A two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers

Abstract

This invention belongs to the field of fluid mixing technology and discloses a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanoparticle drug carriers. The two-phase fluid mixer for the efficient preparation of nucleic acid nanoparticle drug carriers includes a mixing body, which has a first flow channel, a second flow channel, and a mixing channel. The mixing channel includes a main flow channel and multiple branch channels, each connected to the main flow channel. The first and second flow channels are both connected to the main flow channel. The multiple branch channels are arranged sequentially along the axial direction of the main flow channel, with the axes of the branch channels forming an angle with the axis of the main flow channel. The branch channels are used to change the flow direction of the fluid flowing into them, so that the flow direction of the fluid flowing out of the branch channels intersects and mixes with the flow direction of the fluid in the main flow channel. The two-phase fluid mixer for the efficient preparation of nucleic acid nanoparticle drug carriers provided by this invention has high rapid fluid mixing performance and can be used to prepare lipid nanoparticles with good particle size uniformity.

Description

Technical Field

[0001] This invention relates to the field of fluid mixing technology, and in particular to a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers. Background Technology

[0002] Lipid nanoparticles (LNPs) are a novel drug delivery system capable of delivering bioactive compounds such as RNA, DNA, proteins, peptides, and small molecule drugs. Lipid nanoparticles are typically composed of a mixture of various lipids (e.g., natural or synthetic solid lipids, liquid lipids) in different proportions as a carrier material, which interact with the active biopharmaceutical to adsorb or encapsulate it, forming a nanodelivery system with particle sizes ranging from tens of nanometers to several micrometers, and capable of administration via multiple routes. Current lipid nanoparticles (LNPs) can be formed by rapidly mixing an aqueous phase fluid and an organic phase fluid (e.g., a solution of natural or synthetic cationic lipid molecules).

[0003] In existing technologies, aqueous and organic phase fluids are mixed using a mixing device. This device includes a first flow channel, a second flow channel, and a mixing channel. Both the first and second flow channels are connected to one end of the mixing channel, allowing for rapid mixing of the aqueous and organic phase fluids within the mixing channel. However, because the mixing channel is a straight-flow channel with a uniform diameter, the aqueous and organic phase fluids cannot be fully mixed, resulting in poor mixing performance. Furthermore, the uniformity of the prepared lipid nanoparticles' size needs improvement.

[0004] Therefore, there is an urgent need for a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, which has a high mixing effect.

[0006] Based on the above concept, the technical solution adopted by this invention is as follows:

[0007] A two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers includes a mixing body, wherein the mixing body is provided with a first flow channel, a second flow channel and a mixing flow channel;

[0008] The mixing channel includes a main channel and multiple branch channels, all of which are connected to the main channel. The first channel and the second channel are both connected to the main channel. The multiple branch channels are arranged sequentially along the axial direction of the main channel. The axial direction of the branch channels is set at an angle to the axial direction of the main channel. The branch channels are used to change the flow direction of the fluid flowing into them, so that the flow direction of the fluid flowing out of the branch channels intersects and mixes with the flow direction of the fluid in the main channel.

[0009] Optionally, a plurality of the branch channels are alternately arranged on both sides of the main channel along the axial direction of the main channel.

[0010] Optionally, the number of branch channels on both sides of the main channel is the same.

[0011] Optionally, the branch channel located on the first side of the main flow channel is a first branch channel. The inner wall of the first branch channel includes a first inclined wall, a first arcuate wall, a first upper wall, and a first lower wall. The first upper wall and the first lower wall are disposed opposite to each other. The first inclined wall and the first arcuate wall are both connected between the first upper wall and the first lower wall. The first inclined wall is connected to the first arcuate wall and the wall of the main flow channel. The end of the first arcuate wall away from the first inclined wall is connected to the wall of the main flow channel. The first inclined wall is disposed at an angle to the inner wall of the main flow channel. The first arcuate wall protrudes in a direction away from the axis of the main flow channel.

[0012] Optionally, the branch channel located on the second side of the main flow channel is a second branch channel. The inner wall of the second branch channel includes a second inclined wall, a second arcuate wall, a second upper wall, and a second lower wall. The second upper wall and the second lower wall are disposed opposite to each other. The second inclined wall and the second arcuate wall are both connected between the second upper wall and the second lower wall. The second inclined wall is connected to the second arcuate wall and the wall of the main flow channel. The end of the second arcuate wall away from the second inclined wall is connected to the wall of the main flow channel. The second inclined wall is disposed at an angle to the inner wall of the main flow channel. The second arcuate wall protrudes in a direction away from the axis of the main flow channel.

[0013] Optionally, the angle between the first inclined wall and the inner wall of the main flow channel is greater than or equal to the angle between the second inclined wall and the inner wall of the main flow channel.

[0014] Optionally, the main flow channel includes a first sub-flow channel and a second sub-flow channel, the flow area of ​​the first sub-flow channel is larger than the flow area of ​​the second sub-flow channel, the branch channel is disposed opposite to and connected to the second sub-flow channel, and both the first flow channel and the second flow channel are connected to the first sub-flow channel.

[0015] Optionally, the length of the first sub-channel in the first direction is w, and the length of the first sub-channel in the second direction is h;

[0016] When the connection point between the first arc wall and the wall of the second sub-channel is located to the left of the axis of the first sub-channel, the distance between the connection point between the first arc wall and the wall of the second sub-channel and the axis of the first sub-channel is d, d / w∈(0,0.5);

[0017] When the connection point between the first arc wall and the wall of the second sub-channel is located to the right of the axis of the first sub-channel, the distance between the connection point between the first arc wall and the wall of the second sub-channel and the axis of the first sub-channel is d', where d' / w∈(0,0.5).

[0018] The length of the first sub-channel in the second direction is h, h / w∈(0,1), and the first direction is perpendicular to the second direction.

[0019] Optionally, both the first branch channel and the second branch channel are provided. The first branch channel is closer to the end of the first sub-channel that connects to the first channel than the second branch channel. The distance between the connection point of the second branch channel and the second sub-channel and the end face of the first sub-channel away from the second sub-channel is 2.5w-3.5w.

[0020] Optionally, the outer surface of the first inclined wall is tangent to the outer surface of the first arcuate wall, and the outer surface of the second inclined wall is tangent to the outer surface of the second arcuate wall.

[0021] Optionally, the angle between the axial direction of the first flow channel and the axial direction of the second flow channel is an obtuse angle.

[0022] The beneficial effects of this invention are:

[0023] The present invention provides a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanoparticle carriers. The mixing channel includes a main channel and multiple branch channels. The first and second channels are connected to the main channel to enable mixing in the main channel. The fluid in the main channel can enter the branch channels, and the branch channels can change the flow direction of the fluid flowing into them, so that the flow direction of the fluid flowing out of the branch channels intersects with the flow direction of the fluid in the main channel. This achieves the purpose of disturbing the fluid in the main channel, allowing the two fluids to mix better and improving the mixing effect of the fluid in the mixing channel. When used to prepare lipid nanoparticles, it has high fluid rapid mixing performance, thus enabling the preparation of lipid nanoparticles with good particle size uniformity. Attached Figure Description

[0024] Figure 1 This is a schematic diagram of the structure of the hybrid body provided in an embodiment of the present invention;

[0025] Figure 2 This is a schematic diagram of the structure of a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, provided by an embodiment of the present invention. Figure 1 ;

[0026] Figure 3This is a schematic diagram of the structure of a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, provided by an embodiment of the present invention. Figure 2 ;

[0027] Figure 4 This is a schematic diagram of the structure of a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, provided by an embodiment of the present invention. Figure 3 ;

[0028] Figure 5 This is a schematic diagram of another two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers provided in this embodiment of the invention. Figure 1 ;

[0029] Figure 6 This is a schematic diagram of another two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers provided in this embodiment of the invention. Figure 2 ;

[0030] Figure 7 This is a schematic diagram of another two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers provided in this embodiment of the invention. Figure 3 ;

[0031] Figure 8 This is a schematic diagram of another two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers provided in this embodiment of the invention. Figure 4 ;

[0032] Figure 9 This is a streamline diagram of the fluid in a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers provided in the embodiments of the present invention;

[0033] Figure 10 This is a diagram showing the mixing behavior at different cross sections of a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, provided in this embodiment of the invention.

[0034] Figure 11 This is the relationship curve between total flow rate and mixing efficiency provided in the embodiments of the present invention;

[0035] Figure 12 The relationship between α and β provided in the embodiments of the present invention. Figure 1 ;

[0036] Figure 13 The relationship between α and β provided in the embodiments of the present invention. Figure 2 ;

[0037] Figure 14 The relationship between α and θ provided in the embodiments of the present invention Figure 1 ;

[0038] Figure 15The relationship between α and θ provided in the embodiments of the present invention Figure 2 ;

[0039] Figure 16 The relationship between β and θ provided in the embodiments of the present invention Figure 1 ;

[0040] Figure 17 The relationship between β and θ provided in the embodiments of the present invention Figure 2 ;

[0041] Figure 18 This is a particle size distribution diagram of LNPs provided in the embodiments of the present invention;

[0042] Figure 19 This is a graph showing the relationship between total flow rate and liposome size provided in an embodiment of the present invention;

[0043] Figure 20 This is a graph showing the relationship between total flow rate and PDI provided in an embodiment of the present invention;

[0044] Figure 21 This is a graph showing the percentage of different liposome sizes at each flow rate, provided in an embodiment of the present invention.

[0045] Figure 22 This is a graph showing the relationship between the flow rate ratio and the size of the liposomes provided in an embodiment of the present invention;

[0046] Figure 23 This is a graph showing the relationship between flow ratio and PDI provided in an embodiment of the present invention;

[0047] Figure 24 This is a graph showing the proportion of different liposome sizes at each flow rate ratio, provided in an embodiment of the present invention.

[0048] Figure 25 This is a graph showing the relationship between total lipid content and liposome size provided in an embodiment of the present invention;

[0049] Figure 26 This is a graph showing the relationship between total lipid content and PDI provided in an embodiment of the present invention;

[0050] Figure 27 This refers to the percentage of different liposome sizes for each total lipid content provided in the embodiments of the present invention.

[0051] In the picture:

[0052] 100. Mixing body; 110. First flow channel; 120. Second flow channel; 130. First inlet; 140. Second inlet; 150. Mixing outlet; 160. Upper plate; 170. Lower plate; 200. Mixing flow channel; 210. Main flow channel; 211. First sub-flow channel; 212. Second sub-flow channel; 220. Branch flow channel; 221. First inclined wall; 222. First arc wall; 223. First upper wall; 224. First lower wall; 225. Second inclined wall; 226. Second arc wall; 227. Second upper wall; 228. Second lower wall; 229. Horizontal wall; X, First direction; Y, Second direction; Z, Third direction. Detailed Implementation

[0053] To make the technical problems solved by the present invention, the technical solutions adopted, and the technical effects achieved clearer, the technical solutions of the present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention. Furthermore, it should be noted that, for ease of description, only the parts related to the present invention are shown in the accompanying drawings, not all of them.

[0054] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0055] In the description of this invention, unless otherwise explicitly specified and limited, the terms "connected," "linked," and "fixed" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0056] In this invention, unless otherwise explicitly specified and limited, "above" or "below" the second feature can include direct contact between the first and second features, or contact between the first and second features through another feature between them. Furthermore, "above," "over," and "on top" of the second feature includes the first feature directly above or diagonally above the second feature, or simply indicates that the first feature is at a higher horizontal level than the second feature. "Below," "below," and "under" the second feature includes the first feature directly below or diagonally below the second feature, or simply indicates that the first feature is at a lower horizontal level than the second feature. In the description of this embodiment, unless otherwise specified, "multiple" specifically refers to two or more.

[0057] In the description of this embodiment, the terms "upper," "lower," "right," etc., refer to the orientation or positional relationship shown in the accompanying drawings. They are used only for ease of description and simplification of operation, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the present invention. In addition, the terms "first" and "second" are used only for distinction in description and have no special meaning.

[0058] This embodiment provides a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, which can be used for the preparation of lipid nanoparticles and has a high mixing effect.

[0059] like Figures 1 to 8 As shown, a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers includes a mixing body 100. The mixing body 100 has a first flow channel 110, a second flow channel 120, and a mixing channel 200. The first flow channel 110 and the second flow channel 120 are used for the flow of different substances. For example, the first flow channel 110 can contain water, and the second flow channel 120 can contain organic matter. In some alternative embodiments, such as... Figure 1 As shown, the mixing body 100 has a first inlet 130, a second inlet 140, and a mixing outlet 150. The two ends of the first flow channel 110 are connected to the first inlet 130 and the mixing flow channel 200, respectively. The two ends of the second flow channel 120 are connected to the second inlet 140 and the mixing flow channel 200, respectively. The end of the mixing flow channel 200 away from the first flow channel 110 is connected to the mixing outlet 150.

[0060] In some optional embodiments, the mixing body 100 may include an upper plate 160 and a lower plate 170 that are snapped together. Grooves are provided on both the side of the upper plate 160 facing the lower plate 170 and the side of the lower plate 170 facing the upper plate 160. These grooves form a first flow channel 110, a second flow channel 120, and a mixing flow channel 200. By providing the upper plate 160 and the lower plate 170, maintenance is facilitated when the mixing flow channel 200 becomes blocked.

[0061] like Figure 3 As shown, the mixing channel 200 includes a main channel 210 and a plurality of branch channels 220, all of which are connected to the main channel 210. For example, the mixing channel 200 in this embodiment is "tree-shaped". The first channel 110 and the second channel 120 are both connected to the inlet of the main channel 210, allowing fluid in the first channel 110 and the second channel 120 to flow into the main channel 210.

[0062] like Figure 3 or Figure 4As shown, multiple branch channels 220 are sequentially arranged along the axial direction of the main channel 210, and the axis of each branch channel 220 is set at an angle to the axis of the main channel 210. In this embodiment, the axial direction of the main channel 210 is referred to as the third direction Z. In this embodiment, one end of the branch channel 220 is connected to the main channel 210, and the other end of the branch channel 220 is blocked and not connected to any channel, so that the fluid entering the branch channel 220 can also flow out of the branch channel 220. The branch channel 220 is used to change the flow direction of the fluid flowing into it, so that the flow direction of the fluid flowing out of the branch channel 220 intersects with the flow direction of the fluid in the main channel 210, thereby allowing the fluid flowing out of the branch channel 220 to mix better with the fluid in the main channel 210.

[0063] The two-phase fluid mixer provided in this embodiment is suitable for the efficient preparation of nucleic acid nanomedicine carriers. The mixing channel 200 includes a main channel 210 and multiple branch channels 220. The first channel 110 and the second channel 120 are both connected to the main channel 210 so that mixing can take place in the main channel 210. The fluid in the main channel 210 can enter the branch channels 220, and the branch channels 220 can change the flow direction of the fluid flowing into them, so that the flow direction of the fluid flowing out of the branch channels 220 intersects with the flow direction of the fluid in the main channel 210. This achieves the purpose of disturbing the fluid in the main channel 210, so that the two fluids can be mixed better, and the mixing effect of the fluid in the mixing channel 200 is improved. When used to prepare lipid nanoparticles, it has high fluid rapid mixing performance, so it can prepare lipid nanoparticles with good particle size uniformity.

[0064] Optionally, multiple branch channels 220 are alternately arranged on both sides of the main channel 210 along the axial direction of the main channel 210. This arrangement can further improve the mixing effect of the fluid. Figure 9 As shown, fluid flowing out of one branch channel 220 on one side of the mixing body 100 will flow into another branch channel 220 on the other side under the action of inertial force. Fluid flowing out of the other branch channel 220 will flow into another branch channel 220 on one side under the action of inertial force. This allows the fluid flow direction to not be entirely along the axis of the main channel 210. Consequently, when the fluid changes direction, the mixing degree of the two fluids flowing into the mixing channel 200 from the first channel 110 and the second channel 120 is increased, thereby improving the mixing effect. Figure 9 This is a streamline diagram of a fluid, where different colors represent different fluid velocities.

[0065] It should be noted that, as Figure 9As shown, when the fluid flows in the mixing channel 200, the flow velocity increases due to the branch channel 220. This not only improves the mixing efficiency but also increases the mixing rate, making the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers unnecessary to apply external energy. Therefore, the application range of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers is broadened.

[0066] Optionally, the number of branch channels 220 on both sides of the main channel 210 is the same to further improve the mixing effect. It is understood that the number of branch channels 220 on both sides of the main channel 210 can also be different; this embodiment does not limit this. In this embodiment, the more branch channels 220 there are, the better the mixing effect of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers.

[0067] Optionally, the multiple branch channels 220 can be divided into multiple channel groups, which are arranged sequentially along the axial direction of the main channel 210. Each channel group includes one branch channel 220 located on one side of the main channel 210 and one branch channel 220 located on the other side of the main channel 210. In this embodiment, the more channel groups there are, the higher the mixing efficiency. Therefore, as many channel groups as possible can be set while meeting the size requirements of the mixing body 100.

[0068] In some optional embodiments, the length of the branch channel 220 in the second direction Y is equal to the length of the main channel 210 in the second direction Y, in order to reduce energy loss caused by the change in diameter. It should be noted that the second direction Y can be the thickness direction of the mixing bulk. For example, the lengths of the first channel 110 and the second channel 120 in the second direction Y are equal to the length of the main channel 210 in the second direction Y, to ensure the uniformity and stability of the mixing.

[0069] In this embodiment, the branch channel 220 can have various specific structures, and this embodiment provides a specific structure of the branch channel 220.

[0070] In some alternative embodiments, for ease of description, the branch channel 220 located on the first side of the main channel 210 is referred to as the first branch channel. For example... Figure 4 and Figure 7 As shown, the inner wall of the first branch channel includes a first inclined wall 221, a first arcuate wall 222, a first upper wall 223, and a first lower wall 224. The first upper wall 223 and the first lower wall 224 are disposed opposite each other in the second direction Y. In this embodiment, the second direction Y can be the thickness direction of the mixing body.

[0071] The first inclined wall 221 and the first arcuate wall 222 are both connected between the first upper wall 223 and the first lower wall 224. The first inclined wall 221, the first arcuate wall 222, the first upper wall 223, and the first lower wall 224 cooperate to form an opening for connecting the main flow channel 210. That is, the first inclined wall 221 is connected to the first arcuate wall 222 and the wall of the main flow channel 210, and the end of the first arcuate wall 222 away from the first inclined wall 221 is connected to the wall of the main flow channel 210. This opening can be relatively large, facilitating fluid flow into and out of the first branch channel. When the fluid flows from the main flow channel 210 into the branch channel 220, it approaches the first inclined wall 221 and flows along it. That is, the first inclined wall 221 provides initial guidance for the fluid, which then collides with the first arcuate wall 222, is further guided by the first arcuate wall 222, and then re-enters the main flow channel 210. By setting the first circular arc wall 222, the flow guiding effect of the fluid can be improved, the backflow of the fluid can be prevented, and the impact on the fluid flow rate can be reduced.

[0072] In this embodiment, the first inclined wall 221 is set at an angle to the inner wall of the main flow channel 210. For example, the angle between the first inclined wall 221 and the inner wall of the main flow channel 210 is greater than 0 degrees and less than 90 degrees. Preferably, the angle between the first inclined wall 221 and the inner wall of the main flow channel 210 is 20 degrees to 25 degrees. More preferably, the angle between the first inclined wall 221 and the inner wall of the main flow channel 210 is 20 degrees, 23.10 degrees, 24 degrees, 25 degrees, etc. Furthermore, the first arc-shaped wall 222 protrudes in a direction away from the axis of the main flow channel 210, so that the first branch channel can have a larger volume, making it suitable for situations with large flow rates.

[0073] Similarly, the branch channel 220 located on the second side of the main channel 210 is the second branch channel. In this embodiment, as... Figure 4 and Figure 8 As shown, the inner wall of the second branch channel includes a second inclined wall 225, a second arcuate wall 226, a second upper wall 227, and a second lower wall 228. The second upper wall 227 and the second lower wall 228 are arranged opposite each other in the second direction Y. The second inclined wall 225 and the second arcuate wall 226 are both connected between the second upper wall 227 and the second lower wall 228. The second inclined wall 225 is connected to the wall of the second arcuate wall 226 and the main channel 210. The end of the second arcuate wall 226 away from the second inclined wall 225 is connected to the wall of the main channel 210, allowing the channel opening formed by the second inclined wall 225, the second arcuate wall 226, the second upper wall 227, and the second lower wall 228 to be relatively large, facilitating fluid flow into and out of the second branch channel through this opening.

[0074] The second inclined wall 225 is set at an angle to the inner wall of the main flow channel 210. For example, the angle between the second inclined wall 225 and the inner wall of the main flow channel 210 is greater than 0 degrees and less than 90 degrees. Preferably, the angle between the second inclined wall 225 and the inner wall of the main flow channel 210 is 20 degrees to 25 degrees. More preferably, the angle between the second inclined wall 225 and the inner wall of the main flow channel 210 is 20 degrees, 23.10 degrees, 24 degrees, 25 degrees, etc. Furthermore, the second arc-shaped wall 226 protrudes in a direction away from the axis of the main flow channel 210, so that the second branch channel can have a larger volume, making it suitable for situations with large flow rates.

[0075] Optionally, the angle between the first inclined wall 221 and the inner wall of the main flow channel 210 is greater than or equal to the angle between the second inclined wall 225 and the inner wall of the main flow channel 210. Preferably, the angle between the first inclined wall 221 and the inner wall of the main flow channel 210 is equal to the angle between the second inclined wall 225 and the inner wall of the main flow channel 210 to achieve a better mixing effect.

[0076] In some alternative embodiments, such as Figure 3 or Figure 6 As shown, the main flow channel 210 includes a first sub-flow channel 211 and a second sub-flow channel 212. The flow area of ​​the first sub-flow channel 211 is larger than that of the second sub-flow channel 212; that is, the cross-sectional area of ​​the first sub-flow channel 211 is larger than that of the second sub-flow channel 212. A branch channel 220 is disposed opposite to and connected to the second sub-flow channel 212. Both the first flow channel 110 and the second flow channel 120 are connected to the first sub-flow channel 211. By setting the flow area of ​​the second sub-flow channel 212 to be smaller than that of the first sub-flow channel 211, when the fluid in the first sub-flow channel 211 flows to the second sub-flow channel 212, a larger amount of fluid can flow into the branch channel 220 without short-circuiting the branch channel 220. This allows more fluid to flow out of the branch channel 220 and mix with the fluid in the second sub-flow channel 212, improving the fluid mixing effect.

[0077] Further optional, such as Figure 7As shown, the inner wall of the first branch channel also includes a horizontal wall 229. The horizontal wall 229 is set perpendicular to the inner wall of the main channel 210, and the horizontal wall 229 connects the inner wall of the main channel 210 and the first inclined wall 221. The setting of the horizontal wall 229 can reduce the flow area of ​​the second sub-channel 212, so as to improve the mixing effect. It should be noted that in this embodiment, one of the first branch channels is closest to the junction of the first channel 110, the second channel 120 and the first sub-channel 211. In order to ensure the inlet area of ​​the mixing channel 200, this first branch channel does not have a horizontal wall 229. That is, the first inclined wall 221 of this first branch channel is directly connected to the inner wall of the second sub-channel 212 or the first sub-channel 211. The first inclined walls 221 of the other first channels are all connected to the inner wall of the second sub-channel 212 through the horizontal wall 229. Optionally, as Figure 3 As shown, the length of the first sub-channel 211 in the first direction X is w.

[0078] like Figure 3 As shown, when the connection point between the first arc wall 222 and the wall of the second sub-channel 212 is located to the left of the axis of the first sub-channel 211, that is, when one side wall of the second sub-channel 212 is located to the left of the axis of the first sub-channel 211, the distance between the connection point between the first arc wall 222 and the wall of the second sub-channel 212 and the axis of the first sub-channel 211 is d, and d / w∈0,0.5; where the value of w ranges from 0 to positive infinity. Preferably, the value of d / w is 0.2, 0.24, 0.3, 0.4, 0.45, etc.

[0079] When the connection point between the first arcuate wall 222 and the wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211, that is, when one side wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211, the distance between the connection point between the first arcuate wall 222 and the wall of the second sub-channel 212 and the axis of the first sub-channel 211 is d' (not shown in the figure), d' / w∈(0,0.5); preferably, the value of d' / w is 0.2, 0.24, 0.3, 0.4, 0.45, etc. More preferably, the value of d' / w is 0.24.

[0080] It should be noted that the connection point between the first arc-shaped wall 222 and the wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211. This achieves a better mixing effect compared to having the connection point to the left of the axis of the first sub-channel 211. Optionally, as... Figure 4As shown, the length of the first sub-channel 211 in the second direction Y is h, where h / w ∈ (0, 1). Preferably, the value of h / w is 0.1, 0.5, 0.6, 0.8, etc. The first direction X is perpendicular to the second direction Y.

[0081] Further optional, such as Figure 3 As shown, both a first branch channel and a second branch channel are provided. The first branch channel is closer to the end of the first sub-channel 211 that connects to the first channel 110 than the second branch channel. The first branch channel is located on the left side and at the bottom, while the second branch channel is located on the right side and at the top. The distance between the connection point of the second branch channel and the second sub-channel 212 and the end face of the first sub-channel 211 away from the second sub-channel 212 is 2.5w-3.5w. Preferably, as shown... Figure 3 As shown, the distance between the connection position of the second branch channel and the second sub-channel 212 and the end face of the first sub-channel 211 away from the second sub-channel 212 is 3w.

[0082] It should be noted that the first branch channel and the second branch channel may have overlapping portions in the first direction X, so that the fluid flowing out of the first branch channel can enter the second branch channel more quickly, reducing the pressure loss caused by the sharp reduction in the flow area.

[0083] Optionally, such as Figure 2 and Figure 3 As shown, the angle between the axial direction of the first flow channel 110 and the axial direction of the second flow channel 120 is an obtuse angle to prevent the fluid velocity in one flow channel from being too high and flowing into the other flow channel, so that the fluid in both the first flow channel 110 and the second flow channel 120 can flow into the mixing flow channel 200. This improves the reliability of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers.

[0084] In this invention, the flow field of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanoparticle drug carriers provided in this embodiment is simulated using computational fluid dynamics (CFD) methods, and the CFD simulation results are fitted using the response surface methodology (RSM). The connection point between the first arcuate wall 222 and the wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211. Compared to the connection point being located to the left of the axis of the first sub-channel 211, this achieves better mixing results. Furthermore, this embodiment aims to obtain the optimal d' / w, h / w, and b parameters, thereby obtaining the optimal parameters for the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanoparticle drug carriers.

[0085] like Figures 12 to 17As shown, by combining CFD and RSM methods, the optimal values ​​for d' / w (i.e., the connection position between the first arc wall 222 and the wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211), h / w, and b are 0.24, 0.59, and 23.10 degrees, respectively. When these parameters are selected, the mixing effect of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers is the best. Figures 12 to 17 In this context, α represents d' / w and d / w. A positive value of α means α = d' / w, that is, in... Figures 12-15 In this context, when α = 0.25, it means d' / w = 0.25; a negative α represents α = d / w, that is, in... Figures 12-15 In the above, when α = -0.25, it means d / w = 0.25; β = h / w and θ = b are used.

[0086] In this invention, a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers is repeatedly expanded based on the optimal parameters (d' / w = 0.24, h / w = 0.59, b = 23.10 degrees), and the flow field of the expanded mixer is analyzed. Figures 7 to 9 The two-phase fluid mixer shown, suitable for the efficient preparation of nucleic acid nanomedicine carriers, is formed by the repeated stacking of six branch channels 220. Specifically, d' / w (where the connection point between the first arcuate wall 222 and the wall of the second sub-channel 212 is located to the right of the axis of the first sub-channel 211), h / w, and b are set to 0.24, 0.59, and 23.10°, respectively, and the number of branch channels 220 is 6. Aqueous and organic phase fluids enter the mixing body 100 through two inlets (i.e., the first inlet 130 and the second inlet 140), and the mixed fluid flows out from the mixing outlet 150. Figure 9 As shown, under the optimal structure, the two-phase fluids within the mixed body 100 easily generate a chaotic fluid effect and undergo mutual mixing.

[0087] In this invention, under optimal parameters (d' / w = 0.24, h / w = 0.59, b = 23.10 degrees, w = 1 mm, and 6 branches out of 220), the mixing efficiency of a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers was analyzed under different total flow rates (aqueous phase flow rate + organic phase flow rate). Figure 10 and Figure 11 As shown, the results indicate that: 1. The mixing efficiency of the two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers increases with the increase of the total flow rate; 2. The mixing efficiency increases with the increase of the number of branch channels 220, and the mixing efficiency is best when the number of branch channels 220 is greater than or equal to 6; 3. When the total flow rate is ≥10 mL / min, the mixing efficiency of the two-phase fluid is 100%. Figure 11The horizontal axis represents the total flow rate in units of 10 mL / min, and the vertical axis represents the mixing efficiency. Figure 10 In the diagram, I represents the mixing effect of the fluid in the mixing channel 200 at a cross-section near the first channel 110; II represents the mixing effect of the fluid in the mixing channel 200 at a cross-section in the middle of the mixing channel 200; and III represents the mixing effect of the fluid in the mixing channel 200 at a cross-section at the end of the mixing flow.

[0088] In this invention, LNPs preparation tests were conducted under optimal parameters (d' / w = 0.24, h / w = 0.59, b = 23.10 degrees, w = 1 mm, and 6 branches out of 220). The particle size and polymer dispersibility index (PDI) of LNPs synthesized using a two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers were analyzed under different total flow rates (aqueous phase flow rate + organic phase flow rate). Figure 18 As shown, the morphology of the synthesized LNPs was characterized by scanning electron microscopy. The results showed that the two-phase fluid mixer of the present invention, which is suitable for the efficient preparation of nucleic acid nanomedicine carriers, can synthesize nanoparticles with a particle size of less than 150 nm and a uniform particle size distribution.

[0089] In addition, such as Figures 19 to 27 As shown, by testing the particle size and PDI of LNPs prepared under different flow rates, the results indicate that the two-phase fluid mixer of this invention, suitable for the efficient preparation of nucleic acid nanomedicine carriers, can adjust the particle size and PDI of LNPs by regulating the flow field characteristics. This demonstrates that the two-phase fluid mixer of this invention has unique advantages in the preparation of LNPs. Therefore, the two-phase fluid mixer of this invention, suitable for the efficient preparation of nucleic acid nanomedicine carriers, can be used for the custom synthesis of LNPs within a specific particle size range. Figure 19 , Figure 22 and Figure 25 The vertical axis represents the size of liposomes, in nanometers. Figure 19 neutralization Figure 20 The horizontal axis represents the total flow rate, with units of mL / min; Figure 22 and Figure 23 The horizontal axis in the graph represents the flow rate ratio. Figure 25 and Figure 26 The horizontal axis in the figures represents total lipid content, in millimeters. Figure 20 , Figure 23 and Figure 26 The vertical axis in the figure is PDI; Figure 21 , Figure 24 and Figure 27 The horizontal axis in the figure represents the size of liposomes, in nanometers. Figure 21Different colored lines and different line types represent different flow rates. Figure 21 The vertical axis represents the percentage of different liposome sizes at each flow rate; Figure 24 Different colored lines and different types of lines represent different flow rates. Figure 24 The vertical axis represents the proportion of different liposome sizes at each flow rate ratio; Figure 27 The different colored lines represent different total lipid contents. Figure 27 The vertical axis represents the percentage of different liposome sizes for each total lipid content.

[0090] The two-phase fluid mixer provided in this embodiment is suitable for the efficient preparation of nucleic acid nanomedicine carriers. The mixing channel 200 includes a main channel 210 and multiple branch channels 220. The first channel 110 and the second channel 120 are both connected to the main channel 210 so that mixing can take place in the main channel 210. The fluid in the main channel 210 can enter the branch channels 220, and the branch channels 220 can change the flow direction of the fluid flowing into them, so that the flow direction of the fluid flowing out of the branch channels 220 intersects with the flow direction of the fluid in the main channel 210. This achieves the purpose of disturbing the fluid in the main channel 210. Even if the flow rate of the fluid entering the mixing channel 200 is relatively slow, the fluid can be mixed better, thus improving the mixing effect of the fluid in the mixing channel 200.

[0091] Note that the above description is merely a preferred embodiment of the present invention and the technical principles employed. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, and various obvious changes, readjustments, and substitutions can be made without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in detail through the above embodiments, the present invention is not limited to the above embodiments, and may include many other equivalent embodiments without departing from the concept of the present invention, the scope of which is determined by the scope of the appended claims.

Claims

1. A two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers, characterized in that, It includes a mixing body (100), which is provided with a first flow channel (110), a second flow channel (120) and a mixing flow channel (200); The mixing channel (200) includes a main channel (210) and a plurality of branch channels (220) all connected to the main channel (210). The first channel (110) and the second channel (120) are both connected to the main channel (210). The plurality of branch channels (220) are arranged sequentially along the axial direction of the main channel (210), and the axis of the branch channels (220) is parallel to the axis of the main channel (210). The lines are set at an angle. One end of the branch channel (220) is connected to the main channel (210), and the other end of the branch channel (220) is blocked. The fluid entering the branch channel (220) flows out of the branch channel (220). The branch channel (220) is used to change the flow direction of the fluid flowing into it, so that the flow direction of the fluid flowing out of the branch channel (220) intersects and mixes with the flow direction of the fluid in the main channel (210). Multiple branch channels (220) are alternately arranged on both sides of the main channel (210) along the axial direction of the main channel (210); The branch channel (220) located on the first side of the main channel (210) is the first branch channel. The inner wall of the first branch channel includes a first inclined wall (221), a first arcuate wall (222), a first upper wall (223), and a first lower wall (224). The first upper wall (223) and the first lower wall (224) are arranged opposite to each other. The first inclined wall (221) and the first arcuate wall (222) are both connected to the first upper wall (223) and the first lower wall. Between (224), the first inclined wall (221) is connected to the first arc wall (222) and the wall of the main flow channel (210). The end of the first arc wall (222) away from the first inclined wall (221) is connected to the wall of the main flow channel (210). The first inclined wall (221) is set at an angle to the inner wall of the main flow channel (210). The first arc wall (222) protrudes in the direction away from the axis of the main flow channel (210). The branch channel (220) located on the second side of the main channel (210) is a second branch channel. The inner wall of the second branch channel includes a second inclined wall (225), a second arcuate wall (226), a second upper wall (227), and a second lower wall (228). The second upper wall (227) and the second lower wall (228) are arranged opposite to each other. The second inclined wall (225) and the second arcuate wall (226) are both connected to the second upper wall (227) and the second lower wall. Between (228), the second inclined wall (225) is connected to the second arc wall (226) and the wall of the main flow channel (210). The end of the second arc wall (226) away from the second inclined wall (225) is connected to the wall of the main flow channel (210). The second inclined wall (225) is set at an angle to the inner wall of the main flow channel (210). The second arc wall (226) protrudes in the direction away from the axis of the main flow channel (210). The main flow channel (210) includes a first sub-flow channel (211) and a second sub-flow channel (212). The branch flow channel (220) is arranged opposite to and connected to the second sub-flow channel (212). The first flow channel (110) and the second flow channel (120) are both connected to the first sub-flow channel (211). The length of the first sub-channel (211) in the first direction X is w, and the length of the first sub-channel (211) in the second direction Y is h; When the connection point between the first arc wall (222) and the wall of the second sub-channel (212) is located to the left of the axis of the first sub-channel (211), the distance between the connection point between the first arc wall (222) and the wall of the second sub-channel (212) and the axis of the first sub-channel (211) is d, d / w∈(0,0.5); When the connection point between the first arc wall (222) and the wall of the second sub-channel (212) is located to the right of the axis of the first sub-channel (211), the distance between the connection point between the first arc wall (222) and the wall of the second sub-channel (212) and the axis of the first sub-channel (211) is d', d' / w∈(0,0.5); The length of the first sub-channel (211) in the second direction (Y) is h, h / w∈(0,1), the first direction X is perpendicular to the second direction Y, and the second direction Y is the thickness direction of the hybrid body (100).

2. The two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers according to claim 1, characterized in that, The number of branch channels (220) on both sides of the main channel (210) is the same.

3. The two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers according to claim 1, characterized in that, The angle between the first inclined wall (221) and the inner wall of the main flow channel (210) is greater than or equal to the angle between the second inclined wall (225) and the inner wall of the main flow channel (210).

4. The two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers according to claim 1, characterized in that, The flow area of ​​the first sub-channel (211) is greater than the flow area of ​​the second sub-channel (212).

5. The two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers according to claim 1, characterized in that, Both the first branch channel and the second branch channel are provided. The first branch channel is closer to the end of the first sub-channel (211) that connects to the first channel (110) than the second branch channel. The distance between the connection position of the second branch channel and the second sub-channel (212) and the end face of the first sub-channel (211) that is away from the second sub-channel (212) is 2.5w-3.5w.

6. The two-phase fluid mixer suitable for the efficient preparation of nucleic acid nanomedicine carriers according to claim 1, characterized in that, The outer surface of the first inclined wall (221) is tangent to the outer surface of the first arc wall (222), and the outer surface of the second inclined wall (225) is tangent to the outer surface of the second arc wall (226).

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