EP1280597B1 - Method for preparing a monodispersed double emulsion - Google Patents

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

The invention relates to a process for the preparation of double emulsions monodisperses, of the water-in-oil-in-water type, by the implementation of a high pressure homogenizer.

The interest of double emulsions is widely recognized in fields as diverse as the pharmaceutical, cosmetic, phytosanitary, food and / or coatings type paintings.

Double emulsions of water-in-oil-in-water type in particular the encapsulation of various active substances at the level of the internal water. In 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 methods of preparing emulsions are known monodisperse: a first method is that described in EP 442 831 and EP 517 987. This process involves the fractionation of a primary emulsion of departure, 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 It consists in subjecting a primary viscoelastic emulsion to controlled shear so that the same maximum shear is applied to the entire emulsion. This process has different advantages and in particular allows control of the size of the droplets of the emulsion monodisperse obtained.

When one of these methods is applied to a double emulsion, it is essential not to induce the destruction of the double emulsion, in 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 method of preparation of a double emulsion of water type in oil in water monodisperse, which is not simply about applying one or the other of methods of the prior art to the double polydisperse emulsion correspondingly most desirable.

The invention aims to solve this problem by providing an original process for preparing a monodisperse double emulsion by using a high pressure homogenizer.

In the context of the present description, the double water-type emulsion in oil in water consists of droplets (or globules) of an emulsion reverse, monodisperse, dispersed in a continuous aqueous phase (or phase outer water), the inverse emulsion being itself composed of droplets an internal aqueous phase dispersed in an oily phase.

According to the invention, the term monodisperse characterizes emulsions for which particle size distribution of dispersed phase droplets is very narrow.

Distribution is considered very narrow when polydispersity is less than or equal to 30%, and preferably of the order of 5 to 25%, example between 10 and 20%.

In the context of the invention, the polydispersity is defined as the ratio 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 medium-diameter droplets droplets.

By "inverse emulsion" is meant, in general terms, the dispersion of a aqueous phase in an oily phase.

The term "direct emulsion" refers to the dispersion of a oily phase in an aqueous phase.

Thus, the term "monodisperse inverse emulsion" refers to an emulsion water-in-oil type consisting of droplets of an aqueous phase dispersed in an oily phase, for which the distribution granulometric droplets of aqueous phase is very narrow (polydispersity less than 30%).

The process of the invention leads to a double monodisperse emulsion, that is to say a double emulsion in which the particle size distribution globules is also very narrow (polydispersity less than 30%).

a) soumettre une émulsion Ei de type eau dans huile, polydisperse, comprenant de 50 à 99% en poids d'une phase aqueuse, à un cisaillement contrôlé de telle sorte qu'un même cisaillement maximal soit appliqué à l'ensemble de l'émulsion, de façon à obtenir l'émulsion inverse monodisperse correspondante ;

b) ajouter à ladite émulsion, sans inversion de phase, la quantité nécessaire d'une phase huileuse de dilution de façon à ce que la phase aqueuse de l'émulsion résultante représente moins de 50% en poids du poids total de l'émulsion ; et

c) introduire l'émulsion résultante dans un homogénéisateur haute pression, ensemble avec une phase aqueuse continue, les quantités respectives de ladite émulsion et de ladite phase aqueuse continue étant telles que l'émulsion double monodisperse résultante comprend jusqu'à 50% en poids de gouttelettes d'émulsion inverse (ou globules) par rapport au poids total de l'émulsion, ladite phase aqueuse continue comprenant une concentration en tensioactif hydrophile inférieure ou égale à 0,02 fois la concentration micellaire critique.

More specifically, the invention relates to a process for preparing a water-in-oil-in-water double monodisperse emulsion comprising the steps of:

a) subjecting a polydisperse oil-in-water emulsion Ei comprising from 50 to 99% by weight of an aqueous phase to controlled shear so that a maximum of the same shear is applied to the entire emulsion, so as to obtain the corresponding monodisperse inverse emulsion;

b) adding to said emulsion, without phase inversion, the necessary amount of an oily dilution phase so that the aqueous phase of the resulting emulsion is 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 monodisperse double emulsion comprises up to 50% by weight of inverse emulsion droplets (or globules) 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 micelle concentration.

This process leads to a double monodisperse emulsion consisting of globules of an oil-in-water emulsion dispersed in an aqueous phase external, globules representing not more than 50% of the total weight of the emulsion double. In the double emulsion obtained, the globules consist of droplets of an aqueous phase dispersed in an oily phase, the phase aqueous total contained in the blood cells representing not more than 50% of the weight total of all globules.

The process of the invention is carried out starting from an emulsion Ei, inverse, polydisperse, prepared conventionally according to any one of methods known from the state of the art.

The starting emulsion Ei comprises from 50 to 99% by weight of a phase aqueous, more preferably from 70 to 95%, for example 80 to 90% by weight, by relative to the total weight of the emulsion Ei.

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

By oil is meant according to the invention, any hydrophobic liquid substance or very slightly soluble in water, capable of being put into an aqueous emulsion in presence or absence of one or more suitable surfactants.

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

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

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

The term HLB (Hydrophilic-Lipophilic Balance) refers to the ratio of the hydrophilicity of the polar groups of the surfactant molecules to the hydrophobicity of their lipophilic part. HLB values include 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 that can be used for stabilization of the emulsion is more particularly chosen so as to be able to ensure a good stability of the emulsion.

As examples of suitable surfactants, mention may be made of fatty acid esters, preferably of C ₈ -C ₂₂ , of sorbitol such as span 80. Another type of suitable surfactant is polyglycerol polyricinoleate.

Span 80 is a molecular mixture derived from sorbitol whose main constituent is sorbitan monooleate.

The polyglycerol polyricinoleate has the formula: R ₁ O- (CH ₂ -CH (OR ₂ ) -CH ₂ O) _n -R ₃ or
n is an integer of 2 to 12;
R ₁ , 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- [O-CH ((CH ₂ ) ₅ CH ₃ ) -CH ₂ CH = CH- (CH ₂ ) ₇ -CO] _m - or
m is an integer of 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).

Polyglycerol polyricinoleates preferably used according to the invention are those by which n varies between 2 and 5 (and is for example 3) and m varies between 5 and 10 (and is for example 7).

When 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 only lipophilic surfactant.

In step a) the polydisperse inverse emulsion, Ei, is converted into monodisperse inverse emulsion. The technique used to do this is the one described in WO 97/38787.

It is recalled below:

A means for subjecting the entire emulsion to the same maximum shear consists of subjecting the entire emulsion to a constant shear.

However, the invention does not intend to be limited to this embodiment particular.

In fact, the shear rate can be distinct, at a given time, for two points of the emulsion.

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

As long as the emulsion is in flow when subjected to shear, each part of the emulsion can thus be subjected to a rate of shear that varies over time. Shear is said to be controlled when whatever the variation in time of the shear rate, this one passes by a maximum value that is the same for all parts of the emulsion, to a given moment that may differ from one place to another of the emulsion.

In a preferred manner, in order to control the shear, one introduces the double polydisperse emulsion in a suitable device.

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

Briefly, a suitable device is a duvet cell in which the shear is constant, the Couette cell consisting of two cylinders concentric in rotation with respect to each other.

A second device is a cell consisting of two parallel plates in motion oscillating relative to each other and between which one forces the polydisperse inverse emulsion.

Another device is a cell made up of two disks concentric in rotation relative to each other and between which circulates the polydisperse inverse emulsion.

These cells are commonly used in commercial devices, in particular rheometers for measuring the properties viscoelastic liquids (eg: CARRIMED or RHEOMETRICS).

The maximum value of the shear rate to which the emulsion is subjected primary depends on the frequency of rotation, oscillation frequency and / or the amplitude of oscillation of the movement of the plates, cylinders and disks of devices described above.

In general, it has been found that a high value of the maximum shear rate leads to the formation of emulsions consisting of emulsion droplets E _i of very small size and having a very narrow particle size distribution.

In order to increase the value of the maximum shear rate, the man the trade can play on several parameters, namely the rotation frequency, the oscillation frequency and / or the oscillation amplitude of the movement of the plates, cylinders and discs of the devices described above, as well as on the size of the respective speakers of these different devices in the direction perpendicular to the direction of flow imposed by the movement of the surface.

It should be noted that the maximum shear rate varies linearly with oscillation amplitude and / or the frequency of movement and so inversely proportional to the size of the enclosure in one direction perpendicular to the flow.

It is preferred that the maximum shear rate be between 1 and 1.10 ⁵ s ^-1 , 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 inverse emulsion, polydisperse, either homogeneous (absence of fractures) during his passing through any of the devices described above.

More specifically, when controlled shear is achieved by contacting said emulsion with a moving solid surface, a homogeneous flow is characterized by a constant velocity gradient in a direction perpendicular to the moving solid surface.

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

It should be noted that, in the case of the Couette device, this dimension d is defined by the difference (R ₃ -R ₂ ) in which R ₂ and R ₃ are respectively the radii of the inner and outer cylinders of the Couette device.

In the case of the cell consisting of two parallel plates in motion oscillating relative to each other, this dimension d is defined by the distance separating the two plates in a direction that is perpendicular.

In the case of the cell consisting of two concentric disks in rotation relative to each other, this dimension is defined by the distance separating the two disks in the direction of the axis of rotation of the disk in movement.

In general, a heterogeneous flow can be made uniform by reducing the size of the enclosure and more particularly by reducing its dimension in the direction perpendicular to the direction of flow.

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

At the end of stage a), an inverse emulsion of which the size of the dispersed aqueous phase droplets is between 0.05 μm and 50 μm, preferably between 0.1 μm and 10 μm.

In step b), the monodisperse inverse emulsion obtained in step a) is diluted by addition of an oily dilution phase.

To do this, it is possible to use an oily phase of the same composition that 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 emulsion Ei.

The addition of the oily dilution phase is carried out conventionally without phase inversion. A simple method consists in adding dropwise said oily addition phase to the monodisperse inverse emulsion maintained with moderate stirring. For this purpose shearing less than 100 s ^-1 is generally appropriate. Depending on the formulation of the inverse emulsion and, in particular, depending on the amount of surfactant present, it is possible to envisage other methods of addition such as, for example, the one-time addition of the oily dilution phase, to the emulsion kept stirring.

After dilution, it is important that the mass fraction of 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, more preferably less than 0.20.

According to a preferred embodiment of the invention, the viscosity of the inverse 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 inverse emulsion, in a high pressure homogenizer.

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

Such homogenizers include 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 Milky Fat Globule, Center for Agricultural Publishing and Documentation, Wegeningen, The Netherlands, 1974; or by P. Walstra in Formation of emulsions, Encydopedia of emulsion technology, Paul Becher, vol. 1, p. 57-127, Marcel Dekker Ed., New York, 1983.

In this type of homogenizer, the liquids are forced to very high pressure (a few hundred bars, for example 100 to 400 bars) to go to through a very narrow aperture of millimeter or micrometer size. This opening is usually placed in a valve system but it may be a slot or a simple circular hole. The opening usually presents a diameter of between 10 μm and 1 mm. Passing through this opening narrow, the emulsion undergoes a violent acceleration as well as a sudden fall pressure (the pressure downstream of the opening is of the order of 1 bar). Forces cavitation, shear and resulting turbulence emulsification.

According to the invention, one forces, in the homogenization valve or in the orifice, the inverse emulsion obtained at the end of step b) and an aqueous phase, said continuous. Said continuous aqueous phase will constitute the aqueous phase outer of the double emulsion exiting the high pressure homogenizer. He must It is to be understood that the continuous aqueous phase is an aqueous solution.

An example of a suitable homogenizer is a homogenizer of Gaulin type such as the model marketed by LabPlant Limited. In a way preferred, this model does not require premixing of the phases. The 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. Pushing on pistons, a press forces both liquids to penetrate simultaneously into the homogenisation chamber before passing them through the circular orifice Release.

• une vitesse d'injection de la phase aqueuse et de l'émulsion inverse monodisperse variant entre 100 et 500 m/s, mieux encore entre 150 et 350 m/s ;
• une pression dans la chambre où s'effectue le contact de l'émulsion inverse et de la phase aqueuse continue comprise entre 100 et 400 bars (de 0,1.10⁸ Pa à 0,4.10⁸ Pa) ;
• un orifice circulaire en sortie de la chambre d'homogénéisation de 0,1 à 1 mm.

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

• an injection rate of the aqueous phase and of the monodisperse inverse emulsion varying between 100 and 500 m / s, better still between 150 and 350 m / s;
• a pressure in the chamber where contact is made between the inverse emulsion and the continuous aqueous phase of between 100 and 400 bar (0.1 × 10 ⁸ Pa at 0.4 × 10 ⁸ Pa);
• a circular orifice at the outlet of the homogenization chamber of 0.1 to 1 mm.

This is the relative section of the cylindrical tanks located upstream of the homogenization chamber that determines the fraction of globules in the final double emulsion.

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

• le fait que les globules (ou gouttelettes d'émulsion inverse monodisperse) représentent au plus 50% du poids total de l'émulsion ;
• la phase aqueuse totale contenue dans les globules représente au plus 50% du poids total de tous les globules.

This emulsion is characterized by:

• the fact that the globules (or droplets of monodisperse inverse 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 thickener. It may contain one or more surfactants hydrophilic.

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

A second pass may cause a decrease considerable number of internal droplets contained in the globules (by coalescence). This would result in premature leakage of the active ingredient into the external aqueous phase.

So, a second pass in the high pressure homogenizer is it strongly discouraged.

The hydrophilic surfactant concentration of the continuous aqueous phase of step c) is less than 0.02 times the critical micelle concentration; of preferably, it is less than 0.01 times the critical micelle concentration.

Critical Micellar Concentration (CMC) is defined as the concentration beyond which the surfactant molecules associate to form spherical clusters called micelles (see for example "Galenica 5, surface agents and emulsions ", Vol 5.1, page 101, editor: Techniques and Documentation (Lavoisier)).

In the context of the invention, the concentration of hydrophilic surfactant the continuous aqueous phase may be zero. In this case, it is strongly desirable to add to the double monodisperse emulsion coming out of the high-pressure homogenizer, as a stabilizer, a surfactant additional and, advantageously, as soon as possible at the exit of the high pressure homogenizer.

The additional surfactant that can be used as an emulsion stabilizer double monodisperse, 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 possibly 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 about 40.

The additional surfactant meanwhile has preferably a value HLB greater than 12.

• le produit de condensation d'un alcool gras aliphatique, de préférence en C₈-C₂₂, avec un oxyde d'alkylène en C₂-C₃. L'oxyde d'alkylène en C₂-C₃ peut être l'oxyde d'éthylène, l'oxyde de propylène, ou bien un mélange d'oxyde d'éthylène et d'oxyde de propylène dans des proportions quelconques. Un exemple de tels tensioactifs est le produit de condensation de l'alcool laurylique (ou alcool n-dodécylique) avec 30 moles d'oxyde d'éthylène;
• le produit de condensation d'un alkylphénol dans lequel la chaíne alkyle est en C₈-C₂₂ avec un oxyde d'alkylène en C₂-C₃. Là encore, les produits de condensation avec l'oxyde d'éthylène, l'oxyde de propylène ou bien un mélange d'oxyde d'éthylène et d'oxyde de propylène dans des proportions quelconques sont également avantageux. A titre d'exemple de tels tensioactifs, on peut citer le produit de condensation du n-nonylphénol avec 10 moles d'oxyde d'éthylène;
• le produit de condensation d'un acide gras de préférence en C₈-C₂₂ avec un oxyde d'alkylène en C₂-C₃, par exemple l'oxyde d'éthylène ou l'oxyde de propylène ou un mélange d'oxyde d'éthylène et d'oxyde de propylène dans des proportions quelconques. Ces produits de condensation présentent une chaíne alkoxylée au niveau de la fonction hydroxyle du groupe carboxylique. Des tensioactifs préférés de ce groupe sont les produits de condensation obtenus à partir de l'acide oléique, de l'acide palmitique et de l'acide stéarique;
• le produit de condensation d'un glycéride d'acide gras en C₈-C₂₂ avec un oxyde d'alkylène en C₂-C₃ tel que l'oxyde d'éthylène et/ou l'oxyde de propylène. Parmi ceux-ci, le palmitate de glycérol éthoxylé est préféré;
• le produit de condensation d'un ester d'acide gras en C₈-C₂₂ du sorbitol avec un oxyde d'alkylène en C₂-C₃ qui peut être l'oxyde d'éthylène, l'oxyde de propylène ou leurs mélanges. Ces composés sont des polysorbates. Un exemple préféré est vendu sous la dénomination Tween 80 ;
• un polyacrylonitrile ;
• un polylakylèneglycol, de préférence un polyalkylèneglycol dans lequel la partie oxyalkylène est en C₂-C₃ ;
• un copolymère séquencé hydrosoluble d'oxyde d'éthylène et d'oxyde de propylène. De préférence, un copolymère répondant à la formule (1) : H-(OCH₂CH₂)_a-(O-CH(CH₃)-CH₂)_b-(OCH₂CH₂)_a-OH    dans laquelle :
• a est un entier compris entre 50 et 120, de préférence entre 70 et 110 ; et
• b est un entier compris entre 20 et 100, de préférence entre 30 et 70.

As hydrophilic nonionic surfactant, mention may be made of:

• the condensation product of an aliphatic fatty alcohol, preferably C ₈ -C ₂₂ , with a C ₂ -C ₃ alkylene oxide. The C ₂ -C ₃ alkylene oxide may 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 ₂₂ 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 preferably C ₈ -C ₂₂ fatty acid with a C ₂ -C ₃ alkylene oxide, for example ethylene oxide or propylene oxide or a mixture of oxide ethylene and propylene oxide in any proportions. These condensation products have an alkoxylated chain at the hydroxyl group of the carboxylic group. Preferred surfactants of this group are the condensation products obtained from oleic acid, palmitic acid and stearic acid;
• the condensation product of a C ₈ -C ₂₂ fatty acid glyceride with a C ₂ -C ₃ alkylene oxide such as ethylene oxide and / or propylene oxide. Of these, ethoxylated glycerol palmitate is preferred;
• the condensation product of a C ₈ -C ₂₂ fatty acid ester of sorbitol with a C ₂ -C ₃ alkylene oxide which may be ethylene oxide, propylene oxide or mixtures thereof . These compounds are polysorbates. A preferred example is sold under the name Tween 80;
• polyacrylonitrile;
• a polylakylene glycol, preferably a polyalkylene glycol in which the oxyalkylene portion 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 - (O-CH (CH ₃ ) -CH ₂ ) _b - (OCH ₂ CH ₂ ) _a -OH in which :
• a is an integer of from 50 to 120, preferably from 70 to 110; and
• b is an integer from 20 to 100, preferably from 30 to 70.

Such polymers are marketed by ICI under the brand name Synperonic PE®.

Among these, we will advantageously select 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.

The kinematic viscosity of the polymers of Synperonic PE® type is preferably between 150 and 1200 mm ² .s ^-1 at 100 ° C., more preferably between 500 and 1100 mm ² .s ^-1 .

Poloxamer 188 of formula (1) above is more particularly preferred. where a = 75 and b = 30.

• les alkylesters sulfonates de formule R-CH(SO₃M)-COOR', où R représente un radical alkyle en C₈-C₂₀, de préférence en C₁₀-C₁₆, R' un radical alkyle en C₁-C₆, de préférence en C₁-C₃ et M un cation alcalin (sodium, potassium, lithium), ammonium substitué ou non substitué (méthyl-, diméthyl-, triméthyl-, tetraméthylammonium, diméthylpiperidinium ...) ou dérivé d'une alcanolamine (monoéthanolamine, diéthanolamine, triéthanolamine ...). On peut citer tout particulièrement les méthyl ester sulfonates dont le radical R est en C₁₄-C₁₆;
• les alkylsulfates de formule ROSO₃M, où R représente un radical alkyle ou hydroxyalkyle en C₁₀-C₂₄, de préférence en C₁₂-C₂₀ et tout Particulièrement. en C₁₂-C₁₈, M représentant un atome d'hydrogène ou un cation de même définition que ci-dessus, ainsi que leurs dérivés éthoxylénés (OE) et/ou propoxylénés (OP), présentant en moyenne de 0,5 à 6 motifs, de préférence de 0,5 à 3 motifs OE et/ou OP ; parmi ceux-ci on préfère le dodécylsulfate de sodium ;
• les alkylamides sulfates de formule RCONHR'OSO₃M où R représente un radical alkyle en C₂-C₂₂, de préférence en C₆-C₂₀, R' un radical alkyle en C₂-C₃, M représentant un atome d'hydrogène ou un cation de même définition que ci-dessus, ainsi que leurs dérivés éthoxylénés (OE) et/ou propoxylénés (OP), présentant en moyenne de 0,5 à 60 motifs OE et/ou OP ;
• les sels d'acides gras saturés ou insaturés en C₈-C₂₄, de préférence en C₁₄-C₂₀, les alkylbenzènesulfonates en C₉-C₂₀, les alkylsulfonates primaires ou secondaires en C₈-C₂₂, les alkylglycérol sulfonates, les acides polycarboxyliques sulfonés décrits dans GB - A - 1 082 179, les sulfonates de paraffine, les N-acyl N-alkyltaurates, les alkylphosphates, les alkyliséthionates, les alkylsuccinamates les alkylsulfosuccinates, les monoesters ou diesters de sulfosuccinates, les N-acyl sarcosinates, les sulfates d'alkylglycosides, les polyéthoxycarboxylates, le cation étant un métal alcalin (sodium, potassium, lithium), un reste ammonium substitué ou non substitué (méthyl-, diméthyl-, triméthyl-, tetraméthylammonium, diméthylpiperidinium ...) ou dérivé d'une alcanolamine (monoéthanolamine, diéthanolamine, triéthanolamine ...) ;
• les phosphates ou alkylphosphates esters ; et
• les alginates.

Suitable examples of hydrophilic anionic surfactants are:

• the alkyl ester sulphonates of formula R-CH (SO ₃ M) -COOR ', in which R represents a C ₈ -C ₂₀ alkyl radical, preferably C ₁₀ -C ₁₆ radical, R' a C ₁ -C ₆ alkyl radical; , preferably C ₁ -C ₃ and M an alkali metal cation (sodium, potassium, lithium), substituted or unsubstituted ammonium (methyl-, dimethyl-, trimethyl-, tetramethylammonium, dimethylpiperidinium ...) or an alkanolamine derivative (monoethanolamine, diethanolamine, triethanolamine ...). Mention may in particular be made of methyl ester sulphonates whose radical R is C ₁₄ -C ₁₆ ;
• alkyl sulphates of formula ROSO ₃ M, in which R represents a C ₁₀ -C ₂₄ , preferably C ₁₂ -C _20, alkyl and hydroxyalkyl radical, and in particular. C ₁₂ -C ₁₈ , M representing a hydrogen atom or a cation of the same definition as above, and their ethoxylenated derivatives (EO) and / or propoxylenés (OP), having an average of 0.5 to 6 patterns, preferably from 0.5 to 3 EO and / or OP units; among these, sodium dodecyl sulphate is preferred;
• the alkylamide sulphates of formula RCONHR'OSO ₃ M where R represents a C ₂ -C ₂₂ alkyl radical, preferably C ₆ -C ₂₀ radical, R 'represents a C ₂ -C ₃ alkyl radical, M represents an atom of hydrogen or a cation of the same definition as above, as well as their ethoxylenated (EO) and / or propoxylenated (PO) derivatives, having on average from 0.5 to 60 EO and / or OP units;
• saturated or unsaturated C ₈ -C ₂₄ , preferably C ₁₄ -C ₂₀ fatty acid salts, C ₉ -C ₂₀ alkylbenzenesulfonates, primary or secondary C ₈ -C ₂₂ alkylsulfonates, alkylglycerol sulphonates, the sulfonated polycarboxylic acids described in GB-A-1 082 179, paraffin sulfonates, N-acyl N-alkyltaurates, alkylphosphates, alkylisethionates, alkylsuccinamates alkylsulfosuccinates, monoesters or diesters of sulfosuccinates, N-acyl sarcosinates , the alkyl glycoside sulphates, the polyethoxycarboxylates, the cation being an alkali metal (sodium, potassium, lithium), a substituted or unsubstituted ammonium residue (methyl-, dimethyl-, trimethyl-, tetramethylammonium, dimethylpiperidinium ...) or derivative an alkanolamine (monoethanolamine, diethanolamine, triethanolamine ...);
• phosphates or alkylphosphates esters; and
• alginates.

• les sels d'ammonium quaternaire tels que le bromure de tétradécyltriméthylammonium et
• les sels d'addition d'amines grasses avec des acides. Par amine grasse, on entend les amines à longues chaínes hydrocarbonées, c'est-à-dire comprenant de 8 à 24 atomes de carbone. Un exemple d'amine grasse préférée est la dodécylamine.

As a hydrophilic cationic surfactant, it is possible to use:

• quaternary ammonium salts such as tetradecyltrimethylammonium bromide and
• the addition salts of fatty amines with acids. The term "fatty amine" means amines with long hydrocarbon chains, that is to say comprising from 8 to 24 carbon atoms. An example of a preferred fatty amine is dodecylamine.

• ceux de type bétaïne comme les bétaïnes, les sulfo-bétaïnes, les amidoalkylbétaïnes, les sulfo-bétaïnes, les alkylsultaïnes, les alkyitriméthylsulfobétaïnes,
• les produits de condensation d'acides gras et d'hydrolysats de protéines,
• les alkylampho-propionates ou -dipropionates,
• les dérivés amphotères des alkylpolyamines comme l'AMPHIONIC XL commercialisé par RHONE-POULENC, AMPHOLAC 7T/X et AMPHOLAC 7C/X commercialisés par BEROL NOBEL,
• les cocoamphoacétates et cocoamphodiacétates.

Other surfactants are amphoteric and zwitterionic hydrophilic surfactants:

• those of betaine type such as betaines, sulfobetaines, amidoalkylbetaines, sulfobetaines, alkylsultaines, alkyltrimethylsulfobetaines,
• the condensation products of fatty acids and of 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 selected from a fatty acid ester of sorbitol; the condensation product of a fatty acid ester of sorbitol with a alkylene oxide; an alkyl sulphate or an ethoxylated and / or propoxylated derivative of this one ; 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 an ester fatty acid sorbitol; the condensation product of a fatty acid ester of sorbitol with an alkylene oxide; a water-soluble block copolymer ethylene oxide and propylene oxide; and their mixtures.

The concentration of additional surfactant is to be adjusted by the man of art to ensure the encapsulation of the active ingredient and prevent breakage 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 time his 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 substance active water-soluble.

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

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

It can thus be chosen from vitamins (E, C), enzymes, insulin, analgesic, antimitotic, anti-inflammatory or antiglaucomatous agents, vaccines, anti-cancer agents, narcotic antagonists, detoxification agents (salicylates, barbiturates), depilatory agents, corrective agents or masks taste, water soluble salts, acids, bases, vinegar, glucose, dyes, preservatives or their mixtures.

When the active substance is not in the form of organic salt or mineral or water-soluble polymer, it is advantageous to add to said phase a salt such as an alkali metal chloride (NaCl or KCl) or a water-soluble polymer such as alginate, hydroxyethylcellulose, carboxymethylcellulose or a poly (acrylic acid) or a carbohydrate monosaccharide such as fructose, lyxose, arabinose, ribose, xylose, glucose, altrose, mannose, idose, galactose, erythrosis, threose, sorbose, fucose or rhamnose, glucose being clearly preferred.

The concentration of active substance depends on the nature of the substance active and the intended application.

When the emulsion Ei comprises such an active substance, it is desirable that the continuous aqueous phase of step c) comprises one or several osmotic pressure balancing agents.

As balancing agents that can be used according to the invention, the man of the profession may implement any of the balancing agents commonly used in the art.

Particularly preferred examples are sorbitol, glycerol and mineral salts such as ammonium salts and alkali metal salts or alkaline earth metal.

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

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

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

The process of the invention makes it possible to prepare double emulsions the size of the globules varies between 1 and 50 μm, especially in the range 2 and 20 μm, more preferably between 2 and 10 μm.

The droplet diameter value of the emulsion Ei can be measured by implementing any of the known methods of 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 suitable method for the case of emulsions consisting of at least 65% by weight of dispersed phase is to fill the double emulsion cell 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, there is a diffusion ring whose position directly gives the average diameter 2a of the droplets using the conventional formula: 2a = λ. (N.sin / 2) -1  being the angle formed by the position of the ring and the initial beam,
where λ is the wavelength of light, and
n being the index of refraction 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 larger the diameter of the the final double emulsion is weak.

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

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

C est la concentration résiduelle cherchée en tensioactif ;

C_T est la concentration totale du tensioactif lipophile dans l'émulsion inverse, à savoir la somme du tensioactif initialement présent dans l'émulsion Ei et du tensioactif lipophile présent dans la phase huileuse de dilution ajoutée à l'étape b) ;

Ø est la fraction volumique des gouttelettes de phase aqueuse, à savoir le rapport du volume de la phase aqueuse de l'émulsion inverse sur le volume total de l'émulsion inverse ;

R est le rayon moyen des gouttelettes d'eau ;

Na est le nombre d'Avogadro ;

a₀ est la surface occupée par le tensioactif adsorbé à l'interface huile-eau ;

a₀ peut être obtenu à partir de la courbe donnant l'évolution de la tension interfaciale eau/huile en fonction de la concentration du tensioactif lipophile en utilisant l'équation de Gibbs (la méthode de calcul est bien connue dans la technique ; elle est notamment décrite dans Physical Chemistry, fifth edition, P.W. Atkins, Oxford University Press, 1994).

A good approximation of the amount of residual (non-adsorbed) surfactant remaining in the oily continuous phase of the monodisperse inverse emulsion obtained at the end of step b) is given by the equation: C = C T 3Ø at 0 R (1 - Ø) Na in which :

C is the desired residual concentration of surfactant;

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

Ø is the volume fraction of the droplets of aqueous phase, namely the ratio of the volume of the aqueous phase of the inverse emulsion to the total volume of the inverse emulsion;

R is the average radius of the water droplets;

Na is the number of Avogadro;

₀ is the area occupied by the adsorbed surfactant 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 by using the Gibbs equation (the calculation method is well known in the art; especially described in Physical Chemistry, fifth edition, PW Atkins, Oxford University Press, 1994).

Alternatively, it is possible to adjust, experimentally and a posteriori, the amount of surfactant remaining in the oily phase of the inverse emulsion: amount that does not take into account the surfactant adsorbed at the water-oil interface.

To do this, simply exchange the oily phase of the inverse emulsion whose exact concentration of lipophilic surfactant is unknown with one oily surfactant concentration replacement known.

i) centrifugation de l'émulsion inverse monodisperse à une force centrifuge appropriée de façon à éviter toute coalescence des gouttelettes de phase aqueuse et jusqu'à décantation des phases. De préférence, la force centrifuge est maintenue au-dessous de 15000 g (où g est l'accélération de la pesanteur, à savoir environ 9,8 ms^-2). Habituellement, cette centrifugation est mise en oeuvre pendant moins de 30 minutes. A l'issue de la centrifugation, on obtient deux phases : une première phase constituée de gouttelettes de phase aqueuse et une phase huileuse ; dans la plupart des cas, la phase huileuse est la phase sumageante, la phase sédimentée étant constituée de gouttelettes de phase aqueuse ;

ii) séparation de la phase huileuse de façon connue en soi et, par exemple, par prélèvement à la pipette ;

iii) addition d'une phase huileuse de remplacement de formulation connue et notamment dont la concentration en tensioactif lipophile est connue ;

iv) redispersion de l'émulsion sous un cisaillement approprié de façon à éviter un fractionnement ultérieur de l'émulsion inverse. Une agitation mécanique modérée est généralement appropriée. Pour ce faire, on utilisera par exemple un vibreur mécanique. En variante, on peut laisser l'émulsion au repos pendant plusieurs heures. Une simple agitation manuelle permet ensuite de la redisperser.

This exchange is carried out simply by those skilled in the art, for example by carrying out the following treatment steps:

i) centrifugation of the monodisperse inverse emulsion at a suitable centrifugal force so as to avoid any coalescence of the aqueous phase droplets and until the phases are decanted. Preferably, the centrifugal force is maintained below 15,000 g (where g is the acceleration of gravity, namely 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 droplets of aqueous phase;

ii) separating the oily phase in a manner known per se and, for example, by pipetting;

iii) addition of an oil phase of replacement of known formulation and in particular whose concentration of lipophilic surfactant is known;

iv) redispersion of the emulsion under appropriate shear so as to avoid subsequent fractionation of the inverse emulsion. Moderate mechanical agitation is generally appropriate. To do this, use for example a mechanical vibrator. Alternatively, the emulsion can be left standing for several hours. A simple manual agitation then allows redispersing.

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

Generally, this sequence is repeated at least twice.

Knowledge of the exact concentration (referred to as concentration real) in surfactant of the oily phase allows a perfect control of the size globules of the final double emulsion.

The method of the invention finds applications in many areas such as pharmaceuticals, cosmetics, the field of detergents, the field of liquid crystal display, the field of phytosanitary and water-based paints. The emulsions of the invention are also useful in the treatment of surfaces.

The following examples, which refer to FIGS. 1 to 4, illustrate further before the invention.

For all the examples, the device used for the preparation of emulsions monodisperse inverses from corresponding polydisperse emulsions is the Couette cell shown in Figure 1: this consists of two concentric cylinders 2 and 3 in constant rotation relative to each other. Sure FIG. 1, the inner cylinder 2 is stationary whereas the outer cylinder 3 is with a uniform rotational movement with respect to a drive axis 15. The concentric cylinders 2 and 3 define an annular enclosure 4. To the upper and lower ends of the enclosure 4 are arranged two bearings sealed ball bearings 5 and 6 annular. A cover 7 whose dimensions correspond to those of the outer cylinder 3 closes the upper part of the device 1.

The cylinders 2 and 3 concentric are offset relative to each other in the direction of the length so that the lower part 8 of the cylinder internal rests on a plane support 9.

The quilt cell 1 shown in FIG. a supply duct 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 feed duct is connected to a reservoir 12 containing the emulsion polydisperse. The polydisperse emulsion feed rate is controlled by a piston 13. The lower part of the chamber 4 diametrically opposite the point 11 is provided with a discharge line 14 of the monodisperse emulsion which passes through the flat support 9.

The device of FIG. 1 allows the continuous preparation of the emulsion monodisperse target. During production, enclosure 4 is powered by continuous emulsion polydisperse by the pipe 10. The polydisperse emulsion circulates in the chamber 4 while being subjected to shear forces generated by the uniform rotation of the outer cylinder 3 on itself.

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 velocity to the point of contact with the surface of the outer cylinder 3 to the difference (R ₃ -R ₂ ) where R ₂ and R ₃ are respectively the radii of the inner and outer cylinders 2 and 3.

The size of emulsion droplets E _i 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 by introducing into it sodium chloride.

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

This inverse emulsion is then sheared at a shear rate of 1890 s ^-1 in a Couette device characterized by a gap of 100 .mu.m. The inverse emulsion obtained Ei ° is monodisperse, the average diameter of the droplets of internal aqueous phase being 0.35 .mu.m.

The inverse emulsion Ei ° is then diluted in the dodecane, so as to that the dispersed aqueous phase represents about 20% of the total mass emulsion. This dilution operation consists in gradually adding the dodecane with the inverse emulsion Ei °, while maintaining a weak agitation and constant.

The inverse emulsion obtained is "washed" so as to know the concentration of lipophilic surfactant in the oily continuous phase. We perform three cycles of centrifugation or replace the oily phase supernatant by a solution consisting of dodecane and 2% by weight of sorbitan monooleate.

• Composition de la phase continue : Dodécane et 2% en poids de monooléate de sorbitane ;
• Composition de la phase dispersée : Solution aqueuse de chlorure de sodium à 0,4M ;
• Rapport du volume de la phase dispersée aqueuse sur le volume total de l'émulsion inverse : environ 20% ;
• Diamètre moyen des gouttes de solution aqueuse : 0,35µm ;
• Polydispersité de la distribution volumique des tailles des gouttelettes de solution aqueuse: environ 25%, la polydispersité étant définie comme le rapport de l'écart type de la courbe représentant la variation du volume occupé par la matière dispersée en fonction du diamètre des gouttelettes au diamètre moyen des gouttelettes de phase aqueuse.

The diluted inverse 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 solution of sodium chloride;
• Ratio of the volume of the aqueous dispersed phase to the total volume of the inverse emulsion: about 20%;
• Average diameter of the drops of aqueous solution: 0.35μm;
• Polydispersity of the volume distribution of the droplets of aqueous solution: about 25%, 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 to the diameter medium droplets of aqueous phase.

The particle size distribution of the diluted inverse emulsion is shown in Figure 2.

The high pressure homogenizer comprises 2 tanks for the introduction of a continuous aqueous phase on the one hand, and of the inverse emulsion diluted on the other go. The previous inverse emulsion is introduced into one of the tanks and the aqueous continuous phase of the final double emulsion (continuous aqueous phase) in the other. The continuous aqueous phase consists of water, 10.5% weight of glucose (this amount of glucose has been chosen to balance the osmotic pressures with the aqueous dispersed phase of the inverse emulsion, consisting of 0.4M salt) and 0.005 times sodium dodecyl sulfate critical micellar concentration. Both fluids are then emulsified in the mixing chamber of the homogenizer at a pressure of about 300 bar. The diameter of the outlet orifice chosen is 0.62 mm.

At the output of the device of the high-pressure homogenizer, we add sodium dodecyl sulphate immediately to obtain a concentration of 0.1 times the critical micelle concentration in the continuous aqueous double emulsion.

• Composition de la phase continue aqueuse: eau, 10,5% en poids de glucose et dodécylsulfate de sodium à 0,1 fois la CMC ;
• Composition de la phase dispersée : composition de l'émulsion inverse précédente ;
• Rapport du volume de la phase dispersée d'émulsion inverse sur le volume total de l'émulsion double : environ 50% ;
• Diamètre moyen des globules d'émulsion inverse : 3,5µm ;
• Polydispersité de la distribution volumique des tailles des globules d'émulsion inverse : environ 25%, la polydispersité étant définie comme le rapport de l'écart type de la courbe représentant la variation du volume occupé par la matière-dispersée en fonction du diamètre des globules au diamètre moyen des globules d'émulsion inverse.

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 sulphate at 0.1 times CMC;
• Composition of the dispersed phase: composition of the previous inverse emulsion;
• Ratio of the volume of the dispersed inverse emulsion phase to the total volume of the double emulsion: about 50%;
• Mean diameter of the inverse emulsion globules: 3.5 μm;
• Polydispersity of the volume distribution of the sizes of the inverse emulsion globules: about 25%, the polydispersity being defined as the ratio of the standard deviation of the curve representing the variation of the volume occupied by the matter-dispersed as a function of the diameter of the globules to the average diameter of the cells of inverse emulsion.

FIG. 3 represents the particle size distribution of the emulsion double final.

EXAMPLE 2 Study of the influence of the concentration of sorbitan monooleate in the oily continuous phase of the inverse emulsion and 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 inverse emulsion is washed by operating as in Example 1 with a continuous phase consisting of dodecane and sorbitan monooleate with 1% and 2% by weight. We thus obtain two inverse emulsions with two sorbitan monooleate concentrations in the oily continuous phase.

For each of these inverse emulsions, 4 double emulsions are prepared from continuous aqueous phases at different concentrations of sodium dodecyl sulphate in the continuous aqueous phase: 0.003, 0.005 and 0.02 times the CMC. For each of the double emulsions obtained, the average diameter of the globules. Figure 4 shows the evolution of this diameter in function of the concentration of sodium dodecyl sulphate in the continuous phase aqueous solution of the double emulsion for two concentrations of monooleate sorbitan in the oily continuous phase of the inverse emulsion. It will be noted that abcisse SDS / CMC represents the ratio of the concentration of dodecyl sulphate of sodium on critical micellar concentration.

There is a decrease in the size of the globules of the double emulsion with the concentration of sodium dodecyl sulphate.

Moreover, for a concentration of sodium dodecyl sulphate, finds that the size of the globules of the double emulsion is even smaller that the concentration of sorbitan monooleate is important (see Figure 4).

Claims (20)

1. A method for preparing a monodispersed double water/oil/water emulsion, characterised in that it comprises the following steps:

   a) subjecting a polydispersed oil-in-water emulsion IE comprising 50 to 99 wt.% of an aqueous phase to a controlled shearing such that a common maximum shearing is applied to the entire emulsion, so as to obtain the corresponding monodispersed invert emulsion;

   b) adding to the said emulsion; without phase inversion, the necessary amount of diluting oily phase so that the aqueous phase of the resulting emulsion represents less than 50 wt.% of the emulsion total weight; and

   c) introducing the resulting emulsion into a high-pressure homogeniser together with a continuous aqueous phase, the respective amounts of the said emulsion and the said 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 said continuous aqueous phase comprising a hydrophilic surfactant concentration less than or equal to 0.02 times the critical micellar concentration.
2. A method according to Claim 1, characterised in that the controlled shearing is achieved by contacting the said polydispersed emulsion IE with a solid surface in motion, the speed gradient characterising the flow of the emulsion being constant in a direction perpendicular to the said solid surface in motion.
3. A method according to either Claim 1 or Claim 2, characterised in that the shearing is achieved with the aid of a cell composed of two concentric cylinders rotating relative to one another.
4. A method according to either Claim 1 or Claim 2, characterised in that the shearing is achieved with the aid of a cell composed of two parallel plates in reciprocating motion relative to one another.
5. A method according to either Claim 1 or Claim 2, characterised in that the shearing is achieved with the aid of a cell composed of two concentric discs rotating relative to one another.
6. A method according to any one of the preceding claims, characterised in that the maximum value of the shearing rate is 1 to 1·10⁵ s^-1, preferably 100 to 5000 s^-1.
7. A method according to any one of the preceding claims, characterised in that the emulsion IE comprises 70 to 95 wt.% of aqueous phase, preferably 80 to 90 wt.%.
8. A method according to any one of the preceding claims, characterised in that, in step b), the quantity of oily phase added is such that the resulting aqueous phase of the emulsion represents 35 wt.% or less of the total emulsion weight, preferably 20 wt.% or less.
9. A method according to any one of the preceding claims, characterised in that, in step c), the viscosity of the emulsion introduced into the high-pressure homogeniser on the one hand, and the viscosity of the continuous aqueous phase on the other hand, are less than 0.1 Pa·s, preferably less than 0.01 Pa·s.
10. A method according to any one of the preceding claims, characterised in that the surfactant present in the continuous aqueous phase from step c) has a lipophilic-hydrophilic ratio (HLB value) greater than 20, and preferably greater than 30.
11. A method according to any one of the preceding claims, characterised in that the continuous aqueous phase from step c) comprises, as the 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 or propoxylenated derivative thereof, a quaternary ammonium salt, or mixtures thereof.
12. A method according to any one of the preceding claims, characterised in that the surfactant concentration of the continuous aqueous phase from step c) is less than 0.01 times the critical micellar concentration.
13. A method according to any one of the preceding claims, characterised in that they aqueous phase of the emulsion IE comprises an active substance and the continuous aqueous phase from step c) comprises an agent for balancing the osmotic pressure.
14. A method according to any one of the preceding claims, characterised in that an additional surfactant is added as a stabiliser to the monodispersed double emulsion resulting from step c).
15. A method according to Claim 14, characterised in that the said surfactant has a lipophilic-hydrophilic ratio (HLB value) greater than 12.
16. A method according to either Claim 14 or Claim 15, characterised in that the surfactant is selected from among a fatty acid ester of sorbitol, the condensation product of a fatty acid ester of sorbitol with an alkylene oxide, a sequenced water-soluble copolymer of ethylene oxide and propylene oxide, and mixtures thereof.
17. A method according to any one of the preceding claims, characterised in that the concentration of hydrophilic surfactant in the continuous aqueous phase from step c) is adjusted so as to vary the size of the invert emulsion droplets in the final double emulsion.
18. A method according to any one of Claims 1 to 16, characterised in that the actual concentration of the lipophilic surfactant present in the oily phase of the monodispersed invert emulsion obtained at the end of step b) is adjusted so as to vary the size of the invert emulsion droplets in the final double emulsion.
19. A method according to Claim 18, characterised in that the actual concentration of the lipophilic surfactant is adjusted by the implementation, after step b) and before step c), of the treatment sequence composed of the following steps:

    i) centrifuging the invert emulsion originating from step b) without inducing coalescence of the droplets, until phase decantation is achieved;

    ii) separating the oily phase in a way which is known per se;

    iii) adding to the residual phase composed of aqueous-phase droplets sedimented out and stabilised with the lipophilic surfactant, a replacement oily phase of defined lipophilic surfactant concentration;

    iv) redispersing the emulsion with appropriate shearing so as to prevent subsequent fragmentation of the aqueous-phase droplets.
20. A method according to Claim 19, characterised in that, prior to implementation of step c), the invert emulsion originating from step b) is subjected at least twice, and in order, to the said treatment sequence composed of steps i) to iv).

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