Micro-channel reactor as well as use method and application thereof

Abstract

The invention discloses a micro-channel reactor and a using method and application thereof.The micro-channel reactor comprises a control system, an ultrasonic generator, a micro-reactor body, a raw material conveyor and an auxiliary conveying assembly, and the ultrasonic generator is connected with the micro-reactor body; the control system is connected with the ultrasonic generator, the raw material conveyor and the auxiliary conveying assembly. A main channel and a conveying channel are arranged in the microreactor, the main channel is a linear channel or a broken-line-shaped channel, one end of the conveying channel is communicated with the main channel, the main channel is divided into a left channel and a right channel, and a plurality of raw material conveyors are arranged on the outer side of the left channel and the outer side of the right channel respectively in the material flowing direction. The outer ends, away from the conveying channel, of the left channel and the right channel are each provided with an auxiliary conveying assembly, and the auxiliary conveying assemblies convey compressed gas into the left channel / the right channel. The micro-channel reactor is applied to the fields of LNP preparation, drug synthesis and cosmetics. According to preset experimental scheme parameters, the volume and flow velocity of liquid can be automatically and accurately controlled, the accuracy and repeatability of experiments are ensured, the complexity and errors of manual operation are greatly reduced, the experimental efficiency is improved, and the purposes of high-throughput preparation and screening are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of microchannel reactors, and in particular relates to a microchannel reactor and a use method and application thereof. Background Art

[0002] Microchannel reactors, also known as microreactors, can achieve instantaneous uniform mixing of materials and efficient heat transfer, so many reactions that cannot be achieved in conventional reactors can be achieved in microreactors. At present, microreactors are widely used in laboratories, used in conjunction with research, and the prepared products are used in experimental tests. However, there are still many shortcomings in existing microreactors, such as insufficient automation, such as difficulty in continuously preparing different samples, and manual cleaning of microreactors between two preparations, which leads to the need to spend a lot of time doing extra work during the research process. Take the preparation of LNP as an example. LNP, i.e., lipid nanoparticles, is a nanoscale drug formed based on lipid self-assembly. In the process of studying LNP, a large number of experiments are required to explore drugs suitable for preparing LNP and explore the optimal preparation scheme. If the existing microreactor is used, this work will be extremely cumbersome and difficult to carry out for a long time. Due to the relatively complex LNP preparation process, the workload before and after the preparation is large, and it is impossible to achieve rapid and efficient screening of a large number of LNP candidate drugs. In addition, the technical difficulties that have a greater impact include the existence of dead volume and particle clogging in conventional microreactors. The existence of dead volume in microreactors can lead to problems such as reagent waste, increased experimental errors, and further reduction in screening efficiency. The problems existing in LNP preparation also exist in the use of microreactors for drug synthesis, cosmetic preparation, etc. Therefore, it is necessary to propose a new type of microchannel reactor to solve the above problems. Summary of the invention

[0003] In order to solve the above technical problems, the purpose of the present invention is to provide a microchannel reactor and its use method and application, which can automatically and accurately control the volume and flow rate of the liquid according to the preset experimental scheme parameters, ensure the accuracy and repeatability of the experiment, greatly reduce the tediousness and errors of manual operation, improve the experimental efficiency, and achieve the purpose of high-throughput preparation and screening.

[0004] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0005] In a first aspect of the present invention, the present invention provides a microchannel reactor, comprising a control system, an ultrasonic generator, a microreactor body, a raw material conveyor and an auxiliary conveying component, wherein the ultrasonic generator is connected to the microreactor body, and the control system is respectively connected to the ultrasonic generator, the raw material conveyor and the auxiliary conveying component;

[0006] A main channel and a delivery channel are arranged in the microreactor, wherein the main channel is a straight channel or a zigzag channel, and one end of the delivery channel is connected to the main channel, dividing the main channel into a left channel and a right channel;

[0007] Along the material flow direction of the left channel, a plurality of raw material conveyors are arranged outside the left channel and communicated with the left channel, a one-way valve is arranged between the raw material conveyor and the left channel, an auxiliary conveying component is arranged at one end of the left channel away from the conveying channel, a one-way valve is arranged between the auxiliary conveying component and the left channel, and the auxiliary conveying component conveys compressed gas into the left channel;

[0008] Along the material flow direction of the right channel, multiple raw material conveyors are arranged outside the right channel and connected to the right channel, a one-way valve is arranged between the raw material conveyor and the right channel, an auxiliary conveying component is arranged at the end of the right channel away from the conveying channel, a one-way valve is arranged between the auxiliary conveying component and the right channel, and the auxiliary conveying component conveys compressed gas into the right channel.

[0009] Preferably, the auxiliary delivery assembly includes a compressed gas delivery pipe and a valve, the valve is connected to the outer end of the left channel / right channel through a pipeline and a one-way valve is provided at the connection, and the compressed gas delivery pipe is connected to the valve.

[0010] More preferably, the auxiliary conveying component also includes a cleaning liquid conveyor, and the valve is a two-inlet-one-out switching valve, the two inlets of the switching valve are respectively connected to the cleaning liquid conveyor and the compressed gas delivery pipe, and the outlet of the switching valve is connected to the outer end of the left channel / right channel.

[0011] Preferably, the length of the left channel is the same as or different from the length of the right channel.

[0012] More preferably, the length of the left channel is greater than the length of the right channel.

[0013] Preferably, the direction in which the raw material conveyor connected to the left channel injects raw material is the same as the direction in which the material flows in the left channel, and the direction in which the raw material conveyor connected to the right channel injects raw material is the same as the direction in which the material flows in the right channel.

[0014] In a second aspect of the present invention, the present invention provides a method for using a microchannel reactor, including preparation and cleaning, as follows:

[0015] Preparation: First, close the switching valve to prevent compressed gas or cleaning liquid from entering the microreactor body. According to the preparation plan, the raw materials are respectively loaded into multiple raw material conveyors, wherein the raw material conveyors loaded with raw materials are distributed along the material flow direction in the main channel according to the order and timing of the raw materials being successively input into the microreactor body;

[0016] Multiple raw materials are sequentially input into the microreactor body according to the input timing to form a mixed material for mixing or reaction;

[0017] After all the raw materials are input into the microreactor body, the switching valve is switched to input compressed gas, and the compressed gas pushes the mixed material along the material flow direction. The mixed material forms products during the flow process in the microreactor body, and the final products flow out along the conveying channel;

[0018] Cleaning: After the preparation of a product is completed, all the products leave the microreactor body, and then the switching valve is switched to input cleaning liquid to clean the main channel and the delivery channel of the microreactor body. After the cleaning is completed, the switching valve is switched to input compressed gas again to force the microreactor body to drain and dry;

[0019] Repeat the preparation and cleaning steps to achieve continuous preparation.

[0020] Preferably, in the step of preparing, both the left channel and the right channel are used for preparation, or only the left channel or the right channel is used for preparation.

[0021] Preferably, in the steps of preparing and cleaning, the compressed gas is one or more of compressed air, compressed oxygen, compressed nitrogen and compressed inert gas.

[0022] In the third aspect of the present invention, the present invention provides an application of a microchannel reactor, and the above-mentioned microchannel reactor is used in the fields of LNP, PLGA, drug synthesis, and customized cosmetic product emulsification.

[0023] Beneficial effects:

[0024] The present invention accurately controls the mixing process or reaction progress in the microreactor body to achieve actual automatic addition and mixing of raw materials. The present invention automatically and accurately controls the volume and flow rate of the liquid according to preset experimental scheme parameters to ensure the accuracy and repeatability of the experiment. In combination with a robot or a robotic arm, the present invention can achieve full automation of experimental operations, automatically perform operations such as sample preparation, instrument cleaning, sample separation and detection, greatly reduce the tediousness and errors of manual operations, improve experimental efficiency, and achieve the purpose of high-throughput preparation and screening. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Shown is a schematic diagram of the present invention.

[0026] Reference numerals: 1-microreactor body, 2-ultrasonic generator, 3-raw material conveyor, 4-switching valve, 5-cleaning liquid conveyor, 6-compressed gas conveying pipe, 7-check valve;

[0027] 11-main channel, 12-transport channel, 111-left channel, 112-right channel. DETAILED DESCRIPTION

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the specific implementation methods of the present invention will be described below with reference to the accompanying drawings. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings and other implementation methods can be obtained based on these drawings without creative work.

[0029] The present invention proposes a microchannel reactor, comprising a control system, an ultrasonic generator 2, a microreactor body 1, a raw material conveyor 3 and an auxiliary conveying assembly, wherein the ultrasonic generator 2 is connected to the microreactor body 1, a plurality of raw material conveyors 3 are connected to the microreactor body 1, and their function is to inject liquid raw materials into the microreactor, the auxiliary conveying assembly is connected to the microreactor, and its function includes injecting compressed gas into the microreactor, and the control system is connected to the ultrasonic generator 2, the raw material conveyor 3 and the auxiliary conveying assembly. The technical scheme of the present invention is described in detail below with a specific structure.

[0030] like Figure 1 As shown, a main channel 11 and a delivery channel 12 are arranged in the microreactor. The main channel 11 is a straight channel or a zigzag channel. One end of the delivery channel 12 is connected to the main channel 11, that is, the main channel 11 and the delivery channel 12 form a T-shaped channel structure or a Y-shaped channel structure, so that the main channel 11 is divided into a left channel 111 and a right channel 112. It is easy to understand that the left channel 111 and the right channel 112 are both straight channels. When the main channel 11 is a zigzag channel, the delivery channel 12 is connected to the bend of the main channel 11. Figure 1 As shown, the delivery channel 12 is connected to the middle part of the main channel 11, and the lengths of the left channel 111 and the right channel 112 are different. In addition, the lengths of the left channel 111 and the right channel 112 can also be different, which depends on the actual design.

[0031] The left channel 111 takes the direction toward the conveying channel 12 as the material flow direction. Along the material flow direction of the left channel 111, multiple raw material conveyors 3 are arranged on the outside of the left channel 111 and are connected to the left channel 111. A one-way valve 7 is arranged between the raw material conveyor 3 and the left channel 111 to limit the material in the left channel 111 from flowing back into the raw material conveyor 3. An auxiliary conveying component is arranged at the end of the left channel 111 away from the conveying channel 12. A one-way valve 7 is arranged between the auxiliary conveying component and the left channel 111. The auxiliary conveying component conveys compressed gas into the left channel 111.

[0032] The right channel 112 takes the direction toward the conveying channel 12 as the material flow direction. Along the material flow direction of the right channel 112, multiple raw material conveyors 3 are arranged on the outside of the right channel 112 and are connected to the right channel 112. A one-way valve 7 is arranged between the raw material conveyor 3 and the right channel 112 to limit the material in the right channel 112 from flowing back into the raw material conveyor 3. An auxiliary conveying component is arranged at the end of the right channel 112 away from the conveying channel 12. A one-way valve 7 is arranged between the auxiliary conveying component and the right channel 112, and the auxiliary conveying component conveys compressed gas into the right channel 112.

[0033] In the present invention, the raw material conveyor 3 is a conveying device that can be automatically controlled, such as a conveying pump and a corresponding raw material container. The conveying pump is connected to the raw material container and the microreactor body 1 through a pipeline, and the raw material is pumped into the microreactor body 1. The types of raw materials loaded in the multiple raw material conveyors 3 outside the left channel 111 and the right channel 112 can be the same or different. In order to reduce the resistance of raw material injection, the raw material conveyor 3 connected to the left channel 111 is tilted, and the direction of injecting raw materials is the same as the direction of material flow in the left channel 111. Similarly, the raw material conveyor 3 connected to the right channel 112 is also tilted, and the direction of injecting raw materials is the same as the direction of material flow in the right channel 112.

[0034] In the present invention, the lengths of the left channel 111 and the right channel 112 are known, the connection points between the multiple raw material conveyors 3 outside the left channel 111 and the left channel 111 are determined, and the connection points between the multiple raw material conveyors 3 outside the right channel 112 and the right channel 112 are determined. Taking the left channel 111 as an example, along the material flow direction, the distance between any two raw material conveyors 3 and the connection points inside the left channel 111 is determined, and taking the raw material conveyor 3 farthest from the conveying channel 12 as the starting point, under the conditions of a specific raw material injection flow rate and injection pressure, the time for the raw material injected at the starting point to flow to the position of each subsequent raw material conveyor 3 can be calculated. Therefore, as long as the time for each raw material conveyor 3 to inject raw materials in the left channel 111 and the right channel 112 is controlled, the mixing or reaction in the microreactor body 1 can be more accurately controlled.

[0035] In the present invention, when it is necessary to control the mixing of multiple raw materials in sequence, the left channel 111 and the right channel 112 can be put into use at the same time according to the preparation requirements, or only one of them can be used. For ease of explanation, the present invention takes the preparation of lipid nanoparticles LNP for encapsulating drugs as an example. The drug is dissolved in organic matter, which is easy to understand. For water-soluble drugs, they can also be dissolved in the aqueous phase. The encapsulation of the drug is also achieved by collision mixing. In addition, the present invention is also applicable to the synthesis of drugs or other substances. The present invention includes but is not limited to the following mixing methods:

[0036] Mixing method 1: Only the left channel 111 or the right channel 112 is used to realize LNP self-assembly through two-phase collision. The lipid organic phase and the aqueous phase containing the drug are injected through different raw material conveyors 3. The organic phase collides with the aqueous phase, and the lipid and the drug are precipitated to complete the encapsulation of the drug by the lipid to form lipid nanoparticles. LNP self-assembly can also be realized through three-phase collision. The drug organic phase is first injected to collide and mix with the aqueous phase to precipitate the drug, and then the lipid organic phase is input again. The precipitated lipid encapsulates the drug to form lipid nanoparticles.

[0037] Mixing method 2: Using the left channel 111 and the right channel 112 at the same time, LNP self-assembly is achieved through three-phase collision. For example, the water phase and the drug-containing organic phase are first injected into the left channel 111 for collision and mixing, so that the drug is precipitated first, and the lipid-containing organic phase is injected into the right channel 112. The mixed solution containing the drug precipitated particles flows forward to the transport channel 12 and collides with the lipid-containing organic phase. The lipid precipitation encapsulates the drug particles to form lipid nanoparticles.

[0038] Mixing method three: using the left channel 111 and the right channel 112 at the same time, LNP self-assembly is achieved through the collision of the two. The left channel 111 is respectively injected with organic raw materials such as lipids and drugs required for LNP self-assembly, and mixed first to form an organic phase. The right channel 112 is injected with the aqueous phase required for LNP self-assembly. Along the flow direction of the materials, the organic phase and the aqueous phase collide and mix, and the lipids encapsulate the drugs to form lipid nanoparticles.

[0039] It is easy to understand that the left channel 111 and the right channel 112 converge at the delivery channel 12, which is a place with lower pressure in the microreactor body 1. The material will enter the delivery channel 12 and be discharged instead of entering the adjacent channels, especially when compressed gas is input, it is even less likely for the material to enter the adjacent channels.

[0040] In the present invention, the main channel 11 is preferably straight, that is, the angle between the left channel 111 and the right channel 112 is 180°. The advantage of this structure is that the materials in the left channel 111 and the right channel 112 collide with each other to the greatest extent, avoiding the generation of other force components, and facilitating subsequent cleaning. It is easy to understand that the main channel 11 can also be a broken line, and the angle between the left channel 111 and the right channel 112 is an obtuse angle, such as 90 to 180°, which is designed according to experimental requirements and is not specifically limited by the present invention.

[0041] The ultrasonic generator 2 is connected to the microreactor body 1. It is easy to understand that the connection method between the ultrasonic generator 2 and the microreactor body 1 is similar to that of the existing ultrasonic microchannel reaction device. For example, the ultrasonic generator 2 is connected to the microreactor body 1 based on the center position of the microreactor body 1. The ultrasonic generator 2 provides uniform and stable ultrasonic waves to the microreactor body 1, so that the materials in the main channel 11 and the conveying channel 12 generate ultrasonic cavitation, and promote the mixing or reaction of the raw materials in the microreactor body 1.

[0042] The present invention does not limit the configuration of the delivery channel 12. It is easy to understand that the delivery channel 12 can be straight, curved, or spirally coiled. The delivery channel 12 of appropriate length and shape can be designed according to the experiment. Regardless of whether the left channel 111 and the right channel 112 are used at the same time or only one of them is used, when the material enters the delivery channel 12, all the raw materials are in a fully mixed state, so the length or shape of the delivery channel 12 will affect the time the material stays in the microreactor body 1.

[0043] In the present invention, the structures of the two auxiliary conveying components outside the left channel 111 and the right channel 112 are the same, and their functions are also the same. Taking the left channel 111 as an example, after the multiple raw material conveyors 3 inject all the raw materials into the left channel 111 as set, the auxiliary conveying component located at the outer end of the left channel 111 inputs compressed gas into the left channel 111 to push the materials in the left channel 111 forward, thereby avoiding the existence of dead volume materials in the left channel 111. Similarly, the auxiliary conveying component located at the outer end of the right channel 112 also inputs compressed gas into the right channel 112 to push the materials forward.

[0044] Specifically, the auxiliary delivery component includes a compressed gas delivery pipe 6 and a valve. The valve is connected to the outer end of the left channel 111 / right channel 112 through a pipeline, and a one-way valve 7 is provided at the connection. The compressed gas delivery pipe 6 is connected to the valve, and compressed gas is input into the left channel 111 / right channel 112 according to the set time.

[0045] The compressed gas delivery pipe 6 is connected to an external gas compressor such as an air compressor, and the gas compressor provides clean and dry compressed gas for the present invention. In the present invention, the compressed gas can be compressed air or other pure compressed gases, such as compressed oxygen, compressed nitrogen, compressed inert gas, etc., depending on the preparation needs.

[0046] It is easy to understand that the valve is an electrically controlled valve, which is convenient for automatic control.

[0047] Further, the auxiliary delivery component also includes a cleaning liquid delivery device 5, and the valve is a two-inlet and one-outlet switching valve 4, the two inlets of the switching valve 4 are respectively connected to the cleaning liquid delivery device 5 and the compressed gas delivery pipe 6, and the outlet of the switching valve 4 is connected to the outer end of the left channel 111 / right channel 112. The switching valve 4 is used to cut off or input compressed gas or input cleaning liquid. The cleaning liquid delivery device 5 is a delivery device that can be automatically controlled, such as a delivery pump and a corresponding cleaning liquid container. The delivery pump is connected to the cleaning liquid container and the microreactor body 1 through a pipeline, and the cleaning liquid is pumped into the microreactor body 1.

[0048] The activation of the auxiliary conveying component is related to the preparation process. Specifically, when the raw material conveyor 3 inputs raw materials into the left channel 111 / right channel 112, the auxiliary conveying component does not convey compressed gas; after all the raw materials are input into the microreactor body 1, the switching valve 4 switches to allow compressed gas to be input into the microreactor body 1 to promote the flow of materials and avoid the situation where dead volume materials exist in the microreactor body 1; after the preparation is completed, the switching valve 4 switches to allow cleaning liquid to be input into the microreactor body 1, and the main channel 11 and the conveying channel 12 are cleaned as a whole starting from the outer ends of the left channel 111 and the right channel 112.

[0049] It is easy to understand that whether to input compressed gas depends on whether to input raw materials. For example, when only the left channel 111 is used, only the auxiliary conveying assembly outside the left channel 111 can be enabled to input compressed gas into the left channel 111. Since the pressure of the microreactor body 1 is relatively low when the conveying channel 12 is used, most of the materials in the left channel 111 will flow into the conveying channel 12 instead of the right channel 112. In addition, when only one side of the channel is enabled, the auxiliary conveying assemblies on both sides can also input compressed air at the same time, and the materials finally flow out from the conveying channel 12. During cleaning, the two cleaning liquid conveyors 5 outside the microreactor body 1 are put into use at the same time to clean the inside of the microreactor.

[0050] The invention can be matched with a material receiving hole plate and a waste liquid collecting tank and the like. Qualified products are collected in the material receiving hole plate, and cleaning liquid or unqualified products are collected in the waste liquid collecting tank.

[0051] In the present invention, the control system is an existing conventional control system. Specifically, the control system is connected to the ultrasonic generator 2 to control the start and stop of the ultrasonic generator 2 and the frequency of the ultrasonic wave emitted, etc. The control system is connected to the raw material conveyor 3 to control the timing, delivery flow rate, delivery pressure, etc. of the raw material conveyor 3 to convey the raw material to the microreactor body 1. The control system is connected to the auxiliary conveying component to control the switching direction of the switching valve 4, as well as the delivery timing, delivery flow rate and delivery pressure of the cleaning liquid conveyor 5. The control system can also be connected to an external gas compressor to control the generation of compressed gas.

[0052] The present invention can accurately control the mixing or reaction in the microreactor body 1, and realize the actual automatic addition and mixing of raw materials. The present invention can automatically and accurately control the volume and flow rate of the liquid according to the preset experimental scheme parameters to ensure the accuracy and repeatability of the experiment. In the case of a robot or a robotic arm, the present invention can realize the full automation of the experimental operation, automatically perform operations such as sample preparation, instrument cleaning, sample separation and detection, etc., greatly reduce the tediousness and errors of manual operation, improve experimental efficiency, and achieve the purpose of high-throughput preparation and screening.

[0053] Based on the above-mentioned microchannel reactor, the present invention also proposes a method for using the microchannel reactor, including preparation and cleaning, as follows:

[0054] Preparation: First, the switching valve 4 is closed to prevent the compressed gas or cleaning liquid from entering the microreactor body 1. According to the preparation plan, the raw materials are respectively loaded into the multiple raw material conveyors 3, wherein the raw material conveyors 3 loaded with raw materials are distributed along the material flow direction in the main channel 11 according to the order and timing of the raw materials being successively input into the microreactor body 1;

[0055] Multiple raw materials are sequentially input into the microreactor body 1 according to the input timing to form a mixed material for mixing or reaction;

[0056] After all the raw materials are input into the microreactor body 1, the switching valve 4 is switched to input compressed gas, and the compressed gas pushes the mixed material along the material flow direction. The mixed material forms products during the flow in the microreactor body, and the final products flow out along the delivery channel 12;

[0057] Cleaning: After the preparation of a product is completed, all the products leave the microreactor body 1, and then the switching valve 4 is switched to input cleaning liquid to clean the main channel 11 and the delivery channel 12 of the microreactor body 1. After the cleaning is completed, the switching valve 4 is switched to input compressed gas again to force the microreactor body 1 to drain and dry;

[0058] Repeat the preparation and cleaning steps to achieve continuous preparation.

[0059] In the preparation step, the left channel 111 and the right channel 112 can be used simultaneously, or only the left channel 111 or the right channel 112 can be used. For example, when preparing LNP by three-phase mixing, the left channel 111 and the right channel 112 can be used simultaneously. The left channel 111 realizes the collision and mixing of the aqueous phase and the drug organic phase to precipitate drug nanoparticles, and the lipid organic phase input into the right channel 112 collides and mixes with the material in the left channel 111, lipids precipitate, and the drug nanoparticles are encapsulated to form lipid nanoparticles. Alternatively, only the left channel 111 or the right channel 112 is used to realize the three-phase mixing to prepare LNP.

[0060] The technical solution of the present invention is described below through specific embodiments.

[0061] Example 1

[0062] This embodiment provides a method for preparing mRNA-LNP (lipid nanoparticles loaded with mRNA) by using a microchannel reactor of the present invention using both the left channel 111 and the right channel 112. First, the required raw materials are prepared: including an aqueous solution containing mRNA, an organic solvent phase containing lipids, and auxiliary components. In order to improve the encapsulation efficiency and stability of mRNA-LNP, an appropriate lipid composition is selected, such as ionic lipids, co-lipids, cholesterol, and targeting molecules.

[0063] Then, the microchannel reactor of the present invention is set. The switching valve 4 is closed to prevent the compressed gas or cleaning liquid from entering the microreactor body 1. According to the preparation scheme, the various raw materials mentioned above are loaded in multiple raw material conveyors respectively. The aqueous phase solution containing mRNA is injected into the left channel 111, and the organic phase containing lipids and auxiliary components are injected into the right channel 112.

[0064] The control system accurately controls the delivery time, flow rate and pressure of each raw material to ensure that the two solutions meet and mix efficiently in the main channel 11 in the microreactor body 1. The ultrasonic generator 2 provides uniform and stable ultrasonic waves to promote the mixing or reaction of the raw materials in the microreactor body 1 to form a mixed material.

[0065] After the raw materials are completely input into the microreactor body 1, the switching valve 4 is switched to input compressed gas, and the compressed gas pushes the mixed material along the material flow direction. During the flow in the microreactor body, through collision and mixing, the mRNA and lipids are quickly self-assembled to form LNP under the action of ultrasound.

[0066] Finally, the formed mRNA-LNP flows out along the delivery channel 12, is collected and subsequently operated. After one product preparation is completed, the switching valve 4 is switched to input cleaning liquid to clean the main channel 11 and the delivery channel 12 of the microreactor body 1. After the cleaning is completed, the switching valve 4 is switched to input compressed gas again to force the microreactor body 1 to drain and dry, providing conditions for the next preparation.

[0067] This embodiment uses the scheme of the left and right channels at the same time, while ensuring the efficient mixing of the two solutions, greatly improving the preparation efficiency and quality of mRNA-LNP. In addition, the microchannel reactor of the present invention realizes the precise control of the volume and flow rate of the liquid through the automatic control of the preset experimental scheme parameters, ensures the accuracy and repeatability of the experiment, realizes the purpose of high-throughput preparation and screening, and is an efficient and reliable mRNA-LNP preparation method.

[0068] Example 2

[0069] In the present embodiment, a method for preparing mRNA-LNP using only a single channel scheme using the microchannel reactor of the present invention is provided. This embodiment particularly focuses on the efficient preparation process of mRNA-LNP using the left channel 111.

[0070] First, prepare the raw materials involved, including the water-based solution in which the mRNA is dissolved and the organic phase solution in which the lipids and auxiliary components are mixed. The selection of appropriate lipid components is the key to ensuring the stability and biocompatibility of mRNA-LNP, which may include cationic lipids, auxiliary lipids, cholesterol, and PEGylated lipids.

[0071] The steps for setting up the microchannel reactor are as follows: adjust the microreactor as required so that only the left channel 111 is enabled, and ensure that the auxiliary conveying components connected thereto are in a closed state to prevent the compressed gas or cleaning liquid from accidentally entering. Based on the preparation plan, the above raw materials are respectively loaded in each relevant raw material conveyor 3. In particular, the aqueous phase solution containing mRNA, lipids and the organic phase of the auxiliary components are injected into the left channel 111. Under the condition of ensuring precise control of the conveying time, flow rate and pressure of each raw material, all components will be tilted and input through the same or different raw material conveyors 3 to achieve effective mixing with the aqueous phase solution.

[0072] When all the raw materials have been delivered to the microreactor body 1, the switching valve 4 changes state to allow the compressed gas to propel the mixed material through the direction of material flow. Inside the microreactor, the dynamic flow of the mixed material and the ultrasonic wave generated by the ultrasonic generator 2 promote the rapid self-assembly of mRNA and lipid to form mRNA-LNP. Finally, the formed mRNA-LNP is collected through the delivery channel 12 at the output end for further processing and analysis.

[0073] After the preparation process is completed, the switching valve 4 is switched to the cleaning mode, and the cleaning liquid is input to thoroughly clean the main channel 11 and the delivery channel 12 of the microreactor body 1. After completion, the switching valve 4 is switched to the compressed gas mode again to force the microreactor body 1 to drain and dry it, so as to prepare for the next round of preparation.

[0074] Example 3

[0075] This embodiment shows a method for preparing PEG-PLGA (polyethylene glycol-polylactic acid-glycolic acid) nanoparticles using a scheme of using the left channel 111 and the right channel 112 simultaneously in the microchannel reactor of the present invention. First, the required raw materials are prepared, including an organic solvent solution of a PLGA-PEG block copolymer and an anti-solvent aqueous phase for preparing nanoparticles. Then, the microchannel reactor 1 of the present invention is set up according to the technical scheme. Make sure that the switching valve 4 is closed to prevent compressed gas or cleaning fluid from accidentally entering the microreactor body 1. According to the preparation scheme, the organic solvent solution of PLGA-PEG is input through the raw material conveyor 3 connected to the left channel 111, and at the same time, the aqueous phase is input through the raw material conveyor 3 connected to the right channel 112.

[0076] Through the control system of the microchannel reactor of the present invention, the raw material delivery time, flow rate and pressure of the left and right channels are accurately controlled to ensure that the organic solvent solution and the aqueous phase meet and mix rapidly at the main channel 11 in the microreactor body 1. At the same time, the ultrasonic generator 2 generates uniform and stable ultrasonic waves to promote rapid mixing or reaction of materials in the microreactor body 1 and accelerate the formation of PEG-PLGA nanoparticles.

[0077] After all the raw materials are completely input into the microreactor body 1, the switching valve 4 is operated to input compressed gas to push the mixed material forward along the material flow direction. The mixed material formed in the microreactor body 1 is rapidly self-assembled through collision, and finally forms stable PEG-PLGA nanoparticles under the action of ultrasound.

[0078] The formed PEG-PLGA nanoparticles are collected through the delivery channel 12 at the output end, and then separated and purified. After completing one preparation process, the cleaning liquid is input into the microreactor body 1 through the switching valve 4 to thoroughly clean the main channel 11 and the delivery channel 12 of the microreactor body. After the cleaning is completed, the switching valve 4 is used again to switch to the input of compressed gas for forced drainage and drying, so as to prepare for the next preparation work.

[0079] The embodiments provided by the present invention are described in detail above. Specific examples are used herein to describe the principles and implementation methods of the present invention, and the description of the above embodiments is only used to help understand the core idea of ​​the present invention. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A microchannel reactor, characterized in that: The invention comprises a control system, an ultrasonic generator (2), a microreactor body (1), a raw material conveyor (3) and an auxiliary conveying component, wherein the ultrasonic generator (2) is connected to the microreactor body (1), and the control system is respectively connected to the ultrasonic generator (2), the raw material conveyor (3) and the auxiliary conveying component; A main channel (11) and a transport channel (12) are arranged in the microreactor, wherein the main channel (11) is a straight channel or a folded channel, and one end of the transport channel (12) is connected to the main channel (11), so that the main channel (11) is divided into two parts, namely a left channel (111) and a right channel (112); Along the material flow direction of the left channel (111), a plurality of the raw material conveyors (3) are arranged outside the left channel (111) and are in communication with the left channel (111); a one-way valve (7) is arranged between the raw material conveyors (3) and the left channel (111); an auxiliary conveying component is arranged at one end of the left channel (111) away from the conveying channel (12); a one-way valve (7) is arranged between the auxiliary conveying component and the left channel (111); and the auxiliary conveying component conveys compressed gas into the left channel (111); Along the material flow direction of the right channel (112), a plurality of the raw material conveyors (3) are arranged outside the right channel (112) and are in communication with the right channel (112); a one-way valve (7) is arranged between the raw material conveyors (3) and the right channel (112); an auxiliary conveying component is arranged at one end of the right channel (112) away from the conveying channel (12); a one-way valve (7) is arranged between the auxiliary conveying component and the right channel (112); and the auxiliary conveying component conveys compressed gas into the right channel (112).

2. The microchannel reactor according to claim 1, characterized in that: The auxiliary delivery component comprises a compressed gas delivery pipe (6) and a valve, wherein the valve is connected to the outer end of the left channel (111) / right channel (112) through a pipeline and a one-way valve (7) is provided at the connection, and the compressed gas delivery pipe (6) is connected to the valve.

3. The microchannel reactor according to claim 2, characterized in that: The auxiliary conveying assembly also includes a cleaning liquid conveyor (5), and the valve is a two-inlet and one-outlet switching valve (4), the two inlets of the switching valve (4) are respectively connected to the cleaning liquid conveyor (5) and the compressed gas conveying pipe (6), and the outlet of the switching valve (4) is connected to the outer end of the left channel (111) / right channel (112).

4. The microchannel reactor according to claim 1, characterized in that: The length of the left channel (111) is the same as or different from the length of the right channel (112).

5. The microchannel reactor according to claim 4, characterized in that: The length of the left channel (111) is greater than the length of the right channel (112).

6. The microchannel reactor according to claim 1, characterized in that: The direction in which the raw material conveyor (3) connected to the left channel (111) injects raw material is the same as the direction in which the material flows in the left channel (111), and the direction in which the raw material conveyor (3) connected to the right channel (112) injects raw material is the same as the direction in which the material flows in the right channel (112).

7. A method for using a microchannel reactor, characterized in that: The microchannel reactor according to any one of claims 1 to 6 comprises the following steps of preparing and cleaning: Preparation: First, the switching valve (4) is closed to prevent the compressed gas or cleaning liquid from entering the microreactor body (1), and the raw materials are respectively loaded into a plurality of raw material conveyors (3) according to the preparation plan, wherein the raw material conveyors (3) loaded with raw materials are distributed along the material flow direction in the main channel (11) according to the order and timing of the raw materials being successively input into the microreactor body (1); Multiple raw materials are sequentially input into the microreactor body (1) according to input timing to form a mixed material, and then mixed or reacted; After all the raw materials are input into the microreactor body (1), the switching valve (4) is switched to input compressed gas, and the compressed gas pushes the mixed material along the material flow direction. The mixed material forms products during the flow process in the microreactor body, and the final products flow out along the conveying channel (12); Cleaning: After the preparation of a product is completed, all the products leave the microreactor body (1), and then the switching valve (4) is switched to input cleaning liquid to clean the main channel (11) and the delivery channel (12) of the microreactor body (1). After the cleaning is completed, the switching valve (4) is switched to input compressed gas again to force the microreactor body (1) to drain and dry; Repeat the preparation and cleaning steps to achieve continuous preparation.

8. The method of use according to claim 7, characterized in that: In the step of preparing, the left channel (111) and the right channel (112) are used simultaneously, or only the left channel (111) or only the right channel (112) is used.

9. The method of use according to claim 7, characterized in that: In the steps of preparing and cleaning, the compressed gas is one or more of compressed air, compressed oxygen, compressed nitrogen and compressed inert gas.

10. An application of a microchannel reactor, characterized in that: The microchannel reactor as described in any one of claims 1 to 6 is used in the fields of LNP, PLGA, drug synthesis and customized cosmetics.

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