EP3377204B1 - Method and apparatus for forming emulsions - Google Patents

Method and apparatus for forming emulsions Download PDF

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Publication number
EP3377204B1
EP3377204B1 EP16806262.8A EP16806262A EP3377204B1 EP 3377204 B1 EP3377204 B1 EP 3377204B1 EP 16806262 A EP16806262 A EP 16806262A EP 3377204 B1 EP3377204 B1 EP 3377204B1
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Prior art keywords
main channel
pressure
external solution
fluid
tank
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German (de)
French (fr)
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EP3377204A1 (en
Inventor
Olivier Couture
Mickael Tanter
Claudia ERRICO
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Ecole Superieure de Physique et Chimie Industrielles de Ville Paris
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Ecole Superieure de Physique et Chimie Industrielles de Ville Paris
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    • 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
    • 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
    • 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 nano-emulsions, in particular in medical applications.
  • emulsions which can be activated by ultrasound are used which are intended to transport, for example, a medicament or a marker in the human body in order to activate it locally in a target zone.
  • the document WO2011007082A1 gives an example of such an emulsion which is particularly effective.
  • the object of the present invention is therefore to propose a process for the manufacture of emulsions which both makes it possible to produce larger quantities of emulsion and is reliable.
  • the first main channel constitutes a river in the microfluidic sense, which permanently cleans the mouth of the microchannels in the first main channel, thus avoiding blockage of the microchannels by possible debris or the like.
  • the present invention provides a method and a device for producing emulsions.
  • the method and the device of the invention are particularly suitable for producing double emulsions such as that shown diagrammatically on the figure 1 , but the method and the device of the invention can also be used to manufacture other types of emulsions, in particular simple emulsions.
  • this double emulsion which is described in more detail in the document WO2011007082A1 , contains a secondary emulsion of microdrops 1 in an aqueous solution 2, these microparticles 1 having a diameter D of less than 20 ⁇ m. Only one of the microparticles 1 is represented on the figure 1 for simplicity.
  • the microdrops 1 comprise a substantially spherical external wall 4, produced by a first emulsifier, in particular a surfactant such as for example “Pluronic F68” ®.
  • This external wall 4 encapsulates a gaseous precursor liquid 3 vaporizable by ultrasound (or more generally a compound activated by ultrasound) containing a primary emulsion of nanodrops 5 having a diameter of less than 5 ⁇ m, preferably from 0.3 to 1 ⁇ m.
  • the gaseous precursor can be a fluorinated oil, in particular 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 (sold by the company Du Pont under the brand “Krytox 157 FSH” ®).
  • a fluorinated surfactant such as poly (perfluoropropylene glycol) carboxylate (sold by the company Du Pont under the brand “Krytox 157 FSH” ®).
  • the external 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 medicament.
  • This double emulsion can be manufactured using the microfluidic device 10 of the figures 2 to 4 , which is also usable for producing other types of emulsions, in particular any emulsion comprising drops 1 as an emulsion in an external solution 2, the drops containing a fluid 3 (liquid or gaseous).
  • the first main channel 11 and the microchannels 13 can for example be etched in a glass plate, polydimethylsiloxane or the like, covered by a glass, polydimethylsiloxane or other closure plate.
  • the fluid 3 of the first main channel 11 is added with the nanodrops 5 in the case where the above-mentioned double emulsion is formed.
  • the external solution 2 can be added with surfactant, so the fluid 3 forms drops 1 at the outlet of the microchannels, on its 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 ⁇ m and a depth of less than 10 ⁇ m.
  • microchannels 13 There are a large number of microchannels 13, for example more than 100 or even several hundred (only a part of these microchannels is represented on the 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 avoid 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 avoid clogging of the microchannels 13.
  • the second main channel 12 can for example be engraved in the aforementioned glass plate, covered by a closing glass plate.
  • the second main channel 12 can also have a passage section at least 5 times greater than the section of each microchannel 13.
  • the first main channel 11 connects first and second closed tanks 16, 17 to each other and the pressurizing means 22-26 are adapted to keep the first and second tanks 16, 17 under overpressure, respectively to first and second pressures P1, P2 different, higher than atmospheric pressure.
  • the pressures in question are provided for alternately circulating the fluid 3 in opposite directions along the first main channel 11, by varying the first and second pressures so that the first pressure P1 is alternately greater and less than the second pressure P2.
  • the second main channel 12 can connect third and fourth tanks 20, 21 to each other and the microfluidic device comprises pressurizing means 22-26 to keep the third and fourth closed tanks 20, 21 under overpressure, respectively to third and fourth pressures P3, P4 different, higher than atmospheric pressure but lower than the first and second pressures P1, P2 above, and the pressurizing means 22-26 are provided for alternately circulating the external solution 2 in opposite directions the along the second main channel 12, by varying the third and fourth pressures so that the third pressure P3 is alternately greater and less than the fourth pressure P4.
  • the above-mentioned pressures in the tanks can be generated in particular by a 22-26 multi-channel pressure generator system, for example of the MFCS®-EZ type sold by the company Fluigent®.
  • a 22-26 multi-channel pressure generator system for example of the MFCS®-EZ type sold by the company 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 pressure sources are controlled by a central unit 22, for example a computer or the like.
  • the operation of the device is as follows.
  • the first reservoir 16 is filled, for example, with the fluid 3, containing for example the nanodrops 5
  • the third reservoir 20 is filled, for example, with the external solution 2 added 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 are gradually filled, and part of the fluid 3 passes into the external solution 2 in the form of microdrops.
  • the drops 1 can be denser than the external solution 2, in which case they accumulate in the bottom of the third and fourth reservoirs 20, 21.

Description

DOMAINE DE L'INVENTIONFIELD OF THE INVENTION

La présente invention est relative aux procédés et dispositifs de fabrication d'émulsions.The present invention relates to methods and devices for manufacturing emulsions.

ARRIERE PLAN DE L'INVENTIONBACKGROUND OF THE INVENTION

On utilise largement les émulsions, par exemple des micro ou nano-émulsions, notamment dans les applications médicales. A titre d'exemple, on utilise des émulsions activables par ultrasons qui sont destinées à transporter par exemple un médicament ou un marqueur dans le corps humain pour l'activer localement dans une zone cible. Le document WO2011007082A1 donne un exemple d'une telle émulsion qui est particulièrement efficace.Emulsions are widely used, for example micro or nano-emulsions, in particular in medical applications. By way of example, emulsions which can be activated by ultrasound are used which are intended to transport, for example, a medicament or a marker in the human body in order to activate it locally in a target zone. The document WO2011007082A1 gives an example of such an emulsion which is particularly effective.

Malheureusement, les procédés de fabrication d'émulsion utilisés jusqu'ici ne donnent pas entièrement satisfaction. Les procédés utilisés sont généralement lents, par exemple lorsqu'on utilise un microcanal unique fonctionnant par focalisation hydrodynamique.Unfortunately, the emulsion manufacturing methods used so far are not entirely satisfactory. The methods used are generally slow, for example when using a single microchannel operating by hydrodynamic focusing.

Des tentatives ont été effectuées pour augmenter la production (voir par exemple Cohen et al., "Parallelised production of fine and calibrated émulsions by coupling flow-focusing technique and partial wetting phenomenon." Microfluidics and Nanofluidics 17, no. 5 (2014): 959-966 ), mais ces tentatives ont abouti à des dispositifs microfluidiques peu fiables, sujets au blocage.Attempts have been made to increase production (see for example Cohen et al., "Parallelised production of fine and calibrated emulsions by coupling flow-focusing technique and partial wetting phenomenon." Microfluidics and Nanofluidics 17, no. 5 (2014): 959-966 ), but these attempts have resulted in unreliable microfluidic devices, prone to blockage.

Les documents WO2006/039568 et EP1197262A2 présentent des dispositifs microfluidiques sujets aux mêmes difficultés.The documents WO2006 / 039568 and EP1197262A2 present microfluidic devices subject to the same difficulties.

OBJETS ET RESUME DE L'INVENTIONOBJECTS AND SUMMARY OF THE INVENTION

La présente invention a donc pour objet de proposer un procédé de fabrication d'émulsions qui à la fois permette de produire de plus grandes quantités d'émulsion et soit fiable.The object of the present invention is therefore to propose a process for the manufacture of emulsions which both makes it possible to produce larger quantities of emulsion and is reliable.

A cet effet, l'invention propose un procédé microfluidique de fabrication d'une émulsion comprenant des gouttes en émulsion dans une solution externe, les gouttes contenant un fluide, procédé dans lequel:

  • on fait circuler le fluide le long d'un premier canal principal,
  • on prélève une partie du fluide circulant dans le premier canal principal, par une pluralité de microcanaux disposés le long du premier canal principal, qui communiquent chacun individuellement avec ledit premier canal principal et débouchent chacun individuellement dans un espace rempli de solution externe, le premier canal principal étant maintenu à une pression supérieure audit espace rempli de solution externe, le premier canal principal ayant une section de passage au moins 5 fois supérieure à chaque microcanal,
  • on forme les gouttes lorsque le fluide passe de chaque microcanal dans ledit espace rempli de solution externe,
procédé dans lequel on fait circuler le fluide le long du premier canal principal entre un premier réservoir et un deuxième réservoir maintenus en surpression respectivement à une première pression et à une deuxième pression différente de la première pression, les première et deuxième pressions étant supérieures à la pression atmosphérique, et on fait circuler alternativement le fluide en sens opposés le long du premier canal principal, en faisant varier les première et deuxième pressions de façon que la première pression soit alternativement supérieure et inférieure à la deuxième pression.To this end, the invention provides a microfluidic process for manufacturing an emulsion comprising emulsion drops in an external solution, the drops containing a fluid, process in which:
  • the fluid is circulated along a first main channel,
  • a part of the fluid circulating in the first main channel is taken, by a plurality of microchannels arranged along the first main channel, which each communicate individually with said first main channel and each open out individually into a space filled with external solution, the first channel main being maintained at a pressure greater than said space filled with external solution, 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,
process in which the fluid is circulated along the first main channel between a first reservoir and a second reservoir maintained at 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 atmospheric pressure, and the fluid is circulated alternately in opposite directions along the first main channel, by varying the first and second pressures so that the first pressure is alternately greater and less than the second pressure.

Grâce à ces dispositions, le premier canal principal constitue une rivière au sens microfluidique, qui nettoie en permanence l'embouchure des microcanaux dans le premier canal principal, évitant ainsi les le blocage des microcanaux par d'éventuels débris ou similaires.Thanks to these provisions, the first main channel constitutes a river in the microfluidic sense, which permanently cleans the mouth of the microchannels in the first main channel, thus avoiding blockage of the microchannels by possible debris or the like.

Dans divers modes de réalisation du procédé selon l'invention, on peut éventuellement avoir recours en outre à l'une et/ou à l'autre des dispositions suivantes :

  • ledit espace rempli de solution externe est un deuxième canal principal et on fait circuler la solution externe le long dudit deuxième canal principal, le deuxième canal principal ayant une section de passage au moins 5 fois supérieure à chaque microcanal : cette disposition permet également de nettoyer en permanence le débouché des microcanaux dans le deuxième canal principal ;
  • on fait circuler la solution externe le long du deuxième canal principal entre un troisième réservoir et un quatrième réservoir maintenus en surpression respectivement à une troisième pression et à une quatrième pression différente de la troisième pression, les troisième et quatrième pressions étant supérieures à la pression atmosphérique, et on fait circuler alternativement la solution externe en sens opposés le long du deuxième canal principal, en faisant varier les troisième et quatrième pressions de façon que la troisième pression soit alternativement supérieure et inférieure à la quatrième pression : cette disposition permet de garantir l'absence de pollution de l'émulsion réalisée, puisque la fabrication a lieu en surpression sans ouverture des troisième et quatrième réservoirs ;
  • les gouttes ont un diamètre inférieur à 20 µm et le fluide contient des nanogouttes ayant un diamètre inférieur à 5 µm ;
  • la solution externe contient un agent tensioactif.
In various embodiments of the method according to the invention, it is also possible to have recourse to one and / or the other of the following provisions:
  • 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 by permanently the outlet of the microchannels in the second main channel;
  • the external solution is circulated along the second main channel between a third reservoir and a fourth reservoir maintained under overpressure respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than atmospheric pressure , and the external solution is circulated alternately 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: this arrangement makes it possible to guarantee the absence of pollution of the emulsion produced, since the manufacturing takes place under overpressure without opening the third and fourth tanks;
  • the drops have a diameter of less than 20 μm and the fluid contains nanodrops having a diameter of less than 5 μm;
  • the external solution contains a surfactant.

Par ailleurs, l'invention a également pour objet un dispositif microfluidique de fabrication d'une émulsion comprenant des gouttes en émulsion dans une solution externe, les gouttes contenant un fluide,
le dispositif comprenant:

  • un premier canal principal rempli de fluide et reliant entre eux un premier réservoir et un deuxième réservoir,
  • des moyens pour faire circuler le fluide le long du premier canal principal,
  • un espace rempli de solution externe,
  • une pluralité de microcanaux disposés le long du premier canal principal, qui communiquent chacun individuellement avec ledit premier canal principal et débouchent chacun individuellement dans ledit espace rempli de solution externe (2), lesdits microcanaux étant adaptés pour former les gouttes dans l'espace rempli de solution externe, le premier canal principal ayant une section de passage au moins 5fois supérieure à chaque microcanal,
  • des moyens de mise en pression pour maintenir le premier canal principal à une pression supérieure audit espace rempli de solution externe,
les moyens de mise en pression étant adaptés pour maintenir le premier réservoir et le deuxième réservoir en surpression, respectivement à une première pression et à une deuxième pression différente de la première pression, les première et deuxième pressions étant supérieures à la pression atmosphérique, et les moyens de mise en pression étant prévus pour faire circuler alternativement le fluide en sens opposés le long du premier canal principal, en faisant varier les première et deuxième pressions de façon que la première pression soit alternativement supérieure et inférieure à la deuxième pression.Furthermore, 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 connecting a first reservoir and a second tank,
  • means for circulating the fluid along the first main channel,
  • a space filled with external solution,
  • a plurality of microchannels arranged along the first main channel, which each communicate individually with said first main channel and each open out individually into said space filled with external solution (2), said microchannels being adapted to form the drops in the space filled with 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 higher than said space filled with external solution,
the pressurizing means being adapted to maintain the first tank and the second tank under overpressure, 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 the pressurizing means being provided for alternately circulating the fluid in opposite directions along the first main channel, by varying the first and second pressures so that the first pressure is alternately greater and less than the second pressure.

Dans divers modes de réalisation du dispositif microfluidique selon l'invention, on peut éventuellement avoir recours en outre à l'une et/ou à l'autre des dispositions suivantes :

  • ledit espace rempli de solution externe est un deuxième canal principal et le dispositif microfluidique comporte des moyens pour faire circuler la solution externe le long dudit deuxième canal principal, le deuxième canal principal ayant une section de passage au moins 10 fois supérieure à chaque microcanal ;
  • le deuxième canal principal relie entre eux un troisième réservoir et un quatrième réservoir et le dispositif microfluidique comporte des moyens de mise en pression pour maintenir le troisième réservoir et le quatrième réservoir en surpression, respectivement à une troisième pression et à une quatrième pression différente de la troisième pression, les troisième et quatrième pressions étant supérieures à la pression atmosphérique, et les moyens de mise en pression sont prévus pour faire circuler alternativement la solution externe en sens opposés le long du deuxième canal principal, en faisant varier les troisième et quatrième pressions de façon que la troisième pression soit alternativement supérieure et inférieure à la quatrième pression.
In various embodiments of the microfluidic device according to the invention, one can optionally have recourse to one and / or the other of the following arrangements:
  • said space filled with external solution 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 connects a third reservoir and a fourth reservoir to each other and the microfluidic device comprises pressurizing means for maintaining the third reservoir and the fourth reservoir under overpressure, respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than 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 press is alternately higher and lower than the fourth press.

BREVE DESCRIPTION DES DESSINSBRIEF DESCRIPTION OF THE DRAWINGS

D'autres caractéristiques et avantages de l'invention apparaîtront au cours de la description suivante d'un de ses modes de réalisation, donné à titre d'exemple non limitatif, en regard des dessins joints.Other characteristics and advantages of the invention will appear during the following description of one of its embodiments, given by way of nonlimiting example, with reference to the accompanying drawings.

Sur les dessins :

  • la figure 1 est une vue schématique d'une microparticule en émulsion dans une solution aqueuse, pouvant être obtenue par un procédé selon une forme de réalisation de l'invention,
  • la figure 2 est un schéma de principe d'un exemple de dispositif microfluidique selon une forme de réalisation de l'invention,
  • la figure 3 est une vue de détail de la figure 2, et
  • la figure 4 montre des nanoparticules en émulsion dans le fluide de départ utilisé dans le dispositif des figures 2 et 3.
In the drawings:
  • the figure 1 is a schematic view of a microparticle in emulsion in an aqueous solution, obtainable by a method according to an embodiment of the invention,
  • the figure 2 is a block diagram of an example of a microfluidic device according to an embodiment of the invention,
  • the figure 3 is a detail view of the figure 2 , and
  • the figure 4 shows nanoparticles in emulsion in the starting fluid used in the device figures 2 and 3 .

DESCRIPTION PLUS DETAILLEEMORE DETAILED DESCRIPTION

Sur les différentes figures, les mêmes références désignent des éléments identiques ou similaires.In the different figures, the same references denote identical or similar elements.

La présente invention propose un procédé et un dispositif pour réaliser des émulsions.The present invention provides a method and a device for producing emulsions.

A titre d'exemple, le procédé et le dispositif de l'invention sont particulièrement adaptés pour réaliser des émulsions doubles telle que celle schématisée sur la figure 1, mais le procédé et le dispositif de l'invention sont également utilisables pour fabriquer d'autres types d'émulsions, notamment des émulsions simples.By way of example, the method and the device of the invention are particularly suitable for producing double emulsions such as that shown diagrammatically on the figure 1 , but the method and the device of the invention can also be used to manufacture other types of emulsions, in particular simple emulsions.

Comme représenté schématiquement sur la figure 1, cette émulsion double, qui est décrite plus en détail dans le document WO2011007082A1 , contient une émulsion secondaire de microgouttes 1 dans une solution aqueuse 2, ces microparticules 1 ayant un diamètre D inférieur à 20 µm. Une seule des microparticules 1 est représentée sur la figure 1 par mesure de simplicité.As shown schematically on the figure 1 , this double emulsion, which is described in more detail in the document WO2011007082A1 , contains a secondary emulsion of microdrops 1 in an aqueous solution 2, these microparticles 1 having a diameter D of less than 20 μm. Only one of the microparticles 1 is represented on the figure 1 for simplicity.

Les microgouttes 1 comprennent une paroi externe 4 sensiblement sphérique, réalisée par un premier émulsifiant, notamment un surfactant tel que par exemple le « Pluronic F68 » ®.The microdrops 1 comprise a substantially spherical external wall 4, produced by a first emulsifier, in particular a surfactant such as for example “Pluronic F68” ®.

Cette paroi externe 4 encapsule un liquide précurseur gazeux 3 vaporisable par ultrasons (ou plus généralement un composé activable par ultrasons) contenant une émulsion primaire de nanogouttes 5 ayant un diamètre inférieur à 5 µm, de préférence de 0,3 à 1 µm. Le précurseur gazeux peut être une huile fluorée, notamment un perfluorocarbone, par exemple du perfluorohexane ou le perfluoropentane.This external wall 4 encapsulates a gaseous precursor liquid 3 vaporizable by ultrasound (or more generally a compound activated by ultrasound) containing a primary emulsion of nanodrops 5 having a diameter of less than 5 μm, preferably from 0.3 to 1 μm. The gaseous precursor can be a fluorinated oil, in particular a perfluorocarbon, for example perfluorohexane or perfluoropentane.

Ces nanoparticules 5 présentent chacune une paroi externe 7 sensiblement sphérique qui est formée par un deuxième émulsifiant, par exemple un surfactant fluoré tel que du poly(perfluoropropylène glycol) carboxylate (commercialisé par la société Du Pont sous la marque « Krytox 157 FSH » ®).These 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 (sold by the company Du Pont under the brand "Krytox 157 FSH" ®).

La paroi externe 7 encapsule un liquide interne 6, par exemple de l'eau ou plus généralement une solution aqueuse, qui contient un agent actif, notamment un marqueur ou un médicament.The external 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 medicament.

Plus précisément, l'agent actif peut être :

  • un marqueur choisi notamment parmi les colorants optiques (par exemple la fluorescéine) et les agents de contraste pour imagerie médicale (notamment agents de contraste pour IRM, rayons X, ultrasons ou autres);
  • un marqueur destiné à servir de cible pour un agent thérapeutique ;
  • un agent thérapeutique choisi notamment parmi les agents de chimiothérapie anticancéreuse, des médicaments antivasculaires, des toxines et l'ARN messager, l'ADN, etc.
More specifically, the active agent can be:
  • a marker chosen in particular from optical dyes (for example fluorescein) and contrast agents for medical imaging (in particular contrast agents for MRI, X-rays, ultrasound or others);
  • a marker to serve as a target for a therapeutic agent;
  • a therapeutic agent chosen in particular from anticancer chemotherapy agents, antivascular drugs, toxins and messenger RNA, DNA, etc.

Cette émulsion double peut être fabriquée à l'aide du dispositif microfluidique 10 des figures 2 à 4, qui est également utilisable pour réaliser d'autres types d'émulsions, en particulier toute émulsion comprenant des gouttes 1 en émulsion dans une solution externe 2, les gouttes contenant un fluide 3 (liquide ou gazeux).This double emulsion can be manufactured using the microfluidic device 10 of the figures 2 to 4 , which is also usable for producing other types of emulsions, in particular any emulsion comprising drops 1 as an emulsion in an external solution 2, the drops containing a fluid 3 (liquid or gaseous).

Le dispositif microfluidique 10 comprend:

  • un premier canal principal 11 (aussi appelé « rivière » en langage de microfluidique) rempli de fluide 3,
  • des moyens 22-24 pour on faire circuler le fluide 3 le long du premier canal principal 11 en créant des différences de pression,
  • un espace 12 rempli de solution externe 2,
  • une pluralité de microcanaux 13 disposés le long du premier canal principal 11, qui communiquent chacun individuellement avec ledit premier canal principal 11 et débouchent chacun individuellement dans ledit espace 12 rempli de solution externe 2,
  • des moyens de mise en pression 22-26 pour maintenir le premier canal principal 11 une pression supérieure audit espace 12 rempli de solution externe.
The microfluidic device 10 comprises:
  • a first main channel 11 (also called “river” in microfluidic language) filled with fluid 3,
  • means 22-24 for circulating the fluid 3 along the first main channel 11 by creating pressure differences,
  • a space 12 filled with external solution 2,
  • a plurality of microchannels 13 arranged along the first main channel 11, which each communicate individually with said first main channel 11 and each open out individually into said space 12 filled with external solution 2,
  • pressurizing means 22-26 for maintaining the first main channel 11 at a pressure greater than said space 12 filled with external solution.

Le premier canal principal 11 et les microcanaux 13 peuvent par exemple être gravés dans une plaque de verre, polydimethylsiloxane ou autre, recouverte par une plaque de fermeture en verre, polydimethylsiloxane ou autre.The first main channel 11 and the microchannels 13 can for example be etched in a glass plate, polydimethylsiloxane or the like, covered by a glass, polydimethylsiloxane or other closure plate.

Le fluide 3 du premier canal principal 11 est additionné des nanogouttes 5 dans le cas où on forme l'émulsion double susmentionnée.The fluid 3 of the first main channel 11 is added with the nanodrops 5 in the case where the above-mentioned double emulsion is formed.

La solution externe 2 peut être additionnée de tensioactif, de façon le fluide 3 forme des gouttes 1 en sortie des microcanaux, à son arrivée dans l'espace 12 rempli de solution externe.The external solution 2 can be added with surfactant, so the fluid 3 forms drops 1 at the outlet of the microchannels, on its arrival in the space 12 filled with external solution.

Les microcanaux 13 sont de section bien plus faible que le premier canal principal 11, par exemple moins de 20% de la section du premier canal principal 11. Les microcanaux ont généralement une largeur inférieure à 10 µm et une profondeur inférieure à 10 µm.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 μm and a depth of less than 10 μm.

Les microcanaux 13 sont en grand nombre, par exemple plus de 100 voire plusieurs centaines (seule une partie de ces microcanaux est représentée sur les figures 2 et 3).There are a large number of microchannels 13, for example more than 100 or even several hundred (only a part of these microchannels is represented on the figures 2 and 3 ).

Grâce à la circulation de fluide dans le premier canal principal 11, on limite ou évite le bouchage des microcanaux 13 notamment par des nanogouttes.Thanks to the circulation of fluid in the first main channel 11, the clogging of the microchannels 13 is limited or avoided, in particular by nanodrops.

Avantageusement, ledit espace rempli de solution externe 2 peut être un deuxième canal principal 12 (aussi appelé « rivière » en langage de microfluidique) et le dispositif microfluidique comporte des moyens 22, 25, 26 pour faire circuler la solution externe 2 le long dudit deuxième canal principal 12, ce qui contribue également à éviter le bouchage des microcanaux 13.Advantageously, 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 avoid clogging of the microchannels 13.

Le deuxième canal principal 12 peut per exemple être gravé dans la plaque de verre susmentionnée, recouverte par une plaque de verre de fermeture.The second main channel 12 can for example be engraved in the aforementioned glass plate, covered by a closing glass plate.

Le deuxième canal principal 12 peut également avoir une section de passage au moins 5 fois supérieure à la section de chaque microcanal 13.The second main channel 12 can also have a passage section at least 5 times greater than the section of each microchannel 13.

Avantageusement, le premier canal principal 11 relie entre eux des premier et deuxième réservoirs fermés 16, 17 et les moyens de mise en pression 22-26 sont adaptés pour maintenir les premier et deuxième réservoirs 16, 17 en surpression, respectivement à des première et deuxième pressions P1, P2 différentes, supérieures à la pression atmosphérique. Les pressions en question sont prévues pour faire circuler alternativement le fluide 3 en sens opposés le long du premier canal principal 11, en faisant varier les première et deuxième pressions de façon que la première pression P1 soit alternativement supérieure et inférieure à la deuxième pression P2.Advantageously, the first main channel 11 connects first and second closed tanks 16, 17 to each other and the pressurizing means 22-26 are adapted to keep the first and second tanks 16, 17 under overpressure, respectively to first and second pressures P1, P2 different, higher than atmospheric pressure. The pressures in question are provided for alternately circulating the fluid 3 in opposite directions along the first main channel 11, by varying the first and second pressures so that the first pressure P1 is alternately greater and less than the second pressure P2.

Avantageusement, le deuxième canal principal 12 peut relier entre eux des troisième et quatrième réservoirs 20, 21 et le dispositif microfluidique comporte des moyens de mise en pression 22-26 pour maintenir les troisième et quatrième réservoirs fermés 20, 21 en surpression, respectivement à des troisième et quatrième pressions P3, P4 différentes, supérieures à la pression atmosphérique mais inférieures aux première et deuxième pressions P1, P2 susmentionnées, et les moyens de mise en pression 22-26 sont prévus pour faire circuler alternativement la solution externe 2 en sens opposés le long du deuxième canal principal 12, en faisant varier les troisième et quatrième pressions de façon que la troisième pression P3 soit alternativement supérieure et inférieure à la quatrième pression P4.Advantageously, the second main channel 12 can connect third and fourth tanks 20, 21 to each other and the microfluidic device comprises pressurizing means 22-26 to keep the third and fourth closed tanks 20, 21 under overpressure, respectively to third and fourth pressures P3, P4 different, higher than atmospheric pressure but lower than the first and second pressures P1, P2 above, and the pressurizing means 22-26 are provided for alternately circulating the external solution 2 in opposite directions the along the second main channel 12, by varying the third and fourth pressures so that the third pressure P3 is alternately greater and less than the fourth pressure P4.

Les pressions susmentionnées dans les réservoirs peuvent être générées notamment par un système générateur de pression 22-26 multivoies, par exemple de type MFCS®-EZ commercialisé par la société Fluigent®. Un tel système comporte plusieurs sources de pression indépendantes 23-26, connectées respectivement aux réservoirs 16, 17, 20, 21 et produisant respectivement les pressions P1-P4. Ces sources de pressions sont commandées par une unité centrale 22, par exemple un ordinateur ou autre.The above-mentioned pressures in the tanks can be generated in particular by a 22-26 multi-channel pressure generator system, for example of the MFCS®-EZ type sold by the company 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 pressure sources are controlled by a central unit 22, for example a computer or the like.

Le fonctionnement du dispositif est le suivant.The operation of the device is as follows.

Au début du processus de fabrication de l'émulsion, on remplit par exemple le premier réservoir 16 avec le fluide 3, contenant par exemple les nanogouttes 5, et on remplit par exemple le troisième réservoir 20 avec la solution externe 2 additionnée de tensioactif. L'unité centrale 22 commande alors les sources de pression 23-26 pour que P1>P2>P3>P4, de sorte que le premier canal principal 11 est parcouru par le fluide 3 dans le sens de la flèche 11a (figure 2) et que le deuxième canal principal 12 est parcourus par la solution externe 2 dans le sens de la flèche 12a. Pendant ce temps, les deuxième et quatrième réservoirs 17, 21 se remplissent progressivement, et une partie du fluide 3 passe dans la solution externe 2 sous forme de microgouttes.At the start of the emulsion manufacturing process, the first reservoir 16 is filled, for example, with the fluid 3, containing for example the nanodrops 5, and the third reservoir 20 is filled, for example, with the external solution 2 added with surfactant. The central unit 22 then 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. During this time, the second and fourth reservoirs 17, 21 are gradually filled, and part of the fluid 3 passes into the external solution 2 in the form of microdrops.

Lorsque le premier réservoir 16 est vide, on modifie les pressions P1, P2 pour que P2>P1, et l'écoulement s'établit dans le sens opposé à la flèche 11a. P1 et P2 restent supérieures à la pression en tout point dans le deuxième canal principal 12.When the first reservoir 16 is empty, the pressures P1, P2 are modified so that P2> P1, and the flow is established in the direction opposite to the arrow 11a. P1 and P2 remain above the pressure at any point in the second main channel 12.

De même, lorsque le troisième réservoir 20 est vide, on modifie les pressions P3, P4 pour que P4>P3, et l'écoulement s'établit dans le sens opposé à la flèche 12a. P3 et P4 restent inférieures à la pression en tout point dans le premier canal principal 11.Similarly, when the third reservoir 20 is empty, the pressures P3, P4 are modified so that P4> P3, and the flow is established in the direction opposite to the arrow 12a. P3 and P4 remain below the pressure at all points in the first main channel 11.

Au fur et à mesure de ces mouvements alternatifs, on fait passer dans la solution externe 2, sous forme de microgouttes en émulsion, tout le fluide 3 initialement contenu dans le premier réservoir 16, et ce de façon rapide et fiable, sans risquer de polluer l'émulsion réalisée avec des impuretés externes puisqu'il n'y a pas d'ouverture des réservoirs pendant tout le processus.As these reciprocating movements are made, all the fluid 3 initially contained in the first reservoir 16 is passed through the external solution 2, in the form of microdroplets in emulsion, quickly and reliably, without risking polluting the emulsion produced with external impurities since there is no opening of the tanks during the whole process.

Eventuellement, les gouttes 1 peuvent être plus denses que la solution externe 2, auquel cas elles s'accumulent dans le fond des troisième et quatrième réservoirs 20, 21.Optionally, the drops 1 can be denser than the external solution 2, in which case they accumulate in the bottom of the third and fourth reservoirs 20, 21.

Claims (8)

  1. A microfluidic method for manufacturing an emulsion comprising drops (1) in emulsion in an external solution (2), the drops containing a fluid (3), in which method:
    - the fluid (3) is being circulated along a first main channel (11),
    - a portion of the fluid (3) circulating in the first main channel (11) is withdrawn, via a plurality of microchannels (13) positioned along the first main channel (11), which each communicate individually with said first main channel (11) and each emerge individually in a space (12) filled with external solution (2), the first main channel (11) being maintained at a greater pressure than said space (12) filled with external solution, the first main channel (11) having a passage cross-section at least 5 times greater than each microchannel (13),
    - the drops are formed when the fluid passes from each microchannel (13) into said space (12) filled with external solution (2),
    the method being characterized in that the fluid (3) is being circulated along the first main channel (11) between a first tank (16) and a second tank (17) which are maintained 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 the fluid (3) is being circulated alternately in opposite directions along the first main channel (11), the first and second pressures being varied so that the first pressure is alternately greater and lower than the second pressure.
  2. The microfluidic method according to claim 1, in which said space filled with external solution (2) is a second main channel (12) and the external solution (2) is being circulated along said second main channel (12), the second main channel (12) having a passage cross-section at least 5 times greater than each microchannel (13).
  3. The microfluidic method according to claim 2, in which the external solution (2) is being circulated along the second main channel (12) between a third tank (20) and a fourth tank (21) which are maintained under excess pressure respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than atmospheric pressure, and the external solution (2) is being circulated alternately in opposite directions along the second main channel (12), the third and fourth pressures being varied so that the third pressure is alternately greater and lower than the fourth pressure.
  4. The microfluidic method according to any one of the preceding claims, in which the drops (1) have a diameter (D) of less than 20 µm and the fluid (3) contains nanodrops having a diameter of less than 5 µm.
  5. The microfluidic method according to any one of the preceding claims, in which the external solution (2) contains a surface-active agent.
  6. A microfluidic device for manufacturing an emulsion comprising drops (1) in emulsion in an external solution (2), the drops containing a fluid (3), the device comprising:
    - a first main channel (11) filled with fluid (3) and connecting together a first tank (16) and a second tank (17),
    - means for causing the fluid (3) to circulate along the first main channel (11),
    - a space (12) filled with external solution (2),
    - a plurality of microchannels (13) positioned along the first main channel (11), which each communicate individually with said first main channel (11) and each emerge individually in said space (12) filled with external solution (2), said microchannels being adjusted in order to form the drops (1) in the space (12) filled with external solution, the first main channel (11) having a passage cross-section at least 5 times greater than each microchannel (13),
    - pressurizing means (22-26) for maintaining the first main channel (11) at a greater pressure than said space (12) filled with external solution, said device being characterized in that the pressurizing means (22-26) being adapted to maintain the first tank (16) and the second tank (17) 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 the pressurizing means (22-26) being provided in order to circulate the fluid (3) alternately in opposite directions along the first main channel (11), the first and second pressures being varied so that the first pressure is alternately greater and lower than the second pressure.
  7. The microfluidic device according to claim 6, in which said space filled with external solution (2) is a second main channel (12) and the microfluidic device comprises means (22, 25, 26) for circulating the external solution (2) along said second main channel (12), the second main channel (12) having a passage cross-section at least 5 times greater than each microchannel (13).
  8. The microfluidic device according to claim 7, in which the second main channel (12) connects together a third tank (20) and a fourth tank (21) and the microfluidic device comprises pressurizing means (22-26) for maintaining the third tank (20) and the fourth tank (21) under excess pressure respectively at a third pressure and at a fourth pressure different from the third pressure, the third and fourth pressures being greater than atmospheric pressure, and the pressurizing means (22-26) are provided in order to circulate the external solution (2) alternately in opposite directions along the second main channel (12), the third and fourth pressures being varied so that the third pressure is alternately greater and lower than the fourth pressure.
EP16806262.8A 2015-11-18 2016-11-08 Method and apparatus for forming emulsions Active EP3377204B1 (en)

Applications Claiming Priority (2)

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FR1561082A FR3043571A1 (en) 2015-11-18 2015-11-18 METHOD AND DEVICE FOR MANUFACTURING EMULSIONS
PCT/FR2016/052890 WO2017085373A1 (en) 2015-11-18 2016-11-08 Method and device for producing emulsions

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JP3511238B2 (en) * 2000-10-13 2004-03-29 独立行政法人食品総合研究所 Microsphere manufacturing method and manufacturing apparatus
ATE376451T1 (en) * 2003-05-16 2007-11-15 Velocys Inc METHOD FOR GENERATING AN EMULSION BY USING MICROCHANNEL PROCESS TECHNOLOGY
CN1188209C (en) * 2003-05-27 2005-02-09 清华大学 Low energy-consumption continuous-preparing method of micro emulsion
US7622509B2 (en) * 2004-10-01 2009-11-24 Velocys, Inc. Multiphase mixing process using microchannel process technology
FR2948024B1 (en) 2009-07-17 2020-01-10 Centre National De La Recherche Scientifique - Cnrs - ULTRASOUND ACTIVABLE EMULSION AND MANUFACTURING METHOD THEREOF.

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BR112018009943A2 (en) 2018-11-13
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EP3377204A1 (en) 2018-09-26
FR3043571A1 (en) 2017-05-19
JP2019501012A (en) 2019-01-17

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