EP3624932A1

EP3624932A1 - Method for preparing biodegradable capsules and capsules obtained

Info

Publication number: EP3624932A1
Application number: EP18722633.7A
Authority: EP
Inventors: Damien DEMOULIN; Todor KHRISTOV; Jamie WALTERS; Alicia SADAOUI
Original assignee: Calyxia SAS
Current assignee: Calyxia SAS
Priority date: 2017-05-15
Filing date: 2018-05-15
Publication date: 2020-03-25
Also published as: JP2023095871A; KR20240019382A; CN110785224A; JP2020520794A; US20200164332A1; US11845053B2; WO2018210857A1; FR3066116A1; KR20200044724A; FR3066116B1

Abstract

The present invention relates to a method for preparing solid microcapsules, comprising the following steps: a) adding, with stirring, a composition C1 to a polymeric composition C2 comprising at least one aliphatic or aromatic ester or polyester, additionally bearing at least one function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate functions and mixtures thereof, whereby an emulsion (E1) is obtained comprising droplets of composition C1 dispersed in the composition C2; b) adding, with stirring, the emulsion (E1) to a composition C3, whereby a double emulsion (E2) is obtained comprising droplets dispersed in the composition C3; c) applying shear to the emulsion (E2), whereby a double emulsion (E3) is obtained comprising droplets of controlled size dispersed in the composition C3; and d) polymerizing the composition C2, whereby solid microcapsules dispersed in the composition C3 are obtained.

Description

PROCESS FOR PREPARING BIODEGRADABLE CAPSULES AND CAPSULES OBTAINED

The present invention relates to a process for preparing biodegradable capsules. It also relates to the capsules as obtained and compositions containing them.

Many compounds, called active ingredients, are added to the formulated products in order to confer interesting application properties or increase their performance.

However, in many cases, these substances react negatively with other components of the formulated product, which has adverse effects on stability as well as a decrease in performance.

The encapsulation of the active ingredients represents a very interesting way to overcome the limitation of performance or stability of the formulated products that contain them while benefiting from the effect of the active ingredient at the time of use of this formulated product.

However, the fate of microcapsules after releasing their contents remains a major concern since they become a waste that can accumulate in the environment. For this reason, the development of microcapsules having the ability to be biodegradable is of paramount importance.

Very many capsules have been developed to isolate active ingredients in formulated products. These capsules result from manufacturing processes such as spray-drying, interfacial polymerization, interfacial precipitation or solvent evaporation among many others.

Some of these microcapsules have an envelope formed of an uncrosslinked material such as a hydrogel or a thermoplastic polymer. If this hydrogel or thermoplastic polymer is formed of materials known to be biodegradable, then the envelope of the microcapsules formed with this material will be deemed to be biodegradable. The main biodegradable materials used for this type of capsules belong to the family of polyesters, in particular polyhydroxyalkanoates (for example polylactic acid or polyglycolic acid), or polysaccharides (for example alginate, starch or dextran). However, the diffusion through the casing of this type of capsule is relatively fast, thus limiting their performance. Indeed, the encapsulated compound can quickly leak outside the capsule or, conversely, the chemical species degrading the encapsulated compound can quickly enter the capsule.

Others of these microcapsules have an envelope resulting from the reaction of monomers which react chemically with each other and form a crosslinked material through which diffusion is greatly slowed down, thus improving the performance of the capsules. This category includes urea and formaldehyde capsules, which are widely used, but which unfortunately are not biodegradable.

There is therefore a technical need for forming capsules formed of a crosslinked envelope that are both biodegradable and with very good retention and protection properties of the active ingredients they contain.

The present invention therefore aims to provide a method for encapsulating active ingredients avoiding the aforementioned problems of leakage of said active ingredients, and the capsules obtained by this method.

The present invention also aims to provide capsules containing at least one active ingredient and having excellent biodegradability properties.

Thus, the present invention relates to a method for preparing solid microcapsules comprising the following steps:

a) the addition, with stirring, of a composition C1, comprising at least one active agent, in a polymeric composition C2, the compositions C1 and C2 being immiscible with one another,

the viscosity of the composition C2 being between 500 mPa.s and 100 000 mPa.s at 25 ° C., and preferably being greater than the viscosity of the composition C1,

the composition C2 comprising:

at least one monomer or polymer selected from the group consisting of aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides and carbonates or polycarbonates, further bearing at least a function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, carboxylate, and mixtures thereof, at least one crosslinking agent, and

optionally at least one photoinitiator or a crosslinking catalyst, whereby an emulsion (E1) comprising drops of composition C1 dispersed in composition C2 is obtained;

b) the addition, with stirring, of the emulsion (E1) in a composition C3, the compositions C2 and C3 not being miscible with each other,

the viscosity of the composition C3 being between 500 mPa.s and 100 000 mPa.s at 25 ° C, and preferably being greater than the viscosity of the emulsion (E1),

whereby a double emulsion (E2) comprising drops dispersed in the composition C3 is obtained;

c) the application of shear to the emulsion (E2),

whereby a double emulsion (E3) is obtained comprising controlled size drops dispersed in the composition C3; and

d) the polymerization of the composition C2, whereby solid microcapsules dispersed in the composition C3 are obtained.

In the present application, the terms "microcapsules" and "capsules" are used indifferently.

The method of the invention therefore makes it possible to prepare solid microcapsules comprising a core and a solid envelope completely encapsulating at its periphery the heart, in which the core is a composition C1 comprising at least one active ingredient.

Preferably, the solid microcapsules obtained by the process of the invention are formed of a core containing at least one active ingredient (composition C1) and a solid envelope (obtained from composition C2) completely encapsulating at its periphery said core.

In the search for high performance microcapsules in terms of retention and protection, the inventors have surprisingly and unexpectedly found that it is possible from non-biodegradable materials to obtain, under certain conditions, biodegradable microcapsules.

Thus, the microcapsules obtained by the method of the invention, in view of the choice of specific monomers and polymers in the composition C2, have the ability to be biodegradable.

Biodegradability is defined here as the ability to be degraded in a natural environment, as defined in OECD standards: OECD 301 (Easy Biodegradability), ie OECD 301A (Dissolved Organic Carbon Disappearance Test (COD)), OECD 301B (C0 ₂ Release Test), OECD 301C (Modified MITI Test (I)), OECD 301D (Closed Bottle Test), OECD 301 E (Modified OECD Screening Test), OECD 301 F (Manometric Respirometry Test), or OECD 304A (Intrinsic Biodegradability in Soil), OECD 306 (Biodegradability in seawater) and OECD 310 (Immediate biodegradability - release of C0 ₂ in tightly closed flasks).

The method of the invention also has the advantage of not requiring the use of surfactants or emulsifiers which could accelerate and make uncontrolled the release of active ingredients to the outside of the capsule; and / or react with the components of the formulated product in which the capsules are intended to be incorporated.

The method of the invention consists in producing a double emulsion composed of droplets containing at least one active agent, wrapped in a crosslinkable liquid phase. These double drops are then rendered monodisperse in size before being converted by crosslinking or polymerization in rigid capsules. The preparation involves 4 steps described below in detail.

Step a)

Step a) of the process according to the invention consists in preparing a first emulsion (E1).

The first emulsion consists of a dispersion of droplets of the composition C1 (containing at least one active ingredient) in a C1-immiscible polymeric composition C2, created by dropwise addition of C1 to C2 with stirring.

During step a), a composition C1 is added to a crosslinkable polymeric composition C2, this step being carried out with stirring, which means that the composition C2 is stirred, typically mechanically, while the composition C1 is added, and this in order to emulsify the mixture of compositions C1 and C2.

The addition of the composition C1 in the composition C2 is typically carried out dropwise. During step a), the composition C1 is at a temperature of between 0 ° C. and 100 ° C., preferably between 10 ° C. and 80 ° C., and preferably between 15 ° C. and 60 ° C. During step a), the composition C2 is at a temperature of between 0 ° C. and 100 ° C., preferably between 10 ° C. and 80 ° C., and preferably between 15 ° C. and 60 ° C.

Under the conditions of addition of step a), the compositions C1 and C2 are not miscible with each other, which means that the amount (by weight) of the composition C1 capable of being solubilized in the composition C2 is less than or equal to 5%, preferably less than 1%, and preferably less than 0.5%, relative to the total weight of composition C2, and that the amount (by weight) of the composition C2 capable of to be solubilized in composition C1 is less than or equal to 5%, preferably less than 1%, and preferably less than 0.5%, relative to the total weight of composition C1.

Thus, when the composition C1 comes into contact with the composition C2 with stirring, the latter is dispersed in the form of drops, called simple drops.

The immiscibility between compositions C1 and C2 also makes it possible to avoid the migration of the active ingredient from composition C1 to composition C2.

Composition C2 is stirred to form an emulsion comprising drops of composition C1 dispersed in composition C2. This emulsion is also called "simple emulsion" or emulsion C1-in-C2.

To implement step a), any type of stirrer usually used to form emulsions, such as, for example, a mechanical stirrer, a static emulsifier, an ultrasonic homogenizer, a membrane homogenizer or a homogenizer may be used. at high pressure, a colloid mill, a high shear disperser or a high speed homogenizer.

Composition C1

The composition C1 comprises at least one active ingredient A. This composition C1 serves as a carrier for the active ingredient A in the process of the invention, within the drops formed during the process of the invention and the solid capsules obtained. According to a first variant of the process of the invention, the composition C1 is monophasic, that is to say it is the pure active A or a solution comprising the active A in solubilized form .

According to one embodiment, the active agent is solubilized in composition C1.

According to this variant, the composition C1 typically consists of a solution of the active ingredient A in an aqueous solution, or an organic solvent, or a mixture of organic solvents, the active ingredient A being present in a mass content of between 1% and 99%. %, relative to the total mass of the composition C1. The active agent A may be present in a mass content ranging from 5% to 95%, from 10% to 90%, from 20% to 80%, from 30% to 70%, or from 40% to 60%, relative to to the total mass of the composition C1.

According to one embodiment, the composition C1 consists of the asset A.

According to another embodiment of the invention, the composition C1 is a biphasic composition, which means that the active agent is dispersed, either in liquid form or in solid form, in the composition C1 and is not totally solubilized in said composition C1.

According to one embodiment, the active agent is dispersed in the form of solid particles in the composition C1.

According to this embodiment, the composition C1 can consist of a dispersion of solid particles of the active agent in an organic solvent or in a mixture of organic solvents.

According to this embodiment, the composition C1 may consist of a dispersion of solid particles of the active agent in an aqueous phase, which comprises water and optionally hydrophilic organic solvents.

The asset used is for example:

a crosslinking agent, a hardener, an organic or metal catalyst (such as an organometallic or inorganometallic complex of platinum, palladium, titanium, molybdenum, copper, zinc) used to polymerize polymer and elastomer formulations; rubber, paint, adhesive, seal, mortar, varnish or coating;

a dye or a pigment for formulations of elastomers, paint, coating, adhesive, seal, mortar, or paper;

- a fragrance (as defined by the International Fragrance Association (IFRA) molecule list and available on the website www.ifraorg.org) detergents such as detergents, home care products, cosmetics and personal care products, textiles, paints, coatings;

aroma, vitamin, amino acid, protein, lipid, probiotic, antioxidant, pH corrector, preservative for food compounds and animal feed;

a softener, a conditioner for detergents, detergents, cosmetics and personal care products. As such, the usable assets are for example listed in US Patents 6,335,315 and US 5,877,145;

an anti-discoloration agent (such as an ammonium derivative), an antifoaming agent (such as an alcohol ethoxylate, an alkylbenzene sulfonate, a polyethylene ethoxylate, an alkylethoxysulfate or alkylsulfate) for detergents and laundry and home care products; a brightening agent, also called a color activator (such as a stilbene derivative, a coumarin derivative, a pyrazoline derivative, a benzoxazole derivative or a naphthalimide derivative) for detergents, detergents, cosmetics and personal care products;

a biologically active compound such as an enzyme, a vitamin, a protein, a plant extract, an emollient, a disinfectant, an antibacterial agent, an anti-UV agent, a drug for cosmetic and personal care products , to textiles. Among these biologically active compounds include: vitamins A, B, C, D and E, para-aminobenzoic acid, alpha hydroxy acids (such as glycolic acid, lactic acid, malic acid, tartaric acid or citric acid), camphor, ceramides, polyphenols (such as flavonoids, phenolic acid, ellagic acid, tocopherol, ubiquinol), hydroquinone, hyaluronic acid, isopropyl isostearate, isopropyl palmitate, oxybenzone, panthenol, proline, retinol, retinyl palmitate, salicylic acid, sorbic acid, sorbitol, triclosan, tyrosine;

a disinfecting agent, an antibacterial agent, an anti-UV agent, for paints and coatings;

a fertilizer, herbicide, insecticide, pesticide, fungicide, repellent or disinfectant for agrochemicals; a flame retardant, also known as a flame retardant, (such as a brominated polyol such as tetrabromobisphenol A, a halogenated or non-halogenated organophosphorus compound, a chlorinated compound, an aluminum trihydrate, an antimony oxide, a zinc borate red phosphorus, melamine, or magnesium dihydroxide) for use in plastic materials, coatings, paints and textiles;

- a photonic crystal or photochromophore for paints, coatings and polymeric materials forming curved and flexible screens;

a product known to those skilled in the art as phase change materials (PCMs) capable of absorbing or returning heat when they undergo a phase change, intended for the storage of 'energy. Examples of PCM and their applications are described in Farid et al., Energy Conversion and Management, 2004, 45 (9-10), 1597-1615. As examples of PCM, mention may be made of molten aluminum phosphate salts, ammonium carbonate, ammonium chloride, cesium carbonate, cesium sulfate, calcium citrate, calcium chloride, calcium chloride and the like. calcium hydroxide, calcium oxide, calcium phosphate, calcium saccharate, calcium sulphate, cerium phosphate, iron phosphate, lithium carbonate, lithium sulphate, magnesium chloride , magnesium sulphate, manganese chloride, manganese nitrate, manganese sulphate, potassium acetate, potassium carbonate, potassium chloride, potassium phosphate, rubidium carbonate, sulphate of rubidium, disodium tetraborate, sodium acetate, sodium bicarbonate, sodium bisulfate, sodium citrate, sodium chloride, sodium hydroxide, sodium nitrate, sodium percarbonate, sodium persulfate, sodium phosphate, propiona sodium sulphite, sodium selenite, sodium silicate, sodium sulphate, sodium tellurate, sodium thiosulfate, strontium hydrophosphate, zinc acetate, zinc chloride, sodium thiosulfate , paraffinic hydrocarbon waxes, polyethylene glycols.

Composition C2

The composition C2 is intended to form the future solid envelope of The volume fraction of C1 in C2 can vary from 0.1 to 0.6 in order to control the thickness of the envelope of the capsules obtained at the end of the process.

According to one embodiment, the ratio between the volume of composition C1 and the volume of composition C2 varies between 1: 10 and 10: 1. Preferably, this ratio is between 1: 3 and 5: 1, preferably between 1: 3 and 3: 1.

Preferably, the viscosity of the composition C2 at 25 ° C is between 1000 mPa.s and 50,000 mPa.s, preferably between 2000 mPa.s and 25,000 mPa.s, and for example between 3000 mPa. s and 15,000 mPa.s.

Preferably, the viscosity of the composition C2 is greater than the viscosity of the composition C1.

The viscosity is measured using a Haake Rheostress ™ 600 rheometer equipped with a cone of 60 mm diameter and 2 degrees angle, and a temperature control cell set at 25 ° C. The value of the viscosity is read for a shear rate of 10 s ^-1 .

According to this embodiment, the destabilization kinetics of the drops of the emulsion (E1) is significantly slow, which allows the envelope of the microcapsules to be polymerized during step d) before the emulsion is destabilized. . The polymerization, once completed, then provides a thermodynamic stabilization. Thus, the relatively high viscosity of the composition C2 ensures the stability of the emulsion (E1) obtained at the end of step a).

Preferably, the interfacial tension between compositions C1 and C2 is low. Typically, these interfacial tensions vary between 0 mN / m and 50 mN / m, preferably between 0 mN / m and 20 mN / m.

The low interfacial tension between the compositions C1 and C2 also advantageously makes it possible to ensure the stability of the emulsion (E1) obtained at the end of step a).

The composition C2 contains at least one monomer or polymer as defined below, at least one crosslinking agent, and optionally at least one photoinitiator or crosslinking catalyst, thus making it crosslinkable.

According to one embodiment, the composition C2 comprises from 50% to 99% by weight of monomer or polymer as defined below, or a mixture of monomers or polymers as defined below, relative to the total weight of the composition C2.

According to one embodiment, the composition C2 comprises from 1% to 20% by weight of crosslinking agent or of a mixture of crosslinking agents, relative to the total weight of the composition C2.

According to one embodiment, the composition C2 comprises from 0.1% to 5% by weight of photoinitiator or a mixture of photoinitiators, relative to the total weight of the composition C2.

According to one embodiment, the composition C2 comprises from 0.001% to 20% by weight of crosslinking agent relative to the weight of said composition C2.

According to the invention, the term "monomer" or "polymer" denotes any base unit suitable for the formation of a solid material by polymerization, either alone or in combination with other monomers or polymers. The term "polymer" also includes oligomers.

These monomers are chosen from monomers comprising at least one reactive functional group chosen from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate functions.

The monomers or polymers used in the composition C2 are chosen from aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides, and carbonates or polycarbonates, said polymers bearing, in addition to at least one reactive functional group selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, and carboxylate functions.

Preferably, the monomers or polymers used in the composition C2 are chosen from aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides, and carbonates or polycarbonates, said polymers additionally bearing at least one reactive functional group selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, and carboxylate functions, said monomers or polymers listed above do not carrying no other reactive function different from acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, and carboxylate functions.

According to one embodiment, the monomers or polymers used in the composition C2 do not carry a urethane function.

Preferably, the monomers or polymers used in the composition C2 are chosen from aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides, and carbonates or polycarbonates, said polymers additionally bearing at least one reactive functional group selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, and carboxylate functions, said non-functional monomers or polymers urethane.

Preferably, the monomers or polymers used in the composition C2 are chosen from aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides, and carbonates or polycarbonates, said polymers further bearing a single reactive function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, and carboxylate functions. Thus, according to this embodiment, the monomers or polymers of the composition C2 do not carry a function other than those listed above, and therefore in particular do not carry a urethane function.

Examples of such monomers or polymers include, but are not limited to, the following compounds and mixtures thereof:

the family of aliphatic or aromatic esters and polyesters comprising especially polyglycolides (PGA), polylactides (PLA), poly (lactide-co-clycolide) (PLGA), poly (ortho esters) such as polycaprolactone (PCL) polydiaxanone, poly (ethylene succinate), poly (butylene succinate) (PBS), poly (ethylene adipate), poly (butylene adipate), poly (ethylene sebacate), poly (butylene sebacate), poly (valero lactone) (PVL), poly (decalactone), polyhydroxyvalerate, poly (beta-malic acid), poly-3-hydroxybutyrate (PHB), poly-3-hydroxy-butyrate-co-3- hydroxyvalerate (P-3HB-3HV), poly-3-hydroxybutyrate-co-4-hydroxybutyrate (P-3HB-4HB), poly-3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxybutyrate (P- 3HB-3HV-4HB), poly (3-hydroxy valerate), poly (3-hydroxypropionate), poly (3- hydroxycaproate), poly (3-hydroxyoctanoate), poly (3-hydroxydecanoate), poly (3-hydroxyundecanoate), poly (3-hydroxydodecanoate), poly (3-hydroxybutyrate-co-3-hydroxyvalerate), poly (3-hydroxybutyrate-co-3-hydroxydecanoate), poly (3-hydroxybutyrate-co-3-hydroxypropionate), poly (3-hydroxybutyrate-co-3-hydroxyoctanoate), poly (3-hydroxyheptanoate), poly (3-hydroxyhexanoate), poly (2-hydroxybutyrate), poly (3-hydroxybutyrate-co-4-hydroxybutyrate), poly (3-hydroxybutyrate-co-3-hydroxyhexanoate), poly (3-hydroxybutyrate) -co-3-hydroxyhexanoate), poly (4-hydroxybutyrate), poly (4-hydroxybutyrate-co-2-hydroxybutyrate), poly (4-hydroxypropionate), poly (4-hydroxyvalerate), poly (5-hydroxybutyrate), hydroxybutyrate), poly (5-hydroxyvalerate), poly (6-hydroxyhexanoate), poly (alkylene alkanoate), poly (alkylene dicarboxylate), poly (butylene adipate), poly (butylene adipate-co-terephthalate) ), poly (butylene carbonate), poly (butylen pyelate), poly (butylene succinate), poly (butylene succinate-co-adipate), poly (butylene succinate-co-carbonate), poly (butylene sebacate), poly (butylene sebacate-co-terephthalate) poly (butylene succinate-co-terephthalate), poly (butylene succinate-co-lactate), poly (cyclohexene carbonate), polydiaxanone, poly (ethylene azelate), poly (ethylene carbonate), poly ( ethylene decamethylate), poly (ethylene furanoate), poly (ethylene oxalate), poly (ethylene succinate), poly (ethylene succinate-co-adipate), poly (ethylene sebacate), poly (ethylene succinate-co) terephthalate), poly (ethylene suterate), poly (hexamethylene sebacate), poly (glycolide-co-caprolactone), poly (lactide-co-epsilon-caprolactone), polymandelide, poly (B-malic acid) ), poly (b-propiolactone), poly (propylene succinate), poly (tetramethylene adipate-co-terephthalate), poly (tetramethylene carbonate), poly (trimethylene carbonate), poly (tetramethylene succinate) -co- (tetramethylene carbonate), poly (trimethylene adipate), poly (methylene adipate-costephthalate), poly (tetramethylene adipate), poly (tetramethyl glycolide) ), poly (butylene succinate), poly (valerolactone), additionally bearing at least one reactive functional group selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone phosphate and carboxylate;

the family of anhydrides or polyanhydrides such as those derived from polysebacic acid, polyadipic acid, polyterephthalic acid, poly (bis (p-carboxyphenoxy) alkane acid, or more broadly polyanhydrides described as example in Advanced Drug Delivery Reviews 54 (2002) 889-910, further carrying at least one reactive function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate functions;

the family of saccharides and polysaccharides, especially comprising carrageenans, dextrans and cyclodextrins, for example hyaluronic acid, agarose, chitosan, chitin, alginate, starch, cellulose and its derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or methyl hydroxypropyl cellulose, additionally carrying at least one reactive function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate functions;

the family of ethers and polyethers, especially comprising polyethylene glycols, also bearing at least one reactive functional group chosen from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate; and

the family of amides and polyamides, especially comprising the poly (ester amide) or polyphthalamide, also bearing at least one reactive functional group selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate.

Preferably, the monomers or polymers used in the composition C2 are chosen from aliphatic or aromatic esters or polyesters also bearing at least one reactive functional group chosen from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether and epoxy functional groups. siloxane, amine, lactone, phosphate, and carboxylate, said monomers or polymers not carrying urethane function.

Preferably, the monomers or polymers used in the composition C2 are not aliphatic or aromatic esters or polyesters bearing at least one urethane function.

By "crosslinking agent" is meant a compound carrying at least two reactive functional groups capable of crosslinking a monomer or a polymer, or a mixture of monomers or polymers, during its polymerization.

The crosslinking agent may be chosen from molecules carrying at least two identical or different functions chosen from the group consisting of the functions acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate and carboxylate.

As crosslinking agent, there may be mentioned in particular:

diacrylates, such as 1,6-hexanediol diacrylate, 1,6-hexanediol dimethacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, 1,9-nonanediol dimethacrylate, 1,4-butanediol dimethacrylate, 1, 3-butanediol dimethacrylate, 1,10-decanediol dimethacrylate, bis (2-methacryloxyethyl) N, N'-1,9-nonylene biscarbamate, 1,4-butanediol diacrylate, 1,5-pentanediol dimethacrylate, allyl methacrylate, N, N'-methylenebisacrylamide, 2,2-bis [4- (2-hydroxy-3-methacryloxypropoxy) phenyl] propane, tetraethylene glycol diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, triethylene glycol dimethacrylate, polyethylene glycol diglycidyl ether, N, N-diallylacrylamide or glycidyl methacrylate;

multifunctional acrylates such as dipentaerythritol pentaacrylate, 1,1,1-trimethylolpropane triacrylate, 1,1,1-trimethylolpropane trimethacrylate, ethylenediamine tetramethacrylate, pentaerythritol triacrylate or pentaerythritol tetraacrylate; and

acrylates which also have another reactive function, such as propargyl methacrylate, N-acryloxysuccinimide, N- (2-hydroxypropyl) methacrylamide, N- (t-BOC-aminopropyl) methacrylamide, monoacryloxyethyl phosphate, acrylic anhydride 2- (tert-butylamino) ethyl methacrylate, Ν, Ν-diallylacrylamide or glycidyl methacrylate.

According to one embodiment, the composition C2 comprises from 0.001% to 20% by weight of crosslinking agent (s) relative to the total weight of said composition.

By "photoinitiator" is meant a compound capable of fragmenting under the effect of light radiation.

The photoinitiators which can be used according to the present invention are known in the art and are described, for example in "Photoinitiators in the crosslinking of coatings", G. Li Bassi, Double Liaison - Chemistry of Paints, No. 361, November 1985, p. 34-41; "Industrial applications of photoinduced polymerization", Henri Strub, L'Actualité Chimique, February 2000, p.5-13; and "Photopolymers: theoretical considerations and reaction of taking", Marc, JM Abadie, Double Liaison - Chemistry of the Paintings, n ° 435-436, 1992, p.28-34. These photoinitiators include:

α-hydroxyketones, such as 2-hydroxy-2-methyl-1-phenyl-1-propanone, sold for example under the names DAROCUR® 1 173 and 4265, IRGACURE® 184, 2959, and 500 by the company BASF, and ADDITOL® CPK by CYTEC;

α-aminoketones, especially 2-benzyl-2-dimethylamino-1- (4-morpholinophenyl) -butanone-1, sold, for example, under the names Irgacure® 907 and 369 by the company BASF;

aromatic ketones marketed for example under the name ESACURE® TZT by LAMBERTI; or the thioxanthones marketed for example under the name ESACURE® ITX by LAMBERTI, and quinones. These aromatic ketones most often require the presence of a hydrogen donor compound such as tertiary amines and especially alkanolamines. It is possible to mention the tertiary amine ESACURE® EDB sold by the company LAMBERTI.

the α-dicarbonyl derivatives, the most common representative of which is benzyldimethylketal, marketed under the name IRGACURE® 651 by BASF. Other commercial products are marketed by LAMBERTI under the name ESACURE® KB1, and

acylphosphine oxides, such as, for example, bis-acylphosphine oxides (BAPO) sold for example under the names IRGACURE® 819, 1700, and 1800, DAROCUR® 4265, LUCIRIN® TPO, and LUCIRIN® TPO-L by the company BASF.

Among the photoinitiators, mention may also be made of aromatic ketones such as benzophenone, phenylglyoxylates, such as the methyl ester of phenylglyoxylic acid, oxime esters, such as [1- (4-phenylsulfanylbenzoyl) heptylideneamino] benzoate, sulphonium salts, iodonium salts and oxime sulphonates.

According to one embodiment, the composition C2 may further comprise an additional monomer or polymer capable of improving the properties of the microcapsule casing and / or of giving new properties to the microcapsule casing.

Among these additional monomers or polymers, there may be mentioned monomers or polymers bearing a group sensitive to pH, temperature, UV or IR. These additional monomers or polymers can induce the rupture of the solid microcapsules and subsequently the release of their contents, after stimulation via, for example, pH, temperature, UV or IR.

These additional monomers or polymers may be chosen from monomers or polymers bearing at least one of the following groups:

a group that is sensitive to pH, such as primary, secondary or tertiary amines, carboxylic acids, phosphate, sulphate, nitrate or carbonate groups;

a UV-sensitive or UV-cleavable group (or photochromic group) such as azobenzene, spiropyran, 2-diazo-1, 2-naphthoquinone, o-nitrobenzyl, thiol, or 6-nitro-veratroyloxycarbonyl, for example poly (ethylene) oxide) -block-poly (2-nitrobenzylmethacrylate), and other block copolymers, as described in particular in Liu et al., Polymer Chemistry 2013, 4, 3431-3443;

an IR-sensitive or IR-cleavable group such as o-nitrobenzyl or 2-diazo-1,2-naphthoquinone, for example the polymers described in Liu et al., Polymer Chemistry 2013, 4, 3431-3443;

a group sensitive to hydrolysis, such as poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), polycaprolactone, polyhydroxybutyrate, chitosan, dextran, agarose, cellulose and derivatives thereof; and

a temperature-sensitive group such as poly (N-isopropylacrylamide). Step b)

Step b) of the process according to the invention consists in preparing a second emulsion (E2).

The second emulsion consists of a dispersion of droplets of the first emulsion in a composition C3 immiscible with C2, created by dropwise addition of the emulsion (E1) in C3 with stirring.

During step b), the emulsion (E1) is at a temperature between 15 ° C and 60 ° C. During step b), the composition C3 is at a temperature between 15 ° C and 60 ° C.

Under the addition conditions of step b), the compositions C2 and C3 are not miscible with each other, which means that the amount (by weight) of the C2 composition capable of being solubilized in the composition C3 is less than or equal to 5%, preferably less than 1%, and preferably less than 0.5%, relative to the total weight of composition C3, and that the amount (in weight) of the composition C3 capable of being solubilized in the composition C2 is less than or equal to 5%, preferably less than 1%, and preferably less than 0.5%, relative to the total weight of composition C2.

Thus, when the emulsion (E1) comes into contact with the composition C3 with stirring, the latter is dispersed in the form of drops, called double drops, the dispersion of these emulsion drops (E1) in the continuous phase C3 being called emulsion (E2).

Typically, a double drop formed during step b) corresponds to a single drop of composition C1 as described above, surrounded by a composition envelope C2 which completely encapsulates said single drop.

The double drop formed during step b) may also comprise at least two simple drops of composition C1, said simple drops being surrounded by a composition envelope C2 which completely encapsulates said single drops.

Thus, said double drops comprise a heart consisting of one or more single drops of composition C1, and a layer of composition C2 surrounding said heart.

The resulting emulsion (E2) is generally a double polydisperse emulsion (C1-in-C2-in-C3 emulsion or C1 / C2 / C3 emulsion), which means that the double drops do not have a distinct size distribution in the emulsion (E2).

The immiscibility between the compositions C2 and C3 makes it possible to avoid mixing between the layer of composition C2 and the composition C3 and thus ensures the stability of the emulsion (E2).

The immiscibility between the compositions C2 and C3 also makes it possible to prevent the water-soluble substance of the composition C1 from migrating from the heart of the drops to the composition C3.

To implement step b), it is possible to use any type of stirrer usually used to form emulsions, such as, for example, a mechanical stirrer with a pale color, a static emulsifier, an ultrasonic homogenizer, a membrane homogenizer, a high pressure homogenizer, a colloid mill, a high shear disperser or a high speed homogenizer.

Composition C3

According to one embodiment, the viscosity of the composition C3 at 25 ° C is higher than the viscosity of the emulsion (E1) at 25 ° C.

According to the invention, the viscosity of the composition C3 at 25 ° C is between 500 mPa.s and 100,000 mPa.s.

Preferably, the viscosity of the composition C3 at 25 ° C. is between 3,000 mPa.s and 100,000 mPa.s, preferably between 5,000 mPa.s and 80,000 mPa.s, for example between 7,000 mPa.s. and 70,000 mPa.s.

According to this embodiment, given the very high viscosity of the continuous phase formed by the composition C3, the destabilization rate of the double drops of the emulsion (E2) is significantly slow compared to the duration of the process of the invention. , which then provides a kinetic stabilization of the emulsions (E2) and then (E3) until the polymerization of the capsule shell is completed. The capsules once polymerized are thermodynamically stable.

Thus, the very high viscosity of the composition C3 ensures the stability of the emulsion (E2) obtained at the end of step b).

A low surface tension between C3 and the first emulsion and a high viscosity of the system advantageously ensure the kinetic stability of the double emulsion (E2), preventing it from being out of phase for the duration of the manufacturing process.

Preferably, the interfacial tension between compositions C2 and C3 is low. The low interfacial tension between the compositions C2 and C3 also advantageously makes it possible to ensure the stability of the emulsion (E2) obtained at the end of step b).

The volume fraction of the first emulsion in C3 can be varied from 0.05 to 0.5 in order, on the one hand, to improve the production yield and, on the other hand, to vary the mean diameter of the capsules. At the end of this step, the size distribution of the second emulsion is relatively wide. According to one embodiment, the ratio between the emulsion volume (E1) and the composition volume C3 varies between 1: 10 and 10: 1. Preferably, this ratio is between 1: 9 and 3: 1, preferably between 1: 9 and 1: 1.

According to one embodiment, the composition C3 further comprises at least one connected polymer, preferably with a molecular weight greater than 5000 g. mol ^"1 , and / or at least one polymer of molecular weight greater than 5,000 g. mol ^{" 1} , and / or solid particles such as silicates.

According to one embodiment, the composition C3 comprises at least one connected polymer, preferably with a molecular weight greater than 5,000 g. mol ^"1, preferably between 10 000 g. ^{mol" 1} and 500 000 g. mol ^"1 , for example between 50,000 g mol ^-1 and 300,000 g. mol ^"1 .

By "branched polymer" (or branched polymer) is meant a polymer having at least one branch point between its two end groups, a branch point (also called branch point) being a point of a chain on which is fixed a side chain also called branch or hanging chain.

Among the branched polymers, there may be mentioned for example graft polymers, comb, or star polymers or dendrimers.

According to one embodiment, the composition C3 comprises at least one polymer with a molecular weight greater than 5,000 g. mol ^"1, preferably between 10 000 g. ^{mol" 1} and 500 000 g. mol ^"1 , for example between 50,000 g mol ^-1 and 300,000 g. mol ^"1 .

As a polymer that can be used in the composition C3, mention may be made of the following compounds, used alone or mixed together:

cellulose derivatives, such as cellulose ethers: methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or methylhydroxypropyl cellulose;

polyacrylates (also called carbomers), such as polyacrylic acid (PAA), polymethacrylic acid (PMAA), poly (hydroxyethyl methacrylate) (pHEMA), poly (N-2-hydroxypropyl methacrylate) (pHPMA) ; polyacrylamides such as poly (N-isopropylacrylamide) (PNIPAM);

polyvinylpyrrolidone (PVP) and its derivatives;

polyvinyl alcohol (PVA) and its derivatives;

poly (ethylene glycol), poly (propylene glycol) and their derivatives, such as poly (ethylene glycol) acrylate / methacrylate, poly (ethylene glycol) diacrylate / dimethacrylate, polypropylene carbonate;

polysaccharides such as carrageenans, carob gum or tara gums, dextran, xanthan gums, chitosan, agarose, hyaluronic acids, gellan gum, guar gum, gum arabic, gum tragacanth, diuretic gum, oat gum, karaya gum, ghatti gum, curdian gum, pectin, konjac gum, starch;

protein derivatives such as gelatin, collagen, fibrin, polylysine, albumin, casein;

silicone derivatives such as polydimethylsiloxane (also called dimethicone), alkyl silicones, aryl silicones, alkyl aryl silicones, polyethylene glycol dimethicones, polypropylene glycol dimethicone;

waxes, such as diester waxes (alkanediol diesters, hydroxyl acid diesters), triester waxes (triacylglycerols, triesters of alkane-1,2-diol, ω-hydroxy acid and fatty acid, esters of hydroxymalonic acid, fatty acid and alcohol, triesters of hydroxyl acids, fatty acid and fatty alcohol, triesters of fatty acid, hydroxyl acid and diol) and polyester waxes (polyesters of acids bold). The fatty acid esters which may be used as waxes in the context of the invention are, for example, cetyl palmitate, cetyl octanoate, cetyl laurate, cetyl lactate, cetyl isononanoate and stearate. cetyl, stearyl stearate, myristyl stearate, cetyl myristate, isocetyl stearate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl monostearate, or cetyl glyceryl palmitate;

fatty acids which can be used as waxes such as cerotic acid, palmitic acid, stearic acid, dihydroxystearic acid, behenic acid, lignoceric acid, arachidic acid, myristic acid, lauric acid, tridecyclic acid, pentadecyclic acid, margaric acid, nonadecyclic acid, henicosylic acid, tricosylic acid, pentacosylic acid, heptacosylic acid, montanic acid or nonacosylic acid; fatty acid salts, in particular fatty acid aluminum salts, such as aluminum stearate, hydroxyl aluminum bis (2-ethylhexanoate);

- isomeric jojoba oil;

- hydrogenated sunflower oil;

hydrogenated coconut oil;

hydrogenated lanolin oil;

castor oil and its derivatives, especially modified hydrogenated castor oil or compounds obtained by esterification of castor oil with fatty alcohols;

polyurethanes and their derivatives;

styrenic polymers such as styrene butadiene; and

polyolefins such as polyisobutene.

According to one embodiment, the composition C3 comprises solid particles such as clays, silicas and silicates.

As solid particles that can be used in the composition C3, mention may be made of clays and silicates belonging in particular to the category of phyllosilicates (also known as layered silicas). By way of example of a silicate that may be used in the context of the invention, mention may be made of Bentonite, Hectorite, Attapulgite, Sepiolite, Montmorillonite, Saponite, Sauconite, Nontronite, Kaolinite, Talc. , Sepiolite, Chalk. The fumed synthetic silicas can also be used. The clays, silicates and silicas mentioned above can advantageously be modified by organic molecules such as polyethers, ethoxylated amides, quaternary ammonium salts, long-chain diamines, long-chain esters, polyethylene glycols, polypropylene glycols.

These particles can be used alone or mixed together.

According to one embodiment, the composition C3 comprises at least one polymer with a molecular weight greater than 5,000 g. mol- ¹ and solid particles Any mixture of the compounds mentioned above may be used.

Step c)

Step c) of the process according to the invention consists in refining the size of the drops of the second emulsion (E2). This step may consist in applying a homogeneous controlled shear to the emulsion (E2), said shear rate applied being between 10 s ^-1 and 100,000 s ^-1 .

According to one embodiment, the double polydisperse drops obtained in step b) are subjected to a size refinement consisting of shearing them capable of breaking them into new double drops of homogeneous and controlled diameters. Preferably, this fragmentation step is carried out using a Couette type high-shear cell according to a process described in patent application EP 15 306 428.2.

According to one embodiment, in step c), the second emulsion (E2), obtained at the end of step b), consisting of polydisperse double droplets dispersed in a continuous phase, is subjected to a shear in a mixer, which applies a homogeneous controlled shear.

Thus, according to this embodiment, step c) consists of applying homogenous controlled shear to the emulsion (E2), said shear rate applied being between 1000 s ^-1 and 100,000 s ^-1 .

According to this embodiment, in a mixer, the shear rate is said to be controlled and homogeneous, regardless of the duration, when it passes to an identical maximum value for all parts of the emulsion, at a given instant that may vary. from one point of the emulsion to another. The exact configuration of the mixer is not essential according to the invention, as long as the entire emulsion has been subjected to the same maximum shear out of this device. Mixers adapted to perform step c) are described in particular in US 5,938,581.

The second emulsion can undergo homogeneous controlled shear as it flows through a cell formed by:

- two concentric rotary cylinders (also called Couette type mixer);

- two parallel rotating discs; or

- two parallel oscillating plates. According to this embodiment, the shear rate applied to the second emulsion is between 1,000 s ^-1 and 100,000 s ^-1 , preferably between 1,000 s ^-1 and 50,000 s ^-1 , and preferably between 2,000 s ^"1 and 20,000 s ^{" 1} .

According to this embodiment, during step c), the second emulsion is introduced into the mixer and is then subjected to shear resulting in the formation of the third emulsion. The third emulsion (E3) is chemically identical to the second emulsion (E2) but consists of monodisperse double drops while the emulsion (E2) consists of double polydisperse drops. The third emulsion (E3) typically consists of a dispersion of double drops comprising a core consisting of one or more drops of composition C1 and a layer of composition C2 encapsulating said core, said double drops being dispersed in composition C3.

The difference between the second emulsion and the third emulsion is the size variance of the double drops: the drops of the second emulsion are polydisperse in size while the drops of the third emulsion are monodisperse, thanks to the fragmentation mechanism described above.

Preferably, according to this embodiment, the second emulsion is introduced continuously into the mixer, which means that the quantity of double emulsion (E2) introduced at the mixer inlet is the same as the quantity of third emulsion ( E3) at the mixer outlet.

Since the size of the drops of the emulsion (E3) corresponds essentially to the size of the drops of the solid microcapsules after polymerization, it is possible to adjust the size of the microcapsules and the thickness of the envelope by adjusting the speed of the shear during step c), with a strong correlation between droplet size decrease and shear rate increase. This makes it possible to adjust the resulting dimensions of the microcapsules by varying the shear rate applied during step c).

According to a preferred embodiment, the mixer implemented during step c) is a Couette type mixer, comprising two concentric cylinders, an outer cylinder of inner radius R ₀ and an inner cylinder of outer radius R ,, the cylinder external being fixed and the inner cylinder being rotated with an angular velocity ω.

A Couette type mixer adapted for the process of the invention may be provided by T.S.R. France.

According to one embodiment, the angular velocity ω of the internal rotating cylinder of the Couette type mixer is greater than or equal to 30 rad.s ^-1 . For example, the angular velocity ω of the inner rotating cylinder of the Couette type mixer is about 70 rad.s ^-1 .

The dimensions of the outer fixed cylinder of the Couette type mixer may be chosen to modulate the space (d = R ₀ - R) between the rotating inner cylinder and the fixed outer cylinder.

According to one embodiment, the space (d = R ₀ - R) between the two concentric cylinders of the Couette type mixer is between 50 μηι and 1,000 μηι, preferably between 100 μηι and 500 μηι, for example between 200 μηι and 400 μηι.

For example, the distance d between the two concentric cylinders is equal to 100 μηι.

According to this embodiment, during step c), the second emulsion is introduced at the inlet of the mixer, typically via a pump, and is directed towards the space between the two concentric cylinders, the outer cylinder being fixed and the inner cylinder being rotated at an angular velocity ω.

When the double emulsion is in the space between the two cylinders, the shear rate applied to said emulsion is given by the following equation:

^{Y =} (R ₀ - R _i )

in which :

- ω is the angular velocity of the rotating internal cylinder,

R ₀ is the internal radius of the fixed outer cylinder, and

- R, is the outer radius of the inner cylinder in rotation.

According to another embodiment, when the viscosity of the composition C3 is greater than 2000 mPa.s at 25 ° C., the step c) consists in applying to the emulsion (E2) a shear rate of less than 1000 s ^"1 .

According to this embodiment, the fragmentation step c) can be carried out using any type of mixer usually used to form emulsions with a shear rate of less than 1000 s ^-1 , in which case the viscosity of the composition C3 is greater than 2,000 mPa.s, namely under conditions such as those described in the patent application FR 16 61787.

The geometric characteristics of the double drops formed at the end of this stage will dictate those of the future capsules. According to this embodiment, in step c), the emulsion (E2), consisting of polydisperse drops dispersed in a continuous phase, is subjected to shear, for example in a mixer, at a low shear rate, to be less than 1,000 s ^"1 .

According to this embodiment, the shear rate applied in step c) is, for example, between 10 s ^-1 and 1000 s ^-1 .

Preferably, the shear rate applied in step c) is strictly less than 1000 s ^-1 .

According to this embodiment, the emulsion drops (E2) can be efficiently fragmented into fine and monodisperse emulsion drops (E3) only if a high shear stress is applied thereto.

The shear stress σ applied to a drop of emulsion (E2) is defined as the tangential force per unit area of drop resulting from the macroscopic shear applied to the emulsion during its stirring during step d).

The shear stress σ (expressed in Pa), the viscosity of the composition C3 η (expressed in Pa s) and the shear rate γ (expressed in s ^-1 ) applied to the emulsion (E2) during its stirring at course of step d) are related by the following equation:

σ = ηγ

Thus, according to this embodiment, the high viscosity of the composition C3 makes it possible to apply a very high shear stress to the emulsion drops (E2) in the mixer, even if the shear rate is low and the shear inhomogeneous.

To implement step c) according to this embodiment, it is possible to use any type of stirrer usually used to form emulsions, such as, for example, a mechanical stirrer, a static emulsifier, an ultrasonic homogenizer, a homogenizer membrane, a high pressure homogenizer, a colloid mill, a high shear disperser or a high speed homogenizer.

According to a preferred embodiment, a simple emulsifier such as a mechanical stirrer with pale or a static emulsifier is used to implement step c). Indeed, this is possible because this embodiment requires neither controlled shear nor shear greater than 1,000 s ^-1 . Step d)

Step d) of the process of the invention consists of the crosslinking and therefore the formation of the shell of the solid microcapsules according to the invention.

This step makes it possible both to achieve the expected retention performance of the capsules and to ensure their thermodynamic stability, permanently preventing any destabilizing mechanism such as coalescence or ripening.

According to one embodiment, when the composition C2 comprises a photoinitiator, step d) is a photopolymerization step of exposing the emulsion (E3) to a light source capable of initiating the photopolymerization of the composition C2, in particular to a UV light source emitting preferably in the wavelength range of between 100 nm and 400 nm, and in particular for a duration of less than 15 minutes.

According to this embodiment, step d) consists in subjecting the emulsion (E3) to photopolymerization, which will allow the photopolymerization of the composition C2. This step will make it possible to obtain microcapsules encapsulating the water-soluble substance as defined above.

According to one embodiment, step d) consists in exposing the emulsion (E3) to a light source capable of initiating the photopolymerization of the composition C2.

Preferably, the light source is a source of UV light.

According to one embodiment, the UV light source emits in the wavelength range of between 100 nm and 400 nm.

According to one embodiment, the emulsion (E3) is exposed to a light source for less than 15 minutes, and preferably for 5 to 10 minutes.

During step d), the envelope of the aforementioned double drops, consisting of photocrosslinkable composition C2, is cross-linked and thus converted into a viscoelastic polymeric envelope, encapsulating and protecting the water-soluble substance from being released in the absence of mechanical triggering. .

According to another embodiment, when the composition C2 does not comprise a photoinitiator, step d) is a polymerization step, without exposure to a light source, the duration of this polymerization step d) being preferably between 8 hours and 100 hours and / or this step d) is carried out at a temperature between 20 ° C and 80 ° C.

According to this embodiment, the polymerization is initiated for example by exposure to heat (thermal initiation), or simply by contacting the monomers, polymers and crosslinking agents with each other, or with a catalyst. The polymerization time is then generally greater than several hours.

Preferably, step d) of polymerization of the composition C2 is carried out for a period of between 8 hours and 100 hours, at a temperature between 20 ° C and 80 ° C.

The composition obtained at the end of step d), comprising solid microcapsules dispersed in the composition C3, is ready for use and can be used without any additional step of post-treatment of the capsules is required.

The thickness of the envelope of the microcapsules thus obtained is typically between 0.1 μm and 20 μm, preferably between 0.2 μm and 8 μm, and preferably between 0.2 μm and 5 μm.

According to one embodiment, the solid microcapsules obtained at the end of step d) are devoid of surfactant.

The method of the invention has the advantage of not requiring a surfactant, in any of the steps described. The process of the invention thus makes it possible to reduce the presence of additives which could modify the properties of the final product obtained after release of the active ingredient.

The present invention also relates to a series (or set) of solid microcapsules, obtainable by the method as defined above, in which each microcapsule comprises:

a core comprising a composition C1 as defined above, and

a solid envelope completely encapsulating at its periphery the core, in which the mean diameter of said microcapsules is between 1 μηι and 30 μηι, the thickness of the rigid envelope is between 0.1 μηι and 20 μηι, preferably between 0.2 μηι and 8 μηι, and preferably between 0.2 μηι and 5 μηι, and the standard deviation of the microcapsule diameter distribution is less than 50%, in particular less than 25%, or less than 1 μηι. Preferably, the solid microcapsules obtained by the process of the invention are formed of a core containing at least one active ingredient (composition C1) and a solid envelope (obtained from composition C2) completely encapsulating at its periphery said core.

As indicated above, the process of the invention makes it possible to obtain monodisperse particles. Also, the series of solid microcapsules mentioned above is formed of a population of monodisperse particles in size. Thus, the standard deviation of the diameter distribution of the microcapsules is less than 50%, in particular less than 25%, or less than 1 μm.

The size distribution of the solid microcapsules can be measured by light scattering technique using a Mastersizer 3000 (Malvern Instruments) equipped with a Hydro SV cell.

According to one embodiment, the aforementioned solid microcapsules comprise a solid envelope entirely composed of crosslinked polymer (obtained from composition C2).

As indicated above, the process of the invention makes it possible to obtain solid microcapsules. The present invention therefore also relates to solid microcapsules comprising a core and a solid envelope completely encapsulating at its periphery the heart, in which the core is a composition C1 as defined above, and wherein said solid envelope is made of crosslinked polymer. ,

the diameter of said microcapsule being between 1 μηι and 30 μηι and the thickness of the rigid envelope being between 0.1 μηι and 20 μηι, preferably between 0.2 μηι and 8 μηι, and preferably between 0.2 μηι and 5 μηι.

The present invention also relates to a composition comprising a series of solid microcapsules as defined above.

The expressions "between ... and ...", "from ... to ..." and "from ... to ..." must be understood as inclusive, unless otherwise specified.

The following examples illustrate the present invention without limiting its scope. EXAMPLES

Example 1 Manufacture of Biodegradable Solid Capsules According to the Invention

A mechanical stirrer (Ika Eurostar 20) equipped with a deflocculating stirring propeller is used to carry out all the stirring steps.

Step a): Preparation of the first emulsion (El)

The composition C1 is stirred at 1000 rpm until complete homogenization and then left to stand for one hour at room temperature. The composition C1 is then added dropwise to the composition C 2 with stirring at 2000 rpm with a ratio of 3: 7. The first emulsion (E1) is thus obtained.

Step b): Preparation of the second emulsion (E2)

The composition C3 is stirred at 1000 rpm until complete homogenization and then left to stand for one hour at room temperature. The first emulsion (E1) is then added dropwise to the composition C3 with stirring at 1000 rpm. This gives the second emulsion (E2).

Step c): Refining in size of the second emulsion

The second polydisperse emulsion (E2) obtained in the previous step is stirred at 1000 rpm for 10 minutes. A monodisperse emulsion (E3) is thus obtained.

Step d): Cross-linking of the capsule shell

The second monodisperse emulsion (E3), obtained in the previous step, is irradiated for 10 minutes with the aid of a UV light source (Dymax LightBox ECE 2000) having a maximum light intensity of 0.1 W / cm ² at a wavelength of 365 nm.

The microcapsules obtained have a good size distribution, namely an average size of 15 μηι and their size distribution has a standard deviation of 6.1 μηι or 41%.

For the biodegradation tests, the microcapsules are washed by means of several centrifugation - redispersion steps in order to completely eliminate the alginate. A soil sample is taken and purified in order to extract the bacterial content which is then placed in a liquid culture medium containing the microcapsules according to the invention as sole source of carbon. After 5 days of incubation at room temperature, the microcapsules are imaged under an optical microscope and a scanning electron microscope. A biofilm is observed on the microcapsules, indicating the proliferation of bacteria from the carbon source that represents the envelope. Traces of erosion and fractures are observed on the microcapsule envelope, confirming a bacterial digestion of the microcapsules. Example 2 Manufacture of Biodegradable Solid Polyester Capsules According to the Invention

Step a): Preparation of the first emulsion (El)

Compositions C1 and C2 are stirred at 2000 rpm until complete homogenization. The composition C1 is then added dropwise to the composition C 2 with stirring at 2000 rpm with a ratio of 5: 5. The first emulsion (E1) is thus obtained.

Step b): Preparation of the second emulsion (E2)

Composition C3 is stirred at 3500 rpm until complete homogenization and then allowed to stand for one hour at room temperature. The first emulsion (E1) is then added to the composition C3 and then stirred at 2,000 rpm. This gives the second emulsion (E2). Step c): Refining in size of the second emulsion

The second polydisperse emulsion (E2) obtained in the previous step is stirred at 2000 rpm for 3 minutes. A monodisperse emulsion (E3) is thus obtained.

Step d): Cross-linking of the capsule shell

The microcapsules obtained have a good size distribution, namely an average size of 5 μηι and their size distribution has a standard deviation of 1 μηι or 20%.

For the biodegradation tests, the microcapsules are washed by means of several centrifugation - redispersion steps in order to completely eliminate the alginate.

A BioDScreen® analysis was performed to determine the aerobic biodegradability of the microcapsules. The BioDScreen® (Scanae) method is a microplate screnning method using fluorescence detection.

BioDScreen® is based on the use of a bioreactant, derived from resazurin, that is sensitive to the metabolic activity of bacteria; this reagent is reduced in a fluorescent form proportional to the bacterial degradation of the sample.

The biodegradability rates correspond to an analysis of the biodegradability under the BioDScreen®-A method over 10 days of incubation at 30 ° C, with an inoculum from the purification plant.

In Example 2, the biodegradability rate at 10 days of incubation is 45% with a standard deviation of 3% and a plateau phase reached after 4 hours. Example 3 Manufacture of Biodegradable Solid Polyepoxy Capsules According to the Invention

Step a): Preparation of the first emulsion (El)

Step b): Preparation of the second emulsion (E2)

Step d): Cross-linking of the capsule shell

The microcapsules obtained have a good size distribution, namely an average size of 8 μηι and their size distribution has a standard deviation of 1, 4 μηι or 18%.

For the biodegradation tests, the microcapsules are washed by means of several centrifugation - redispersion steps in order to completely eliminate the alginate. A BioDScreen® (Scanae) analysis was performed to determine the aerobic biodegradability of the microcapsules, according to the indications mentioned above in Example 2.

The rate of biodegradability at 10 days of incubation is 31% with a standard deviation of 3%.

Claims

A process for preparing solid microcapsules comprising the steps of:

the composition C2 comprising:

at least one monomer or polymer selected from the group consisting of aliphatic or aromatic esters or polyesters, anhydrides or polyanhydrides, saccharides or polysaccharides, ethers or polyethers, amides or polyamides and carbonates or polycarbonates, further bearing at least a function selected from the group consisting of acrylate, methacrylate, vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, carboxylate, and mixtures thereof,

at least one crosslinking agent, and

c) the application of shear to the emulsion (E2),

2. The method of claim 1, wherein the composition C2 comprises at least one monomer or polymer selected from the group consisting of aliphatic or aromatic esters or polyesters, further bearing at least one function selected from the group consisting of acrylate functions, methacrylate , vinyl ether, N-vinyl ether, epoxy, siloxane, amine, lactone, phosphate, carboxylate, and mixtures thereof.

3. Method according to claim 1 or 2, wherein the composition C2 comprises from 0.001% to 20% by weight of crosslinking agent (s) relative to the total weight of said composition.

4. Preparation process according to any one of claims 1 to

3, in which step c) consists of applying a homogeneous controlled shear to the emulsion (E2), said shear rate applied being between

1,000 s ^"1 and 100,000 s ^{" 1} .

5. Preparation process according to any one of claims 1 to

4, in which, when the viscosity of the composition C3 is greater than

2000 mPa.s at 25 ° C, step c) consists in applying to the emulsion (E2) a shear rate of less than 1000 s ^-1 .

6. Preparation process according to any one of claims 1 to

5, wherein, when the composition C2 comprises a photoinitiator, step d) is a photopolymerization step of exposing the emulsion (E3) to a light source capable of initiating the photopolymerization of the composition C2, in particular at a UV light source emitting preferably in the wavelength range between 100 nm and 400 nm, and in particular for a period of less than 15 minutes.

7. Preparation process according to any one of claims 1 to 5, wherein, when the composition C2 does not comprise a photoinitiator, step d) is a polymerization step, without exposure to a light source, the duration this step d) of polymerization being preferably between 8 hours and 100 hours and / or this step d) being carried out at a temperature between 20 ° C and 80 ° C.

The process according to any one of claims 1 to 7, wherein the composition C3 further comprises at least one branched polymer, preferably having a molecular weight greater than 5,000 g. mol ^"1 , and / or at least one polymer of molecular weight greater than 5,000 g. mol ^{" 1} , and / or solid particles such as silicates.

9. A series of solid microcapsules, obtainable according to the method according to one of claims 1 to 8, wherein each microcapsule comprises:

a core comprising a composition C1 according to claim 1, and

a solid envelope completely encapsulating at its periphery the core, in which the mean diameter of said microcapsules is between 1 μηι and 30 μηι, the thickness of the rigid envelope is between 0.1 μηι and 20 μηι and the difference -Type of the microcapsule diameter distribution is less than 50%, especially less than 25%, or less than 1 μηι.

10. Composition comprising a series of solid microcapsules according to claim 9.