Device for synthesis of lipid nanoparticles

Abstract

The present invention provides a synthesis device for lipid nanoparticles. The synthesis device for lipid nanoparticles comprises a mixing section, comprising two feeding units and a mixing unit, wherein one of the two feeding units is used to pass an ethanol solution containing lipids into the inlet of the mixing unit, and the other of the two feeding units is used to pass a liquid containing a drug into the inlet of the mixing unit; a dilution section comprises a dilution unit and a liquid supply unit, wherein the liquid supply unit is used to pass a dilution solution into the inlet of the dilution unit, and the inlet of the dilution unit is connected to the outlet of the mixing unit; a post-processing section comprises a liquid exchange unit, a concentration unit and a product collection unit which are connected in sequence, wherein the mixed solution discharged from the dilution unit enters the concentration unit through the liquid exchange unit for filtration and concentration, and the product collection unit collects the filtered product. The technical solution of the present invention solves the problem of the risk of contamination in synthesizing lipid nanoparticles in the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of lipid nanoparticle synthesis, in particular to a lipid nanoparticle synthesis device. Background Art

[0002] Nanosized lipid particles are a type of pharmaceutical preparation that has a wide range of applications in solubilization of various poorly soluble drugs, nucleic acid drug delivery, cell-targeted delivery, and sustained drug release. At present, nanosized lipid microspheres mainly include liposomes and lipid nanoparticles (LNP). Liposomes and LNPs differ in function, structure, and synthesis scheme. The main structure of liposomes is an aqueous solution wrapped by a phospholipid bilayer, which is mainly used for the delivery of conventional drugs. The main structure of LNP is a lipid particle wrapped by a phospholipid monolayer, and its lipid core is wrapped with several smaller aqueous functional areas. It is mainly used for the delivery of drugs with strong negative charge (such as nucleic acids, some proteins, etc.). In recent years, these nano-sized lipid particles have gradually become a valuable pharmaceutical product, producing a variety of representative drug preparations, such as paclitaxel liposome preparations, mRNA (messenger ribonucleic acid) vaccines for Covid-19, etc., providing clinical solutions for drugs that were previously difficult to enter clinical applications due to their difficulty in dissolving, high toxicity, and poor stability in the blood environment, and have made significant contributions to the treatment of various diseases.

[0003] The existing synthesis and post-processing schemes of lipid nanoparticles are all batch and segmented schemes. For liposomes, thin film hydration method is usually used for synthesis. The scheme is mainly to dissolve lipids in ethanol, apply them on a membrane, evaporate the solvent, deposit lipids on the membrane, and then place the membrane in water. By changing the temperature of the water, the lipids are dispersed from the membrane to obtain liposomes, and then the membrane is dispersed, sieved and continuously passed through the equipment to characterize its size. Steps such as obtaining liposomes with a suitable size. The solution is then transferred and subjected to tangential flow filtration and filtration sterilization steps to obtain usable liposomes. LNP is generally prepared by colliding water and ethanol in an impact jet reactor (IJM) and rapidly mixing to obtain LNP. The LNP is then transferred and filtered in a set of tangential flow filtration devices, and then filtered after transfer to sterilize, thereby obtaining usable LNP.

[0004] Conventional techniques for synthesizing lipid nanoparticles in the prior art often require multiple steps during the synthesis process, using a large number of different equipment in several experimental areas, requiring frequent transfer of materials and intermediates, and the synthesis and post-processing processes require a long time and a large number of experienced personnel, which is not conducive to the development and application of lipid particles. In addition, due to the high sensitivity of lipid nanoparticle-related materials, the transfer process not only brings additional contamination risks, but also requires specific conditions (such as freezing, etc.), thereby increasing costs. Summary of the invention

[0005] The main purpose of the present invention is to provide a synthetic device for lipid nanoparticles to solve the problem of contamination risk in the synthetic lipid nanoparticles in the prior art.

[0006] In order to achieve the above-mentioned purpose, the present invention provides a synthesis device for lipid nanoparticles, which comprises a mixing part, including two feeding units and a mixing unit, one of the two feeding units is used to pass an ethanol solution containing lipids into the inlet of the mixing unit, and the other of the two feeding units is used to pass a liquid containing a drug into the inlet of the mixing unit; a dilution part, including a dilution unit and a liquid supply unit, the liquid supply unit is used to pass a dilution solution into the inlet of the dilution unit, and the inlet of the dilution unit is connected to the outlet of the mixing unit; a post-processing part, including a liquid replacement unit, a concentration unit and a product collection unit connected in sequence, the liquid replacement unit is connected to the outlet of the dilution unit, the mixed solution discharged from the dilution unit is treated by the liquid replacement unit and then enters the concentration unit for filtration and concentration, and the product collection unit is used to collect the product filtered by the concentration unit.

[0007] Furthermore, the mixing unit is a microfluidic chip having a flow channel with a specific structure, one end of the microfluidic chip forms an inlet of the mixing unit, and the other end of the microfluidic chip forms an outlet of the mixing unit.

[0008] Furthermore, the ethanol solution and the liquid containing the drug are mixed rapidly in the mixing unit at the millisecond level, with a flow rate ratio between 1:1 and 1:10 and a total flow rate between 10-200 ml / h.

[0009] Furthermore, the synthesis device of lipid nanoparticles also includes a monitoring unit, which includes: a microscope, the mixing unit is installed on the microscope's carrier, and the microscope is used to obtain the image of the mixing unit; a microscope camera, which is used to shoot the image obtained by the microscope; a light source, which is installed on a reserved interface of the microscope; a controller, which is used to monitor and process the collected data in real time, and the controller is controlled and connected to the microscope camera.

[0010] Furthermore, the feeding unit includes: a storage module, which is used to store an ethanol solution containing lipids; a first liquid inlet pipeline, one end of which is connected to the inlet of the mixing unit, and the other end of which is connected to the storage module; and a first pump body, which is arranged on the first liquid inlet pipeline.

[0011] Furthermore, the dilution unit is a microfluidic chip having a specific dilution channel structure, one end of the microfluidic chip forms an inlet of the dilution unit, and the other end of the microfluidic chip forms an outlet of the dilution unit.

[0012] Furthermore, the liquid supply unit includes: a first liquid storage bottle for storing a diluted solution; a second liquid inlet pipeline, one end of which is connected to the first liquid storage bottle, and the other end of which is connected to the inlet of the dilution unit; and a second pump body, which is arranged on the second liquid inlet pipeline.

[0013] Further, the liquid exchange unit includes: a filtering component, including a first shell and a first filter element located in the first shell, the first filter element is used to divide the interior of the first shell into a first filter chamber and a first waste liquid chamber, the inlet of the first filter chamber is connected to the outlet of the dilution unit; a liquid supply module, including a second liquid storage bottle and a third liquid inlet pipeline, one end of the third liquid inlet pipeline is connected to the second liquid storage bottle; a mixing component, having a mixing chamber and a first inlet, a second inlet and a first outlet connected to the mixing chamber, the outlet of the first filter chamber is connected to the first inlet, the other end of the third liquid inlet pipeline is connected to the second inlet, and the first outlet is connected to the concentration unit; and / or, the liquid exchange unit is one or more, and multiple liquid exchange units are arranged in series, the inlet of the first liquid exchange unit among the multiple liquid exchange units is connected to the outlet of the dilution unit, and the outlet of the last liquid exchange unit among the multiple liquid exchange units is connected to the inlet of the concentration unit.

[0014] Furthermore, the concentration unit includes a second shell and a second filter element located in the second shell, the second filter element is used to separate the interior of the second shell into a second filter chamber and a second waste liquid chamber, the inlet of the second filter chamber is connected to the outlet of the liquid exchange unit, and the outlet of the second filter chamber is connected to the product collection unit.

[0015] Furthermore, a feed pipeline is provided between the concentration unit and the product collection unit, and a back pressure valve and / or a first flow meter is provided on the feed pipeline.

[0016] Furthermore, a filter is provided on the feed pipeline, and the filter is used to filter bacteria in the product.

[0017] Furthermore, the synthesis device of lipid nanoparticles also includes: a second flowmeter, arranged on one of the two first liquid inlet pipelines; a third flowmeter, arranged on the other of the two first liquid inlet pipelines; a first pressure gauge, arranged on the other of the two first liquid inlet pipelines; and a second pressure gauge, arranged on one of the two first liquid inlet pipelines.

[0018] Furthermore, the lipid nanoparticle synthesis device also includes a fourth flow meter, which is arranged on the second liquid inlet pipeline.

[0019] The technical scheme of the present invention is applied, the ethanol solution containing lipid enters the mixing unit through one of the two feeding units, the liquid containing the drug also enters the mixing unit through the other of the two feeding units, in the mixing unit, the two fluids quickly contact and mix, the mixed liquid flows out through the outlet of the mixing unit and enters the dilution unit, the diluted solution and the mixed liquid are mixed in the dilution unit, the diluted liquid enters the liquid exchange unit in the post-processing part from the outlet of the dilution unit, after the liquid exchange unit replaces the buffer solution, it enters the concentration unit for concentration and filtration, the concentrated product is collected by the product collection unit, the whole synthesis process realizes the continuous synthesis and post-processing of lipid nanoparticles, there is no need to frequently transfer materials and intermediates, the synthesis efficiency is greatly improved, the complexity of operation, the risk of pollution and the cost are reduced, and the consistency and stability of the final product are guaranteed. This design is suitable for rapid synthesis on a laboratory scale and continuous production in industrial production, making the preparation of lipid nanoparticles more efficient and controllable, and reducing the synthesis cost of lipid nanoparticles. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0021] Figure 1 A schematic structural diagram of an embodiment of a synthetic device for lipid nanoparticles of the present invention is shown;

[0022] Figure 2 Shows Figure 1 Figure 2. Test data of the monitoring unit of the lipid nanoparticle synthesis device.

[0023] The above drawings include the following reference numerals:

[0024] 100, mixing unit; 200, diluting unit; 300, post-processing unit; 11, first pressure gauge; 12, second pressure gauge; 13, third flow meter; 14, second flow meter; 15, microscope; 16, microscope camera; 17, light source; 18, fourth flow meter; 19, second pump body; 20, first pump body; 21, first liquid storage bottle; 22, isolation bottle; 23, third pump body; 24, third pressure gauge; 25, second liquid storage bottle; 26, fourth pump body; 27, mixing component; 28, first waste liquid bottle; 29, second waste liquid bottle; 30, mixing unit; 34, third waste liquid bottle; 35, back pressure valve; 36. The first flow meter; 37. The filter; 38. The first liquid inlet pipeline; 40. The dilution unit; 41. The sixth liquid inlet pipeline; 42. The second liquid inlet pipeline; 43. The fourth liquid inlet pipeline; 44. The fifth liquid inlet pipeline; 45. The third liquid inlet pipeline; 46. The seventh liquid inlet pipeline; 50. The liquid exchange unit; 500. The filter component; 501. The first filter chamber; 502. The first waste liquid chamber; 52. The feed pipeline; 54. The first liquid outlet pipeline; 55. The second liquid outlet pipeline; 56. The third liquid outlet pipeline; 70. The concentration unit; 701. The second filter chamber; 702. The second waste liquid chamber; 80. The product collection unit. DETAILED DESCRIPTION

[0025] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0026] like Figure 1 As shown, an embodiment of the present invention provides a synthesis device for lipid nanoparticles. The synthesis device for lipid nanoparticles includes: a mixing section 100, including two feeding units and a mixing unit 30, one of the two feeding units is used to pass an ethanol solution containing lipids into the inlet of the mixing unit 30, and the other of the two feeding units is used to pass a liquid containing a drug into the inlet of the mixing unit 30; a dilution section 200, including a dilution unit 40 and a liquid supply unit, the liquid supply unit is used to pass a dilution solution into the inlet of the dilution unit 40, and the inlet of the dilution unit 40 is connected to the outlet of the mixing unit 30; a post-processing section 300, including a liquid replacement unit 50, a concentration unit 70 and a product collection unit 80 connected in sequence, the liquid replacement unit 50 is connected to the outlet of the dilution unit 40, the mixed solution discharged from the dilution unit 40 is processed by the liquid replacement unit 50 and enters the concentration unit 70 for filtration and concentration, and the product collection unit 80 is used to collect the product filtered by the concentration unit 70.

[0027] In the above technical scheme, the ethanol solution containing lipid enters the mixing unit 30 through one of the two feeding units, and the liquid containing the drug also enters the mixing unit 30 through the other of the two feeding units. In the mixing unit 30, the two fluids quickly contact and mix, and the mixed liquid flows out through the outlet of the mixing unit 30 and enters the dilution unit 40. The diluted solution and the mixed liquid are mixed in the dilution unit 40, and the diluted liquid enters the liquid exchange unit 50 in the post-processing unit 300 from the outlet of the dilution unit 40. After the buffer is replaced by the liquid exchange unit 50, it enters the concentration unit 70 for concentration and filtration, and the concentrated product is collected by the product collection unit 80. The entire synthesis process realizes the continuous synthesis and post-processing of lipid nanoparticles, without the need to frequently transfer materials and intermediates, greatly improving the synthesis efficiency, reducing the complexity of the operation, the risk of pollution and the cost, while ensuring the consistency and stability of the final product. This design is suitable for rapid synthesis on a laboratory scale and continuous production in industrial production, making the preparation of lipid nanoparticles more efficient and controllable, and reducing the synthesis cost of lipid nanoparticles.

[0028] Specifically, in an embodiment of the present invention, the drug-containing liquid is an aqueous solution containing an active pharmaceutical ingredient (API), which may be a nucleic acid (such as mRNA, siRNA) or a chemotherapy drug (such as paclitaxel, doxorubicin) or other drug ingredients that need to be delivered in vivo (such as amikacin), etc.

[0029] Specifically, in the embodiments of the present invention, the ethanol solution containing lipids can be a lipid that meets the formula required for LNP (cationic lipid + phospholipid + cholesterol + PEG lipid) synthesis or a lipid that meets the formula required for liposome (phospholipid + cholesterol) synthesis, or other types of nanolipid materials.

[0030] Specifically, in an embodiment of the present invention, the post-processing unit 300 is mainly divided into functional domains such as buffer replacement, concentration, and sterilization. Its main function is to replace the buffer system of the LNP solution, stabilize the LNP and convert it to a state suitable for instrument testing or biological experiments.

[0031] like Figure 1 As shown, in an embodiment of the present invention, the mixing unit 30 is a microfluidic chip having a specific structural flow channel, one end of the microfluidic chip forms the inlet of the mixing unit 30, and the other end of the microfluidic chip forms the outlet of the mixing unit.

[0032] In the above technical solution, the ethanol solution containing lipids and the liquid containing drugs enter the mixing unit 30 from two feeding units respectively, and the two liquids flow out from the outlet of the mixing unit 30 after being fully mixed in the mixing channel.

[0033] Specifically, in the embodiment of the present invention, microfluidics is a process technology for synthesizing, separating, purifying, etc. a variety of biomedical materials by precisely manipulating micrometer-scale fluids. Compared with traditional reaction equipment, microfluidics has more precise control over fluids, consumes less material, and transfers mass and heat more rapidly, and can better meet some extremely harsh reaction processes requiring reaction conditions, thereby obtaining the function of synthesizing biomedical materials that are difficult to synthesize using conventional schemes. In addition, its function of precisely controlling reactants greatly improves the product itself and its uniformity on a time scale, improves the quality of the product, thereby reducing the loss of raw materials in the synthesis process of some materials with extremely high parameter requirements, reducing costs, and making microfluidics play an increasingly important role in the fields of fine chemistry and biosynthesis where raw materials are expensive, reaction conditions are strict, product quality requirements are high, and finished products have high added value. Therefore, the mixing unit 30 adopts a microfluidic chip.

[0034] Preferably, in an embodiment of the present invention, the mixing unit 30 is a conventional PDMS (polydimethylsiloxane) microfluidic chip, and its internal structure is a spiral, low dead zone microfluidic mixing structure. The specific structure of the PDMS microfluidic chip can refer to the prior art and will not be repeated here. However, microfluidic chips with other structures and the function of mixing lipid-containing ethanol solutions and drug-containing liquids are still within the protection scope of the invention. Alternatively, the mixing unit 30 can be a microfluidic chip with other materials (such as glass, PMMA, resin, etc.) and is still within the protection scope.

[0035] Specifically, in the embodiments of the present invention, the specific structure of the specific structure flow channel can refer to the invention with publication number 220370901U, which will not be repeated here.

[0036] like Figure 1 As shown, in an embodiment of the present invention, an anti-adsorption layer is provided on the inner wall of the mixing channel.

[0037] Through the above settings, the biomolecules involved in the synthesis of lipid nanoparticles (LNP) may be adsorbed on the inner wall surface of the mixing channel, resulting in material loss. The setting of the anti-adsorption layer can significantly reduce this adsorption phenomenon, maintain the purity of the fluid in the channel and the concentration of active ingredients, and improve the synthesis efficiency.

[0038] Specifically, in the embodiments of the present invention, materials that are theoretically low in lipid adsorption, such as glass, can be selected as the material of the microfluidic chip, or the PDMS surface can be modified using some schemes, such as by depositing PVA (polyvinyl alcohol) on the surface, adding PEG-PDMS (polyethylene glycol-modified polydimethylsiloxane) block copolymers into the PDMS system, and by coating the inner wall of the mixing channel with glass to form an anti-adsorption layer, so as to reduce the adsorption of biological materials or active ingredients of drugs on the surface of the microfluidic chip.

[0039] like Figure 1 As shown, in an embodiment of the present invention, the synthesis device of lipid nanoparticles includes a monitoring unit, which includes a microscope 15, a mixing unit 30 installed on the carrier of the microscope 15, and the microscope 15 is used to obtain the image of the mixing unit 30; a microscope camera 16 is used to shoot the image obtained by the microscope 15; a light source 17 is installed on a reserved interface of the microscope 15; and a controller is used to monitor and process the collected data in real time, and the controller is controlled and connected to the microscope camera 16.

[0040] In the above technical solution, the combination of the microscope 15 and the microscope camera 16 can capture the mixing state of the two liquids inside the mixing unit 30 in real time. In this way, problems existing in the mixing process of the two liquids can be discovered in time, so that corresponding measures can be taken to ensure the stability and repeatability of the lipid nanoparticle synthesis process.

[0041] Specifically, in the embodiment of the present invention, the microscope camera 16 is one of CCD, sCMOS and EM-CCD, and the specific structures of the microscope 15 and the light source 17 can refer to the prior art and will not be described in detail here.

[0042] Specifically, in the embodiment of the present invention, the monitoring unit also includes a controller, and the controller (e.g., a computer) is a computer program script that automatically collects data from the microscopic camera 16, processes data, and outputs judgment results. Its function is to monitor the key process (the ethanol solution containing lipids and the liquid containing drugs are mixed in the mixing unit 30) of the key component (mixing unit 30) in the synthesis device of lipid nanoparticles in real time. Here, the microscopic camera 16 is used to continuously shoot the state of the liquid in the mixing unit 30 in real time, and the picture is transmitted to the computer via a data line, and the program script is used to extract the fluorescence intensity information of the tracer molecule, and then the intensity data of the key detection sites (generally hundreds to thousands of pixels) are extracted, and the key control parameter mixing degree M is calculated based on the data. According to the mixing degree M and the judgment statement in the program, the mixing state "Good", "OK" or "Bad" (such as Figure 2 As shown), the mixing state of the two solutions in the mixing unit 30 (microfluidic chip) is monitored in real time, thereby controlling the stability during the long-term synthesis of LNPs.

[0043] like Figure 1 As shown, in an embodiment of the present invention, the feeding unit includes: a storage module, the storage module is used to store an ethanol solution containing lipids; a first liquid inlet pipeline 38, one end of the first liquid inlet pipeline 38 is connected to the inlet of the mixing unit 30, and the other end of the first liquid inlet pipeline 38 is connected to the storage module; a first pump body 20, which is arranged on the first liquid inlet pipeline 38.

[0044] In the above technical solution, the lipid-containing ethanol solution (or liquid containing drugs) enters the mixing unit 30 from the storage module through the first liquid inlet pipeline 38 under the action of the first pump body 20, so that the two liquids can be fully mixed in the mixing unit 30.

[0045] Specifically, in the embodiment of the present invention, the mixing unit 30 has two inlets, which are respectively connected to the two first liquid inlet pipes 38 to allow the lipid-containing ethanol solution and the drug-containing liquid to be introduced into the mixing unit 30 .

[0046] Specifically, in an embodiment of the present invention, the first pump body 20 may be a syringe pump or other pumps with low flow rate fluctuation over time, for example, a precision HPLC (high performance liquid chromatography) pump.

[0047] Specifically, in the embodiment of the present invention, the storage module and the first pump body 20 are integrated, specifically a continuous injection pump.

[0048] It should be noted that, in the embodiment of the present invention, the lipid-containing ethanol solution and the drug-containing liquid are input into the mixing unit 30 through two feeding units at a certain flow rate ratio, and millisecond-level rapid mixing is achieved in the mixing unit 30. The flow rate ratio can be between 1:1 and 1:10, and the total flow rate is between 10-200 ml / h, which is within the protection range.

[0049] Specifically, in the embodiment of the present invention, the ethanol solution containing lipids and the liquid containing drugs can generate LNP precursors after being mixed in the mixing unit 30 .

[0050] like Figure 1 As shown, in an embodiment of the present invention, the dilution unit 40 is a microfluidic chip with a specific dilution channel structure, one end of the microfluidic chip forms the inlet of the dilution unit 40, and the other end of the microfluidic chip forms the outlet of the dilution unit 40.

[0051] In the above technical solution, the lipid-containing ethanol solution and the drug-containing liquid enter the dilution unit 40 after being mixed in the mixing unit 30. The diluted solution enters the dilution unit 40, and the two are mixed in the dilution flow channel. The diluted solution can reduce the ethanol content in the lipid-containing ethanol solution. In addition, the pH of the solution changes from acidic to neutral, thereby obtaining complete lipid nanoparticles.

[0052] Specifically, in an embodiment of the present invention, the dilution unit 40 is similar to the mixing unit 30 in terms of material, assembly method, and structure, and only the structure of its internal dilution flow channel is different. The specific structure of the specific dilution flow channel is to proportionally enlarge the specific structural flow channel, for example, by 2 times, 3 times, 4 times, more times or other non-integer times.

[0053] Specifically, in the embodiments of the present invention, the dilution solution is an aqueous solution containing a buffer solution, the pH of the buffer solution is between 6-10, and can be selected from citrate buffer, PBS buffer, Tris-HCl buffer or other buffer solutions that meet the pH conditions and are not biotoxic.

[0054] Specifically, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a sixth liquid inlet pipeline 41, the dilution unit 40 has two inlets and an outlet, one end of the sixth liquid inlet pipeline 41 is connected to the outlet of the mixing unit, the other end of the sixth liquid inlet pipeline 41 is connected to one of the two inlets of the dilution unit 40, the liquid supply unit is connected to the other of the two inlets of the dilution unit 40, the flow rate ratio of the lipid-containing ethanol solution and the drug-containing liquid (referred to as solution A for short) to the dilution solution (referred to as solution B for short) is between 1:3 and 1:25, the flow rates of solution A and solution B are related, the flow rate of solution B should be determined by the flow rate of solution A, and the flow rate of solution A should not be determined by the flow rate of solution B.

[0055] like Figure 1 As shown, in an embodiment of the present invention, the liquid supply unit includes: a first liquid storage bottle 21, used to store a dilution solution; a second liquid inlet pipeline 42, one end of the second liquid inlet pipeline 42 is connected to the first liquid storage bottle 21, and the other end of the second liquid inlet pipeline 42 is connected to the inlet of the dilution unit 40; a second pump body 19, which is arranged on the second liquid inlet pipeline 42.

[0056] In the above technical solution, the dilution solution in the first liquid storage bottle 21 enters the dilution unit 40 through the second liquid inlet pipeline 42 under the action of the second pump body 19, and the lipid-containing ethanol solution, the drug-containing liquid and the dilution solution are mixed in the dilution unit 40. The dilution solution can reduce the ethanol content in the lipid-containing ethanol solution. At the same time, the pH of the solution changes from acidic to neutral, thereby generating lipid nanoparticles and improving the stability of the lipid nanoparticles.

[0057] Specifically, in the embodiment of the present invention, the second pump body 19 may be a syringe pump, a continuous syringe pump or a HPLC (high performance liquid chromatography) pump.

[0058] like Figure 1 As shown, in an embodiment of the present invention, the filter component 500 includes a first shell and a first filter element located in the first shell, the first filter element is used to separate the interior of the first shell into a first filter chamber 501 and a first waste liquid chamber 502, and the inlet of the first filter chamber 501 is connected to the outlet of the dilution unit 40; the liquid supply module includes a second liquid storage bottle 25 and a third liquid inlet pipeline 45, and one end of the third liquid inlet pipeline 45 is connected to the second liquid storage bottle 25; the mixing component 27 has a first mixing chamber and a fifth inlet, a sixth inlet and a third outlet connected to the first mixing chamber, the outlet of the first filter chamber 501 is connected to the first inlet, the other end of the third liquid inlet pipeline 45 is connected to the second inlet, and the first outlet is connected to the concentration unit 70.

[0059] In the above technical scheme, the diluted solution enters the first filter chamber 501 from the dilution unit 40, and after being filtered by the first filter element, the waste liquid enters the first waste liquid chamber 502, and the solution containing lipid nanoparticles enters the mixing component 27, and the buffer solution enters the mixing component 27 from the second liquid storage bottle 25 through the third liquid inlet pipeline 45. The solution containing lipid nanoparticles and the buffer solution are mixed in the mixing component 27 to improve the stability of the lipid nanoparticles, and then enter the concentration unit 70 for concentration.

[0060] Specifically, in an embodiment of the present invention, the filter component 500 is a tangential flow filter (TFF). In this embodiment, the feed liquid containing LNP flows out from the upper layer (i.e., the first filter chamber) of the tangential flow filter, and the solution without LNP flows out from the lower layer (i.e., the first waste liquid chamber) of the tangential flow filter device. The tangential flow filter can make the feed liquid containing LNP flow through the tangential flow filter only once, instead of circulating multiple times in the device like a traditional tangential flow filter. Among them, the first filter element is a simple membrane structure, a membrane package structure, or a hollow fiber membrane structure of the filter membrane. The pore size of the first filter element is 20 nm or 100kDa or 50kDa or 20KDa or 10KDa or 3500Da, etc. The material of the first filter element can be selected from PES, regenerated cellulose, ceramics, or polyvinylidene fluoride, etc. The support layer of the first filter element is preferably non-woven fabric, and the remaining support layer materials or the design without support layer still fall within the protection scope of the present invention.

[0061] Specifically, Figure 1As shown, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a first waste liquid bottle 28 and a first liquid outlet pipeline 54, one end of the first liquid outlet pipeline 54 is connected to the first waste liquid bottle 28, and the other end of the first liquid outlet pipeline 54 is connected to the first waste liquid cavity, and the solution without LNP flows from the first liquid outlet pipeline 54 to the first waste liquid bottle 28.

[0062] Specifically, in an embodiment of the present invention, a fourth pump body 26 is provided on the third liquid inlet pipeline 45. The fourth pump body 26 can be a continuous injection pump, an HPLC pump, a conventional peristaltic pump or a plunger pump, etc. The second liquid storage bottle 25 stores a buffer solution, and the buffer solution can be selected according to the experimental conditions, such as a standard PBS solution; a Tris-HCl buffer solution suitable for a nucleic acid system; or a non-buffered isotonic solution system such as a physiological saline solution, an isotonic sucrose solution, etc. Replacing the solvent of the LNP with the above-mentioned suitable solvent system can improve the stability of the lipid nanoparticles.

[0063] like Figure 1 As shown, in an embodiment of the present invention, there are one or more fluid exchange units 50, and multiple fluid exchange units 50 are arranged in series, the inlet of the first fluid exchange unit 50 among the multiple fluid exchange units 50 is connected to the outlet of the dilution unit 40, and the outlet of the last fluid exchange unit 50 among the multiple fluid exchange units 50 is connected to the inlet of the concentration unit 70.

[0064] In the above technical solution, by setting up multiple liquid replacement units 50, the concentration and buffer replacement effect can be enhanced. Each level of liquid replacement unit 50 can further remove impurities and residual organic solvents that are not completely replaced in the previous level, thereby obtaining a purer lipid nanoparticle solution.

[0065] Specifically, in an embodiment of the present invention, two liquid exchange units 50 are provided, and the diluted solution enters the first first filter chamber 501 from the dilution unit 40, and after being filtered by the first first filter element, the waste liquid enters the first first waste liquid chamber 502, and the solution containing lipid nanoparticles enters the first mixing component 27, and the buffer enters the first mixing component 27 from the second liquid storage bottle 25 through the first third liquid inlet pipeline 45, and the solution containing lipid nanoparticles and the buffer are mixed in the first mixing component 27, and the feed liquid containing LNP is mixed with the buffer and enters the second first filter chamber 501, and after being filtered by the second first filter element, the waste liquid enters the second first waste liquid chamber 502, and the solution containing lipid nanoparticles enters the second mixing component 27, and the buffer enters the second mixing component 27 from the second second liquid storage bottle 25 through the second third liquid inlet pipeline 45, and the solution containing lipid nanoparticles and the buffer are mixed in the second mixing component 27 to further improve the stability of the lipid nanoparticles, and then enter the concentration unit 70 for concentration.

[0066] Specifically, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes two seventh liquid inlet pipelines 46, one end of one of the seventh liquid inlet pipelines 46 is connected to the first first filter chamber 501, and the other end is connected to the second first filter chamber 501, and one end of the other seventh liquid inlet pipeline 46 is connected to the second first filter chamber 501, and the other end is connected to the concentration unit 70.

[0067] Specifically, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a second waste liquid bottle 29 and a second liquid outlet pipeline 55, one end of the second liquid outlet pipeline 55 is connected to the second waste liquid bottle 29, and the other end of the second liquid outlet pipeline 55 is connected to the second first waste liquid chamber 502, and the solution not containing LNP flows from the second liquid outlet pipeline 55 to the second waste liquid bottle 29.

[0068] Specifically, in the embodiments of the present invention, the number of the liquid replacement units 50 may be 1, 3, 4, or 5 or more, which still falls within the protection scope of the invention.

[0069] Specifically, in the embodiment of the present invention, the mixing component 27 is a three-way mixer.

[0070] like Figure 1 As shown, in an embodiment of the present invention, the concentration unit 70 includes a second shell and a second filter element located in the second shell, the second filter element is used to separate the interior of the second shell into a second filter chamber 701 and a second waste liquid chamber 702, the inlet of the second filter chamber 701 is connected to the outlet of the liquid exchange unit 50, and the outlet of the second filter chamber 701 is connected to the product collection unit 80.

[0071] In the above technical solution, the concentration unit 70 divides the interior of the second shell into a second filter chamber and a second waste liquid chamber through a second filter element. This design allows lipid nanoparticles to pass through the second filter chamber, while the buffer solution and the solution without LNP are retained in the second waste liquid chamber, thereby achieving efficient concentration of the lipid nanoparticle solution to improve the purity of the lipid nanoparticles. The lipid nanoparticle solution concentrated by the concentration unit 70 enters the product collection unit 80.

[0072] Specifically, in the embodiment of the present invention, the specific structure of the concentration unit 70 is the same as that of the liquid replacement unit 50, and the concentration efficiency of the concentration unit 70 is about 4-10 times, which will not be repeated here.

[0073] Specifically, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a third waste liquid bottle 34 and a third liquid outlet pipeline 56, one end of the third liquid outlet pipeline 56 is connected to the third waste liquid bottle 34, and the other end of the third liquid outlet pipeline 56 is connected to the second waste liquid chamber, and the solution not containing LNP flows from the third liquid outlet pipeline 56 to the third waste liquid bottle 34.

[0074] Specifically, in an embodiment of the present invention, a single liquid exchange unit 50 can replace about 80-90% of the buffer solution, and two liquid exchange units 50 can replace about 95-99% of the buffer solution, thereby reducing the ethanol in the lipid nanoparticle synthesis device to a range that can be tolerated by biological experiments and has little effect on LNP.

[0075] like Figure 1 As shown, in the embodiment of the present invention, a feed pipeline 52 is provided between the concentration unit 70 and the product collection unit 80 , and a back pressure valve 35 and / or a first flow meter 36 are provided on the feed pipeline 52 .

[0076] In the above technical solution, on the one hand, by adjusting the back pressure valve 35, the operating conditions of the two liquid exchange units 50 and the concentration unit 70 can be changed to ensure that the solvent is filtered out with sufficient efficiency and the rated liquid exchange and concentration efficiency are achieved. Particles, while avoiding damage to the particles due to excessive pressure; on the other hand, the first flow meter 36 can monitor the flow rate of the liquid in the feed pipeline 52 in real time. Through the monitoring of the first flow meter 36, the liquid flow rate from the concentration unit 70 to the product collection unit 80 can meet the process requirements.

[0077] Specifically, in an embodiment of the present invention, the back pressure valve 35 is actuated by the elastic force of a built-in spring. When the pressure of the lipid nanoparticle synthesis device is lower than the set pressure, the diaphragm blocks the pipeline under the action of the spring force; and when the system pressure is greater than the set pressure, the diaphragm compresses the spring, the pipeline is connected, and the liquid passes through the back pressure valve 35.

[0078] Specifically, in the embodiment of the present invention, a single concentration unit 70 is the preferred solution in this application scenario. If two, three or more concentration units are selected to be connected in series to achieve a higher concentration multiple, it still falls within the protection scope of the present invention.

[0079] like Figure 1 As shown, in the embodiment of the present invention, a filter 37 is further provided on the feed pipeline 52, and the filter 37 is used to filter bacteria in the product.

[0080] In the above technical solution, by setting the filter 37, impurities such as microorganisms and bacteria can be removed, thereby improving the safety and stability of the lipid nanoparticles, thereby improving the product quality of the lipid nanoparticles.

[0081] Specifically, in the embodiment of the present invention, the filter 37 is a syringe filter, which is directly connected to the concentration unit 70 through the feed line 52. The material containing LNP flows through the filter, and the bacteria, viruses, etc. inside are trapped in front of the filter due to their large size. The sterile solution passes through the filter and flows into the collection bottle. It should be noted that the above-mentioned syringe filter is a preferred design under this scheme, and other forms of filters, such as plate filters and tube filters, are still within the scope of protection. In this filter, the gap size of the filter membrane is 0.22um (it should be noted that 0.22um is a conventional, standard filtration and sterilization scheme, which should generally not be changed, but if non-standard sizes, such as 0.1um, 0.45um, 0.8um or other sizes are used, it still falls within the scope of protection of this invention), and the filter membrane material is polytetrafluoroethylene, PES, nylon or regenerated cellulose, etc.

[0082] like Figure 1 As shown, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes: a fourth liquid inlet pipeline 43; an isolation bottle 22, a first end of the fourth liquid inlet pipeline 43 is connected to the outlet of the dilution unit 40, and a second end of the fourth liquid inlet pipeline 43 extends into the isolation bottle 22; a fifth liquid inlet pipeline 44, a third end of the fifth liquid inlet pipeline 44 extends into the isolation bottle 22, a fourth end of the fifth liquid inlet pipeline 44 is connected to the inlet of the liquid exchange unit 50, and the second end is located above the third end; a third pump body 23, which is arranged on the fifth liquid inlet pipeline 44.

[0083] In the above technical solution, the liquid diluted by the dilution unit 40 enters the isolation bottle 22 through the fourth liquid inlet pipeline 43. Under the action of the third pump body 23, the liquid enters the liquid exchange unit 50 through the fifth liquid inlet pipeline 44 for filtration to purify the lipid nanoparticles.

[0084] Specifically, in an embodiment of the present invention, the interior of the isolation bottle 22 is filled with air or nitrogen, and the pressure is one atmosphere. The pressure of the post-processing section 300 is separated from the mixing section 100 by the isolation bottle 22. In this way, the pressure of the post-processing section 300 is difficult to act on the mixing section 100. In this way, the phenomenon of the structure in the mixing section 100 being broken due to the excessive pressure of the post-processing section 300 can be avoided.

[0085] Specifically, in an embodiment of the present invention, the third pump body 23 can transport the liquid in the isolation bottle 22 to the first first filter chamber 501, and the fourth pump body 26 can be a continuous injection pump, an HPLC pump, a conventional peristaltic pump or a plunger pump.

[0086] In one embodiment, the isolation bottle 22 and the third pump body 23 can be omitted, and the second outlet of the dilution unit 40 can be directly connected to the liquid replacement unit 50. This design is still within the scope of the invention.

[0087] like Figure 1 As shown, in an embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a second flowmeter 14, which is arranged on one of the two first liquid inlet pipelines 38; a third flowmeter 13, which is arranged on the other first liquid inlet pipeline 38 of the two first liquid inlet pipelines 38; a first pressure gauge 11, which is arranged on the other first liquid inlet pipeline 38 of the two first liquid inlet pipelines 38; and a second pressure gauge 12, which is arranged on one of the two first liquid inlet pipelines 38.

[0088] like Figure 1 As shown, in the embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a fourth flowmeter 18, which is arranged on the second liquid inlet pipeline 42.

[0089] Specifically, in the embodiment of the present invention, the synthesis device of lipid nanoparticles also includes a real-time detection unit, including a first pressure gauge 11, a second pressure gauge 12, a third pressure gauge 24, a third flowmeter 13 (arranged on another first liquid inlet pipeline 38), a second flowmeter 14 (arranged on the first liquid inlet pipeline 38), a fourth flowmeter 18 (arranged on the second liquid inlet pipeline 42) and a first flowmeter 36 (arranged on the feed pipeline 52) and a microscope 15-microscope camera 16 imaging system, these real-time monitoring devices are connected to a controller (e.g., a computer), and the monitoring data can be directly displayed on the computer and recorded by the computer. The function of the second flowmeter 14 is to measure the flow rate of the lipid-containing ethanol solution, the function of the third flowmeter 13 is to measure the flow rate of the API-containing aqueous solution, the function of the fourth flowmeter 18 is to measure the flow rate of the diluent, and the function of the first flowmeter 36 is to measure the flow rate of the solution of the final prepared product. The main function of these flowmeters is to monitor the flow rate value of each raw material liquid input and the stability of its flow rate on the time scale, and to control the stability of the entire synthesis process by controlling the key parameter "flow rate" in the reaction process. The function of the first pressure gauge 11 is to measure the pressure at the end of the lipid-containing ethanol solution, the function of the second pressure gauge 12 is to measure the pressure at the end of the API-containing aqueous solution, and the function of the third pressure gauge 24 is to measure the pressure provided to the TFF component. The functions of the first pressure gauge 11 and the second pressure gauge 12 are to monitor the pressure at the front end of the synthesis device of lipid nanoparticles to prevent the synthesis device of lipid nanoparticles from being damaged due to overpressure, and the function of the third pressure gauge 24 is to monitor the pressure of the concentration unit 70, cooperate with the first flow meter 36, and the operating state of the post-processing unit 300 to observe whether it is due to the blockage of the first filter element or the second filter element. The function has dropped significantly.

[0090] Specifically, in the embodiments of the present invention, the present invention intends to realize the synthesis, purification, concentration and other functions of lipid nanoparticles through the disclosed synthesis device of lipid nanoparticles, and its main purpose is: first, to realize the continuous synthesis and post-processing of lipid nanoparticles, without the need to transfer reagents during the synthesis process, and the synthesized lipid nanoparticles can be directly used in biological experiments without the need for additional post-processing processes; second, to realize a fully enclosed lipid nanoparticle synthesis and post-processing scheme. During the entire synthesis and post-processing process of the post-processing unit 300, the reagents are enclosed in the equipment cavity and are not in contact with the external environment; third, the rapid synthesis of lipid nanoparticles is realized. It only takes 15-20 minutes to synthesize a batch of lipid nanoparticles sufficient for laboratory cell experiments or animal experiments; fourth, the complexity of lipid nanoparticle synthesis is reduced. Users only need to turn on the equipment, load reagents, and wait for a period of time to obtain the desired lipid nanoparticles without complicated operations.

[0091] Specifically, in the implementation of the present invention, the synthesis device of lipid nanoparticles, its key features are composed of a mixing section 100, a dilution section 200, a post-processing section 300, a real-time detection unit, and a monitoring unit. The key function of the synthesis device of lipid nanoparticles is to synthesize LNP, liposomes and other medical lipid particles with nanometer size (preferably 50-200nm in diameter). The synthesis device of lipid nanoparticles has the advantage that it can continuously synthesize and post-process nanolipid particles, and the synthesized nanolipid particles can be directly applied to subsequent instrument tests, biological experiments and other specific experiments. The synthesis device of lipid nanoparticles is characterized by rapid synthesis (about 15-20min), simple operation, no transfer step, and complete isolation from the external atmospheric environment. A post-processing section 300 for nanolipid particles, its key feature is that it is composed of several unidirectional tangential flow filter devices, which can realize the liquid replacement and concentration functions of nanoparticles.

[0092] Specifically, in the embodiments of the present invention, a number of experiments have been conducted to demonstrate the effectiveness of the synthesis device for lipid nanoparticles disclosed in the present invention, including verification of the overall synthesis device for lipid nanoparticles and verification of the internal modules of the device, as shown in Table 1.

[0093] Table 1

[0094]

[0095] Through the above tests, the particle size of the final synthesized product was characterized by DLS equipment, and the content of API before and after cleavage was characterized by the kit, so as to calculate the encapsulation efficiency. The average particle size of the LNP product was 82.66nm, the encapsulation efficiency was 81.13%, and the average particle size of the liposome product was 125.9nm, the encapsulation efficiency was 74.03%, and the synthesis was relatively successful, proving the ability of the equipment to synthesize a variety of nano-sized lipid particles.

[0096] Specifically, in the embodiment of the present invention, for the mixing unit 30 and the dilution unit 40, we used rhodamine B dissolved in water as a tracer molecule, and characterized the mixing effect by taking fluorescent images of different positions in the mixing unit 30 and analyzing them. It was found through experiments that the mixing unit 30 has a good ability to mix water and ethanol at a total flow rate of 10-80ml / h, and according to the above mixed liquid: diluent ratio, under the matching flow rate conditions, the dilution unit 40 can effectively achieve the subsequent dilution of the mixed liquid. In addition, we also tested the real-time detection unit and the monitoring unit there, and the program script output is as follows: Figure 2 As shown, the reliability of the real-time detection unit and the monitoring unit is proved, and the mixing unit 30 can maintain stable and efficient mixing over a period of time.

[0097] Specifically, in the embodiment of the present invention, for the two liquid replacement units 50, we analyzed their ability to pass the liquid containing LNP under different pressures, and based on their ability to pass the liquid containing LNP, calculated the capacity of the replacement buffer after passing through the two liquid replacement units 50 and the concentration unit 70, as shown in Table 2:

[0098] Table 2

[0099]

[0100] Then, the ability of the tangential flow filtration component to remove unreacted small molecule products was tested using the membrane detection method in GB / T 32360-2015, with PEG-8000 at a concentration of 0.1% as a model molecule. After filtration, the PEG concentration in the solution was lower than 0.003%, proving that its ability to remove unreacted small molecules was greater than 30 times.

[0101] From the above description, it can be seen that the above-mentioned embodiment of the present invention achieves the following technical effects: the ethanol solution containing lipid enters the mixing unit through one of the two feeding units, and the liquid containing the drug also enters the mixing unit through the other feeding unit of the two feeding units. In the mixing unit, the two fluids quickly contact and mix, and the mixed liquid flows out through the outlet of the mixing unit and enters the dilution unit, and the diluted solution and the mixed liquid are mixed in the dilution unit. The diluted liquid enters the liquid exchange unit in the post-processing part from the outlet of the dilution unit, and enters the concentration unit after replacing the buffer solution through the liquid exchange unit for concentration and filtration. The concentrated product is collected by the product collection unit, and the entire synthesis process realizes the continuous synthesis and post-processing of lipid nanoparticles, without the need to frequently transfer materials and intermediates, greatly improving the synthesis efficiency, reducing the complexity of the operation, the risk of pollution and the cost, while ensuring the consistency and stability of the final product. This design is suitable for rapid synthesis on a laboratory scale and continuous production in industrial production, making the preparation of lipid nanoparticles more efficient and controllable, and reducing the synthesis cost of lipid nanoparticles.

[0102] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A synthetic device for lipid nanoparticles, characterized in that: include: A mixing unit, comprising two feeding units and a mixing unit, wherein one of the two feeding units is used to pass an ethanol solution containing lipids into the inlet of the mixing unit, and the other of the two feeding units is used to pass a liquid containing a drug into the inlet of the mixing unit; A dilution section, comprising a dilution unit and a liquid supply unit, wherein the liquid supply unit is used to introduce a dilution solution into an inlet of the dilution unit, and the inlet of the dilution unit is connected to an outlet of the mixing unit; A post-processing unit, comprising a liquid replacement unit, a concentration unit and a product collection unit which are connected in sequence, wherein the liquid replacement unit is connected to the outlet of the dilution unit, the mixed solution discharged from the dilution unit is processed by the liquid replacement unit and then enters the concentration unit for filtration and concentration, and the product collection unit is used to collect the product after being filtered by the concentration unit; The lipid nanoparticle synthesis device comprises a monitoring unit, the monitoring unit comprises a microscope, the mixing unit is mounted on a carrier of the microscope, the microscope is used to obtain a picture of the mixing unit; a microscopic camera is used to shoot the picture obtained by the microscope; A light source is installed on a reserved interface of the microscope; a controller is used for real-time monitoring and processing of collected data, and the controller is connected to the microscope camera control; The liquid exchange unit includes a filtering component, including a first shell and a first filter element located in the first shell, the first filter element is used to divide the interior of the first shell into a first filter chamber and a first waste liquid chamber, the inlet of the first filter chamber is connected to the outlet of the dilution unit; a liquid supply module, including a second liquid storage bottle and a third liquid inlet pipeline, one end of the third liquid inlet pipeline is connected to the second liquid storage bottle; a mixing component, having a mixing chamber and a first inlet, a second inlet and a first outlet connected to the mixing chamber, the outlet of the first filter chamber is connected to the first inlet, the other end of the third liquid inlet pipeline is connected to the second inlet, and the first outlet is connected to the concentration unit. There are one or more liquid exchange units, and multiple liquid exchange units are arranged in series.

2. The lipid nanoparticle synthesis device according to claim 1, characterized in that: The mixing unit is a microfluidic chip with a flow channel of a specific structure. One end of the microfluidic chip forms the inlet of the mixing unit, and the other end of the microfluidic chip forms the outlet of the mixing unit.

3. The synthesis device of lipid nanoparticles according to claim 1, characterized in that: The ethanol solution and the liquid containing the drug are mixed rapidly in the mixing unit at the millisecond level, with a flow rate ratio between 1:1 and 1:10 and a total flow rate between 10-200 ml / h.

4. The synthesis device of lipid nanoparticles according to claim 1, characterized in that: The feeding unit comprises: A storage module, wherein the storage module is used to store an ethanol solution containing lipids; a first liquid inlet pipeline, one end of which is in communication with the inlet of the mixing unit, and the other end of which is in communication with the storage module; The first pump body is arranged on the first liquid inlet pipeline.

5. The synthetic device of lipid nanoparticles according to claim 1, characterized in that: The dilution unit is a microfluidic chip with a specific dilution channel structure. One end of the microfluidic chip forms the inlet of the dilution unit, and the other end of the microfluidic chip forms the outlet of the dilution unit.

6. The synthesis device of lipid nanoparticles according to any one of claims 1 to 5, characterized in that: The liquid supply unit comprises: A first liquid storage bottle, used for storing the diluted solution; a second liquid inlet pipeline, one end of which is connected to the first liquid storage bottle, and the other end of which is connected to the inlet of the dilution unit; The second pump body is arranged on the second liquid inlet pipeline.

7. The synthesis device of lipid nanoparticles according to any one of claims 1 to 5, characterized in that The inlet of the first one of the plurality of liquid replacement units is communicated with the outlet of the diluting unit, and the outlet of the last one of the plurality of liquid replacement units is communicated with the inlet of the concentrating unit.

8. The synthesis device of lipid nanoparticles according to any one of claims 1 to 5, characterized in that: The concentration unit includes a second shell and a second filter element located in the second shell, the second filter element is used to separate the interior of the second shell into a second filter chamber and a second waste liquid chamber, the inlet of the second filter chamber is connected to the outlet of the liquid replacement unit, and the outlet of the second filter chamber is connected to the product collection unit.

9. The synthesis device of lipid nanoparticles according to any one of claims 1 to 5, characterized in that: A material delivery pipeline is provided between the concentration unit and the product collection unit, and a back pressure valve and / or a first flow meter is provided on the material delivery pipeline.

10. The lipid nanoparticle synthesis device according to claim 9, characterized in that: The feed pipeline is also provided with a filter, and the filter is used to filter bacteria in the product.

11. The lipid nanoparticle synthesis device according to claim 4, characterized in that: The synthetic device of the lipid nanoparticles also includes: A second flow meter is arranged on one of the two first liquid inlet pipelines; A third flow meter is arranged on the other of the two first liquid inlet pipelines; A first pressure gauge is arranged on the other of the two first liquid inlet pipelines; A second pressure gauge is disposed on one of the two first liquid inlet pipelines.

12. The lipid nanoparticle synthesis device according to claim 6, characterized in that: The lipid nanoparticle synthesis device also includes a fourth flow meter, which is arranged on the second liquid inlet pipeline.

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