EP1280597A1

EP1280597A1 - Method for preparing a monodispersed double emulsion

Info

Publication number: EP1280597A1
Application number: EP01931824A
Authority: EP
Inventors: Fernando Leal Calderon; Philippe Gorria; Jérôme Bibette
Original assignee: Centre National de la Recherche Scientifique CNRS
Current assignee: Centre National de la Recherche Scientifique CNRS
Priority date: 2000-05-09
Filing date: 2001-05-09
Publication date: 2003-02-05
Anticipated expiration: 2021-05-09
Also published as: DE60107073D1; CA2408419A1; AU2001258517B2; US20040116541A1; EP1280597B1; FR2808703B1; FR2808703A1; CA2408419C; ES2227188T3; WO2001085319A1; ATE281881T1; WO2001085319A9; JP2003532523A; DE60107073T2; AU5851701A; JP4643109B2

Abstract

A method for preparing a monodispersed double water/oil/water emulsion, comprises: a) subjecting a polydispered oil-in-water emulsion Ei comprising 55 to 99 wt. % of an aqueous phase, to a controlled shearing to obtain the corresponding monodispersed invert emulsion; b) adding to the emulsion, without phase inversion, the necessary amount of diluting oil phase so that the aqueous phase of the resulting emulsion represents at least 50 wt. % of the emulsion total weight; and c) introducing the resulting emulsion into a high pressure homogenizer, together with a continuous aqueous phase, the respective amounts of the emulsion and the continuous aqueous phase being such that the resulting double emulsion comprises up to 50 wt. % of invert emulsion droplets relative to the emulsion total weight, the continuous aqueous phase comprising a hydrophilic surfactant concentration not more that 0.02 times the critical micellar concentration.

Description

"Process for the preparation of a double monodisperse emulsion".

The invention relates to a process for the preparation of double monodisperse emulsions, of the water in oil in water type, by using a high pressure homogenizer. The advantage of double emulsions is widely recognized in fields as diverse as the pharmaceutical, cosmetic, phytosanitary, food and / or paint type coatings.

The double water-in-oil-in-water emulsions in particular allow the encapsulation of various active substances in the internal aqueous phase. Under well-defined conditions, it is indeed possible to cause the release of the active substances, encapsulated while controlling their release kinetics.

In the art, double monodisperse emulsions are particularly sought after because of their homogeneity: they allow in particular a regular and controllable release of the active ingredients.

Various processes are known for preparing monodisperse emulsions: a first process is that described in EP 442 831 and EP 517 987. This process involves the fractionation of a primary starting emulsion, polydisperse, by successive creamings. It is long and tedious and not easily applicable on an industrial scale. A second method is described in FR 97 00 690. It consists in subjecting a starting viscoelastic primary emulsion, at a shear controlled such ^that the same maximum shear is applied to the entire emulsion. This process has various advantages and in particular allows control of the size of the droplets of the monodisperse emulsion obtained.

When one or the other of these methods is applied to a double emulsion, it is essential not to induce the destruction of the double emulsion, by causing for example the coalescence of the droplets forming the emulsion or the premature leakage. of the active ingredient. Under these conditions, it is understood that the development of a process for the preparation of a double water-in-oil-in-water monodisperse emulsion, which does not consist simply in applying one or the other of the More specifically, the invention relates to a process for the preparation of a double monodisperse water-in-oil-in-water emulsion comprising the steps consisting in: a) subjecting a water-in-oil, polydisperse Ei emulsion comprising from 50 to 99% by weight of an aqueous phase to a controlled shearing so that the same maximum shear is applied to ^the entire emulsion, so as to obtain the corresponding monodispersed invert emulsion; b) adding to said emulsion without phase inversion, the necessary amount of an oil phase of dilution so that the aqueous phase of ^the resulting emulsion represents less than 50% by weight of the total weight of the emulsion; and c) introducing the resulting emulsion into a high pressure homogenizer, together with a continuous aqueous phase, the respective amounts of said emulsion and said continuous aqueous phase being such that the resulting double monodisperse emulsion comprises up to 50% by weight droplets of reverse emulsion (or globules) relative to the total weight of the emulsion, said continuous aqueous phase comprising a concentration of hydrophilic surfactant less than or equal to 0.02 times the critical micellar concentration.

This process leads to a monodisperse doubie emulsion consisting of globules of an oil in water emulsion dispersed in an external aqueous phase, the globules representing at most 50% of the total weight of the double emulsion. In the double emulsion obtained, the globules consist of droplets of an aqueous phase dispersed in an oily phase, the total aqueous phase contained in the globules representing at most 50% of the total weight of all the globules.

The process of the invention is carried out starting from an Ei, reverse, polydisperse emulsion, prepared in a conventional manner according to any of the processes known from the state of the art. The starting Ei emulsion comprises from 50 to 99% by weight of an aqueous phase, better still from 70 to 95%, for example from 80 to 90% by weight, relative to the total weight of the Ei emulsion.

The oily phase is not miscible with water. It includes one or more distinct oils, the nature of which is not critical in itself.

The term “oil” is understood to mean, according to the invention, any hydrophobic liquid substance or very sparingly soluble in water, capable of being put into an aqueous emulsion in the presence, or not, of one or more suitable surfactants.

Such a hydrophobic and insoluble substance may for example be an organic polymer such as a polyorganosiioxane, a mineral oil such as hexadecane, a vegetable oil such as soybean or peanut oil or liquid crystals (lyotropics or thermotropic).

Preferably, the oily phase contains an aliphatic, cyclic and / or aromatic C ₃ -C ₃₀ hydrocarbon. As an example, the oily phase comprises dodecane.

The Ei emulsion comprises a lipophilic surfactant having a lipophilic / hydrophilic ratio (HLB value) less than 10.

The term HLB (Hydrophilic-Lipophilic Balance) designates the ratio of the hydrophilicity of the polar groups of the surfactant molecules to the hydrophobicity of their lipophilic part. HLB values are notably reported in various basic manuals such as the "Handbook of pharmaceutical excipients, The Pharmaceutical Press, London, 1994)".

In the context of the invention, the nature of the surfactant which can be used for stabilizing the emulsion is more particularly chosen so as to be able to ensure good stability of the emulsion.

Examples of suitable surfactants that may be mentioned are fatty acid esters, preferably in sorbitol such as span 80. Another suitable type of surfactant is polyglycerol polyricinoleate.

Span 80 is a molecular mixture derived from sorbitol, the main constituent of which is sorbitan monooleate.

The polyglycerol polyricinoleate corresponds to the formula:

R ₁ O- (CH ₂ -CH (OR ₂ ) -CH ₂ 0) _π -R ₃ (II) where n is an integer from 2 to 12;

R _{1 f} R ₂ and R ₃ each independently represent H or a radical derived from ricinoleic acid of formula (III), at least one representing this derivative:

H- [0-CH ((CH ₂ ) ₅ CH ₃ ) -CH ₂ -CH = CH- (CH ₂ ) ₇ -CO] _m - (III) where m is an integer from 2 to 10. Preferably, n = 2-10 and m = 2-10; more preferably, n = 2-5 and m = 4-10.

Examples of commercial polyglycerol polyricinoleate are Admul Wol 1403 (Quest), Radiamuls Poly 2253 (Fina) and Grindsted PGPR 90 (Danisco). The polyglycerol polyvinyloleates preferably used according to the invention are those by which n varies between 2 and 5 (and is worth for example 3) and m varies between 5 and 10 (and is worth for example 7).

When the polyglycerol polyricinoleate is used as a surfactant, the surfactant concentration of the oily phase of Ei varies between 60 and 99% by weight.

In some cases, the oily phase may consist of the only lipophilic surfactant.

In step a) the polydisperse reverse emulsion, Ei, is transformed into a monodisperse reverse emulsion. The technique used to do this is that described in application WO 97/38787. It is recalled below: One means for subjecting the whole of the emulsion to the same maximum shear consists in subjecting the whole of the emulsion to a constant shear rate.

However, the invention is not intended to be limited to this particular embodiment. In fact, the shear rate can be distinct, at a given time, for two points of the emulsion. 6

By varying the geometry of the device used to generate the shear forces, it is possible to modulate the shear rate applied to the emulsion in time or / and space.

Provided that the emulsion is in flow when subjected to shearing, each part of the emulsion can thus be subjected to a shearing rate which varies over time. The shear is said to be controlled when, whatever the variation in time of the shear rate, it passes through a maximum value which is the same for all the parts of the emulsion, at a given instant which may differ from one across the emulsion. Preferably, in order to control the shearing, the double polydisperse emulsion is introduced into a suitable device.

Appropriate devices are described in application FR 97 00690 or in international application WO 97/38787.

Briefly, a suitable device is a Duvet cell in which the shear is constant, the Duvet cell being made up of two concentric cylinders in rotation relative to each other.

A second device is a cell made up of two parallel plates in oscillating movement with respect to each other and between which the polydisperse reverse emulsion is forced. Another device is a cell made up of two concentric discs rotating in relation to each other and between which the polydisperse reverse emulsion circulates.

These cells are commonly used in commercial devices, in particular rheometers making it possible to measure the viscoelastic properties of liquids (for example: CARRIMED or RHEOMETR1CS).

The maximum value of the shear rate to which the primary emulsion is subjected depends on the frequency of rotation, the frequency of oscillation and / or the amplitude of oscillation of the movement of the plates, cylinders and discs of the devices described above. above. In general, it has been found that a high value of the maximum shear rate leads to the formation of emulsions consisting of droplets emulsion E, very small and having a very narrow particle size distribution.

In order to increase the value of the maximum shear rate, a person skilled in the art can play on several parameters, namely the frequency of rotation, the frequency of oscillation and / or the oscillation amplitude of the movement of the plates, cylinders. and discs of the devices described above, as well as on the dimension of the respective enclosures of these different devices in the direction perpendicular to the direction of flow imposed by the movement of the surface. It will be noted that the maximum shear rate varies linearly with the amplitude of oscillation and / or the frequency of the movement and inversely proportional with the dimension of the enclosure in a direction perpendicular to the flow.

It is preferred that the maximum shear rate is between 1 and 1.10 ⁵ s ^' , preferably between 100 and 5000 s ^"1 , for example between 500 and 5000 s ^{" 1} .

It is important, according to the invention, that the flow of the starting emulsion, polydisperse, from the start is homogeneous (absence of fractures) during its passage in any of the devices described above.

More precisely when the controlled shearing is carried out by bringing said emulsion into contact with a solid surface in motion, a homogeneous flow is characterized by a constant speed gradient in a direction perpendicular to the solid surface in motion.

One way to control the flow is to play on the dimension d of the speakers in the direction perpendicular to the direction of the flow imposed by the movement of the surface.

It will be noted that, in the case of the Couette device, this dimension d is defined by the difference (R ₃ -R ₂ ) where R ₂ and R ₃ are respectively the radii of the internal and external cylinders of the Couette device.

In the case of the cell consisting of two parallel plates in oscillating movement with respect to each other, this dimension d is defined by the distance separating the two plates in a direction which is perpendicular to them. In the case of the cell made up of two concentric discs rotating in relation to each other, this dimension is defined by the distance separating the two discs in the direction of the axis of rotation of the moving disc. In general, a heterogeneous flow can be made homogeneous by reducing the size of the enclosure and more particularly by reducing its size in the direction perpendicular to the direction of the flow.

Thus in the case of the three devices mentioned above, the dimension d is preferably maintained below 200 μm, for example between 50 and 200 μm, in particular approximately 100 μm.

At the end of step a), an inverse emulsion is generally obtained, the size of the droplets of aqueous phase in dispersion of which is between 0.05 μm and 50 μm, preferably between 0.1 μm and 10 μm.

In step b), the monodisperse reverse emulsion obtained in step a) is diluted by adding an oily dilution phase.

To do this, one can use an oily phase of the same composition as that constituting the emulsion Ei (which is preferred), or an oily phase of different composition. The exact nature of the oily dilution phase is however not crucial according to the invention. In general, the oily dilution phase is as defined above for the oily phase of the Ei emulsion.

The addition of the oily dilution phase is carried out in a conventional manner without phase inversion. A simple method consists in adding dropwise said oily phase of addition to the monodisperse reverse emulsion maintained under moderate stirring. To this end, a shear of less than 100 s ^"1 is generally appropriate. Depending on the formulation of the reverse emulsion and, in particular, depending on the amount of surfactant present, other addition methods may be considered such as, for example , adding at once the oily dilution phase, to the emulsion maintained under stirring. After dilution, it is important that the mass fraction of the aqueous phase

(ratio of the weight of the aqueous phase to the total weight of the emulsion) is less than 0.5, preferably less than 0.35, better still less than 0.20.

According to a preferred embodiment of the invention, the viscosity of the reverse emulsion, as measured at 25 ° C, is less than 0.1 Pa.s, preferably less than 0.01 Pa.s.

In step c), the emulsion resulting from step b), which is a monodisperse reverse emulsion, is treated in a high pressure homogenizer.

The high pressure homogenizer which can be used according to the invention is of the type commonly used for the preparation of stable emulsions from an aqueous phase and an oily phase.

Such homogenizers are in particular as described by W. Clayton in The Theory of emulsions and their technical treatment, 5 ^th edition, Churchill Livingstone, London, 1954; or by LW Phipps in The high pressure dairy homogenizer, the National Institute for research in dairying, 1985; or by H. Mulder and P. Walstra in The milk fat globule, Center for agricultural publishing and documentation, Wegeningen, the Netherlands, 1974; or even by P. Walstra in Formation of emulsions, Encyclopedia of emulsion technology, Paul Becher, vol. 1, p. 57-127, Marcel Dekker Ed., New York, 1983. In this type of homogenizer, liquids at very high pressure (a few hundred bars, for example 100 to 400 bars) are forced to pass through a very narrow opening of millimeter or micrometric size. This opening is generally placed in a valve system but it can be a slot or a simple circular orifice. The opening generally has a diameter of between 10 μm and 1 mm. Passing through this narrow opening, the emulsion undergoes a violent acceleration as well as a sudden pressure drop (the pressure downstream of the opening is of the order of 1 bar). Cavitation and shear forces and the resulting turbulence provide emulsification. According to the invention, the reverse emulsion obtained at the end of step b) and an aqueous phase, called continuous, is forced into the homogenization valve or into the orifice. Said continuous aqueous phase will constitute the aqueous phase external of the double emulsion leaving the high pressure homogenizer. It should be understood that the continuous aqueous phase is an aqueous solution.

An example of a suitable homogenizer is a Gaulin type homogenizer such as the model sold by LabPlant Limited. Preferably, this model does not require premixing of the phases. The reverse emulsion obtained at the end of step b) and the aqueous phase are initially contained in two separate cylindrical tanks surmounted by two pistons, located downstream of a homogenization chamber. By pushing on the pistons, a press forces the two liquids to penetrate simultaneously into the homogenization chamber before passing them through the circular outlet orifice.

In this particular type of homogenizer, the advantageous operating conditions are:

an injection speed of the aqueous phase and of the monodisperse reverse emulsion varying between 100 and 500 m / s, better still between 150 and 350 m / s;

- A pressure in the chamber where the inverse emulsion and the continuous aqueous phase are brought into contact between 100 and 400 bars (from 0.1.10 ⁸ Pa to 0.4.10 ⁸ Pa);

- a circular orifice at the outlet of the homogenization chamber from 0.1 to 1 mm.

It is the relative section of the cylindrical tanks arranged upstream of the homogenization chamber which determines the fraction of globules in the final double emulsion.

At the outlet of the high-pressure homogenizer, a double monodisperse water-in-oil-in-water emulsion is recovered.

This emulsion is characterized by:

- the fact that the globules (or droplets of monodisperse reverse emulsion) represent at most 50% of the total weight of the emulsion;

- the total aqueous phase contained in the globules represents at most 50% of the total weight of all the globules. Advantageously, the continuous aqueous phase used in step c) does not include a thickener. It can contain one or more hydrophilic surfactants.

The final emulsion is produced after a single pass in the high pressure homogenizer.

A second pass would risk causing a considerable decrease in the number of internal droplets contained in the globules (by coalesceπce). This would result in a premature leak of the active ingredient in the external aqueous phase. A second pass through the high pressure homogenizer is therefore strongly discouraged.

The concentration of hydrophilic surfactant in the continuous aqueous phase of step c) is less than 0.02 times the critical micellar concentration; preferably, it is less than 0.01 times the critical micelle concentration. The critical micellar concentration (CMC) is defined as the concentration above which the surfactant molecules combine to form spherical clusters called micelles (see for example "Galenica 5, surfactants and emulsions", vol. 5.1, page 101, editor: Techniques et Documentation (Lavoisier)). In the context of the invention, the concentration of hydrophilic surfactant in the continuous aqueous phase can be zero. In this case, it is highly desirable to add an additional surfactant to the double monodisperse emulsion leaving the high pressure homogenizer, and advantageously as quickly as possible at the outlet of the high pressure homogenizer.

The additional surfactant which can be used as a stabilizer for the double monodisperse emulsion is of the same type as that possibly present in the aqueous dilution phase; it is a hydrophilic surfactant.

This additional surfactant, as well as that optionally present in the aqueous dilution phase of step c) may be nonionic, ionic, zwitterionic or amphoteric. The hydrophilic surfactant of the aqueous dilution phase of step c) advantageously has a lipophilic-hydrophilic ratio (HLB value) greater than 20, preferably greater than 30.

Preferably, the HLB value is approximately 40. The additional surfactant, for its part, preferably has an HLB value greater than 12.

As hydrophilic nonionic surfactants, there may be mentioned:

- The condensation product of an aliphatic fatty alcohol, preferably C ₈ -C ^, with a C ₂ -C ₃ alkylene oxide. The C ₂ -C ₃ alkylene oxide can be ethylene oxide, propylene oxide, or a mixture of ethylene oxide and propylene oxide in any proportions. An example of such surfactants is the condensation product of lauryl alcohol (or n-dodecyl alcohol) with 30 moles of ethylene oxide;

- The condensation product of an alkylphenol in which the alkyl chain is C ₈ -C ^ with a C ₂ -C ₃ alkylene oxide. Again, the condensation products with ethylene oxide, propylene oxide or a mixture of ethylene oxide and propylene oxide in any proportions are also advantageous. By way of example of such surfactants, mention may be made of the condensation product of n-nonylphenol with 10 moles of ethylene oxide; - the condensation product of a fatty acid, preferably C ₃ -C ₂₂ with a C ₂ -C ₃ alkylene oxide, for example ethylene oxide or propylene oxide or a mixture of ethylene oxide and propylene oxide in any proportions. These condensation products have an alkoxylated chain at the hydroxyl function of the carboxylic group. Preferred surfactants from this group are the condensation products obtained from oleic acid, palmitic acid and stearic acid;

- the condensation product of a fatty acid glyceride in with a C ₂ -C ₃ alkylene oxide such as ethylene oxide and / or propylene oxide. Among these, ethoxylated glycerol palmitate is preferred; - the condensation product of a fatty acid ester sorbitol with a C ₂ -C ₃ alkylene oxide which may be ethylene oxide, - _,

IJ

propylene or their mixtures. These compounds are polysorbates. A preferred example is sold under the name Tween 80;

- a polyacrylonitrile;

- a polylakylene glycol, preferably a polyalkylene glycol in which the oxyalkylene part is C ₂ -C ₃ ;

- a water-soluble block copolymer of ethylene oxide and propylene oxide. Preferably, a copolymer corresponding to formula (1):

H- (OCH ₂ CH ₂ ) _a - (0-CH (CH ₃ ) -CH ₂ ) _b - (OCH ₂ CH ₂ ) _a -OH (1) in which: a is an integer between 50 and 120, of preferably between 70 and 110; and b is an integer between 20 and 100, preferably between 30 and 70. Such polymers are sold by ICI under the Synperonic PE ^® brand.

Among these, advantageously those having a molar mass of between 2000 and 15000 g / mol, preferably between 5000 and 14000 g / mol, preferably between 8000 and 12000 g / mol, will be selected.

The kinematic viscosity of Synperonic ^® PE polymers is preferably between 150 and 1200 mm ^2. s ^"1 at 100 ° C., better still between 500 and 1100 mm ² .s- ^1. More particularly preferred is the Poloxamer 188 of formula (I) above in which a = 75 and b = 30.

Suitable examples of hydrophilic anionic surfactants are: - the alkyl esters sulfonates of formula R-CH (Sθ3M) -COOR ', where R represents a C8-C20 alkyl radical. preferably at C ^ QC ^ Q, ^R ' ^uπ C <\ -CQ alkyl radical, preferably at C1-C3 and M an alkali cation (sodium, potassium, lithium), substituted or unsubstituted ammonium (methyl-, dimethyl -, trimethyl-, tetramethyiammonium, dimethyipiperidinium ...) or derived from an alkanolamine (monoethanolamine, diethanolamine, triethanoiamine ...). Mention may very particularly be made of methyl ester sulfonates whose radical R is C14-C-16 ^" . the alkyl sulphates of formula ROSO3M, where R represents a C-10-C24, preferably C12-20 and preferably C12-20 alkyl alkyl or hydroxyalkyl radical _> M representing a hydrogen atom or a cation with the same definition as above, as well as their ethoxylenated (OE) and / or propoxylenated (OP) derivatives, having on average from 0.5 to 6 units, preferably from 0.5 to 3 OE and / or OP units ; among these, sodium dodecyl sulfate is preferred;

- Alkyl sulfates of formula RCONHROSO3M where R represents an alkyl radical in C2-C22. preferably in C6-C20. R 'a C2-C3 alkyl radical, M representing a hydrogen atom or a cation of the same definition as above, as well as their ethoxylenated (OE) and / or propoxylenated (OP) derivatives, having an average of 0, 5 to 60 OE and / or OP patterns;

- the salts of C8-C24 saturated or unsaturated fatty acids, preferably

C-14-C20. C9-C-20 alkylbenzenesulfonates. primary or secondary C8-C22 alkylsulfonates. 'es alkylglycerol sulfonates. sulfonated polycarboxylic acids described in GB - A - 1 082 179, paraffin sulfonates, N-acyl N-alkyltau rates, alkylphosphates, aikylisethionates, alkylsuccinamates, alkylsulfosuccinates, monoesters or diesters of sulfosuccinates, N-acyls sarcosinates, alkyl glycoside sulfates, polyethoxycarboxylates, the cation being an alkali metal (sodium, potassium, lithium), a substituted or unsubstituted ammonium residue (methyl-, dimethyl-, trimethyl-, tetramethylammonium, dimethyipiperidinium ...) or derived from an alkanolamine (monoethanolamine, diethanolamine, triethanolamine ...);

- phosphates or alkylphosphates esters; and - alginates.

As hydrophilic cationic surfactant, it is possible to use:

- quaternary ammonium salts such as tetradecyltrimethylammonium bromide and

- addition salts of fatty amines with acids. By fatty amine is meant amines with long hydrocarbon chains, that is to say comprising from 8 to 24 carbon atoms. An example of a preferred fatty friend is dodecylamine.

Other surfactants are amphoteric and zwitterionic hydrophilic surfactants: - those of betaine type such as betaines, sulfo-betaines, amidoalkylbetaines, sulfo-betaines, alkylsuitains, alkyltrimethylsulfobetaines,

- condensation products of fatty acids and protein hydrolysates,

- alkylamphopropionates or -dipropionates, - amphoteric derivatives of alkylpolyamines such as AMPHIONIC XL marketed by RHONE-POULENC, AMPHOLAC 7T / X and AMPHOLAC 7C / X marketed by BEROL NOBEL,

- cocoamphoacetates and cocoamphodiacetates.

In a particularly advantageous manner, the surfactant present in the continuous aqueous phase of step c) is chosen from a fatty acid ester of sorbitol; the condensation product of a fatty acid ester of sorbitol with an alkylene oxide; an alkyl sulfate or an ethoxylenated and or propoxylenated derivative thereof; a quaternary ammonium salt; and their mixtures.

Furthermore, it is preferred that the additional hydrophilic surfactant added to the final double emulsion leaving the homogenizer is chosen from a fatty acid ester of sorbitol; the condensation product of a fatty acid ester of sorbitol with an alkylene oxide; a water-soluble block copolymer of ethylene oxide and propylene oxide; and their mixtures.

The concentration of additional surfactant is to be adjusted by a person skilled in the art so as to guarantee the encapsulation of the active principle and avoid rupture of the emulsion. As an indication, if the HLB of the hydrophilic surfactant is greater than 30, then the concentration of said surfactant will preferably be less than 1 times its CMC. If the HLB of the hydrophilic surfactant is. less than 20, then the concentration of said surfactant will preferably be less than 100 times its CMC. According to a particularly preferred embodiment of the invention, the aqueous phase of the starting emulsion Ei comprises at least one water-soluble active substance.

Such active substances are preferably in the form of salts or water-soluble polymers.

However, it can be any type of active substance generally used in one or more of the pharmaceutical, cosmetic, phytosanitary, food and / or paint fields.

It can thus be chosen from vitamins (E, C), enzymes, insulin, analgesic, antimitotic, anti-inflammatory or antiglaucomatous agents, vaccines, anti-cancer agents, narcotic antagonists, detoxifying agents

(salicylates, barbiturates), depilatory agents, correcting agents or taste masks, water-soluble salts, acids, bases, vinegar, glucose, colors, preservatives or their mixtures. When the active substance is not in the form of an organic or inorganic salt or of a water-soluble polymer, it is advantageous to add to said internal aqueous phase a salt such as an alkali metal chloride (NaCI or KCI) or a polymer water-soluble such as an alginate, hydroxyethylcellulose, carboxymethylcellulose or a poly (acrylic) acid or alternatively a monosaccharide carbohydrate such as fructose, lyxose, arabinose, ribose, xylose, glucose, altrose , mannose, idose, galactose, erythrose, threose, sorbose, fucose or rhamnose, glucose being much preferred.

The concentration of active substance depends on the nature of the active substance and the intended application. When the emulsion Ei comprises such an active substance, it is desirable that the continuous aqueous phase of step c) comprise one or more agents for balancing the osmotic pressure.

As balancing agents which can be used according to the invention, a person skilled in the art can use any of the balancing agents commonly used in the art. Particularly preferred examples are sorbitol, glycerol and inorganic salts such as ammonium salts and alkali or alkaline earth metal salts.

According to a preferred embodiment of the invention, a monosaccharide carbohydrate is used, such as fructose, lyxose, arabinose, ribose, xylose, glucose, altrose, mannose, idose, galactose, erythrosis, threose, sorbose, fucose or rhamnose, glucose being clearly preferred.

Those skilled in the art will easily fix the concentration of osmotic pressure balancing agent as a function of the concentration of active substance present in the internal aqueous phase.

More specifically, the concentration of balancing agent will be determined so as to ensure the osmotic balance between the internal aqueous phase of the final double emulsion and the external continuous aqueous phase of the double emulsion. It depends on the osmolality of the hydrophilic active substance or substances (present in the internal aqueous phase) as well as on the osmolality of said balancing agent in the continuous aqueous phase.

The process of the invention makes it possible to prepare double emulsions whose size of the globules varies between 1 and 50 μm, in particular in the interval 2 and 20 μm, better still between 2 and 10 μm. The value of the diameter of the droplets of the emulsion Ei can be measured by using any of the methods known from the prior art: two of these methods are commonly used in the art.

The first is phase contrast microscopy, the second is laser particle size. A third method suitable for emulsions consisting of at least 65% by weight of dispersed phase consists in filling the cell with double emulsion allowing the transmission of at least 80% of the incident light. By sending a laser beam through the cell and placing a screen on the path after the cell, we notice a diffusion ring whose position directly gives the average diameter 2a of the droplets using the classic formula:

2a = λ. (N.sinθ / 2) ^'1 θ being the angle formed by the position of the ring and the initial beam, λ being the wavelength of light, and n being the refractive index of the medium.

The concentration of surfactant present in the continuous aqueous phase of step c) determines the size of the globules in the final double emulsion. The higher this concentration, the smaller the diameter of the globules of the final double emulsion.

Another way to control the size of the globules of the final double emulsion is to control the total amount of lipophilic surfactant present in the oily phase of the monodisperse reverse emulsion prepared in step b). This quantity does not correspond exactly to the sum of the lipophilic surfactant initially present in the inverse emulsion Ei and of the lipophilic surfactant possibly present in the oily dilution phase added to step b), but it is less.

In fact, part of the surfactant is adsorbed at the oil-water interface, that is to say on the surface of the droplets of aqueous phase.

A good approximation of the amount of residual surfactant (not adsorbed) remaining in the oily continuous phase of the monodisperse reverse emulsion obtained at the end of step b) is given by the equation:

3 0 C = C _τ a ₀ R (1 - 0) Na

in which :

C is the desired residual concentration of surfactant; C _τ is the total concentration of the lipophilic surfactant in the inverse emulsion, namely the sum of the surfactant initially present in the Ei emulsion and the lipophilic surfactant present in the oily dilution phase added in step b);

0 is the volume fraction of the droplets of aqueous phase, namely the ratio of the volume of the aqueous phase of the reverse emulsion to the total volume of the reverse emulsion;

R is the mean radius of the water droplets;

Na is the Avogadro number; a ₀ is the surface occupied by the surfactant adsorbed at the oil-water interface; a ₀ can be obtained from the curve giving the evolution of the water / oil interfacial tension as a function of the concentration of the lipophilic surfactant using the Gibbs equation (the calculation method is well known in the art; it is notably described in Physical Chemistry, fifth edition,

P.W. Atkins, Oxford University Press, 1994).

As a variant, it is possible to adjust, experimentally and a posteriori, the quantity of surfactant remaining in the oily phase of the reverse emulsion: quantity which does not take into account the surfactant adsorbed at the water-oil interface.

To do this, it is sufficient to exchange the oily phase of the reverse emulsion whose exact concentration of lipophilic surfactant is unknown with an oily phase of replacement of known surfactant concentration.

This exchange is carried out simply by a person skilled in the art, for example by implementing the following processing steps: i) centrifugation of the monodisperse reverse emulsion at an appropriate centrifugal force so as to avoid any coalescence of the droplets of aqueous phase and until the phases have settled. Preferably, the centrifugal force is kept below 15000 g (where g is the acceleration of gravity, ie about 9.8 ms ^"2 ). Usually, this centrifugation is carried out for less than 30 minutes. At the end of the centrifugation, two phases are obtained: a first phase consisting of droplets of aqueous phase and an oily phase; in most cases, the oily phase is the supernatant phase, the sedimented phase consisting of phase droplets aqueous; ii) separation of the oily phase in a manner known per se and, for example, by sampling with a pipette; iii) addition of an oily phase of replacement of known formulation and in particular the concentration of lipophilic surfactant is known; iv ) redispersion of the emulsion under appropriate shearing so as to avoid subsequent fractionation of the reverse emulsion. Moderate mechanical agitation is generally appropriate. e, we will use for example a mechanical vibrator. Alternatively, the emulsion can be left to stand for several hours. A simple manual agitation then makes it possible to redisperse it.

In a particularly advantageous manner, this treatment sequence consisting of steps i) to iv) is repeated several times and in order, the oily phase added to step iii) being identical to each sequence.

Generally, this sequence is repeated at least twice. Knowing the exact concentration (designated actual concentration) of surfactant in the oily phase allows perfect control of the size of the globules of the final double emulsion.

The process of the invention finds applications in numerous fields such as the pharmaceutical, cosmetic fields, the detergents field, the field of liquid crystal display, the field of phytosanitary and water paints. The emulsions of the invention are also useful in the treatment of surfaces.

The following examples which refer to Figures 1 to 4 further illustrate the invention.

For all the examples, the device used for the preparation of monodisperse inverse emulsions from corresponding polydisperse emulsions is the Duvet cell represented in FIG. 1: this consists of two concentric cylinders 2 and 3 in constant rotation l one over the other. In FIG. 1, the internal cylinder 2 is stationary while the external cylinder 3 is driven in a uniform rotational movement relative to a drive axis 15. The concentric cylinders 2 and 3 define an annular enclosure 4. At the upper and lower ends of the enclosure 4 are arranged two sealed ball bearings 5 and 6 annular. A cover 7 whose dimensions correspond to those of the external cylinder 3 closes the upper part of the device 1.

The concentric cylinders 2 and 3 are offset with respect to each other lengthwise so that the lower part 8 of the internal cylinder rests on a flat support 9. The Duvet cell 1 shown in FIG. 1 also comprises a supply conduit 10 in polydisperse emulsion which passes through the support 9 and opens into the upper part 11 of the enclosure 4. The other end of the supply conduit is connected to a reservoir 12 containing the polydisperse emulsion. The flow rate of supply of polydisperse emulsion is controlled by a piston 13. The lower part of the enclosure 4 diametrically opposite point 11 is provided with a discharge pipe 14 for the monodisperse emulsion which passes through the flat support 9.

The device of FIG. 1 allows the continuous preparation of the target monodisperse emulsion. During production, the enclosure 4 is continuously supplied with polydisperse emulsion through the pipe 10. The polydisperse emulsion circulates in the enclosure 4 while being subjected to shear forces generated by the uniform rotation of the external cylinder 3 on himself.

In such a device, the polydisperse emulsion is subjected to a constant shear rate, the shear rate being defined here as the ratio of the linear speed at the point of contact with the surface of the external cylinder 3 to the difference (R ₃ -R ₂ ) where R ₂ and R ₃ are respectively the radii of the inner 2 and outer 3 cylinders.

The size of the Ei emulsion droplets was determined in all cases by phase contrast microscopy and by laser granulometry.

EXAMPLE 1

Preparation of a double monodisperse emulsion

In this example, the presence of an active substance in the internal aqueous phase is simulated by introducing sodium chloride into it.

Firstly, a reverse polydisperse emulsion, water in sorbitan monooleate (SPAN 80) is prepared, this constituent plays both the role of oil and of surfactant. This reverse emulsion is prepared by introducing a 0.4M aqueous solution of sodium chloride in a continuous phase, kept under constant stirring and consisting of monooleate. sorbitan. The amount of aqueous solution added is such that the dispersed aqueous phase represents 85% of the total mass of the emulsion.

This reverse emulsion is then sheared at a shear rate of 1890 s ^"1 in a quilt device characterized by an air gap of 100 μm. The reverse emulsion obtained Ei ° is monodisperse, the mean diameter of the droplets of internal aqueous phase being 0 , 35μm.

The inverse emulsion Ei ° is then diluted in dodecane, so that the dispersed aqueous phase represents approximately 20% of the total mass of the emulsion. This dilution operation consists in gradually adding the dodecane to the Ei ° inverse emulsion, while maintaining low and constant stirring.

The reverse emulsion obtained is "washed" so as to know the concentration of lipophilic surfactant in the continuous oily phase. Three centrifugation cycles are carried out for this, or the supernatant oily phase is replaced by a solution consisting of dodecane and 2% by weight of sorbitan monooleate.

The diluted reverse emulsion is stable and has the following characteristics:

• Composition of the continuous phase: Dodecane and 2% by weight of sorbitan monooleate;

• Composition of the dispersed phase: 0.4M aqueous sodium chloride solution;

• Ratio of the volume of the aqueous dispersed phase to the total volume of the reverse emulsion: approximately 20%; • Average diameter of the drops of aqueous solution: 0.35 μm;

• Polydispersity of the volume distribution of the droplets of aqueous solution: approximately 25%, the polydispersity being defined as the ratio of the standard deviation of the curve representing the variation of the volume occupied by the dispersed material as a function of the diameter of the droplets at mean diameter of the aqueous phase droplets.

The particle size distribution of the dilute reverse emulsion is shown in Figure 2. The high pressure homogenizer includes 2 tanks for the introduction of a continuous aqueous phase on the one hand, and the diluted reverse emulsion on the other hand. The preceding inverse emulsion is introduced into one of the tanks and the continuous aqueous phase of the final double emulsion (continuous aqueous phase) into the other. The continuous aqueous phase consists of water, 10.5% by weight of glucose (this amount of glucose was chosen to balance the osmotic pressures with the aqueous dispersed phase of the reverse emulsion, consisting of 0.4M salt ) and sodium dodecyl sulfate at 0.005 times the critical micelle concentration. The two fluids are then emulsified in the mixing chamber of the homogenizer, at a pressure of around 300 bar. The diameter of the outlet chosen is 0.62mm.

At the outlet of the high-pressure homogenizer device, sodium dodecyl sulphate is immediately added so as to obtain a concentration of 0.1 times the critical micellar concentration in the continuous aqueous phase of the double emulsion.

The final double emulsion is stable and has the following characteristics:

_• Composition of the aqueous continuous phase: water, 10.5% by weight of glucose and sodium dodecyl sulfate at 0.1 times the CMC; • Composition of the dispersed phase: composition of the previous inverse emulsion;

_• Ratio of the volume of the dispersed reverse emulsion phase to the total volume of the double emulsion: approximately 50%;

• Average diameter of the reverse emulsion globules: 3.5 μm; • Polydispersity of the volume distribution of the sizes of the reverse emulsion globules: approximately 25%, the polydispersity being defined as the ratio of the standard deviation of the curve representing the variation of the volume occupied by the dispersed material as a function of the diameter of the globules the mean diameter of the reverse emulsion globules. FIG. 3 represents the particle size distribution of the final double emulsion. 24

EXAMPLE 2

Study of the influence of the concentration of sorbitan monooleate in the oily continuous phase of the reverse emulsion and of the sodium dodecyl sulfate concentration in the aqueous continuous phase of the double emulsion on the diameter of the globules of the double emulsion .

The reverse emulsion is washed by operating as in Example 1 with a continuous phase consisting of dodecane and sorbitan monooleate at 1% and 2% by weight. Two inverse emulsions are thus obtained at two concentrations of sorbitan monooleate in the oily continuous phase.

For each of these reverse emulsions, 4 double emulsions are prepared from aqueous continuous phases at different concentrations of sodium dodecyl sulfate in the aqueous continuous phase: 0, 0.003, 0.005 and 0.02 times the CMC. For each of the double emulsions obtained, the mean diameter of the globules is measured. FIG. 4 shows the evolution of this diameter as a function of the concentration of sodium dodecyl sulphate in the continuous aqueous phase of the double emulsion for two concentrations of sorbitan monooleate in the continuous oily phase of the reverse emulsion. It will be noted that on the abscissa SDS / CMC represents the ratio of the concentration of sodium dodecylsulfate to the critical micellar concentration.

A decrease in the size of the globules of the double emulsion is observed with the concentration of sodium dodecyl sulfate. Furthermore, for a concentration of sodium dodecylsulfate, it is noted that the size of the globules of the double emulsion is all the smaller the higher the concentration of sorbitan monooleate (see FIG. 4).

Claims

1. A method of preparing a double monodisperse emulsion, of the water in oil in water type, characterized in that it comprises the steps consisting in: a) subjecting an Ei emulsion of the water in oil, polydisperse type, comprising from 50 to 99% by weight of an aqueous phase, at a controlled shear such that the same maximum shear is applied to the whole of the emulsion, so as to obtain the corresponding monodisperse inverse emulsion; b) adding to said emulsion, without phase inversion, the necessary quantity of an oily dilution phase so that the aqueous phase of the resulting emulsion represents less than 50% by weight of the total weight of the emulsion; and c) introducing the resulting emulsion into a high pressure homogenizer, together with a continuous aqueous phase, the respective amounts of said emulsion and said continuous aqueous phase being such that the resulting double emulsion comprises up to 50% by weight of droplets of inverse emulsion relative to the total weight of the emulsion, said continuous aqueous phase comprising a hydrophilic surfactant concentration less than or equal to 0.02 times the critical micellar concentration,

2. Method according to claim 1, characterized in that the controlled shearing is achieved by bringing said polydisperse Ei emulsion into contact with a solid moving surface, the speed gradient characterizing the flow of the emulsion being constant in one direction perpendicular to said solid moving surface.

3. Method according to any one of claims 1 and 2, characterized in that the shearing is carried out using a cell consisting of two concentric cylinders in rotation relative to each other.

4. Method according to any one of claims 1 and 2, characterized in that the shearing is carried out using a cell consisting of two parallel plates in oscillating movement with respect to each other.

5. Method according to any one of claims 1 and 2, characterized in that the shearing is carried out using a cell consisting of two concentric discs in rotation relative to one another.

6. Method according to any one of the preceding claims, characterized in that the maximum value of the shear rate is from 1 to 1.10 _ι 5 s ^"1 , preferably from 100 to 5000 s ^{" 1} .

7. Method according to any one of the preceding claims, characterized in that the emulsion Ei comprises from 70 to 95% by weight of aqueous phase, preferably from 80 to 90% by weight.

8. Method according to any one of the preceding claims, characterized in that in step b) the amount of oily phase added is such that the aqueous phase of the resulting emulsion represents 35% by weight or less of the total weight of the emulsion, preferably 20% by weight or less.

9. Method according to any one of the preceding claims, characterized in that in step c) the viscosity of the emulsion introduced into the high pressure homogenizer on the one hand and the viscosity of the aqueous phase continues from on the other hand are less than 0.1 Pa.s, preferably less than 0.01 Pa.s.

10. Method according to any one of the preceding claims, characterized in that the surfactant present in the continuous aqueous phase of step c) has a lipophilic-hydrophilic ratio (HLB value) greater than 20, preferably greater than 30 .

11. Method according to any one of the preceding claims, characterized in that the continuous aqueous phase of step c) comprises, as surfactant, a fatty acid ester of sorbitol; the condensation product of a fatty acid ester of sorbitol with an alkylene oxide; an alkyl sulfate or an ethoxylenated and / or propoxylenated derivative thereof; a quaternary ammonium salt; or their mixtures.

12. Method according to any one of the preceding claims, characterized in that the surfactant concentration of the continuous aqueous phase of step c) is less than 0.01 times the critical micellar concentration.

13. Method according to any one of the preceding claims, characterized in that the aqueous phase of the emulsion Ei comprises an active substance and the continuous aqueous phase of step c) comprises an agent for balancing the osmotic pressure.

14. Method according to any one of the preceding claims, characterized in that one adds to the double monodisperse emulsion resulting from step c) an additional surfactant as stabilizer.

15. The method of claim 14, characterized in that said surfactant has a lipophilic-hydrophilic ratio (HLB value) greater than 12.

16. Method according to any one of claims 14 and 15, characterized in that the surfactant is chosen from a fatty acid ester of sorbitol; the condensation product of a fatty acid ester of sorbitol with an alkylene oxide; a water-soluble block copolymer of ethylene oxide and propylene oxide; and their mixtures. 28

17. Method according to any one of the preceding claims, characterized in that the concentration of hydrophilic surfactant in the continuous aqueous phase of step c) is adjusted to vary the size of the droplets of reverse emulsion in the double final emulsion.

18. Method according to any one of claims 1 to 16, characterized in that one adjusts the actual concentration of the lipophilic surfactant present in the oily phase of the monodisperse reverse emulsion obtained at the end of step b) to vary the size of the reverse emulsion droplets in the final double emulsion.

19. The method of claim 18, characterized in that one adjusts the actual concentration of the lipophilic surfactant by implementation, after step b) and before step c), of the treatment sequence consisting of the steps consisting in: i) centrifuging the reverse emulsion from step b) without causing the aqueous phase droplets to coalesce until the phases have settled; ii) separating the oily phase in a manner known per se; iii) adding to the remaining phase consisting of droplets of aqueous phases which are sedimented and stabilized by the lipophilic surfactant, an oily replacement phase with a determined concentration of lipophilic surfactant; iv) redispersing the emulsion under appropriate shearing so as to avoid subsequent fragmentation of the aqueous phase droplets.

20. Method according to claim 19, characterized in that the reverse emulsion resulting from step b) is subjected at least twice, and in order, to said treatment sequence consisting of steps i) to iv), and this, before implementation of step c).