FR2955257A1 - METHOD OF MANUFACTURING CAPSULES WITH CONTROLLED FALL HEIGHT. - Google Patents

Abstract

The method includes separately conveying in a jacket (32) a first liquid solution (36) and a second liquid solution (40). It comprises the formation at the exit of the jacket (32) from a series of drops (78), each drop (78) comprising a central core (80) formed of first solution (36) and a peripheral film (82). formed of second solution (40). The method includes dropping each drop (78) into a gaseous volume at the outlet of the jacket (32) and immersing each drop (78) in a gelling solution (70) to form a gelled shell. The ratio of the kinetic energy of the drop (78) to the square of its radius when it comes into contact with the gelling solution (70) is greater than 1 J / m2.

Description

The present invention relates to a method of manufacturing a series of capsules, each capsule comprising a liquid core containing at least a first product and a gelled envelope completely encapsulating the core, the process comprising the following steps: - separate conveying in a double jacket of a first liquid solution containing the first product and a second liquid solution containing a liquid polyelectrolyte suitable for gelation; - formation at the exit of the double envelope of a series of drops, each drop comprising a central core formed of first solution and a peripheral film formed of second solution and completely covering the central core; - drop of each drop in a gaseous volume at the exit of the double envelope; - Immersing each drop in a gelling solution containing a reagent adapted to react with the electrolyte product of the film to change it from a liquid state to a gelled state and form the gelled envelope, the central core forming the liquid core; - recovery of formed capsules. Such capsules, which comprise a liquid core encapsulated by a substantially solid gelled envelope, have applications in many technical fields. Thus, in the food industry, these capsules are used to contain various additives that improve the properties of a food product, such as its taste, or its shelf life.

In the pharmaceutical industry or in the cosmetic industry, the aforementioned capsules are in particular filled with biologically or cosmetically active products. They are used in particular to protect their contents and control the release of the product they contain. Such capsules are also used in biochemical applications to immobilize cells in bioreactors or as artificial cells in implants. In all these applications, the capsule casings are generally formed of a biocompatible material with the human body. For this purpose, it is known to form the shell with polymers such as polysaccharides, which are biocompatible, biodegradable and in most cases non-toxic. These polymers can advantageously pass from a liquid state in solution to a substantially more viscous state to form a gel ensuring mechanical retention of the liquid contained in the capsule. Among these polysaccharides, alginates are used in particular to create core-shell structures in which the core is liquid.

However, methods of manufacturing capsules with a controlled morphology (diameter, size of the envelope) are tedious to implement. Thus, current techniques involve for example forming a solid precursor nucleus and growing layer by layer polyelectrolyte bark around the core. Once the desired bark thickness has been obtained, the solid precursor nucleus is dissolved and the liquid product to be encapsulated is impregnated inside the bark. Such a technique is tedious and difficult to implement for mass production. Moreover, it is necessary to have a large amount of product to be encapsulated to impregnate the heart, which is not very economical when these products are expensive.

Also known from US 6,056,992 a method of manufacturing capsules of the aforementioned type, wherein a first solution for forming the core and a second solution which is deposited around the heart are coextruded to form a drop. The second solution contains a clean thermally gelable polymer which is contacted with a high temperature bath to form a gel on the surface of the capsule. Such an approach is not entirely satisfactory. Indeed, in the case where the gelation is thermally induced, it is very slow, which leads to non-homogeneous envelopes thicknesses and difficult to control. In addition, thermal gelation may not be completely reversible. To overcome this problem, it is known to use polyelectrolytes sensitive for example to a solution containing polyvalent ions. In this case, the reaction is rapid, but it is difficult or impossible to form drops comprising a liquid core of the first product and a liquid envelope containing the polyelectrolyte intended to gel without observing a phase separation. The implementation of the coextrusion process is in this case very difficult, especially for alginates. An object of the invention is therefore to obtain a method of manufacturing a series of capsules having thin envelopes and very controlled structure encapsulating a liquid core, this method being simple and effective to implement.

For this purpose, the subject of the invention is a process of the aforementioned type, characterized in that the ratio of the kinetic energy of the drop, to the square of its radius, when it comes into contact with the gelling solution is greater than 1 J / m2. The method according to the invention may comprise one or more of the following characteristics, taken alone or according to any combination (s) technically possible (s): the ratio of the kinetic energy of the drop, the square of its radius, when it comes into contact with the gelling solution is greater than 1.5 J / m2, preferably greater than 2 J / m2, still more preferably greater than 3 J / m2; the ratio of the kinetic energy of the drop (78) to the square of its radius when it comes into contact with the gelling solution is less than 15 J / m 2, advantageously less than 6 J / m 2; the second solution contains at least one surfactant before it comes into contact with the first solution; the total weight percentage of surfactant in the second solution is greater than 0.01% by weight and is advantageously between 0.03% and 0.5% by weight; the ratio of the drop height separating the outlet of the jacket and the upper surface of the gelling solution to the thickness of the film is less than 10 000, and is advantageously less than 7000 and is in particular between 500 and 1500; ; the concentration of surfactant in the second solution is greater than the critical micellar concentration, the ratio of the drop height to the thickness of the film being greater than 3000; the concentration of surfactant in the second solution is less than the critical micelle concentration, the ratio of the drop height to the thickness of the film being less than 3000, advantageously less than 1500; the film has a thickness less than 100 microns, advantageously less than 60 microns, still advantageously between 15 microns and 75 microns, in particular between 20 microns and 60 microns; the first liquid solution contains an oil, the second solution being an at least partially aqueous solution, the film having a thickness of less than 50 microns, advantageously less than 10 microns; the viscosity of the first solution 36 is less than 100 mPa.s, advantageously less than 50 mPa.s, in particular between 0.5 mPa.s and 100 mPa.s, in particular between 0.6 mPa.s and 50 mPa.s; the or each surfactant is chosen from an anionic surfactant, a cationic surfactant, a nonionic surfactant or mixtures thereof; the surfactant is chosen from an alkyl sulphate, an alkyl sulphonate, an alkylarylsulphonate, an alkaline alkylphosphate, a dialkylsulphosuccinate, an alkaline earth salt of saturated or unsaturated fatty acids, an alkylpyridium halide salt or alkylammonium such as n-ethyldodecylammonium chloride or bromide, cetylammonium chloride or bromide, polyoxyethylenated and / or polyoxypropylenated derivatives of fatty alcohols, fatty acids or alkylphenols, or of arylphenols, alkyls glucosides, polysorbates cocamides or mixtures thereof; the or each polyelectrolyte is a polyelectrolyte reactive with multivalent ions, in particular a polysaccharide reactive with multivalent ions such as an alkaline alginate, a gelane or a pectin; the ion-reactive polyelectrolyte is an alkaline alginate advantageously having an α-L-guluronate block content of greater than 50%, especially greater than 55%; the mass content of polyelectrolyte in the second solution is less than 5% by weight and is advantageously between 0.5 and 3% by weight; the ratio of the flow rate of the first solution to the flow rate of the second solution at the outlet of the jacket is between 1 and 200, advantageously between 10 and 200, the gelled envelope having a thickness of between 0.1% and 10%; %, advantageously between 0, 1% and 2% of the diameter of the capsule, after recovery of the capsules formed; and the first solution comprises at least one biologically active product, a cosmetic product or an edible product suitable for consumption.

The invention will be better understood on reading which will be given, given purely by way of example, and with reference to the appended drawings, in which: FIG. 1 is a diagrammatic sectional view along a median vertical plane of a first device for producing capsules according to the invention, during the manufacture of a series of capsules according to the invention; - Figure 2 is an enlarged view, in section along a median vertical plane of a capsule according to the invention manufactured by the method shown in Figure 1; - Figure 3 is a view similar to Figure 1 of a detail of a second capsule manufacturing device according to the invention; - Figure 4 is a view, taken in section along a median vertical plane, of a third device for producing capsules according to the invention.

A first series of capsules 10 made by a method according to the invention is shown in FIG. 1. Referring to FIG. 2, each capsule 10 comprises a liquid core 12 and a gelled outer envelope 14 surrounding the entire outer surface of the capsule. heart 12 to retain the liquid heart 12.

In this example, each capsule 10 is spherical in shape and advantageously has an outside diameter of less than 5 mm and in particular between 1 mm and 3 mm. The liquid core 12 contains at least a first product advantageously chosen from a biologically active product, a cosmetic product, or an edible product suitable for consumption. When the first product is a biologically active product, it is advantageously chosen from anticoagulants, anti-thrombogenic agents, antimitotic agents, anti-proliferation agents, anti-adhesion agents, anti-migration agents, cell adhesion promoters and growth factors. , antiparasitic molecules, anti-inflammatories, angiogenics, angiogenesis inhibitors, vitamins, hormones, proteins, antifungals, antimicrobial molecules, antiseptics or antibiotics. Alternatively, the liquid core 12 contains reagents such as proteins or reagents to form a bioreactor, or to form artificial cells for implants. A cosmetic product that may be contained in the heart is for example cited in the Council Directive 93/35 / EEC dated June 14, 1993. This product is for example a cream, an emulsion, a lotion, a gel and an oil for skin (hands, face, feet, etc.), a foundation (liquid, paste) a preparation for baths and showers (salts, mousses, oils, gels, etc.), a hair care product (hair dyes and bleaches ), a cleaning product (lotions, powders, shampoos), a hair care product (lotions, creams, oils), a styling product (lotions, lacquers, glossines), a product for shaving (soaps, mousses, lotions, etc.), a product intended to be applied to the lips, a sun product, a sunless tanning product, a product for whitening the skin, an anti-wrinkle product. The edible products that are suitable for consumption by a human being or an animal are advantageously purees of vegetables or fruits such as mashed mango, pear puree, coconut puree, onion cream, leeks, carrots, or other preparations that can mix several fruits or vegetables. Alternatively, it is oils such as a food oil, such as olive oil, soybean oil, grape seed oil, sunflower oil, or any other oil extracted from the plants. The core 12 is advantageously in the form of a first pure liquid product, a solution of the or each first product in a liquid solvent, a dispersion such as an emulsion or a suspension of the or each first product. in a liquid. The viscosity of the liquid core 12 is less than 2000 mPa.s. The liquid core 12 is based on a predominantly aqueous phase or on the contrary a predominantly oily phase.

The gelled envelope 14 of the capsules 10 according to the invention comprises a gel containing water and at least one polyelectrolyte reactive with multivalent ions. According to an advantageous embodiment of the invention, the envelope 14 further contains a surfactant resulting from its manufacturing process, as will be described in detail below. For the purposes of the present invention, the term "polyelectrolyte reactive with polyvalent ions" means a polyelectrolyte capable of passing from a liquid state in an aqueous solution to a gelled state under the effect of contact with a gelling solution containing multivalent ions such as alkaline earth metal ions selected for example from calcium ions, barium ions, magnesium ions. In the liquid state, the individual polyelectrolyte chains are substantially free to flow relative to one another. An aqueous solution of 2% by weight of polyelectrolyte then exhibits a purely viscous behavior at the shear gradients characteristic of the forming process. The viscosity of this zero shear solution is between 50 mPa.s and 10,000 mPa.s, advantageously between 3000 mPa.s and 7000 mPa.s.

The individual polyelectrolyte chains in the liquid state advantageously have a molar mass greater than 65000 g / mol. In the gelled state, the individual polyelectrolyte chains form, with the multivalent ions, a coherent three-dimensional network that retains the liquid core and prevents its flow. The individual chains are held together and can not flow freely relative to each other. In this state, the viscosity of the formed gel is infinite. In addition, the gel has a threshold of stress to the flow. This stress threshold is greater than 0.05 Pa. The gel also has a modulus of elasticity that is non-zero and greater than 35 kPa. The three-dimensional gel of polyelectrolyte contained in the envelope 14 traps water and the surfactant. The mass content of the polyelectrolyte in the envelope 12 is for example between 0.5% and 5%.

The polyelectrolyte is preferably a biocompatible polymer that is harmless to the human body. It is for example produced biologically. Advantageously, it is chosen from polysaccharides, synthetic polyelectrolytes based on acrylates (sodium, lithium, potassium or ammonium polyacrylate, or polyacrylamide), synthetic polyelectrolytes based on sulfonates (poly (styrene sulfonate)). sodium, for example). More particularly, the polyelectrolyte is selected from an alkaline earth alginate, such as sodium alginate or potassium alginate, gellan or pectin. Alginates are produced from brown algae called "laminar", referred to as "sea weed". Such alginates advantageously have a content of α-L-guluronate greater than about 50%, preferably greater than 55%, or even greater than 60%. The surfactant is preferably an anionic surfactant, a nonionic surfactant, a cationic surfactant or a mixture thereof. The molecular weight of the surfactant is between 150 g / mol and 10,000 g / mol, advantageously between 250 g / mol and 1500 g / mol. In the case where the surfactant is an anionic surfactant, it is for example chosen from an alkyl sulphate, an alkyl sulphonate, an alkyl aryl sulphonate, an alkaline alkyl phosphate, a dialkyl sulphosuccinate, an alkaline earth salt of saturated or unsaturated fatty acids. These surfactants advantageously have at least one hydrophobic hydrocarbon chain having a number of carbons greater than 5 or even 10 and at least one hydrophilic anionic group, such as a sulphate, a sulphonate or a carboxylate linked to one end of the hydrophobic chain. In the case where the surfactant is a cationic surfactant, it is for example chosen from an alkylpyridium or alkylammonium halide salt such as n-ethyldodecylammonium chloride or bromide, cetylammonium chloride or bromide (CTAB) . These surfactants advantageously have at least one hydrophobic hydrocarbon chain having a number of carbons greater than 5 or even 10 and at least one hydrophilic cationic group, such as a quaternary ammonium cation.

In the case where the surfactant is a nonionic surfactant, it is for example chosen from polyoxyethylenated and / or polyoxypropylenated derivatives of fatty alcohols, fatty acids, or alkylphenols, arylphenols, or from alkyls glucosides, polysorbates, cocamides . The mass content of surfactant in the shell is greater than 0.001% and is advantageously greater than 0.1%.

In this example, the envelope 14 consists exclusively of polyelectrolyte, surfactant, and water. The sum of the mass contents of polyelectrolyte, surfactant, and water is then equal to 100%. The method of manufacturing the capsules 10 according to the invention is implemented in a manufacturing device 30 according to the invention, shown in FIG. 1. The manufacturing device 30 comprises a double envelope 32 for coextruding a series of drops intended for forming capsules 10, means 34 for feeding into the double envelope 32 of a first solution 36 intended to form the liquid core 12, and means 38 for feeding into the double envelope 32 of a second solution 40 intended to The device 30 further comprises a gelling bath 41A disposed under the jacket 32 and a bath 41 B for rinsing and storage. In known manner, the double jacket 32 comprises an inner tube 42 defining a central chamber 44 for circulating the first solution 36, and an outer tube 46 defining, with the inner tube 42, an annular chamber 48 for circulating the second solution 40 The inner tube 42 and the outer tube 46 extend coaxially along a vertical axis A-A '. They open downwards through a formation opening 50 of each drop.

The inner tube 42 advantageously has a diameter greater than 0.5 mm and substantially between 0.6 mm and 2 mm. The outer tube 46 has a diameter greater than the inner tube 42 of at least 0.2 mm, preferably at least 0.4 mm. The maximum diameter of the outer tube 46 is less than 5 mm.

Each tube 42, 46 has a cross-section converging downwards in the vicinity of the opening 50. The means 34 for feeding the first solution 36 comprise a first pump 52 for dispensing the first solution 36, connected hydraulically downstream to the central chamber 44 by a first conduit 54 for conveying.

The first pump 52 is advantageously a syringe pump capable of controlling a given injection rate Q1 of the first solution 36 in the central chamber of between 1 ml / h and 120 ml / h, preferably in the range of between 50 ml / h. h and 80 ml / h. The supply means 38 of the second solution 40 comprise a second pump 56 for dispensing the second solution 40, connected downstream to the annular chamber 48 via a second conveyance pipe 58.

The second pump 56 is advantageously a syringe pump capable of controlling the injection flow rate Q2 of the second solution 40 in the annular chamber 48 that this flow rate Q2 is between 0.005 times and 0.2 times the flow rate Q1 controlled by the first pump 52 .

The first solution 36 is formed by the or each first pure liquid product, a solution of the or each first product in a liquid solvent, a dispersion such as an emulsion or a suspension of the or each first product in a liquid as described. upper. The second solution contains the liquid polyelectrolyte suitable for gelling intended to form the liquid envelope 12, water and, in addition, according to the invention, at least one surfactant for producing the capsules 10. The polyelectrolyte has been described in detail above and will not be rewritten. It is totally dissolved in the water forming the second solution. The mass content of the polyelectrolyte in the second solution is greater than the mass content of the polyelectrolyte in the envelope 14. In the second solution, this mass content is greater than 0.1% and is for example between 0.1% and 5%. % by weight of the second solution. The or each surfactant has been described above. The mass content of surfactant is between 0.01% and 1% by weight of the total mass of the second solution. If the composition of the liquid core 12 is predominantly aqueous, the concentration of surfactant in the second solution is advantageously between 0.01% and 0.5% by weight. If the composition of the liquid core 12 is predominantly oily, the concentration of surfactant is between 0.1% and 0.5% by weight.

Advantageously, the surfactant mass concentration is about 0.03% for an aqueous liquid heart and is about 0.15% for an oily liquid body. The second solution is prepared by dissolving the surfactant in the amount of water needed to form the second solution. Then, the polyelectrolyte is added to the surfactant solution in water and is mixed with a magnetic bar for a given time, for example at least 24 hours, at room temperature. The bath 41A contains a gelling solution 70. This solution 70 is for example an aqueous solution of a type XnI reagent, where X is advantageously a halide ion such as a chloride ion, a bromide ion, an iodide ion or an ion fluoride, and I is advantageously a multivalent cation of an alkaline earth such as calcium, magnesium, or barium, and n and m are greater than or equal to 1.

The multivalent ions present in the gelling solution 70 thus formed are able to react with the polyelectrolyte to form bonds between the different polyelectrolyte chains present in the second solution, when the second solution comes into contact with the gelling solution 70.

In the case where the polyelectrolyte is a sodium alginate (NaAlg), and where the reagent and calcium chloride, the reaction that occurs is as follows: 2NaAlg + Ca C12 - * Ca (Alg) 2 y + 2NaCl Concentration as a reactant in the gelling solution is advantageously between 5% and 20% by weight.

The bath 41A is arranged below and away from the opening 50, so that the drops formed by coextrusion in the jacket 32 fall spontaneously by gravity through a volume of air in the gelling solution 70 where they are immersed. The rinsing bath 41 B comprises a rinsing and storage solution consisting essentially of water.

According to the invention and as will be described below, the height Hc which vertically separates the lowest point of the opening 50 and the surface of the gelling solution 70 located opposite is chosen so that the ratio of energy The kinetics of the coextruded drop through the device 32 as it falls from the opening 50 in the gelling bath 70 to the square of the mean radius of the drop is greater than 1 J / m2.

A first method of forming capsules 10 according to the invention will now be described. This method comprises a step of forming a drop 78 comprising a core 80 of the first solution and an outer film 82 of the second solution by coextrusion in the device 32. The method then comprises a step of dipping the drop 78 in the bath of gelling 41 A, followed by a rinsing / storage step in the rinsing bath 41 B. Initially, the first solution 36 and the second solution 40 are prepared as described above with the weight loads of polyelectrolyte and surfactant described above .

They are then introduced respectively into the pumps 52, 56 which are connected to the jacket 32 respectively by the first pipe 54 and by the second pipe 58. Then, the first pump 52 is activated to convey a continuous stream of first solution 36 through the central chamber 44 with a calibrated flow Q1 advantageously between 10 ml per hour and 80 ml per hour, as seen above.

The second pump 56 is activated to simultaneously convey a continuous flow of second solution 40 through the annular space 48 at a flow rate Q2 controlled for example between 0.005 times and 0.2 times the flow rate Q1 of the first solution 36. The relative adjustment and independent of the flow rates Q1 and Q2 makes it possible to control the thickness of the envelope 14 independently of the outer diameter of the capsule 10. By significantly reducing the flow rate Q2, it is also possible to obtain capsules with a gelled envelope 14 of very thin, especially less than 0.5% of the diameter of the capsule 10, thanks to the presence of the surfactant in the second solution 40.

At the aperture 50, a substantially spherical drop 78 is progressively formed with a core 80 consisting exclusively of the first solution and a thin film 82 of second solution completely surrounding the outer surface of the core 80. The core 80 is composed exclusively of first Solution 36. In the film 82, the polyelectrolyte is maintained in its liquid state as in the second solution. When the weight of the drop 78 is greater than its capillary retention force on the tubes of the jacket 32, the drop 78 is detached from the jacket 32 by gravity and falls into the gelling bath 41 A.

The film 82 is then in contact with the gelling solution. In contact with the multivalent ions from the gelling reagent, the individual polyelectrolyte chains present in the film 82 connect to each other to form a crosslinked network which entraps water and at least partially of the surfactant contained in the second solution.

A gelled envelope 14, adapted to retain the liquid core 12 of the first liquid solution is thus formed. This envelope 14 has a clean mechanical strength, that is to say, it is able to completely surround the liquid core 12 and retain the liquid in the heart 12 to prevent it from diffusing through the envelope 14, especially when the capsule 10 is disposed in a gas such as ambient air.

Then, another drop 78 is then formed at the lower end 50 of the double jacket 32 and the process steps are then identical to those described above. Once the capsules have been formed, they are transferred to the rinse solution 72 for storage. Capsules thus formed thus store various compounds such as biologically active products, proteins, cosmetics, or edible products for consumption by a human or an animal. Surprisingly, the presence of surfactant in the second solution 40 significantly promotes the formation of the capsules 10, in particular by preventing the film 82 from undergoing a detrimental phase separation when it is soaked in the gel solution 70. As indicated above, the the ratio of the kinetic energy Ec of the drop 78 when it enters the gel solution 70 to the square of the radius of the drop 78 is greater than 1 J / m2. This ratio is advantageously greater than 1.5 J / m 2, still advantageously greater than 2.0 J / m 2, especially greater than 3 J / m 2. This kinetic energy is necessary to break the air film separating the drop 78 from the bath during the impact of the drop 78 on the surface of the bath 70. This ratio is also advantageously less than 15 J / m 2, advantageously less than 10 J / m2, especially less than 6 J / m2.

This ratio is, for example, between 1 J / m 2 and 15 J / m 2, advantageously between 2 J / m 2 and 10 J / m 2, advantageously still between 2 J / m 2 and 6 J / m 2. When such ratios are chosen, the authors have found that, surprisingly, the gelation of the film 82 occurs homogeneously over the entire outer surface of the drop 78 in the thickness of the film 78, sufficiently fast for the calcium ions to diffuse isotropically into the film. This is observed, especially for low film thicknesses 82, for example in the thickness ranges of envelopes 14 specified above, and especially for film thicknesses 82 less than 100 microns, or even less than 70 microns, or even less at 50 microns. The thickness of the film 82 is for example between 15 microns and 75 microns, advantageously between 20 microns and 60 microns. This therefore produces capsules having a uniform, thin and resistant gelled envelope 14 with a very high success rate. The kinetic energy Ec is calculated by the following formula: M.g. Hc (1) E = 'R2 where M is the total mass of the drop 78, expressed in kg, g is the acceleration of gravity, expressed in ms-2, Hc is the height of fall, taken between the point le lower of the opening 50 and the surface of the gelling solution 70, expressed in m, R is calculated as the average radius of the drop 78, taken from the center, expressed in m.

It is thus possible to work with flow ratios Q1 / Q2, where Q1 is the flow rate of the first solution and Q2 is the flow rate of the second solution, between 5 and 200, advantageously between 5 and 20, advantageously between 6 and and 20 or between 10 and 20.

According to an advantageous variant, the He / h ratio of the drop height HL to the thickness h of the film 82 is less than 10,000, and is in particular less than 7,000. Advantageously, this ratio is less than 5,000, advantageously less than 1500. This ratio is advantageously greater than 500 and is in particular between 500 and 1500.

The drop height can thus be between 20 mm and 100 mm, advantageously between 30 mm and 70 mm. When the concentration of surfactant in the second solution 40 is greater than the critical micelle concentration, this ratio may be greater than 3000. In the case where this concentration is below the critical micelle concentration, this ratio is generally less than 3000, advantageously less than 1000. These results are advantageously observed when the liquid core 80 is formed from an aqueous solution. It will be noted that the presence of at least one surfactant, especially beyond the critical micelle concentration in the second solution 40, makes it possible to significantly reduce the thickness of the gelled envelope 14 for a given drop height or to increase the drop height, for a given gelled casing thickness 14. For example, for a surfactant concentration in the second solution 40 equal to or greater than the critical micelle concentration, the thickness of the gelled envelope may be less than 50 microns, or even less than 30 microns for a fall height of less than 200. mm. If the surfactant is Sodium Dodecyl Sulfate, its concentration in the second solution 40 is advantageously between 1 mM and 15 mM, with a critical micelle concentration substantially equal to 8 mM. It is furthermore advantageous to add a small amount of one of the surfactants mentioned above, for example CTAB, in the bath 70, for example at a concentration of less than 10 -3 mol / l, advantageously less than 10 -4 mol / I, advantageously less than 2 x 10-5 mol / l Moreover, when the core 12 is oily, the thickness of the envelope 14 can be reduced to a value of less than 50 microns, or even 10 microns, or even 5 microns, especially for a viscosity of the first solution 36 less than 100 mPa.s, advantageously less than 50 mPa.s. This viscosity is for example between 0.5 mPa.s and 100 mPa.s, especially between 0.6 mPa.s and 50 mPa.s. When using the capsules 10, the envelope 12 is broken by shearing, or by mechanical crushing, or by chelation of the multivalent ions, using a suitable salt such as EDTA, in the case where uses calcium ions to form the gel of the envelope. This rupture makes it possible to recover the first product present in the core 12. In a variant of use, the recovered capsules are immersed in a liquid to swell, then burst by controlling the osmotic pressure through the gelled envelope. The opening of the casing 14 then releases the liquid core 12. This applies in particular to capsules containing a syrup. To swell the capsule 10, a polymer such as a polyethylene glycol with a molecular weight greater than 5,000 g / mol is added to the core.

Alternatively, the osmotic pressure is controlled to retract the capsules 10 and decrease their diameter. It is then possible to dry or lyophilize the capsules 10. Alternatively, magnetic particles may be added in the first solution 36 and / or in the second solution 40, to modify the handling of the eggs. As a further variant, flakes are added in the first solution 36 and / or in the second solution 40 to generate an optical effect on the capsules 10. An alternative embodiment of the capsule manufacturing device 10 is illustrated in FIG. Unlike the device shown in FIG. 1, this device comprises, around the double jacket 32, an external gas injection casing 90 extending annularly around and away from the outer tube 46. The outer casing 90 opens axially around the opening 50. It is connected to a pressurized gas source to create, around the drop 78 in formation, a flow of gas directed downwards.

The flow rate of this gas flow can be adjusted to control the size of the drops 78 formed at the outlet of the jacket 32. The capsule manufacturing method 10 using the device 30 according to FIG. 3 differs just from the method used with the device 30 of Figure 1 in that the size of the drops 78 can be adjusted by adjusting the flow of gas.

Figure 4 illustrates a third capsule forming device 30 which comprises a plurality of double envelopes 32 arranged in parallel next to one another. The supply means 34 of the first solution 36 comprise, at the end of the first conduit 54 a common distributor 96 of first solution, into which each central chamber 44 opens double envelopes 32 connected in parallel.

The supply means 38 of the second solution 40 comprise a common distributor 98 of second solution 40 opening in each annular chamber 48 double envelopes 32 connected in parallel. Thus, this device 30 allows to form in parallel a number of drops equal to the number of double envelopes 32 mounted in parallel which increases the overall productivity of the device.

Alternatively, in the case where the core 12 is an emulsion, this emulsion can be manufactured by coextrusion in an additional tube placed in the inner tube 42 during the manufacture of the capsule 10. It is thus possible to form hearts 12 containing, for example, vinaigrette.

Examples of first solution and second solution compositions having been used to successfully form capsules according to the invention are described in Table 1 below, in which all percentages are percentages by weight. The solvent of the second solution is water. PEG is a polyethylene glycol whose molecular weight is also given in the table.

SDS is sodium dodecyl sulfate (anionic surfactant), CTAB is Cetyl Trimethylammonium Bromide (cationic surfactant), Tween 20 is polyoxyethylene sorbitan monolaurate (nonionic surfactant) and Tween 80 is polyoxyethylene mono-oleate sorbitan (nonionic surfactant). Composition first solution for the composition Second solution for the core of the casing WITH SDS Water milliQ 2% sodium alginate, 0.03% SDS Water + 0.5% PEG20000 g / mol 1.5% sodium alginate, 0.03% SDS Water + 0.5% PEG20000 g / mol 2% sodium alginate, 0.03% SDS Water + 0.5% PEG20000 g / mol 3% sodium alginate, 0.03% SDS Water + 1% PEG 20000 g / mol 2% sodium alginate, 0.03% SDS Water + 2 % PEG 20000 g / mol 2% sodium alginate, 0.03% SDS Water + 4% PEG 20000 g / mol 2% sodium alginate, 0.03% SDS Water + 0.5% PEG 35000 g / mol 2% sodium alginate, 0.03% SDS Water + 15% PEG 35000 g / mol 2% sodium alginate, 0.03% SDS Water + 20% PEG 35000 g / mol 2% sodium alginate, 0.03% SDS Mango puree 2% sodium alginate, 0.03% SDS 80 % mango puree + 20% 15% sugar syrup Pear puree 2% sodium alginate, 0.03% SDS 80% pear puree + 20% 15% sugar syrup Cocoa powder solution 2% sodium alginate, 0.03% SDS 10% cocoa powder + 90% syrup 30% sugar Olive oil 2% algin sodium ate, 0.15% SDS Olive oil + 2% mixed basil 2% sodium alginate, 0.15% SDS Soybean oil 2% sodium alginate, 0.15% SDS Grape seed oil 2% sodium alginate, 0.15% SDS Grape Seed Oil 0.5% Sodium Alginate, 0.15% SDS Hexadecane 2% Sodium Alginate, 0.15% SDS WITH CTAB Mill Water 2% Sodium Alginate, 0.02% CTAB Mill Water 2% Sodium Alginate, 0.03% CTAB WITH TWEEN Water MilliQ 2% sodium alginate, 50mM Tween 20 Water MilliQ 2% sodium alginate, 53mM Tween 80 An example of the procedure for the preparation of the capsules is as follows: Formation of the second solution: Composition for capsules before a heart using an anionic surfactant: 20 g of sodium alginate, 1000 g of water and 0.3 g of SDS are prepared. SDS and sodium alginate are then added to the solution. The solution is mixed for at least 24 hours to ensure that the alginate is completely dissolved and the solution is homogeneous. Composition for capsules with an oily heart using anionic surfactant: 20 g of sodium alginate, 1000 g of water and 1.5 g of SDS are prepared. SDS is dissolved in water and sodium alginate is then added. The solution is mixed for at least 24 hours to ensure that the alginate is completely dissolved and the solution is homogeneous.

Composition for capsules with an aqueous core using a cationic surfactant: 20 g of sodium alginate, 1000 g of water and 0.36 g of CTAB are prepared. The CTAB is dissolved in water and the sodium alginate is then added. The solution is mixed for at least 24 hours to ensure that the alginate is completely dissolved and the solution is homogeneous. Composition for capsules having an oily core using a cationic surfactant: 20 g of sodium alginate, 1000 g of water and 1.8 g of CTAB are prepared. The CTAB is dissolved in water and the sodium alginate is then added. The solution is mixed for at least 24 hours to ensure that the alginate is completely dissolved and the solution is homogeneous. Preparation of the first solution The solution of the core can be either aqueous or oily. It can contain one or more phases.

Saline gelling solution bath This bath can be prepared based on 200 g of calcium chloride dissolved in 1000 g of water. Alternatively, it can be prepared based on 50 g of calcium lactate pentahydrate dissolved in 1000 g of water. In a variant, the capsules 10 prepared by the process according to the invention do not have a detectable amount of surfactant of the second solution.

Examples of implementation of the method according to the invention will now be described. Examples include forming a first solution 36 having to form an aqueous or oily core 12 as described above and a second solution 40 comprising an alginate in aqueous solution at 2% by weight, and comprising an anionic surfactant formed by sodium dodecyl sulphate. The sodium dodecyl sulfate concentration in the second solution is variable. The critical micellar concentration of sodium dodecyl sulfate is 8 mM. The relative flow rates of the first solution and the second solution are adjusted to form drops 78 of mass M greater than 20 mg. The size of the dependent drops formed depends on the external size of the injector as well as the surface tension and therefore the surfactant concentration if it is below the critical micelle concentration. The experimental parameters are summarized in the following table: TABLE 2 Example 1 2 3 4 Against Example 1 Example 2 Nature of Aqueous Aqueous Aqueous Aqueous Aqueous Core [SDS] in 1 mM 4 mM 8 mM 8 mM O mM 8 mM solution 40 Mass 43 34 25 25 47 25 medium drop (mg) Height 45 45 45 70 10 10 drop Ho (mm) Drop radius 2.2 2.0 1.8 1.8 2.2 1.8 R (mm) Thickness h 70 70 70 17 70 15 (micron) Report 3.9 3.7 3.4 5.3 0.9 Ec / R2 Report 642 642 642 4117 642 667 H01h State of Satisfactory Satisfactory Satisfied Satisfactory No Few Capsules As can be seen, the presence of a ratio of kinetic energy Ec squared radius greater than 1 J / m2 provides capsules of very satisfactory properties, with low thicknesses. The capsule forming method as described above provides uniformly sized capsules. This makes it possible to use them as a dosage unit in the cosmetic, dermatological or pharmacy field. Thus, it is possible to provide a cosmetic treatment in which a number of capsules to be applied to the skin or to be ingested. The number of capsules to use, the frequency of application of these capsules or ingestion of these capsules and the duration of treatment may vary depending on the characteristics of the person undergoing treatment. In this same technical field, the capsules 10 can be used with a heart 12 which comprises a moisturizing cream for the skin, various hair treatments, gloss for the lips.

Thus, it is possible to burst a capsule containing gloss between the lips of a user, the gloss being distributed by rubbing the lips against each other. In this type of application, flakes can be added in the core 12 or in the envelope 14 of the capsule to obtain optical effects such as gloss, reflections, irradiance.

The capsules 10 according to the invention can also be used in the food industry to obtain flavor beads. Thus, formed capsules containing a food product can be used, for example, to form synthetic caviar. In the food industry, the capsules can also be used as bombs of sweetness being added to beverages. Capsules which contain, for example, a polymer or other product making it possible to inflate or deflate them by osmotic pressure make it possible to drop a product contained in the heart 12 in the beverage or in a liquid dish. Thus, by swelling or deflation of the capsule, it is possible to detonate it to release the product contained in the heart 12.

The capsules 10 according to the invention can also be used in the biotechnological field as a reservoir for the growth of cells, to carry out biological tests for detecting disease. It is thus possible to use capsules 10 according to the invention to facilitate screening under different environmental conditions.

In addition, the addition of magnetic particles in the envelope 14 immobilizes cells in the heart 12 of the capsule 12 to form a bioreactor.

Claims (12)

1. A method of manufacturing a series of capsules (10), each capsule (10) comprising a liquid core (12) containing at least a first product and a gelled envelope (14) completely encapsulating the core (12), the method comprising the following steps: - separate conveying in a jacket (32) of a first liquid solution (36) containing the first product and a second liquid solution (40) containing a liquid polyelectrolyte suitable for gelation; - forming at the outlet of the jacket (32) of a series of drops (78), each drop (78) comprising a central core (80) formed of first solution (36) and a peripheral film (82) formed of second solution (40) and completely covering the central core (80); - Drop each drop (78) in a gaseous volume at the exit of the jacket (32); - immersing each drop (78) in a gelling solution (70) containing a reactant capable of reacting with the electrolyte product of the film (82) to change it from a liquid state to a gelled state and form the gelled envelope (14), the central core (80) forming the liquid core (12); recovering the capsules (10) formed; characterized in that the ratio of the kinetic energy of the drop (78) to the square of its radius when it comes into contact with the gelling solution (70) is greater than 1 J / m2. 2. A process according to claim 1, characterized in that the ratio of the kinetic energy of the drop (78) to the square of its radius, when it comes into contact with the gelling solution is greater than 1.5 J / m 2, advantageously greater than 2 J / m 2, still advantageously greater than 3 J / m 2. 3.- Method according to one of claims 1 or 2, characterized in that the ratio of the kinetic energy of the drop (78), the square of its radius, when it comes into contact with the gelling solution is lower at 15 J / m 2, advantageously less than 6 J / m 2 4. A process according to any one of the preceding claims, characterized in that the second solution (40) contains at least one surfactant before contact with the first solution (36). 5. A process according to claim 4, characterized in that the total weight percentage of surfactant in the second solution (40) is greater than 0.01% by weight and is advantageously between 0.03% and 0.5% by weight. mass. 6. A process according to any one of the preceding claims, characterized in that the ratio of the drop height separating the outlet of the jacket (32) and the upper surface of the gelling solution (70) to the thickness of the film (82) is less than 10,000, and is advantageously less than 7,000 and in particular between 500 and 1,500. 7. A process according to claim 6, taken in combination with one of claims 4 or 5, characterized in that in that the concentration of surfactant in the second solution (40) is greater than the critical micelle concentration, the ratio from the drop height to the thickness of the film (82) being greater than 3000. 8. A process according to claim 6, taken in combination with one of claims 4 or 5, characterized in that the concentration of surfactant in the second solution is less than the critical micelle concentration, the ratio of the drop height to the thickness of the film (82) being less than 3000, advantageously less than 1500. 9. A process according to any one of the preceding claims, characterized in that the film (82) has a thickness less than 100 microns, preferably less than 60 microns, still advantageously between 15 microns and 75 microns, especially between 20 microns and 60 microns. 10. A process according to any one of the preceding claims, characterized in that the first liquid solution (36) contains an oil, the second solution (40) being an at least partially aqueous solution, the film (78) having a thickness less than 50 microns, advantageously less than 10 microns. 11. A process according to claim 10, characterized in that the viscosity of the first solution 36 is less than 100 mPa.s, advantageously less than 50 mPa.s, in particular between 0.5 mPa.s and 100 mPa.s, especially between 0.6 mPa.s and 50 mPa.s. 12. Process according to any one of the preceding claims, characterized in that the gelling solution (70) contains at least one surfactant.