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WO2023186122A1 - Dispositif de mélange d'écoulement à contre-courant et procédé de synthèse de liposomes - Google Patents

Dispositif de mélange d'écoulement à contre-courant et procédé de synthèse de liposomes Download PDF

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Publication number
WO2023186122A1
WO2023186122A1 PCT/CN2023/085568 CN2023085568W WO2023186122A1 WO 2023186122 A1 WO2023186122 A1 WO 2023186122A1 CN 2023085568 W CN2023085568 W CN 2023085568W WO 2023186122 A1 WO2023186122 A1 WO 2023186122A1
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WIPO (PCT)
Prior art keywords
fluid channel
fluid
fluid inlet
mixing chamber
section
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/085568
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English (en)
Chinese (zh)
Inventor
胡勇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Rhegen Biotechnology Co Ltd
Original Assignee
Shenzhen Rhegen Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Rhegen Biotechnology Co Ltd filed Critical Shenzhen Rhegen Biotechnology Co Ltd
Priority to CN202380023791.7A priority Critical patent/CN119278090A/zh
Publication of WO2023186122A1 publication Critical patent/WO2023186122A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/26—Nozzle-type reactors, i.e. the distribution of the initial reactants within the reactor is effected by their introduction or injection through nozzles

Definitions

  • the invention relates to the field of microfluidic control, and in particular, to a counterflow mixing device and method for liposome synthesis.
  • mRNA vaccines have proven their efficacy and market potential.
  • the mainstream delivery method of mRNA vaccines is LNP delivery, and the main production equipment of LNP is microfluidic chip.
  • the current production method has shortcomings such as high production cost and low output.
  • hedging flow is through Two or more fluids flow and conflict with each other, creating a turbulent area, which in turn enhances the heat transfer and mass transfer phenomena during the fluid mixing process.
  • the counterflow concept has achieved good results in chemical production such as drying and mixing of materials.
  • the object of the present invention is to provide a counter flow mixing device and method for liposome synthesis, which can enable the nucleic acid pharmaceutical ingredients and liposome components to be fully mixed evenly in the device, and can be used for standardized and stable production. all Uniform nanoparticles.
  • the present invention proposes a counter flow mixing device for liposome synthesis, wherein the counter flow mixing device has a device body, and a reaction mixing chamber, a first fluid channel and a reaction mixing chamber are provided in the device body. a second fluid channel, the reaction mixing chamber has a first fluid inlet and a second fluid inlet, the first fluid inlet and the second fluid inlet are arranged opposite to each other, the first fluid channel passes through the first fluid inlet Communicated with the reaction mixing chamber, the second fluid channel is connected with the reaction mixing chamber through the second fluid inlet.
  • the present invention also proposes a counterflow mixing method for liposome synthesis.
  • Nanoparticles are prepared through the counterflow mixing device as described above, wherein the liposome mixture enters the reaction mixing chamber from the first fluid channel, The drug solution enters the reaction mixing chamber from the second fluid channel. The liposome mixture and the drug solution collide when they enter the reaction mixing chamber.
  • the cationic liposomes in the liposome mixture The cationic liposomes precipitate rapidly due to changes in the properties of the solution.
  • the precipitated cationic liposomes wrap the pharmaceutical ingredients in the pharmaceutical solution and polymerize and settle together to form nanoparticles.
  • the present invention has the following characteristics and advantages:
  • the liposome mixture and the drug solution enter the reaction mixing chamber from the first fluid channel and the second fluid channel respectively. Since the first fluid inlet and the second fluid channel The fluid inlets are set opposite each other, and the two fluids entering the reaction mixing chamber conflict, forming a turbulent area of opposing flow, which improves the mixing and reaction efficiency of the two fluids, makes the performance more stable, and is suitable for high-quality and high-efficiency production.
  • Figure 1 is a schematic three-dimensional structural diagram of a counterflow mixing device for liposome synthesis proposed by the present invention
  • Figure 2 is a schematic side view of the counterflow mixing device for liposome synthesis proposed by the present invention
  • Figure 3 is a cross-sectional view along the B-B direction in Figure 2;
  • Figure 4 is a diagram showing the stability results of nanoparticles prepared by the counterflow mixing device for liposome synthesis proposed by the present invention.
  • the present invention proposes a counter flow mixing device 100 for liposome synthesis.
  • the counter flow mixing device 100 has a device body 10, and a reaction mixing chamber is provided in the device body 10. 20.
  • the reaction mixing chamber 20 has a first fluid inlet and a second fluid inlet.
  • the first fluid inlet and the second fluid inlet are arranged opposite to each other.
  • the first fluid channel 30 and the second fluid inlet are arranged oppositely.
  • the channel 40 is used to introduce fluid into the reaction mixing chamber 20.
  • the first fluid channel 30 is connected to the reaction mixing chamber 20 through the first fluid inlet
  • the second fluid channel 40 is connected to the reaction mixing chamber 20 through the second fluid inlet.
  • the present invention also proposes a method for liposome synthesis.
  • Nanoparticles are prepared through the counterflow mixing device 100.
  • the liposome mixture and the drug solution enter the reaction mixing chamber from the first fluid channel 30 and the second fluid channel 40 respectively. 20 And hedging occurs.
  • the cationic liposomes in the liposome component rapidly precipitate due to changes in solution properties.
  • the precipitated cationic liposomes wrap the drug ingredients and polymerize and settle together to form nanoparticles.
  • the liposome mixture and the drug solution enter the reaction mixing chamber 20 from the first fluid channel 30 and the second fluid channel 40 respectively. Since the first fluid Entrance Set opposite the second fluid inlet, the two fluids entering the reaction mixing chamber 20 collide, forming a turbulent area of opposing flow, improving the mixing and reaction efficiency of the two fluids, making the performance more stable, and suitable for high-quality and high-efficiency production.
  • the cationic liposomes in the liposome component are rapidly precipitated due to changes in solution properties, and at the same time, a large amount of nucleic acid drug components are wrapped together and rapidly polymerize and settle together.
  • the performance is more stable and suitable for the production of nanoparticles, achieving high-quality and high-efficiency production of nanoparticles.
  • a polymer solution can also be used instead of the liposome mixture;
  • the drug solution includes a nucleic acid drug solution; and
  • the nanoparticles include nanoparticles for nucleic acid vaccines.
  • liposomes with uniform particle size can be quickly produced.
  • the nanoparticles, specifically, the two fluid components are provided with an initial flow rate by the infusion pump.
  • the nucleic acid drug component passes through the second fluid channel 40 and enters the reaction mixing chamber 20 at a constant speed, it also passes through the first fluid channel 30 at a constant speed.
  • the liposome components are jet-mixed, and the two fluids collide with each other and mix rapidly.
  • the cationic liposomes in the liposome component quickly precipitate due to changes in solution properties, and at the same time, a large number of nucleic acid drug components are wrapped together and rapidly polymerize and settle together. Performance More stable, suitable for the production of nanoparticles, achieving high-quality and high-efficiency production of nanoparticles.
  • the counter flow mixing device 100 for liposome synthesis proposed by the present invention has a simple structure, is not prone to clogging, is easy to clean, and has a fast production speed, so that nucleic acid drug components and liposome components can be mixed in the counter flow mixing device 100 It is fully mixed and used to stably produce uniform nanoparticles in standardized large batches.
  • the device body 10 is a metal block
  • the reaction mixing chamber 20, the first fluid channel 30 and the second fluid channel 40 are opened in the metal block by drilling holes in the middle to create channels. inside the metal block.
  • the axis of the first fluid inlet and the axis of the second fluid inlet are located on the same straight line to ensure that the two fluids will conflict after entering the reaction mixing chamber 20 to form a conflicting flow turbulence zone.
  • the first fluid channel 30 includes a first small diameter section 31 and a first large diameter section 32.
  • the first small diameter section 31 is connected to the first fluid inlet and the first small diameter section 31 is connected to the first fluid inlet.
  • the inner diameter of 31 is smaller than the inner diameter of the first large diameter section 32 .
  • the inner diameter of the first large diameter section 32 is 1mm and the length is 2mm
  • the inner diameter of the first small diameter section 31 is 0.3mm and the length is 2mm.
  • the degree is 3.3mm.
  • the first fluid channel 30 further includes a first conduit connection section 33 for connecting with the infusion conduit.
  • the first conduit connection section 33 is connected to the first large diameter section 32.
  • the first conduit connection section 33 is connected to the first large diameter section 32.
  • the inner diameter of the conduit connecting section 33 is larger than the inner diameter of the first large diameter section 32 .
  • the infusion conduit is threadedly connected to the first conduit connection section 33 .
  • the second fluid channel 40 includes a second small diameter section 41 and a second large diameter section 42, the second small diameter section 41 is connected to the second fluid inlet, and the second small diameter section 41 is connected to the second fluid inlet.
  • the inner diameter of 41 is smaller than the inner diameter of the second large diameter section 42 .
  • the inner diameter of the second large diameter section 42 is 1 mm and the length is 2 mm, and the inner diameter of the second small diameter section 41 is 0.3 mm and the length is 3.3 mm.
  • the second fluid channel 40 further includes a second conduit connection section 43 for connecting to the infusion conduit.
  • the second conduit connection section 43 is connected to the second large diameter section 42.
  • the second conduit connection section 43 is connected to the second large diameter section 42.
  • the inner diameter of the conduit connecting section 43 is larger than the inner diameter of the second large diameter section 42 .
  • the infusion catheter is inserted into the second conduit connection section 43 and is threadedly connected with the second conduit connection section 43 .
  • a third conduit connection section 50 is provided in the device body 10.
  • the third conduit connection section 50 is connected with the reaction mixing chamber 20 and leads out the mixed fluid in the reaction mixing chamber 20. .
  • the reaction mixing chamber 20 is cylindrical, the first fluid inlet and the second fluid inlet are respectively opened on the side walls of the reaction mixing chamber 20, and the third conduit connecting section 50 is along the reaction mixing chamber. 20 axis settings.
  • the inner diameter D of the reaction mixing chamber 20 is 3.3 mm, and the height H of the reaction mixing chamber 20 is 6 mm.
  • the inner wall surface of the reaction mixing chamber 20 is smooth and easy to clean.
  • the axis of the first fluid inlet and the axis of the second fluid inlet are arranged perpendicular to the axis of the reaction mixing chamber 20 .
  • the first fluid inlet and the second fluid inlet are respectively opened at the center of the height H of the reaction mixing chamber 20 .
  • first fluid channel 30 and the second fluid channel 40 are coaxially arranged.
  • first fluid channel 30 and the second fluid channel 40 are arranged perpendicular to the axis of the reaction mixing chamber 20 .
  • the counterflow mixing device 100 and method for liposome synthesis proposed by the present invention are used to prepare lipid nanoparticles. They can be applied to different mixing flow rates and can obtain nanoparticles with uniform particle sizes. Specifically:
  • a counter flow mixing device 100 for liposome synthesis is provided.
  • the inner diameter D of the reaction mixing chamber 20 is 3.3 mm.
  • the height H of the reaction mixing chamber 20 is 6 mm.
  • the first fluid inlet and the second fluid inlet are both opened in the reaction chamber.
  • the height H of the mixing chamber 20 is at the center and opposite to each other.
  • the first large diameter section 32 has an inner diameter of 1 mm and a length of 2 mm.
  • the first small diameter section 31 has an inner diameter of 0.3 mm and a length of 3.3 mm.
  • the second large diameter section 42 has an inner diameter of 1 mm and a length of 2 mm. is 1 mm, and the length is 2 mm.
  • the inner diameter of the second thin diameter section 41 is 0.3 mm, and the length is 3.3 mm.
  • lipid solution ionizable lipid MC3, DSPC, cholesterol, mPEG2000-DMG according to the molar ratio of 50:10:38.5:1.5 to prepare a 10mg/ml lipid solution
  • the test temperature is 25°C
  • the N/P ratio is 6:1
  • the flow rate ratio 3 (mRNA solution): 1 (lipid solution)
  • the overall particle size results of the lipid nanoparticles produced by the counterflow mixing device 100 for liposome synthesis proposed by the present invention in each flow rate range are not very different.
  • the nanoparticle size PDI is less than 0.1, which can confirm that the nanoparticles produced by the counterflow mixing device 100 for liposome synthesis proposed in the present invention are uniform and stable, and the mixing efficiency is high.
  • the preparation speed of a single mixing device can reach 480ml/ min, greatly improving the preparation efficiency, and the effect is significantly better than the existing microfluidic chip.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

La présente invention se rapporte au domaine de la commande de micro-écoulement. L'invention concerne un dispositif de mélange d'écoulement à contre-courant et un procédé de synthèse de liposomes. Le dispositif de mélange d'écoulement à contre-courant (100) est pourvu d'un corps de dispositif (10). Une cavité de mélange de réaction (20), un premier canal de fluide (30) et un second canal de fluide (40) sont ménagés dans le corps de dispositif (10). La cavité de mélange de réaction (20) est pourvue d'une première entrée de fluide et d'une seconde entrée de fluide, la première entrée de fluide et la seconde entrée de fluide sont agencées à l'opposé l'une de l'autre, le premier canal de fluide (30) communique avec la cavité de mélange de réaction (20) au moyen de la première entrée de fluide, et le second canal de fluide (30) communique avec la cavité de mélange de réaction (20) au moyen de la seconde entrée de fluide. Au moyen du dispositif de mélange d'écoulement à contre-courant (100) et du procédé, un ingrédient pharmaceutique d'acide nucléique et un composant de liposome peuvent être mélangés entièrement et uniformément dans le dispositif, et des nanoparticules uniformes sont produites de manière standardisée et stable.
PCT/CN2023/085568 2022-04-02 2023-03-31 Dispositif de mélange d'écoulement à contre-courant et procédé de synthèse de liposomes Ceased WO2023186122A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380023791.7A CN119278090A (zh) 2022-04-02 2023-03-31 一种用于脂质体合成的对冲流混合装置及方法

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CN202210340967.9A CN114471217A (zh) 2022-04-02 2022-04-02 一种用于脂质体合成的对冲流混合装置及方法
CN202210340967.9 2022-04-02
CN202223566903.5U CN219091686U (zh) 2022-04-02 2022-12-30 一种用于脂质体合成的对冲流混合装置
CN202223566903.5 2022-12-30

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Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
CN114471217A (zh) * 2022-04-02 2022-05-13 深圳市瑞吉生物科技有限公司 一种用于脂质体合成的对冲流混合装置及方法

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WO2001028670A1 (fr) * 1999-10-20 2001-04-26 The University Of Sheffield Melangeur fluidique
CN106378081A (zh) * 2016-10-31 2017-02-08 山东豪迈化工技术有限公司 一种分流对冲微反应通道及微反应器
CN110605036A (zh) * 2019-08-30 2019-12-24 扬州大学 一种可非等动量受限射流撞击混合的方法
CN215876936U (zh) * 2021-08-04 2022-02-22 上海三为科学仪器有限公司 一种用于制备脂质纳米颗粒的射流混合器及射流混合系统
CN114471217A (zh) * 2022-04-02 2022-05-13 深圳市瑞吉生物科技有限公司 一种用于脂质体合成的对冲流混合装置及方法

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JP5003702B2 (ja) * 2009-03-16 2012-08-15 富士ゼロックス株式会社 マイクロ流体素子及びマイクロ流体制御方法
DE102009054652A1 (de) * 2009-12-15 2011-06-16 Hilti Aktiengesellschaft Statischer Mischer
US11737979B2 (en) * 2019-03-19 2023-08-29 Arcturus Therapeutics, Inc. Method of making lipid-encapsulated RNA nanoparticles
CN211562906U (zh) * 2019-12-03 2020-09-25 广东省新材料研究所 一种微通道反应器

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028670A1 (fr) * 1999-10-20 2001-04-26 The University Of Sheffield Melangeur fluidique
CN106378081A (zh) * 2016-10-31 2017-02-08 山东豪迈化工技术有限公司 一种分流对冲微反应通道及微反应器
CN110605036A (zh) * 2019-08-30 2019-12-24 扬州大学 一种可非等动量受限射流撞击混合的方法
CN215876936U (zh) * 2021-08-04 2022-02-22 上海三为科学仪器有限公司 一种用于制备脂质纳米颗粒的射流混合器及射流混合系统
CN114471217A (zh) * 2022-04-02 2022-05-13 深圳市瑞吉生物科技有限公司 一种用于脂质体合成的对冲流混合装置及方法

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CN219091686U (zh) 2023-05-30
CN114471217A (zh) 2022-05-13
CN119278090A (zh) 2025-01-07

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