EP2943274A1

EP2943274A1 - Method for activating a chemical reaction, solution that can be activated by said method and device for implementing said method

Info

Publication number: EP2943274A1
Application number: EP14701806.3A
Authority: EP
Inventors: Olivier Couture; Mickael Tanter; Patrick Tabeling; Janine Cossy; Mathias Fink
Original assignee: 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
Current assignee: 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
Priority date: 2013-01-08
Filing date: 2014-01-03
Publication date: 2015-11-18
Also published as: WO2014108627A1; US20150343412A1; FR3000688A1; JP2016506300A; FR3000688B1; US9545375B2; JP6469584B2

Abstract

The invention relates to a method which comprises emitting ultrasound into a liquid mixture containing first and second reagents (A, B) in separate phases initially separated by a liquid precursor-gas barrier (3), the ultrasound having a high enough energy level to vaporise the precursor gas, such as to contact the reagents and thus to activate a chemical reaction therebetween.

Description

Process for activating a chemical reaction, solution activatable by this method and device for carrying out this process. FIELD OF THE INVENTION

The present invention relates to methods for activating chemical reactions, solutions activatable by such methods and devices for carrying out such methods.

BACKGROUND OF THE INVENTION

The activation of chemical reactions between reagents is usually done by contacting the reagents. The methods currently used for this contacting, however, do not allow to precisely control, spatially and temporally, the start of the chemical reaction between the reagents.

OBJECTS AND SUMMARY OF THE INVENTION

The present invention is intended to solve this technical problem.

For this purpose, the invention provides a method for activating a chemical reaction in a solution forming a liquid mixture containing at least first and second reagents in separate phases initially separated by at least one vaporizable liquid gaseous precursor barrier, the process comprising an activation step in which ultrasound is emitted into the mixture, with a level of energy sufficient to vaporize the gaseous precursor, so as to bring said reagents into contact.

Thanks to these provisions, as soon as the ultrasonic emulsion is activated, the reactants are brought into intimate contact under the effect of the vaporization of the gaseous precursor, which enables:

to obtain a very fast reaction between the reagents, to control very precisely the start time of the chemical reaction, with a precision that can be for example of the order of a microsecond,

and / or to form, by the reaction between the reagents, a product which is used rapidly on the site of its formation, which can be particularly interesting especially when this product is unstable or when it is difficult to make transit to the place of its use (for example, gaseous or non-soluble or non-encapsulable product), or where it is particularly dangerous and could be harmful to the environment in which it must pass before reaching the target zone of ' use .

The invention may also be particularly useful for studying the kinetics of chemical reactions, especially since the start time of the reaction is perfectly controlled.

In various embodiments of the method according to the invention, one or more of the following provisions may also be used:

the ultrasound is emitted in a localized manner in a medium comprising the mixture, so as to activate the reaction between the reagents only in a given target zone;

said reagents are initially contained in an emulsion comprising, in an external solution, drops comprising at least the first reagent and said gaseous precursor, encapsulated by at least one emulsifier;

the reagents are initially contained in a micro-conduit and separated by at least one drop of gaseous precursor, and said at least one drop of gaseous precursor is vaporized during the activation step.

Furthermore, the subject of the invention is also an ultrasonically activatable solution, forming a liquid mixture containing at least first and second reagents in distinct phases separated by at least one Ultrasonic vapor vaporizable gaseous precursor barrier, said first and second reagents being adapted to react with each other.

In various embodiments of the activatable solution according to the invention, it may optionally be resorted further to one and / or the other of the following provisions:

the first and second reagents are contained in a micro-conduit and separated by at least one drop of gaseous precursor;

the first and second reagents are contained in an emulsion comprising, in an external solution, drops comprising at least the first reagent and said gaseous precursor, encapsulated by at least one emulsifier;

said drops comprise a first external emulsifier membrane and contain first primary drops containing the first reagent and second primary drops containing the second reagent, said first and second primary drops being each delimited by a second emulsifier membrane and being in contact with each other. emulsion in the gaseous precursor;

said drops are distributed between first and second groups of drops, the drops of the first group containing the first reagent and the drops of the second group containing the second reagent;

said drops comprise a first external emulsifier membrane and contain emulsion primary drops in the gaseous precursor, said primary drops being delimited by a second emulsifier membrane and containing either the first reagent or the second reagent;

the second reagent is contained in the external solution;

said drops comprise a first outer membrane of emulsifier and contain drops primary materials delimited by a second emulsifier membrane, said primary drops being emulsified in the gaseous precursor and the primary drops of at least some of said drops containing the first reagent;

said gaseous precursor forms a barrier against the diffusion of the first and second reagents;

said drops have a diameter of less than 20 μηι and said primary drops have a diameter of less than 5 μιη;

the gaseous precursor is a fluorinated oil;

the gaseous precursor is a perfluorocarbon;

the gaseous precursor is perfluorohexane and / or perfluoropentane;

the outer membrane of the drops comprises a first emulsifier;

the membrane of the primary drops contains a fluorinated surfactant;

the fluorinated surfactant contains poly (perfluoropropylene glycol) carboxylate;

the fluorinated surfactant is obtained from poly (perfluoropropylene glycol) carboxylate, perfluorocarbon and ammonium hydroxide;

the primary drops contain an internal liquid and the first reagent contained in the primary drops is in solution in the internal liquid.

Finally, the invention also relates to a device for implementing a method as described above, comprising:

at least one micro-conduit comprising an ultrasonically activatable solution, forming a liquid mixture containing at least first and second reagents in distinct phases separated by at least one ultrasonically vaporizable liquid gaseous precursor barrier, said first and second reagents being adapted to react with each other, said liquid gaseous precursor barrier comprising at least one drop of gaseous precursor gas,

at least one acoustic transducer adapted to emit ultrasound towards the drop of gaseous precursor in order to vaporize it and thus make said first and second reactants react with one another.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the invention will become apparent from the following description of three of its embodiments, given by way of non-limiting example, with reference to the accompanying drawings.

On the drawings:

FIG. 1 is a schematic view of a solution containing microdroplets in emulsion, usable in a first embodiment of the invention,

FIG. 2 is a schematic view of a microdrop of the emulsion of FIG. 1,

FIG. 3 is a block diagram showing an ultrasonic device for locally activating an emulsion containing microdroplets such as that of FIG. 1,

FIG. 4 is a block diagram of the device of FIG. 3,

FIGS. 5 and 6 illustrate the ultrasonic activation of the emulsion of FIG. 2,

FIG. 7 is a schematic view of a microdrop of the emulsion of FIG. 1, according to a variant of the first embodiment of the invention,

FIG. 8 is a schematic view of two microdroplets of the emulsion of FIG. 1, according to another variant of the first embodiment of the invention, FIG. 9 shows an exemplary microfluidic device containing a multiphasic mixture that can be used in a second embodiment of the invention,

and FIG. 10 is a view similar to FIG. 9, illustrating the ultrasonic activation of the multisphasic mixture in the device of FIG. 9.

DESCRIPTION DETAILED

In the different figures, the same references designate identical or similar elements.

The present invention provides a method for activating a chemical reaction between at least first and second reagents A, B by ultrasound.

In general, reagents A, B are initially contained in a solution forming a multiphasic liquid mixture, wherein reagents A, B are separated by a liquid gas precursor, which can be ultrasonically vaporized to react reagents A, B between them. Two embodiments of the invention, as well as variants, will now be described.

First embodiment:

As shown diagrammatically in FIGS. 1 and 2 for a first embodiment of the invention, this emulsion comprises microdroplets 1 in emulsion in a solution 2, for example an aqueous solution. These microdrops 1 may have for example a diameter D less than 20 μιη.

The diameter D is preferably less than 10 μιτι, for example less than 8 μιη and in particular of the order of 5 μιη.

Microdroplets 1 comprise a substantially spherical outer wall 4, made by a first emulsifier, in particular a surfactant such as, for example, "Pluronic F68®". In the first embodiment shown in Figure 2, the emulsion is double, so that the microdrops 1 form a secondary emulsion, and the outer wall 4 (liquid as the wall of a bubble) of each microbubble encapsulates a liquid ultrasonic vapor vapor precursor 3 containing a primary emulsion of primary drops 5.

The gaseous precursor may be a fluorinated oil, especially a perfluorocarbon, for example perfluorohexane or perfluoropentane.

The primary drops 5 have a diameter less than 5 μm, preferably from 0.3 to 1 μm, for example of the order of 500 nm. These primary drops 5 each have a substantially spherical outer wall 7 (liquid like the wall of a bubble) which is formed by a second emulsifier, for example a fluorinated surfactant such as poly (perfluoropropylene glycol) carboxylate (marketed by the company Du Bridge under the brand name "Krytox 157 FSH ®". More specifically, the fluorinated surfactant can be prepared from poly (perfluoropropylene glycol) carboxylate, perfluorocarbon and ammonium hydroxide. By way of example, this surfactant can be obtained by adding to 10 mg of perfluorohexane, 10 mg of Krytox 157 FSH® and 10 ml of ammonium hydroxide (see Holze et al., Biocompatible surfactants for water-in-fluorocarbon emulsions ", Lab Chip, 2008, 1632-1639, Royal Society of Chemistry 2008).

The outer wall 7 encapsulates an internal liquid 6, for example water or more generally an aqueous solution, which contains an active agent. In this case, in the first embodiment of the invention, the primary drops are divided into two groups: a group of first primary drops in which the active agent is a first reagent A and a group of second primary drops in which the active agent is the second reagent B. The first and reagents A, B are adapted to react with each other so as to form a reaction product C, which may be an active agent, for example a drug or a marker which it is desired to deliver in a specific place in a patient's body

The active agent C may for example be a short-lived potent cytotoxic agent.

For example, reagents A and B may be for example: A: 3-azido-7-hydroxy-2H-chromen-2-one and B: 3-hydroxy-2 ', 3', 2 ", 3" -tetramethoxy -7,8-Didehydro-1,2,5,6-dibenzocyclota-1,5,6-triene which react together to give a fluorescent product.

Reagents A and / or B may be hydrophilic. Alternatively, they may optionally be hydrophobic, in which case they may be for example:

either in solution in a non-aqueous internal liquid 6, for example a fluorinated oil,

either by emulsion in an aqueous internal liquid 6, the active agent then being encapsulated (with a fluorinated oil for example) in drops of size less than 1 μιη (for example from 0.3 to 0.4 μm) in emulsion in the internal liquid.

In view of the fact that the primary drops are emulsified in the internal liquid 6, the first and second primary drops are intimately mixed.

In addition, the stability of the double emulsion according to the invention is particularly great since the gaseous precursor forms a barrier for the diffusion of reagents A and B and prevents them from reacting with each other prematurely, which makes it possible to lengthen the product life between manufacture and use, and to avoid unintentional release of reagents A, B and / or formation and diffusion of reaction product C outside the target area.

The double emulsion described above can be obtained for example as described in WO2011 / 007082A1.

When using the ultrasonically activatable emulsion, this emulsion may for example be diffused in a medium 29 (solid or not - for example a part of the body of a patient or any other medium) and some of the microdroplets located at level of a target zone 30 of the medium 29, can then be activated by bursting them under the effect of ultrasound.

In an exemplary embodiment, it may be focused ultrasound which is emitted for example by an ultrasonic device 21 such as that shown in Figure 3. It is nevertheless only an example embodiment, and invention is not limited to this example.

This ultrasound device 21 may especially be an imaging system comprising:

a network 22 of ultrasonic transducers, for example a linear array of the type commonly used in ultrasound, comprising a number n of ultrasonic transducers 22a (for example of the order of 100 to 300 transducers, emitting for example about 2, 5 MHz), the array 22 of transducers being adapted to be brought into contact with a medium 29,

an electronic rack 23 controlling the network 22 of transmitting transducers and able to acquire signals picked up by this network,

a microcomputer 24 for controlling the electronic rack 23, the microcomputer 24 comprising a user interface that includes a screen 25 on which ultrasound images taken by means of the transducer array 22 can be viewed, and said user interface also comprising for example a keyboard 26 associated with a mouse or the like (not shown) and if necessary a pointing device 27 such as a pen optical or similar, which allows for example an operator 28 to delimit an area on the screen 25, as will be explained later.

The electronic rack 23 and the microcomputer 24 together form a control device adapted to control the network 22 of transducers and to acquire and process signals coming from this network. Optionally, one could make ensure the functions of the electronic rack 23 and the microcomputer 24 by a single electronic device.

As shown in FIG. 4, the electronic rack 23 may comprise, for example:

n analog / digital converters 31 (A / D - A / D _n ) individually connected (for example by a cable) to the n transducers (ΊΊ-Τ _η ) of the transducer network 22;

n buffers 32 (Bi-B _n ) respectively connected to the analog / digital converters 31,

an electronic central unit 33 (CPU) communicating with the buffer memories 32 and the microcomputer 24,

a central memory 34 (MEM) connected to the central unit 33,

a signal processing processor 35 (DSP) connected to the central unit 33.

The device 21 may be initially used conventionally in ultrasound imaging mode, to display an image of the target 30 on the screen 25. The operator 28 may for example delimit the target zone 30 by drawing its contour on the screen 25 by, for example, the aforementioned optical pen 27 or any other user interface serving as a pointing device.

When the target zone 30 has been delimited by the operator, it triggers the step of activating the emulsion by successively emitting ultrasonic activation beams, focused at different points. of said target zone 30, so that the entire target zone 30 receives ultrasounds for bursting the microdrops 1 that it contains by vaporizing the gaseous precursor 3 of these microdroplets, as symbolized at 9 in FIG. 5, and leaving subsist for a few nanoseconds or microseconds a cluster 8 of primary drops 5. The perfluorocarbon vaporization takes place in a very short time, of the order of a period of ultrasound, or of the order of one microsecond.

Since the encapsulation of the primary drops 5 is no longer effective with a gaseous phase, and the vaporization of the perfluorocarbon being a violent phenomenon, the reagents A, B initially contained in the primary drops 5 are released almost instantaneously.

As a result of this almost instantaneous release and the fact that the primary drops containing the reagents A and B are initially intimately mixed and separated by at most a few nanometers, the reactants A and B react to give the product C immediately in a period of time. 1 'ordred of the microsecond (as symbolized in 10, figure 6).

This microsecond reaction time is particularly fast in the context of chemistry (for example, classical methods of rapid reaction triggering such as "stop flow" or microfluidic chips operate in time domains beyond of the millisecond).

Each ultrasonic activation beam has a duration and a power dimensioned to activate the emulsion as described above, without damaging the medium 29. For example, each ultrasonic activation beam has a duration of 1 to 1000 με, in particular 10 to 1000 με (microseconds) and said ultrasonic activation beam has a power such that it exerts in the tissues a pressure of less than 8 MPa, in particular less than 6 MPa (mega Pascals), which corresponds to conventional imaging powers.

As already explained above, the invention thus makes it possible to bring to the target zone active agents C that previously could not be conveyed, for example unstable or insoluble or gaseous agents or particularly dangerous or non-emulsifiable by emulsion, by transporting reagents A and B in the emulsion (A and B being stable and preferably soluble or at least emulsifiable by emulsion) and then forming these active agents C locally in the target area of use by ultrasonic activation of the emulsion.

In addition, the focusing of ultrasound by the control of the phase of the transducers, allows to locate the effect of ultrasound in an area whose size can be of the order of the wavelength (for example, of the order 300 microns at 5 MHz in water), which makes it possible to control the formation zone of the active agent C at the millimeter level and avoids affecting areas where it is not necessary to administer the active agent C.

The invention is not limited to water - perfluorocarbon - water double emulsions, but also applies to double oil - perfluorocarbon - water or oil - perfluorocarbon - oil emulsions. The perfluorocarbon may also be replaced by another ultrasonically activatable gaseous precursor.

Moreover, the emulsion according to the invention also makes it possible to react together more than two reagents, but more generally makes it possible to trigger ultrasonically at least one chemical reaction between n reagents A, B, D, ... which are initially separated. from each other by at least one emulsifier membrane, said reaction or reactions being initiated by destroying said at least one emulsifier membrane under the effect of ultrasound. Thus, in the case of at least three reagents A, B, D, ... these reagents can initially be encapsulated separately in the primary drops 5. In this case, one can either immediately trigger a reaction A + B + D - > C, or, when the reagents A, B, D are encapsulated in primary drops of different respective diameters, it is possible to drop sequentially the various compounds A, B, D, ... of the reaction, by example by sequentially applying different ultrasonic pressures. It is thus possible to carry out more complex reactions of the type A + B -> X, X + D-> C, or others.

Moreover, the reagents A, B, D,... Are not necessarily all contained in the same microdrops 1 of the emulsion:

as shown in FIG. 7, one of the reagents may be in solution 1 (reagent B in the example of FIG. 7 which is an example with two reagents);

as shown in FIG. 8, the reagents can be in different microdrops 1.

The microdroplets 1 of the embodiments of FIGS. 7 and 8 may have a double emulsion structure as previously described, as shown in the drawings, but they could possibly be simple emulsions (reagent A being directly in solution in the precursor gaseous in the case of Figure 7, and reagents A, B being directly in solution in the gaseous precursor of their respective microdrops in the case of Figure 8).

Furthermore, the invention can be implemented with any other type of ultrasonic device other than ultrasound imaging, for example a mono ^¬ transducer element or one or more transducer (s) surface.

Second embodiment:

In the second embodiment of the invention, represented in FIG. 9, the invention can be implemented in a microfluidic device 40 comprising at least one micro-conduit 41, having a diameter or equivalent diameter D that can be, for example, of the order of 5 to 20 microns and containing the first and second reagents A, B mentioned above in the form of two distinct liquid phases separated by at least one drop of said liquid precursor gas 3. The device 40 may further comprise at least one acoustic transducer 42 adapted to emit ultrasound to the gaseous precursor drop 3 to vaporize it.

When the drop of gaseous precursor is vaporized by ultrasound emission from transducer 42 (FIG. 10), reagents A and B react very rapidly as explained above for the first embodiment of the invention, to form the reaction product C.

Claims

A method for activating a chemical reaction in a solution forming a liquid mixture containing at least first and second reagents (A, B) in separate phases initially separated by at least one vapor-vaporizable liquid gas precursor barrier (3), the method comprising an activation step in which ultrasound is emitted into the mixture, with a sufficient energy level to vaporize the gaseous precursor, so as to bring said reagents into contact.

2. Method according to claim 1, wherein the ultrasound is emitted locally in a medium comprising the mixture, so as to activate the reaction between the reagents in a given target area.

3. Method according to claim 1 or claim 2, wherein said reagents are initially contained in an emulsion comprising, in an external solution (2), drops (1) comprising at least the first reagent (A) and said gaseous precursor (3), encapsulated by at least one emulsifier (4, 7).

4. The method of claim 1, wherein the reagents (A, B) are initially contained in a micro-conduit and separated by at least one drop of gaseous precursor (3), and said at least one drop of gaseous precursor is vaporized during the activation stage.

5. Ultrasonic activatable solution, forming a liquid mixture containing at least first and second reagents (A, B) in separate phases separated by at least one ultrasonically vaporizable liquid gaseous precursor barrier (3), said first and second reagents being adapted to react with each other.

6. The solution of claim 5, wherein the first and second reagents are contained in a micro-conduit (41) and separated by at least one drop of gaseous precursor (3).

7. Solution according to claim 5, wherein the first and second reagents are contained in an emulsion comprising, in an external solution (2), drops comprising at least the first reagent (A) and said gaseous precursor (3), encapsulated by at least one emulsifier.

8. The solution of claim 7, wherein said drops (1) comprise a first external emulsifier membrane (4) and contain first primary drops (6) containing the first reagent (A) and second primary drops (6). containing the second reagent (B), said first and second primary drops being each delimited by a second emulsifier membrane (7) and being emulsified in the gaseous precursor (3).

9. Solution according to claim 7, wherein said drops (1) are distributed between first and second groups of drops, the drops (1) of the first group containing the first reagent (A) and the drops (1) of the second group containing the second reagent (B).

10. The solution of claim 9, wherein said drops (1) comprises a first external emulsifier membrane (4) and contains emulsion primary drops (6) in the gaseous precursor (3), said primary drops being delimited by a second emulsifier membrane (7) and containing either the first reagent (A) or the second reagent (B).

11. Solution according to claim 7, wherein the second reagent (B) is contained in the external solution (2).

Apparatus for carrying out a process according to claim 4, comprising:

at least one micro-conduit (41) comprising an ultrasonically activatable solution, forming a mixture liquid containing at least first and second reagents (A, B) in separate phases separated by at least one vapor-vaporizable liquid gaseous precursor barrier (3), said first and second reagents being adapted to react with each other, said barrier liquid gaseous precursor comprising at least one drop of liquid gaseous precursor (3),

- At least one acoustic transducer (42) adapted to emit ultrasound to the gaseous precursor drop (3) to vaporize and thus react between said first and second reagents (A, B).