EP3377204A1 - Procede et dispositif de fabrication d'emulsions - Google Patents
Procede et dispositif de fabrication d'emulsionsInfo
- Publication number
- EP3377204A1 EP3377204A1 EP16806262.8A EP16806262A EP3377204A1 EP 3377204 A1 EP3377204 A1 EP 3377204A1 EP 16806262 A EP16806262 A EP 16806262A EP 3377204 A1 EP3377204 A1 EP 3377204A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- main channel
- pressure
- fluid
- external solution
- reservoir
- 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.)
- Granted
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
- B01F23/40—Mixing liquids with liquids; Emulsifying
- B01F23/41—Emulsifying
- B01F23/414—Emulsifying characterised by the internal structure of the emulsion
- B01F23/4143—Microemulsions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
- B01F23/40—Mixing liquids with liquids; Emulsifying
- B01F23/41—Emulsifying
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/30—Injector mixers
- B01F25/31—Injector mixers in conduits or tubes through which the main component flows
- B01F25/314—Injector mixers in conduits or tubes through which the main component flows wherein additional components are introduced at the circumference of the conduit
- B01F25/3142—Injector mixers in conduits or tubes through which the main component flows wherein additional components are introduced at the circumference of the conduit the conduit having a plurality of openings in the axial direction or in the circumferential direction
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
- B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
- B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
Definitions
- the present invention relates to methods and devices for manufacturing emulsions.
- Emulsions are widely used, for example micro or nanoemulsions, especially in medical applications.
- ultrasonically activatable emulsions are used which are intended to transport, for example, a drug or a marker in the human body to activate it locally in a target zone.
- WO2011007082A1 gives an example of such an emulsion which is particularly effective.
- EP1197262A2 disclose microfluidic devices subject to the same difficulties.
- the present invention therefore aims to provide a method of manufacturing emulsions which both allows to produce larger amounts of emulsion and is reliable.
- the invention proposes a microfluidic process for manufacturing an emulsion comprising drops in emulsion in an external solution, the drops containing a fluid, the process in which:
- the fluid is circulated along a first main channel
- a portion of the fluid flowing in the first main channel is taken off by a plurality of microchannels disposed along the first main channel, which each communicate individually with said first main channel and each open individually into a space filled with external solution, the first main channel being maintained at a pressure greater than said outer solution filled space, the first main channel having a passage section at least 5 times greater than each microchannel,
- the drops are formed when the fluid passes from each microchannel into said space filled with external solution
- the fluid is circulated along the first main channel between a first reservoir and a second reservoir maintained at an overpressure respectively at a first pressure and at a second pressure different from the first pressure, the first and second pressures being greater than the first pressure; atmospheric pressure, and alternately flowing the fluid in opposite directions along the first main channel, by varying the first and second pressures so that the first pressure is alternately higher and lower than the second pressure.
- the first main channel is a microfluidic river, which permanently cleans the mouth of the microchannels in the first main channel, thus avoiding the blocking microchannels by any debris or the like.
- said space filled with external solution is a second main channel and the external solution is circulated along said second main channel, the second main channel having a passage section at least 5 times greater than each microchannel: this arrangement also makes it possible to clean permanently the outlet of microchannels in the second main channel;
- the external solution is circulated along the second main channel between a third tank and a fourth tank maintained in overpressure respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than the atmospheric pressure and alternately flowing the outer solution in opposite directions along the second main channel, varying the third and fourth pressures so that the third pressure is alternately greater than and less than the fourth pressure:
- the drops have a diameter less than 20 ⁇ and the fluid contains nanodroplets having a diameter less than 5 ⁇ ;
- the external solution contains a surfactant.
- the subject of the invention is also a microfluidic device for manufacturing an emulsion comprising emulsion drops in an external solution, the drops containing a fluid,
- the device comprising:
- a first main channel filled with fluid and interconnecting a first reservoir and a second tank ,
- microchannels disposed along the first main channel, which each communicate individually with said first main channel and each open individually into said space filled with external solution (2), said microchannels being adapted to form the drops in the filled space of external solution, the first main channel having a passage section at least 5 times greater than each microchannel,
- pressurizing means for maintaining the first main channel at a pressure greater than said space filled with external solution
- the pressurizing means being adapted to maintain the first reservoir and the second reservoir under excess pressure, respectively at a first pressure and at a second pressure different from the first pressure, the first and second pressures being greater than atmospheric pressure, and pressurizing means being provided for alternately flowing the fluid in opposite directions along the first main channel, varying the first and second pressures so that the first pressure is alternately greater and less than the second pressure.
- said outer solution filled space is a second main channel and the microfluidic device comprises means for circulating the external solution along said second main channel, the second main channel having a passage section at least 10 times greater than each microchannel;
- the second main channel interconnects a third reservoir and a fourth reservoir
- the microfluidic device comprises pressurizing means for maintaining the third reservoir and the fourth reservoir in overpressure, respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than the atmospheric pressure, and the pressurizing means are provided for alternately circulating the external solution in opposite directions along the second main channel, by varying the third and fourth pressures; so that the third pressure is alternately greater and less than the fourth pressure.
- FIG. 1 is a schematic view of an emulsion microparticle in an aqueous solution, obtainable by a method according to one embodiment of the invention
- FIG. 2 is a block diagram of an exemplary microfluidic device according to one embodiment of the invention.
- FIG. 3 is a detail view of FIG. 2, and
- FIG. 4 shows emulsion nanoparticles in the starting fluid used in the device of FIGS. 2 and 3.
- the present invention provides a method and apparatus for making emulsions.
- the method and the device of the invention are particularly suitable for producing double emulsions such as that shown diagrammatically in FIG. 1, but the method and the device of the invention can also be used to manufacture other types of emulsions, including simple emulsions.
- this double emulsion which is described in more detail in the document WO2011007082A1, contains a secondary emulsion of microdroplets 1 in an aqueous solution 2, these microparticles 1 having a diameter D less than 20 ⁇ . Only one of the microparticles 1 is shown in FIG. 1 for the sake of simplicity.
- the microdrops 1 comprise a substantially spherical outer wall 4, made by a first emulsifier, in particular a surfactant such as for example the "Pluronic F68" ®.
- This outer wall 4 encapsulates a gaseous precursor liquid 3 vaporizable by ultrasound (or more generally an ultrasonically activatable compound) containing a primary emulsion of nanodroplets 5 having a diameter of less than 5 ⁇ , preferably of 0.3 to 1 ⁇ .
- the gaseous precursor may be a fluorinated oil, especially a perfluorocarbon, for example perfluorohexane or perfluoropentane.
- nanoparticles 5 each have a substantially spherical outer wall 7 which is formed by a second emulsifier, for example a fluorinated surfactant such as poly (perfluoropropylene glycol) carboxylate (marketed by Du Pont under the trademark “Krytox 157 FSH” ®).
- a fluorinated surfactant such as poly (perfluoropropylene glycol) carboxylate (marketed by Du Pont under the trademark "Krytox 157 FSH” ®).
- the outer wall 7 encapsulates an internal liquid 6, for example water or more generally an aqueous solution, which contains an active agent, in particular a marker or a drug.
- an active agent for example a marker or a drug.
- the active agent can be:
- a marker chosen in particular from optical dyes (for example fluorescein) and medical imaging contrast agents (especially contrast agents for MRI, X-rays, ultrasound or other);
- optical dyes for example fluorescein
- medical imaging contrast agents especially contrast agents for MRI, X-rays, ultrasound or other
- a therapeutic agent chosen in particular from cancer chemotherapeutic agents, antivascular drugs, toxins and messenger RNA, DNA, etc.
- This double emulsion can be manufactured using the microfluidic device 10 of FIGS. 2 to 4, which can also be used to produce other types of emulsions, in particular any emulsion comprising emulsion drops 1 in an external solution 2, drops containing a fluid 3 (liquid or gaseous).
- the microfluidic device 10 comprises:
- first main channel 11 also called “river” in microfluidic language
- the first main channel 11 and the microchannels 13 may for example be etched in a glass plate, polydimethylsiloxane or other, covered by a glass closure plate, polydimethylsiloxane or other.
- the fluid 3 of the first main channel 11 is added nanodes 5 in the case where the double emulsion mentioned above is formed.
- the external solution 2 can be added with surfactant, so that the fluid 3 forms drops 1 at the microchannel outlet, on arrival in the space 12 filled with external solution.
- the microchannels 13 are of much smaller section than the first main channel 11, for example less than 20% of the section of the first main channel 11.
- the microchannels generally have a width of less than 10 ⁇ and a depth of less than 10 ⁇ .
- microchannels 13 are in large numbers, for example more than 100 or even hundreds (only a portion of these microchannels is shown in Figures 2 and 3).
- said space filled with external solution 2 can be a second main channel 12 (also called “river” in microfluidic language) and the microfluidic device comprises means 22, 25, 26 for circulating the external solution 2 along said second main channel 12, which also helps to prevent clogging of the microchannels 13.
- second main channel 12 also called “river” in microfluidic language
- the microfluidic device comprises means 22, 25, 26 for circulating the external solution 2 along said second main channel 12, which also helps to prevent clogging of the microchannels 13.
- the second main channel 12 may for example be engraved in the above-mentioned glass plate, covered by a closing glass plate.
- the second main channel 12 may also have a passage section at least 5 times greater than the section of each microchannel 13.
- the first main channel 11 interconnects first and second closed tanks 16, 17 and the pressurizing means 22-26 are adapted to maintain the first and second tanks 16, 17 in overpressure, respectively to first and second PI pressures, P2 different, above atmospheric pressure.
- the pressures in question are provided for alternately flowing the fluid 3 in opposite directions along the first main channel 11, by varying the first and second pressures so that the first pressure PI is alternately greater and less than the second pressure P2.
- the second main channel 12 can connect third and fourth tanks 20, 21 together, and the microfluidic device comprises pressurizing means 22-26 for holding the third and fourth closed tanks 20, 21 in overpressure, respectively to third and fourth pressures P3, P4 different, greater than the atmospheric pressure but lower than the first and second pressures PI, P2 mentioned above, and the pressurizing means 22-26 are provided to circulate alternately the external solution 2 in opposite directions the along the second main channel 12, varying the third and fourth pressures so that the third pressure P3 is alternately higher and lower than the fourth pressure P4.
- the aforementioned pressures in the tanks can be generated in particular by a multi-channel pressure generation system 22-26, for example of the MFCS®-EZ type marketed by Fluigent®.
- a multi-channel pressure generation system 22-26 for example of the MFCS®-EZ type marketed by Fluigent®.
- Such a system comprises several independent pressure sources 23-26, respectively connected to the reservoirs 16, 17, 20, 21 and respectively producing the pressures P1-P4. These sources of pressure are controlled by a central unit 22, for example a computer or other.
- the operation of the device is as follows.
- the first reservoir 16 is filled with the fluid 3, for example containing the nanodroplets 5, and the third reservoir 20 is filled with the external solution 2 supplemented with surfactant.
- the central unit 22 controls the pressure sources 23-26 so that P1> P2> P3> P4, so that the first main channel 11 is traversed by the fluid 3 in the direction of the arrow 11a ( Figure 2) and that the second main channel 12 is traversed by the external solution 2 in the direction of the arrow 12a.
- the second and fourth reservoirs 17, 21 gradually fill up, and part of the fluid 3 passes into the external solution 2 in the form of microdrops.
- the drops 1 may be denser than the external solution 2, in which case they accumulate in the bottom of the third and fourth reservoirs 20, 21.
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Colloid Chemistry (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1561082A FR3043571A1 (fr) | 2015-11-18 | 2015-11-18 | Procede et dispositif de fabrication d'emulsions |
PCT/FR2016/052890 WO2017085373A1 (fr) | 2015-11-18 | 2016-11-08 | Procede et dispositif de fabrication d'emulsions |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3377204A1 true EP3377204A1 (fr) | 2018-09-26 |
EP3377204B1 EP3377204B1 (fr) | 2019-12-25 |
Family
ID=55022594
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16806262.8A Active EP3377204B1 (fr) | 2015-11-18 | 2016-11-08 | Procede et dispositif de fabrication d'emulsions |
Country Status (6)
Country | Link |
---|---|
US (1) | US20180326370A1 (fr) |
EP (1) | EP3377204B1 (fr) |
JP (1) | JP2019501012A (fr) |
BR (1) | BR112018009943A2 (fr) |
FR (1) | FR3043571A1 (fr) |
WO (1) | WO2017085373A1 (fr) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3511238B2 (ja) * | 2000-10-13 | 2004-03-29 | 独立行政法人食品総合研究所 | マイクロスフィアの製造方法および製造装置 |
JP4611989B2 (ja) * | 2003-05-16 | 2011-01-12 | ヴェロシス,インク. | マイクロチャネルプロセス技術を用いてエマルジョンを作製するプロセス |
CN1188209C (zh) * | 2003-05-27 | 2005-02-09 | 清华大学 | 一种低能耗连续制备微乳液的方法 |
US7622509B2 (en) * | 2004-10-01 | 2009-11-24 | Velocys, Inc. | Multiphase mixing process using microchannel process technology |
FR2948024B1 (fr) | 2009-07-17 | 2020-01-10 | Centre National De La Recherche Scientifique - Cnrs - | Emulsion activable par ultrasons et son procede de fabrication. |
-
2015
- 2015-11-18 FR FR1561082A patent/FR3043571A1/fr not_active Withdrawn
-
2016
- 2016-11-08 US US15/774,253 patent/US20180326370A1/en not_active Abandoned
- 2016-11-08 WO PCT/FR2016/052890 patent/WO2017085373A1/fr active Application Filing
- 2016-11-08 JP JP2018525777A patent/JP2019501012A/ja active Pending
- 2016-11-08 BR BR112018009943-0A patent/BR112018009943A2/pt not_active Application Discontinuation
- 2016-11-08 EP EP16806262.8A patent/EP3377204B1/fr active Active
Also Published As
Publication number | Publication date |
---|---|
FR3043571A1 (fr) | 2017-05-19 |
BR112018009943A2 (pt) | 2018-11-13 |
JP2019501012A (ja) | 2019-01-17 |
EP3377204B1 (fr) | 2019-12-25 |
WO2017085373A1 (fr) | 2017-05-26 |
US20180326370A1 (en) | 2018-11-15 |
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