow meter 82 and the flow rate detected by the third ultrasonic flow sensor are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the third ultrasonic flow sensor 62 to calibrate the data of the third ultrasonic flow sensor 62; when the water phase calibration is completed, close the corresponding clamp valve, and manually close the third tube clamp 541 to prevent liquid backflow.

[0121] Step S4, the process of preparing the front-stage waste liquid discharge comprises:

[0122] Step S41, close the first tube clamp 52, the second tube clamp 53 and the third tube clamp 541; first open the fifth tube clamp 92, the sixth tube clamp 93, and the seventh tube clamp 94; then open the first clamp valve 63, the second clamp valve 64, the third clamp valve 65, and the fifth clamp valve 77; open the pneumatic ball valve 84; at this time, open the first centrifugal pump 57, the second centrifugal pump 58, and the third centrifugal pump 59 to drive the liquid to flow through the lipid phase, the water phase, and the dilution phase pipelines, and after merging at the outlet of the microfluidic chip 110, enter the waste liquid collection box 86 through the second pipeline 80, the third pipeline 81, and the fifth pipeline 85; when the flow rate of the waste liquid in the front stage of the preparation reaches the set value, the discharge of the waste liquid in the front stage of the preparation is completed.

[0123] Step S5, the preparation process includes:

[0124] Step S51, after the discharge of the waste liquid in the front stage of the preparation is completed, the first centrifugal pump 57, the second centrifugal pump 58, and the third centrifugal pump 59 continue to work; open the fourth tube clamp 75, close the fifth pinch valve, close the pneumatic ball valve 84, and open the fourth pinch valve 73, so that the preparation liquid flowing out of the outlet of the microfluidic chip 110 enters the finished product collection box 76 from the sixth pipeline 74; when the first weighing sensor 98, the second weighing sensor 99 and the third weighing sensor 100 of the buffer vehicle detect that the liquid in the buffer bag is used up, the preparation is completed; turn off the first centrifugal pump 57, the second centrifugal pump 58, and the third centrifugal pump 59; turn off the first pinch valve 63, the second pinch valve 64, the third pinch valve 65 and the fourth pinch valve 73.

[0125] Step S6, mass flow meter cleaning includes:

[0126] Step S61, after the preparation is completed, open the third tube clamp 541 corresponding to the standard liquid storage bag 48; open the third tube clamp valve 65 and the fifth tube clamp valve; start the third centrifugal pump 59 to allow the standard liquid to enter the mass flow meter 82 from the dilution phase flow path to clean it; when the cleaning time reaches the set time, the cleaning is completed.

[0127] The industrial-grade nano drug preparation device and preparation method have the advantages of convenient operation, compact structure, advanced and simple process, and precise and stable operation. Liquid is loaded through the buffer vehicle component 2 to ensure that the pressure of the liquid entering the pump head remains constant, reduce liquid disturbance, and avoid the liquid level height of the external liquid preparation equipment affecting the flow rate accuracy of the device, thereby improving the stability of the system in nano preparation and enhancing its compatibility in different working environments.

[0128] Furthermore, by using the mass flowmeter 82 to calibrate the first ultrasonic flow sensor 60, the second ultrasonic flow sensor 61 and the third ultrasonic flow sensor 62, the flow rate accuracy at each stage in the preparation of the nano-drug is ensured, thereby improving the stability of the large-scale production process. At the same time, by setting a cleaning process for the mass flowmeter, its accuracy can be more effectively maintained, thereby ensuring the performance of the mass flowmeter.

[0129] Furthermore, by adopting the standard solution pre-filling method in the pre-filling stage, the loss of lipids is effectively reduced, thereby reducing the cost in the large-scale preparation of nanomedicines.

[0130] Furthermore, the nano-drug preparation component 1 has an optimized consumable flow path design and the use of a disposable consumable kit is not only convenient to operate but also can effectively reduce liquid residue, thereby reducing production costs.

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may still be modified, or some or all of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An industrial-grade nano-drug preparation device, characterized in that: include: Nano drug preparation component (1), buffer vehicle component (2), lipid phase storage component (3), water phase storage component (4), dilution phase storage component (5) and harvest phase storage component (6); The buffer vehicle component (2) comprises a lipid phase buffer unit, an aqueous phase buffer unit and a dilution phase buffer unit; the output ends of the lipid phase storage component (3), the aqueous phase storage component (4) and the dilution phase storage component (5) are connected to the input ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit in a one-to-one correspondence; the output ends of the lipid phase buffer unit, the aqueous phase buffer unit and the dilution phase buffer unit are connected to the input end of the nano drug preparation component (1) in a one-to-one correspondence; the output end of the nano drug preparation component (1) is connected to the input end of the harvest phase storage component (6); The nano drug preparation assembly (1) comprises a microfluidic chip (110), a first centrifugal pump (57), a second centrifugal pump (58), a third centrifugal pump (59), a fourth peristaltic pump (78), a first sample injection line (111), a second sample injection line (112), a first line (72), a sixth line (74) and a fluid control unit; The first centrifugal pump (57) is connected to the first inlet end of the microfluidic chip (110) through the first sample injection pipeline (111), the second centrifugal pump (58) is connected to the second inlet end of the microfluidic chip (110) through the second sample injection pipeline (112), the outlet end of the microfluidic chip (110) is provided with a four-way connector, the first end of the four-way connector is connected to the outlet end of the microfluidic chip (110), the third centrifugal pump (59) is connected to the second end of the four-way connector through the first pipeline (72), the fourth peristaltic pump (78) is connected to the third end of the four-way connector through the peristaltic pump tube (79), and the fourth end of the four-way connector is connected to the sixth pipeline (74); The fluid control unit comprises a one-way valve, a pinch valve and a flow sensor which are arranged on the first sample inlet pipeline (111), the second sample inlet pipeline (112) and the first pipeline (72).

2. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: The first centrifugal pump (57), the second centrifugal pump (58) and the third centrifugal pump (59) are all magnetic suspension pumps, and two one-way valves are provided on the first sample inlet pipeline (111), the second sample inlet pipeline (112) and the first pipeline (72).

3. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: Also includes: A standard liquid storage container (48) and a standard liquid pipeline, wherein the standard liquid pipeline comprises a first standard liquid connecting pipeline (49), a second standard liquid connecting pipeline (50) and a third standard liquid connecting pipeline (51); one end of each of the first standard liquid connecting pipeline (49), the second standard liquid connecting pipeline (50) and the third standard liquid connecting pipeline (51) is connected to the outlet of the standard liquid storage container (48); the other end of the first standard liquid connecting pipeline (49) is connected to the third centrifugal pump (59) via a third pump joint connecting pipe (56); the other end of the second standard liquid connecting pipeline (50) is connected to the second centrifugal pump (58) via a second pump joint connecting pipe (55); and the other end of the third standard liquid connecting pipeline (51) is connected to the first centrifugal pump (57) via a first pump joint connecting pipe (54); The third standard liquid connecting pipeline (51), the second standard liquid connecting pipeline (50) and the first standard liquid connecting pipeline (49) are all provided with pipe clamps.

4. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: The device further comprises a waste liquid collection container (86) and a waste liquid pipeline, wherein the waste liquid pipeline comprises a second pipeline (80), a third pipeline (81), a fourth pipeline (83) and a fifth pipeline (85), wherein the fourth pipeline (83) and the fifth pipeline (85) are arranged in parallel between the waste liquid collection container (86) and the third pipeline (81), and the second pipeline (80) and the fourth peristaltic pump (78) are arranged in parallel between the third pipeline (81) and the third end of the four-way connector; The second pipeline (80) is provided with a pinch valve, the fourth pipeline (83) is provided with a mass flow meter (82), and the fifth pipeline (85) is provided with a pneumatic ball valve (84).

5. The industrial-grade nano-drug preparation device according to claim 4, characterized in that: The fourth pipeline (83) and the fifth pipeline (85) are both provided with a first liquid leakage detection sensor (87).

6. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: The harvest phase storage component (6) comprises a second shell (601), a finished product collection container (76) is arranged inside the second shell (601), the inlet of the finished product collection container (76) is connected to the sixth pipeline (74), and a pipe clamp valve and a pipe clamp are arranged on the sixth pipeline (74).

7. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: The buffer vehicle assembly (2) comprises a third housing (201), and a first weighing sensor (98), a second weighing sensor (99) and a third weighing sensor (100) are respectively arranged on the top of the third housing (201), the lower end of the first weighing sensor (98) is connected to a dilution phase buffer bag (95), the lower end of the second weighing sensor (99) is connected to a water phase buffer bag (96), and the lower end of the third weighing sensor (100) is connected to a lipid phase buffer bag (97); The outer wall of the third housing (201) is provided with a first peristaltic pump (101), a second peristaltic pump (102) and a third peristaltic pump (103), respectively; the first peristaltic pump (101) is provided on a lipid phase delivery pipeline (109) for delivering the liquid in the lipid phase storage component (3) to the lipid phase buffer bag (97); the second peristaltic pump (102) is provided on an aqueous phase delivery pipeline (108) for delivering the liquid in the aqueous phase storage component (4) to the aqueous phase buffer bag (96); the third peristaltic pump (103) is provided on a dilution phase delivery pipeline (107) for delivering the liquid in the dilution phase storage component (5) to the dilution phase buffer bag (95); The outlet of the dilution phase buffer bag (95) is connected to the third centrifugal pump (59) via the third buffer vehicle connecting pipeline (91) and the third pump joint connecting pipe (56); the outlet of the water phase buffer bag (96) is connected to the second centrifugal pump (58) via the second buffer vehicle connecting pipeline (90) and the second pump joint connecting pipe (55); the outlet of the lipid phase buffer bag (97) is connected to the first centrifugal pump (57) via the first buffer vehicle connecting pipeline (89) and the first pump joint connecting pipe (54); Pipe clamps are provided on the third buffer car connecting pipeline (91), the second buffer car connecting pipeline (90) and the first buffer car connecting pipeline (89).

8. The industrial-grade nano-drug preparation device according to claim 6, characterized in that: The lipid phase storage component (3) comprises a sixth housing (301), a lipid phase storage bag (104) is arranged in the sixth housing (301), and an outlet of the lipid phase storage bag (104) is connected to the first peristaltic pump (101); The water phase storage component (4) comprises a fourth shell (401), a water phase storage bag (105) is arranged in the fourth shell (401), and the outlet of the water phase storage bag (105) is connected to the second peristaltic pump (102); The dilution phase storage assembly (5) comprises a fifth housing (501), a dilution phase storage bag (106) is arranged inside the fifth housing (501), and an outlet of the dilution phase storage bag (106) is connected to the third peristaltic pump (103).

9. The industrial-grade nano-drug preparation device according to claim 1, characterized in that: The pump heads (38) of the first centrifugal pump (57), the second centrifugal pump (58) and the third centrifugal pump (59), a sterile connector (39), a clamp (40), a flow sensor, a first pipeline (72), a microfluidic chip (110), a four-way connector (44), a three-way connector (45), and a peristaltic pump tube (79) form a disposable consumables kit; The inlet of the flow sensor and the outlet of the pump head (38) are fixed together by the clamp (40), and the three-way connector (45) is used to respectively connect the peristaltic pump tube (79), the four-way connector (44) and the waste liquid pipeline.

10. The industrial-grade nano-drug preparation device according to any one of claims 1 to 9, wherein the nano-drug preparation component (1) further comprises a first shell (7), a touch screen (13) is arranged above the front end surface of the first shell (7), a USB interface (8), a start / stop button (9), an emergency stop button (10) and a signal indicator light (12) are arranged on one side of the touch screen (13), and a barcode scanner (14) is arranged on the other side of the touch screen (13); A control system circuit board is arranged inside the first shell (7), and the USB interface (8), the start / stop button (9), the emergency stop button (10), the signal indicator light (12), the touch screen (13), the barcode scanner (14), and a peristaltic pump, a centrifugal pump, a one-way valve, a pinch valve, a flow sensor, and a mass flow meter arranged on the pipeline are all electrically connected to the control system circuit board.

11. The industrial-grade nano-drug preparation device according to claim 10, characterized in that: A liquid leakage collection tray (19) and a second liquid leakage detection sensor (88) for detecting liquid leakage in the pipeline are arranged in the first housing (7).

12. A method for preparing an industrial-grade nano-drug preparation device according to any one of claims 1 to 11, characterized in that: include: Step S1, loading the buffer vehicle fluid bag; Step S2, pre-filling; Step S3, flow calibration; Step S4, preparing the front-stage waste liquid for discharge; Step S5, preparation; Step S6, cleaning the mass flow meter.

13. The method for preparing an industrial-grade nano-drug preparation device according to claim 12, characterized in that: The step S1, buffer vehicle fluid bag loading includes: Step S11, lipid phase liquid bag loading: the control system circuit board issues a lipid phase loading instruction, and the first peristaltic pump (101) on the buffer vehicle starts working to transfer the liquid in the lipid phase storage bag (104) to the lipid phase buffer bag (97); when the third weighing sensor (100) detects that the liquid in the lipid phase buffer bag (97) reaches the program-set weight, the first peristaltic pump (101) stops working and the loading is completed; Step S12, loading the aqueous phase liquid bag: the control system circuit board issues an aqueous phase loading instruction, and the second peristaltic pump (102) on the buffer vehicle starts working to transfer the liquid in the aqueous phase storage bag (105) to the aqueous phase buffer bag (96); when the second weighing sensor (99) detects that the liquid in the aqueous phase buffer bag (96) reaches the weight set by the program, the second peristaltic pump (102) stops working and the loading is completed; Step S13, loading the dilution phase liquid bag: the control system circuit board issues a dilution phase loading instruction, and the third peristaltic pump (103) on the buffer vehicle starts working to transfer the liquid in the dilution phase storage bag (106) to the dilution phase buffer bag (95); when the first weighing sensor (98) detects that the liquid in the dilution phase buffer bag (95) reaches the program-set weight, the third peristaltic pump (103) stops working and the loading is completed.

14. The method for preparing an industrial-grade nano-drug preparation device according to claim 12, characterized in that: The step S2, pre-filling includes: Step S21, lipid phase pre-filling: open the first tube clamp (52), connect the standard solution storage bag (48) to the first pump connector connection tube (54) through the third standard solution connecting pipeline (51); the control system circuit board issues a lipid phase pre-filling instruction, opens the fourth peristaltic pump (78), the pneumatic ball valve (84) and the clamp valve on the lipid phase pre-filling pipeline, and under the action of the fourth peristaltic pump (78), the standard solution flows from the standard solution storage bag (48) through the first centrifugal pump (57), the first ultrasonic flow sensor (58), and the like. sensor (60) and the fourth one-way valve (69), and enter the microfluidic chip (110); after flowing out from the outlet of the microfluidic chip (110), it enters the waste liquid collection box (86) through the peristaltic pump tube (79) and the fifth pipeline (85); when the first ultrasonic flow sensor (60) detects the flow of liquid within the set time and detects that there are no bubbles in the pipeline, the lipid phase pre-filling is completed; at this time, the corresponding clamp valve is closed, and the first tube clamp (52) is manually closed to prevent the liquid from flowing back; Step S22, water phase pre-filling: open the second tube clamp (53), connect the standard liquid storage bag (48) to the second pump joint connection pipe (55) through the second standard liquid connection pipe (50); the control system circuit board issues a water phase pre-filling instruction, opens the fourth peristaltic pump (78), the pneumatic ball valve (84) and the clamp valve on the water phase pre-filling pipe, and under the action of the fourth peristaltic pump (78), the standard liquid flows from the standard liquid storage bag (48) through the second centrifugal pump (58), the second ultrasonic flow sensor (61) and the second one-way valve (67) into the microfluidic chip (110); after flowing out from the outlet of the microfluidic chip (110), it enters the waste liquid collection box (86) through the peristaltic pump tube (79) and the fifth pipe (85); when the second ultrasonic flow sensor (61) detects that the liquid flows within the set time; and there are no bubbles in the liquid, the water phase pre-filling is completed; at this time, close the corresponding clamp valve, and manually close the second tube clamp (53) to prevent the liquid from flowing back; Step S23, dilution phase pre-filling: open the third tube clamp (541), connect the standard liquid storage bag (48) to the third pump connector connection pipe (56) through the first standard liquid connection pipe (49); the control system circuit board issues a dilution phase pre-filling instruction, opens the fourth peristaltic pump (78), the pneumatic ball valve (84) and the clamp valve on the dilution phase pre-filling pipe, and under the action of the fourth peristaltic pump (78), the standard liquid flows from the standard liquid storage bag (48) through the third centrifugal pump (59), the third ultrasonic flow sensor (62) and the sixth one-way valve (71) into the peristaltic pump pipe (79), flows out of the peristaltic pump pipe (79), and enters the waste liquid collection box (86) through the fifth pipe (85); when the third ultrasonic flow sensor (62) detects that the liquid flows within the set time; and there are no bubbles in the liquid, the dilution phase pre-filling is completed; at this time, close the corresponding clamp valve to prevent the liquid from flowing back.

15. The method for preparing the industrial-grade nano-drug preparation device according to claim 12, characterized in that: Step S3, flow calibration includes: Step S31, lipid phase calibration: open the first tube clamp (52), connect the standard solution storage bag (48) to the first pump joint connection pipe (54) through the third standard solution connection pipe (51); the control system circuit board sends a lipid phase calibration instruction, turns on the first centrifugal pump (57), and under the action of the first centrifugal pump (57), the standard solution flows from the standard solution storage bag (48) through the pump head of the first centrifugal pump (57), the first ultrasonic flow sensor (60) and the fourth one-way valve (69), and enters the microfluidic chip (110); flows out from the outlet of the microfluidic chip (110), and passes through the The liquid enters the waste liquid collection box (86) through the second pipeline (80), the third pipeline (81), the fourth pipeline (83), and the mass flow meter (82); the standard liquid flow rate detected by the mass flow meter (82) and the flow rate detected by the first ultrasonic flow sensor (60) are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the first ultrasonic flow sensor (60) to calibrate the data of the first ultrasonic flow sensor (60); after the lipid phase calibration is completed, the corresponding clamp valve is closed, and the first clamp (52) is manually closed to prevent liquid backflow; Step S32, water phase calibration: open the second tube clamp (53), connect the standard liquid storage bag (48) to the second pump joint connection pipe (55) through the second standard liquid connection pipe (50), and the control system circuit board issues a water phase calibration instruction, and turns on the second centrifugal pump (58). Under the action of the second centrifugal pump (58), the standard liquid flows from the standard liquid storage bag (48) through the pump head of the second centrifugal pump (58), the second ultrasonic flow sensor (61) and the fifth one-way valve (70), and enters the microfluidic chip (110); after flowing out from the outlet of the microfluidic chip (110), it flows through the second The pipeline (80), the third pipeline (81), the fourth pipeline (83), enter the mass flow meter (82), and enter the waste liquid collection box (86); the standard liquid flow rate detected by the mass flow meter (82) and the flow rate detected by the second ultrasonic flow sensor (61) are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the second ultrasonic flow sensor (61) to calibrate the data of the second ultrasonic flow sensor (61); when the water phase calibration is completed, the corresponding clamp valve is closed, and the second clamp (53) is manually closed to prevent liquid backflow; Step S33, dilution phase calibration: open the third tube clamp (541), connect the standard solution storage bag (48) to the third pump joint connection pipe (56) through the first standard solution connection pipe (49); the control system circuit board issues a dilution phase calibration instruction, turns on the third centrifugal pump (59), and under the action of the third centrifugal pump (59), the standard solution flows from the standard solution storage bag (48) through the pump head of the third centrifugal pump (59), the third ultrasonic flow sensor (62), the sixth one-way valve (71), the second pipe (80), the third pipe ( 81), the fourth pipeline (83), the mass flow meter (82), and enter the waste liquid collection box (86); the standard liquid flow rate detected by the mass flow meter (82) and the flow rate detected by the third ultrasonic flow sensor are calculated by a program algorithm to obtain a compensation difference, and the compensation difference is transmitted to the third ultrasonic flow sensor (62) to calibrate the data of the third ultrasonic flow sensor (62); when the water phase calibration is completed, the corresponding clamp valve is closed, and the third tube clamp (541) is manually closed to prevent liquid backflow.

16. The method for preparing an industrial-grade nano-drug preparation device according to claim 12, characterized in that: The step S4, preparing the front-end waste liquid for discharge, comprises: Step S41, close the first tube clamp (52), the second tube clamp (53) and the third tube clamp (541); first open the fifth tube clamp (92), the sixth tube clamp (93) and the seventh tube clamp (94); then open the first clamp valve (63), the second clamp valve (64), the third clamp valve (65) and the fifth clamp valve (77); open the pneumatic ball valve (84); at this time, open the first centrifugal pump (57), the second centrifugal pump (58) and the third centrifugal pump (59) to drive the liquid to flow through the lipid phase, the water phase and the dilution phase pipelines, and after merging at the outlet of the microfluidic chip (110), enter the waste liquid collection box (86) through the second pipeline (80), the third pipeline (81) and the fifth pipeline (85); when the flow rate of the waste liquid in the preparation front stage reaches the set value, the discharge of the waste liquid in the preparation front stage is completed.

17. The method for preparing an industrial-grade nano-drug preparation device according to claim 12, characterized in that: The step S5, preparation comprises: Step S51, after the discharge of the waste liquid in the front stage of the preparation is completed, the first centrifugal pump (57), the second centrifugal pump (58), and the third centrifugal pump (59) continue to work; open the fourth tube clamp (75), close the fifth pinch valve, close the pneumatic ball valve (84), and open the fourth pinch valve (73), so that the preparation liquid flowing out of the outlet of the microfluidic chip (110) enters the finished product collection box (76) from the sixth pipeline (74); when the first weighing sensor (98), the second weighing sensor (99), and the third weighing sensor (100) of the buffer vehicle detect that the liquid in the buffer bag is used up, the preparation is completed; turn off the first centrifugal pump (57), the second centrifugal pump (58), and the third centrifugal pump (59); and turn off the first pinch valve (63), the second pinch valve (64), the third pinch valve (65), and the fourth pinch valve (73).

18. The method for preparing an industrial-grade nano-drug preparation device according to claim 12, characterized in that: The step S6, mass flow meter cleaning comprises: Step S61, after the preparation is completed, open the third tube clamp (541) corresponding to the standard solution storage bag (48); open the third tube clamp valve (65) and the fifth tube clamp valve; start the third centrifugal pump (59) to allow the standard solution to enter the mass flow meter (82) from the dilute phase flow path to clean it; when the cleaning time reaches the set time, the cleaning is completed.

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