Improved process for producing capsules comprising at least one matrix shell containing a lipophilic core

Abstract

The present invention relates to a process for producing capsules comprising a matrix shell containing a lipophilic core, the process comprising the steps of: a. providing a reverse emulsion comprising a first aqueous phase comprising water and a gelation inducer dispersed in a continuous fatty phase; b. providing a second aqueous phase comprising water; c. injecting the reverse emulsion into a first duct opening into the second aqueous phase; d. bringing the dispersion of step c. into contact with an aqueous solution for forming the shell, comprising water and a matrix former; and e. reacting the gelation inducer and the matrix former.

Description

[0001] Description

[0002] Title: Improved manufacturing process for capsules comprising at least one matrix shell containing a lipophilic core

[0003] The invention relates to a method for manufacturing perfume capsules comprising at least one matrix envelope containing at least one lipophilic core.

[0004] Technical field

[0005] Capsules with particle sizes less than 3 mm have found wide application, particularly in the fields of pharmacy, cosmetics, diagnostics, food processing, and materials science. Such capsules can be made from an emulsion of monodisperse drops in a continuous phase. Monodispersity increases stability and allows precise volume control in multiple chemical or biological reactions. Microfluidics offers a suitable platform for forming such monodisperse drops.

[0006] For many applications, it is desirable to provide capsules with an oily core, i.e. a core (or heart) comprising at least one oil, enveloped by a suitable shell. This is mainly due to the fact that many compounds of interest, for example flavors, perfumes, cosmetic or pharmaceutical active ingredients or vitamins are hydrophobic and / or only soluble in a fatty phase, but not in water.

[0007] Prior art

[0008] There are several known methods, in particular microfluidic, for producing capsules from monodisperse drops, and in particular that described in patent application WO2022106361. This method is suitable for forming capsules comprising an oily core comprising at least one perfuming agent, also referred to as “perfuming capsules”, “scented capsules” or “perfume capsules”.

[0009] The manufacture of perfume capsules according to the process described in patent application WO2022106361 is based on the following steps:

[0010] - the encapsulation of an inverse emulsion composed of an aqueous phase comprising at least one salt dispersed in a continuous fatty phase comprising at least one oil and at least one perfuming agent, the inverse emulsion being stabilized by a first surfactant;

[0011] - bringing this inverse emulsion into contact with an aqueous solution comprising at least one second surfactant, in particular polyvinyl alcohol (PVA), whereby a double emulsion is obtained; and

[0012] - bringing this double emulsion into contact with an alginate solution comprising a third surfactant, in particular an ethoxylated surfactant such as, for example, Tween20. The process described in patent application WO2022106361, however, has several drawbacks.

[0013] First, it relies heavily on surfactants. However, the use of surfactants is increasingly criticized, particularly in cosmetics, because they are often irritating and of petrochemical origin, non-biodegradable and very ecotaxic. In addition, ethoxylated surfactants are less and less accepted because of their potential carcinogenicity.

[0014] Furthermore, the capsules obtained with this process, although sprayable, have limitations in terms of active agent concentration, particularly in terms of perfuming agent. In the presence of perfuming agent(s), the capsules obtained with this process also have limitations in terms of olfactory and sensory rendering, which limits the deployment of this technology in the field of perfumery, and in particular fine perfumery (or "Fine Fragrance" in English).

[0015] Statement of the invention

[0016] It is therefore a general aim to advance the state of the art relating to the manufacture of perfume capsules and preferably to propose an improved alternative to the prior art described above.

[0017] Against all expectations, the inventors observed that the manufacture of capsules, and in particular of perfume capsules, remains possible by removing the surfactant from the second aqueous solution. Even more unexpectedly, the inventors observed that this removal is accompanied by unexpected technical effects. Indeed, as described in Example 1 below, the removal of the surfactant from the second aqueous solution of the process according to the prior art described previously allows the removal of the first surfactant, or even of the oil, and / or allows the removal of the third surfactant present in the alginate solution. The present invention thus makes it possible to manufacture capsules by means of a simplified manufacturing process and, above all, requiring less use of surfactants.Furthermore, it provides access to capsules with improved concentrations of active agent(s) while exhibiting similar, or even improved, properties in terms of sphericity and transparency of the lipophilic core. In the case of perfuming capsules, the manufacturing method according to the invention provides access to capsules with improved olfactory and sensory renderings, which makes it possible to broaden the deployment of this technology in the field of perfumery.

[0018] In addition, the capsules thus obtained remain sprayable.

[0019] In other words, the invention makes it possible to dispense with at least one of the three surfactants required in the process described in patent application WO2022106361. The invention even makes it possible to dispense with at least two, or even all three, surfactants required in WO2022106361.

[0020] Furthermore, the invention allows an inverse emulsion whose fatty phase can be entirely composed of perfuming agent(s).

[0021] The invention is therefore based on a microfluidic manufacturing process which, in particular compared to that described in WO2022106361, is simplified, easily industrializable and furthermore advantageously relies on a reduced use of surfactants, on the capacity to significantly increase the concentration of active agent(s), while remaining satisfactory in terms of sprayability and capacity for precise control of the size of the capsules and the thickness of their envelope.

[0022] Summary of the invention

[0023] Thus, the invention relates to a method for manufacturing capsules comprising at least one matrix shell containing at least one lipophilic core, the method comprising at least the steps of: a. providing an inverse emulsion comprising a first aqueous phase dispersed in a continuous fatty phase, said first aqueous phase comprising water and at least one gelling-inducing agent; b. providing a second aqueous phase comprising water, said second aqueous phase being free of surfactant, and in particular free of polyvinyl alcohol and / or polysorbate; c. injecting the inverse emulsion of step a. into at least one first conduit opening into the second aqueous phase of step b., whereby a dispersion is obtained comprising drops of inverse emulsion of step a. dispersed in the second aqueous phase of step b.; d. bringing the dispersion of step c. into contact.with at least one aqueous shell-forming solution comprising water and at least one matrix-forming agent, the gelation-inducing agent and the matrix-forming agent being configured such that they are capable of undergoing a chemical reaction with each other to form a water-insoluble matrix shell; and e. reacting the gelation-inducing agent and the matrix-forming agent, whereby capsules comprising a water-insoluble matrix shell enclosing at least one lipophilic core are obtained.

[0024] A manufacturing method according to the invention is advantageous in that it allows access in particular to capsules whose matrix shell and lipophilic core are transparent. It is understood that steps a. and b. do not necessarily have to be carried out in this order. It may also be possible to carry out step b. first and then step a. or to carry them out simultaneously. It is understood that steps d. and e. can be carried out simultaneously.

[0025] It is understood that the dispersion formed in step c. comprises a plurality of monodisperse drops comprising the inverse emulsion of step a. as a dispersed phase in the second aqueous phase of step b. as a continuous phase. Thus, the dispersion of step c. may be referred to as a water-in-oil-in-water transient emulsion (or "transient double emulsion") in the form of drops dispersed in the second aqueous phase, the drops being formed from the first aqueous phase dispersed in the fatty phase.

[0026] It is further understood that the composition of the lipophilic core of the capsules obtained at the end of step e. is not identical to the composition of the inverse emulsion of step a. and dedicated to forming the core of the capsules, in particular given the fact that the first dispersed aqueous phase and certain reagents react and / or diffuse from the core, in particular towards the aqueous solution for forming the shell. This is particularly the case for the gelling-inducing agent. Nevertheless, the lipophilic core of the capsules obtained at the end of step e. may contain minor amounts of residual dispersed aqueous phase, i.e. minor amounts of water. However, the majority of the lipophilic core of the capsules obtained at the end of step e. is composed of the fatty phase.Typically, the capsules comprise more than 60%, preferably more than 70%, in particular more than 80%, more preferably more than 90%, in particular more than 95%, and most particularly more than 99%, by weight of fatty phase relative to the total weight of the capsule core.

[0027] In step c., each drop of inverse emulsion generated comprises mainly the fatty phase from step a., but also the dispersed aqueous phase which comprises the gelling-inducing agent from step a. Thus, the dispersion formed in step c. is a water-in-oil-in-water dispersion where the continuous aqueous phase is the second aqueous phase. The use of the emulsification step c., i.e. injection of the inverse emulsion forming the core of step a. through at least one first conduit, makes it possible to precisely control the size and ensure a uniform distribution of the size of the dispersion formed in step c. In addition, the method allows rapid capsule production, of the order of 100 g / h (i.e. gram(s) per hour) per conduit or more, or even up to 500 g / h per conduit.

[0028] With a method according to the invention, the matrix grows around the core by a chemical reaction between the gelation-inducing agent, present within each drop of inverse emulsion, and the matrix-forming agent, present in the aqueous shell-forming solution.

[0029] Preferably, step a. comprises at least the substeps of: a1. dissolving the gelling-inducing agent in water to form the first aqueous phase; and a2. mixing the first aqueous phase formed in step a1. with the fatty phase.

[0030] Step a2. can be carried out extemporaneously or simultaneously with step c.

[0031] According to a first embodiment, step a1. and step a2. can be carried out simultaneously. In this case, step a2. cannot be carried out extemporaneously or simultaneously with step c.

[0032] According to a second embodiment, step a2. can be carried out extemporaneously or simultaneously with step c. In this case, step a1. and step a2. cannot be carried out simultaneously. The dissolution of the gelling-inducing agent in the water of the first dispersed aqueous phase of step a. advantageously makes it possible to prevent / avoid clogging of the conduit(s) and to improve the kinetics of formation of the envelope. Indeed, carbonates can cause an accumulation of insoluble salts in the conduit(s).

[0033] The core-forming emulsion provided in step a. may be stable between 2 minutes and 600 minutes, preferably between 5 minutes and 500 minutes, more preferably between 10 minutes and 100 minutes, or even between 15 minutes and 60 minutes, and most preferably between 20 minutes and 30 minutes. Such stability ensures that the drops are not directly destroyed, especially during step c. However, the stability of the drops is also not too high, which would decrease the efficiency of shell formation during step e. and limit the transparency of the lipophilic cores.

[0034] The matrix-forming agent is typically dissolved in the aqueous shell-forming solution.

[0035] The gelation-inducing agent and the shell-forming agent are configured such that they are capable of undergoing a chemical reaction with each other to form a water-insoluble matrix shell. These may, for example, be configured to undergo a complexation reaction, an ion exchange reaction, or an interphase-limited polymerization reaction.

[0036] The invention also relates to a set of capsules comprising a plurality of capsules produced according to the method according to the invention.

[0037] A manufacturing method according to the invention is also particularly advantageous in that it makes it possible to obtain a set of capsules comprising less than 10%, preferably less than 5%, in particular less than 2.5%, or even being free of alcohol(s), in particular ethanol, relative to the total weight of said set.

[0038] The invention also relates to a set of capsules in which the capsules may comprise between 5% and 30%, preferably between 10% and 20%, and better still between 12% and 15%, by weight of active agent(s), in particular perfuming agent(s), relative to the total weight of the capsules.

[0039] The invention also relates to a packaging and dispensing device in the form of a spray of fluid composition, in particular cosmetic, characterized in that it comprises at least: - a container comprising at least one heterogeneous mixture;

[0040] - a guide conduit (or dip tube) placed in the container; and

[0041] - a dispensing member capable of sucking up heterogeneous mixture from the container, transforming the heterogeneous mixture into the fluid composition and dispensing the fluid composition in the form of a spray, the heterogeneous mixture comprising a set of capsules according to the invention dispersed in a continuous phase.

[0042] Such a packaging and dispensing device in the form of a spray may also be referred to as a “spray device”, “spraying device” or “sprayer”.

[0043] Preferably, in such a spray device, the capsules represent a volume fraction of between 50% and 70%, preferably between 55% and 65%, and better still between 57% and 63%, relative to the total volume of the heterogeneous mixture.

[0044] Preferably, in such a spray device, the ratio “internal diameter of the guide duct / diameter of the capsules” is between 1 and 1.25, and preferably between 1.1 and 1.2.

[0045] A packaging and dispensing device in the form of a spray may in particular be as described in the patent application filed under No. FR2314016.

[0046] For the purposes of the present invention, the term "capsule" means a substantially spherical macroscopic element of the core / shell type, in which the shell completely encapsulates the core and the core comprises at least one drop of fatty phase.

[0047] For the purposes of the present invention, the term "macroscopic" means capsules visible to the naked eye. The capsules are advantageously substantially spherical.

[0048] Preferably, the capsules obtained with a method according to the invention and included in an assembly according to the invention have an average diameter of between 250 pm and 3,000 pm, preferably between 500 pm and 2,000 pm, in particular between 1,000 pm and 1,750 pm, and better still between 1,200 pm and 1,500 pm, preferably with a coefficient of variation of less than or equal to 10%, preferably less than or equal to 5%, and better still less than or equal to 3%.

[0049] Preferably, the capsules obtained with a method according to the invention and included in an assembly according to the invention have a lipophilic core which has an average diameter of between 250 pm and 2,500 pm, preferably between 500 pm and 2,000 pm, in particular between 750 pm and 1,500 pm, and better still between 1,000 pm and 1,250 pm, preferably with a coefficient of variation of less than or equal to 10%, preferably less than or equal to 5%, and better still less than or equal to 3%.

[0050] Thus, a method according to the invention makes it possible to form a dispersion in which the phases constituting it form a macroscopically inhomogeneous mixture.

[0051] In view of the above, the envelope is therefore an aqueous phase. Preferably, the envelope is transparent.

[0052] Advantageously, the envelope has a uniform thickness. For the purposes of the present invention, the term “uniform thickness” is understood to mean capsules whose envelope thickness varies according to a standard deviation of less than or equal to 10%, preferably less than or equal to 5%. The envelope may be referred to indifferently by the terms “membrane” or “shell”.

[0053] For the purposes of the present invention, the term "conduit" is understood to mean a conduit having an internal diameter of less than 4 mm, preferably between 1 μm and 3 mm, in particular between 10 μm and 1 mm, or even between 100 μm and 0.5 mm. A conduit for the purposes of the present invention may be referred to indifferently as "micro-conduit", "channel", "micro-channel" or "tube".

[0054] A conduit is configured in particular to transport chemical substances, in fluid form such as a liquid or a gas. A conduit can in particular be described as an elongated and narrow structure, generally of circular or rectangular section, which serves to guide the flow of a fluid from one point to another in a microfluidic device. To avoid any ambiguity, a conduit is distinct and different from a chamber as described in WO2021037999 or in the microfluidic device according to the invention, of the “step-emulsification” type, and illustrated in Figure 3. A conduit can be formed of any material suitable for the use considered in the present invention, and in particular suitable for the nature of the fluids being transported therein. The adjustment of the material falls within the general knowledge of a person skilled in the art. Preferably, the conduit(s) are made of stainless steel, glass, polyetheretherketone (PEEK) or Teflon, in particular when step c.is based on the co-flow microfluidic process described below.

[0055] Unless otherwise stated, in all that follows, we consider that we are at room temperature (for example T=25°C ± 2°C) and atmospheric pressure (760 mm Hg, or 1,013.10 5 Pa or 10 13 mbar). According to the invention, the pH is typically between 3.0 and 8.0, in particular between 4.0 and 7.0.

[0056] Preferably, a method according to the invention does not comprise a step of evaporation, or elimination, of solvent(s), in particular as described in WO2022179982.

[0057] It is understood that a manufacturing method according to the invention does not include a step of dropping drops or capsules by gravity through a volume of air, in particular into a solution in which they are immersed, like the method described in W02010063937, which can therefore be qualified as a method of manufacturing capsules by liquid / air route.

[0058] In other words, a method according to the invention can be described as a liquid / liquid capsule manufacturing method.

[0059] Detailed description

[0060] Inverse emulsion

[0061] Step a. consists of providing an emulsion comprising an aqueous phase dispersed in a continuous fatty phase, the dispersed aqueous phase comprising water and at least one gelling-inducing agent.

[0062] Step a. therefore consists of having an inverse emulsion, also referred to interchangeably by the expression “water-in-oil emulsion” or “IL”.

[0063] For obvious reasons, the inverse emulsion for carrying out step c. is in a liquid (or fluid) form. By "liquid" for the purposes of the present invention, is meant a non-solid inverse emulsion and in particular capable of flowing under its own weight and passing through the conduit(s) in step c.

[0064] To satisfy this condition, the inverse emulsion can be preheated and / or hot injected in step c.

[0065] For obvious reasons, the dispersed aqueous phase and the continuous fatty phase are substantially immiscible.

[0066] For the purposes of the present invention, the term "substantially immiscible" means that the solubility of a first phase in a second phase is advantageously less than 5% by mass, and vice versa.

[0067] The inverse emulsion can be manufactured in a batch or continuous mode. The manufacture of the inverse emulsion in a batch mode corresponds to a manufacture in fixed and distinct quantities, that is to say in batch or batch. Continuous fatty phase

[0068] The fatty phase of step a., also designated “IF2”, may comprise at least one active agent, in particular a perfuming agent, at least one oil, and their mixture.

[0069] Active agent(s)

[0070] The fatty phase of step a. may comprise at least one active agent. An active agent may be chosen from a biological active agent, a pharmaceutical active agent and / or a cosmetic active agent, for example chosen from perfuming agents, moisturizing agents, healing agents, depigmenting agents, UV filters, desquamating agents, antioxidant agents, active agents stimulating the synthesis of dermal and / or epidermal macromolecular agents, dermo-contracting agents, antiperspirant agents, soothing agents, anti-aging agents, anticoagulants, anti-thrombogenic agents, anti-mitotic agents, anti-proliferation, anti-adhesion, anti-migration agents, cell adhesion promoters, growth factors, antiparasitic molecules, anti-inflammatories, angiogenic agents, angiogenesis inhibitors, vitamins, hormones, proteins, antifungals, antimicrobial molecules, antiseptics or antibiotics,flavors, antibodies, peptides, enzymes, RNA, DNA, microorganisms, and mixtures thereof. Preferably, an active agent is a perfuming agent, especially as described below.,

[0071] Of course, the person skilled in the art will take care to choose the possible active agent(s) and / or their quantity in such a way that the advantageous properties of the invention are not or are not substantially altered by the envisaged addition. These adjustments fall within the general knowledge of the person skilled in the art.

[0072] The fatty phase may advantageously comprise from 1% to 100%, preferably from 5% to 90%, in particular from 10% to 80%, and better still from 20% to 70%, by weight of active agent(s) relative to the total weight of the fatty phase.

[0073] The present invention also relates to a process in which the fatty phase may comprise from 20% to 100%, preferably from 30% to 90%, and more preferably from 40% to 80%, by weight of active agent(s), in particular perfuming agent(s), relative to the total weight of the fatty phase. The active agent may already be mixed into the fatty phase or also added only after the aqueous solution formed of the gelling-inducing agent in water is mixed with the fatty phase.

[0074] Perfuming agent(s)

[0075] A perfuming agent according to the invention is a lipophilic agent, i.e. capable of being solubilized or dispersed in an organic solvent, in particular an oil. For the purposes of the invention, however, a perfuming agent is not necessarily solubilized or dispersed in an organic solvent.

[0076] A “perfuming agent”, also indifferently designated as “perfume”, “perfume juice” or “perfume concentrate”, within the meaning of the present invention, may be chosen from compounds having the INCI name “Perfume” or “Fragrance”. Thus, within the meaning of the present invention, the term “perfume” does not designate a mixture comprising a perfume concentrate and alcohol.

[0077] The perfuming agents that can be used according to the invention are ingredients commonly used in perfumery. Their nature does not require a more detailed description here, which cannot be exhaustive, since a person skilled in the art is able to choose them based on his general knowledge and according to the desired olfactory effect. These perfuming agents belong to chemical classes as varied as alcohols, aldehydes, ketones, esters, ethers, acetates, nitriles, terpene hydrocarbons, nitrogenous or sulfurous heterocyclic compounds, as well as essential oils of natural or synthetic origin. Many of these ingredients are also listed in reference texts such as the book by S. Arctander, Perfume and Flavor Chemicals, 1969, Montclair, New Jersey, USA, or its more recent versions, or in other works of a similar nature, as well as in the scientific literature and more recent patents relating to the art of perfumery.

[0078] For example, a perfuming agent is a compound or mixture of compounds that is at least partially volatile at room temperature and whose odor can be detected. A perfuming agent composed of essential oils is generally diluted in order to express its full olfactory potential, that is to say, a perception that evolves during the day after application to the surface to be treated, thanks to the presence of several odorous organic compounds having different volatilities. The development of a perfume includes a step of combining several perfuming raw materials to give a top note, a middle note and a base note to the perfuming composition.

[0079] A fragrance agent can be prepared from natural or synthetic organic fragrance materials.

[0080] Examples of natural fragrance materials are extracts of flowers, leaf stems, fruits, barks, roots, woods, herbs, grasses, resins, balsams, and mixtures thereof.

[0081] These plant-based fragrances can be essential oils, such as bergamot, rose, lavender, sandalwood, cardamom, sage, chamomile, clove, lemon balm, mint, cinnamon leaf, juniper, vetiver, frankincense, galbanum, labdanum, and mixtures thereof.

[0082] For the purposes of the present invention, an essential oil is considered to be a perfuming agent, and therefore cannot be considered to be an oil or an organic solvent, in particular a lipophilic organic solvent.

[0083] Examples of synthetically derived fragrances are hedione, ethylene brassilate, habanolide, benzyl acetate, benzyl benzoate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, citronellyl acetate, citronellyl formate, geranyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate. , benzyl formate, ethyl methyl phenyl glycinate alkylcyclohexyl propionate, styralyl propionate and benzyl salicylate, benzyl ethyl ether, linear alkanals of 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamenaldehyde, hydroxycitronellal, ionones such as alpha-isomethylionone, methylcedrylketone, anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, terpineol, terpenes, and mixtures thereof.

[0084] These compounds often occur as a mixture of two or more of these odorous substances.

[0085] The fatty phase may advantageously comprise from 20% to 100%, preferably from 30% to 90%, and better still from 40% to 80%, by weight of perfuming agent(s) relative to the total weight of the fatty phase. Preferably, the capsules according to the invention comprise between 5% and 30%, preferably between 10% and 20%, and better still between 12% and 15%, by weight of perfuming agent(s) relative to the total weight of the capsules.

[0086] To the extent that the fatty phase may comprise only one or more perfuming agent(s), the core of the capsules is designated by the expression “lipophilic core” and not by the expression “oily core” which would have suggested the necessary presence of at least one oil, which is not obligatory with the present invention.

[0087] Oils)

[0088] According to a first embodiment, the fatty phase of step a. does not comprise oil. In particular, the fatty phase does not comprise oil chosen from hydrocarbon oils of vegetable origin; hydrocarbon oils of animal origin; synthetic esters and ethers, in particular of fatty acids; linear or branched hydrocarbons, of mineral or synthetic origin; silicone oils, such as for example polymethylsiloxanes (PDMS); fatty alcohols having from 8 to 26 carbon atoms; and / or partially hydrocarbon and / or silicone fluorinated oils.

[0089] In particular, the fatty phase does not include any oil selected from Caprylic / Capric Triglyceride, isopentyldiol, caviar oil, and mixtures thereof.

[0090] According to another preferred embodiment, the fatty phase does not comprise silicone oil, and preferably does not comprise polydimethylsiloxane (PDMS).

[0091] According to another embodiment, the fatty phase of step a. may further comprise at least one oil.

[0092] The term "oil" means a fatty substance that is liquid at room temperature and atmospheric pressure. Examples of oils that can be used in a dispersion of the invention include:

[0093] - hydrocarbon oils of vegetable origin, such as hydrogenated jojoba oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated coconut oil;

[0094] - hydrocarbon oils of animal origin, such as perhydro squalene and squalane;

[0095] - synthetic esters and ethers, in particular of fatty acids, such as oils of formulas R1COOR2 and R1OR2 in which RI represents the residue of a C8 to C29 fatty acid, and R2 represents a hydrocarbon chain, branched or not, in C3 to C30, such as for example Purcellin oil, isononyl isononanoate, isodecyl neopentanoate, isopropyl myristate, ethyl-2-hexyl palmitate, octyl-2-dodecyl stearate, octyl-2-dodecyl erucate, isostearyl isostearate; hydroxylated esters such as isostearyl lactate, octylhydroxy stearate, octyldodecyl hydroxy stearate, diisostearyl malate, triisocetyl citrate, fatty alcohol heptanoates, octanoates, decanoates; polyol esters, such as propylene glycol dioctanoate, neopentyl glycol diheptanoate and diethylene glycol diisononanoate;and pentaerythritol esters such as pentaerythrityl tetrabehenate (DUB PTB) or pentaerythrityl tetraisostearate (Prisorine 3631);

[0096] - linear or branched hydrocarbons, of mineral or synthetic origin, such as paraffin oils, volatile or not, and their derivatives, petroleum jelly, polydecenes, hydrogenated polyisobutene such as Parleam oil;

[0097] - silicone oils, such as, for example, volatile or non-volatile polymethylsiloxanes (PDMS) with a linear or cyclic silicone chain, liquid or pasty at room temperature, in particular cyclopolydimethylsiloxanes (cyclomethicones) such as cyclohexasiloxane and cyclopentasiloxane; polydimethylsiloxanes (or dimethicones) comprising alkyl, alkoxy or phenyl groups, pendant or at the end of the silicone chain, groups having from 2 to 24 carbon atoms; phenyl silicones such as phenyltrimethicones, phenyldimethicones, phenyltrimethylsiloxydiphenylsiloxanes, diphenyldimethicones, diphenylmethyldiphenyl trisiloxanes, 2-phenylethyltrimethylsiloxysilicates, and polymethylphenylsiloxanes;

[0098] - fatty alcohols with 8 to 26 carbon atoms, such as cetyl alcohol, stearyl alcohol and their mixture (cetylstearyl alcohol), or octyldodecanol;

[0099] - partially hydrocarbon and / or silicone fluorinated oils such as those described in document JP-A-2-295912;

[0100] - and their mixtures.

[0101] Preferably, the fatty phase of step a. may comprise less than 40%, preferably less than 30%, better still less than 20%, in particular less than 10%, or even less than 5%, by weight of oil(s) relative to the total weight of said fatty phase.

[0102] Of course, the person skilled in the art will take care to choose the possible oils and / or their quantity in such a way that the advantageous properties of the invention are not or are not substantially altered by the envisaged addition. These adjustments fall within the general knowledge of the person skilled in the art. Surfactant(s)

[0103] The inverse emulsion may further comprise at least one surfactant, in particular at least one surfactant capable of forming an inverse emulsion, and in particular having an HLB < 10, and preferably between 2 and 8, and better still between 3 and 5.

[0104] In particular, the inverse emulsion may further comprise at least one non-ionic surfactant, preferably chosen from polyglycerol polyricinoleate (PGPR), a sorbitan derivative, in particular a sorbitan ester, for example sorbitan monooleate, sorbitan trioleate, and mixtures thereof.

[0105] In particular, the inverse emulsion may comprise a surfactant selected from POLYGLYCERYL-2 ISOSTEARATE (3,2), POLYGLYCERYL-6 POLYRICINOLEATE (3,3), POLYGLYCERYL-4 POLYRICINOLEATE (3,5), and mixtures thereof.

[0106] Of course, the person skilled in the art will take care to choose the possible surfactant(s) in the inverse emulsion, in particular in the fatty phase and / or their quantity in such a way that the advantageous properties of the invention are not or are not substantially altered by the envisaged addition. These adjustments fall within the general knowledge of the person skilled in the art.

[0107] According to the invention, the fatty phase may comprise between 0.01% and 2%, preferably between 0.05% and 1.5%, and better still between 0.1% and 1%, by weight of surfactant(s) relative to the total weight of the fatty phase.

[0108] According to a particular embodiment, the inverse emulsion does not comprise surfactant as described above. The removal of this surfactant is particularly unexpected insofar as it goes against the teaching of WO2022106361, where this surfactant is indeed described as necessary to ensure adequate stabilization of the drops of aqueous phase dispersed in the emulsion forming the oily core.

[0109] Lipophilic gelling agent(s)

[0110] According to a first embodiment, the fatty phase of step a. does not comprise a lipophilic gelling agent.

[0111] According to a second embodiment, the fatty phase of step a. may further comprise at least one lipophilic gelling agent. A lipophilic gelling agent, i.e. soluble or dispersible in the fatty phase, may be chosen from organic or mineral, polymeric or molecular gelling agents; fatty substances which are solid at ambient temperature and pressure, in particular chosen from waxes, pasty fatty substances, butters; and mixtures thereof, and preferably from polymeric gelling agents. Such lipophilic gelling agents are described in particular in WO2019002308.

[0112] Examples include THIXCIN® R from Elementis Specialties (INCI: Trihydroxystearin), OILKEMIA™ 5S polymer from Lubrizol (INCI: Caprylic / Capric Triglyceride (and) Polyurethane-79), Estogel M from PolymerExpert (INCI: CASTOR OIL / IPDI COPOLYMER & CAPRYLIC / CAPRIC TRIGLYCERIDE), Hydrogenated Castor Oil / Sebacic Acid Copolymer and its derivatives, notably marketed respectively under the names Estogel Green (or Estogel G) and Estogel Green 40 by PolymerExpert, and their mixtures.

[0113] Advantageously, a lipophilic gelling agent is a heat-sensitive gelling agent, that is to say a gelling agent which reacts to heat, and in particular which is solid at room temperature and liquid at a temperature above 50°C, preferably above 60°C. According to the invention, a dispersion according to the invention may comprise between 0.1% and 30%, preferably between 0.5% and 25%, or even between 1% and 20%, and better still between 2% and 15%, by weight of lipophilic gelling agent(s) relative to the total weight of the fatty phase.

[0114] Preferably, the fatty phase of step a. is free of surfactant and oil, in particular when the fatty phase comprises at least one perfuming agent.

[0115] Preferably, the fatty phase of step a. further comprises at least one oil, or even at least one surfactant, in particular when the active agent present in the fatty phase is other than a perfuming agent.

[0116] The present invention also relates to a process in which the inverse emulsion may further comprise at least one oil and / or at least one surfactant, preferably a non-ionic surfactant, and more preferably a surfactant chosen from polyglycerol polyricinoleate (PGPR), a sorbitan derivative, in particular a sorbitan ester, for example sorbitan monooleate, sorbitan trioleate, and mixtures thereof. First dispersed aqueous phase

[0117] The first dispersed aqueous phase of the inverse emulsion of step a., also designated “IF1”, comprises at least water and at least one gelation-inducing agent.

[0118] Water

[0119] For the purposes of the present invention, an aqueous phase or aqueous solution comprises water. In addition to distilled or deionized water, water suitable for the invention may also be natural spring water or floral water. This is particularly the case for the first dispersed aqueous phase of the inverse emulsion of step a.

[0120] According to one embodiment, the mass percentage of water in the first dispersed aqueous phase is at least 50%, and better still at least 60%, in particular between 50% and 98%, preferably between 60% and 95%, and better still between 70% and 90%, relative to the total mass of the dispersed aqueous phase.

[0121] Gelling-inducing agent(s)

[0122] A gelation-inducing agent is advantageously a salt of at least one inorganic cation, in particular an inorganic salt chosen from an alkaline earth metal salt, in particular an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate, an alkaline earth metal nitrate, and mixtures thereof.

[0123] In certain embodiments in which the gelation-inducing agent is an inorganic salt, as indicated above, the reaction in step e. between the gelation-inducing agent and the matrix-forming agent is an ion-exchange reaction, i.e., ionotropic gelation. Thus, the inorganic salt (and vice versa the matrix-forming agent) is chosen such that its reaction with the matrix-forming agent gives a water-insoluble reaction product. Particularly suitable salts, especially for polysaccharides, may thus be salts of K, Mg, Sr, or Ca. Those skilled in the art understand the term "pseudohalide" to mean polyatomic analogs of halogens, whose chemistry resembles that of true halogens. Non-limiting examples include cyanide, isocyanide, cyanate, isocyanate, methylsulfonyl and triflyl.Non-limiting examples of carboxylates are acetate, formate, lactate, oxalate, butyrate, succinate and the like. The gelation-inducing agent is typically chosen such that it is completely soluble in water at room temperature, i.e., has a water solubility greater than 10g / 100mL, preferably greater than 20g / 100mL, in particular greater than 50g / 100mL. Suitable non-limiting examples of gelation-inducing agents are: CaCh, CaFi, Calcium lactate, MgCh, Sr(OAc)2, and mixtures thereof.

[0124] The inorganic salt is typically a water-soluble salt. However, it is also conceivable to use a powder of a water-insoluble salt as a gelling agent. For example, CaCOa or MgCOa can be used, especially in powder form.

[0125] In some embodiments, the gelation-inducing agent is a composition of a photoacid generator, i.e., a compound configured to produce an acid upon irradiation, preferably UV irradiation, such as diphenyliodonium nitrate, and a chelate of an inorganic salt, particularly an alkaline earth metal salt or an alkali metal salt. The chelate may, for example, be a chelate of a carboxylic acid. A suitable example may be a chelate of strontium and ethylene glycol tetraacetic acid. Upon irradiation with UV light, which may be performed in step d., the photoacid generator generates an acid, which then releases the strontium ions, which in turn react with the matrix-forming agent, for example, sodium alginate to form a water-insoluble matrix shell.

[0126] In some embodiments, the gelation-inducing agent is CO2 or a CO2 generator. A CO2 generator may release CO2 under specific conditions. For example, bicarbonate may release CO2 in the presence of an acid. In some embodiments, the gelation-inducing agent may be a Bronsted acid, for example, a mineral acid or a carboxylic acid. In this case, the matrix-forming agent may be a composition of a polysaccharide, such as an alginate, chitosan, etc., and a suitable water-soluble alkali metal complex or alkaline earth metal complex, such as Ca-Na2-EDTA, Mg-Na2 . EDTA, Sr-Na2 . EDTA, and the like.

[0127] Advantageously, the inverse emulsion of step a. comprises between 2.5% and 60%, preferably between 5% and 50%, and better still between 10% and 40%, by weight of agent(s) inducing gelling relative to the total weight of the first aqueous phase.

[0128] The present invention also relates to a process in which the first aqueous phase of the inverse emulsion of step a. may comprise between 2.5% and 60%, preferably between 5% and 50%, better still between 10% and 40%, by weight of gelling-inducing agent(s) relative to the total weight of the first aqueous phase.

[0129] Preferably, the first dispersed aqueous phase does not comprise a hydrophilic surfactant.

[0130] Second aqueous phase

[0131] Step b. consists of having a second aqueous phase comprising water but being free of surfactant, and in particular free of polyvinyl alcohol and / or polysorbate. The second aqueous phase may indifferently be designated by the expression “second aqueous solution” or “OF”.

[0132] According to one embodiment, the mass percentage of water in the second aqueous phase is at least 50%, in particular at least 60%, better still at least 70%, in particular between 70% and 100%, preferably between 80% and 99%, and better still between 90% and 95%, relative to the total mass of the second aqueous phase.

[0133] For obvious reasons, the second aqueous phase and the fatty phase of the inverse emulsion are immiscible.

[0134] Hydrophilic surfactant(s)

[0135] The second aqueous phase does not include a hydrophilic surfactant.

[0136] In particular, the second aqueous phase does not comprise a hydrophilic surfactant selected from a polyglycerol ester, polyvinyl alcohol (or PVA), polysorbate, saponins, sapogenins, quillaja extract, gum arabic, beta lactoglobulin, sodium dodecyl sulfate, soy lecithin, sodium cesinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

[0137] Preferably, the second aqueous phase does not comprise a surfactant chosen from polyvinyl alcohol (or PVA) and / or polysorbate, in particular Tween or SDS.

[0138] The removal of this surfactant is particularly unexpected insofar as it goes against the teaching of WO2022106361, where this surfactant is in fact described as necessary to ensure sufficient stability for the water-in-oil-in-water double emulsion formed in step c. when it comes into contact with the aqueous solution for forming the shell in step d.

[0139] Hydrophilic gelling agent(s)

[0140] The second aqueous phase in step b. may further comprise at least one hydrophilic gelling agent, notably chosen from agarose, xanthan gum, carrageenan, cellulose and its derivatives, preferably methylcellulose or microcrystalline cellulose, and the like, and mixtures thereof, and preferably xanthan gum.

[0141] Preferably, such a hydrophilic gelling agent is chosen from a natural non-surfactant thickening agent.

[0142] The presence of such a hydrophilic gelling agent makes it possible to further improve the emulsification step c., in particular by limiting the wetting phenomena of the inverse emulsion at the level of the conduit(s). The presence of such a hydrophilic gelling agent is particularly relevant in the case where step c. is based on a co-flow type microfluidic emulsification technique.

[0143] Of course, the person skilled in the art will take care to choose the possible hydrophilic gelling agents and / or their quantity in such a way that the advantageous properties of the invention are not or are not substantially altered by the envisaged addition. These adjustments fall within the general knowledge of the person skilled in the art.

[0144] Preferably, the second aqueous phase of step b. comprises from 0.1% to 15%, preferably from 0.5% to 10%, and better still from 1% to 5%, by weight of hydrophilic gelling agent(s) relative to the total weight of the second aqueous phase.

[0145] Preferably, the second aqueous phase does not comprise carbomer (or acrylic polymer).

[0146] Preferably, the second aqueous phase does not comprise a base, in particular alkali metal hydroxide, and in particular NaOH (or sodium hydroxide).

[0147] The viscosity of the second aqueous phase in step b. is advantageously less than 1,000 cP (or mPa.s), preferably less than 500 cP, in particular less than 250 cP, better still less than 100 cP, and very particularly less than 50 cP.

[0148] If necessary, the liquid character of the second aqueous phase in step b. can be obtained by heating this aqueous phase to a temperature above its melting point, and in particular to a temperature above the highest melting point among the heat-sensitive hydrophilic gelling agent(s) present.

[0149] In particular, the second aqueous phase may be heated to a temperature between 50°C and 150°C, preferably between 60°C and 110°C, and better still between 70°C and 90°C.

[0150] Aqueous envelope-forming solution

[0151] The aqueous shell-forming solution, also referred to as "AF," comprises water and at least one water-soluble matrix-forming agent (or "matrix agent").

[0152] The gelation-inducing agent and the matrix-forming agent are configured such that they are capable of undergoing a chemical reaction with each other to form a water-insoluble matrix shell.

[0153] According to one embodiment, the mass percentage of water in the aqueous solution for forming the envelope is at least 50%, in particular at least 60%, better still at least 70%, in particular between 70% and 99.9%, preferably between 80% and 99%, and better still between 90% and 95%, relative to the total mass of the aqueous solution for forming the envelope.

[0154] For obvious reasons, the second aqueous phase and the aqueous shell-forming solution are miscible.

[0155] For obvious reasons, the aqueous solution forming the envelope and the continuous fatty phase of the inverse emulsion are immiscible.

[0156] For obvious reasons, the aqueous solution for forming the shell in step d. must be in a liquid (or fluid) form, i.e., in a non-solid form. If necessary, the liquid character of the aqueous solution for forming the shell in step d. can be obtained by heating this aqueous solution.

[0157] Water-soluble matrix-forming agent(s)

[0158] In some embodiments, the matrix-forming agent is a polysaccharide or a salt thereof. A suitable salt is a salt form that can be completely dissolved in water. Typically, polysaccharide salts are composed of an anionic polysaccharide component and a suitable countercation. Suitable polysaccharides are selected from chitosan, cellulose, alginate, particularly sodium alginate, carrageenan, agar, agarose, pectins, gellan, starch, and mixtures thereof. Preferred polysaccharides are alginate, preferably sodium alginate, chitosan, carrageenan and cellulose, more preferably alginate, preferably sodium alginate, chitosan. In some embodiments, the polysaccharides may be solubilized by adjusting the pH, for example, by basifying the pH of the aqueous shell-forming solution.

[0159] In some embodiments, the matrix-forming agent and the gelation-inducing agent are selected such that the formed water-insoluble matrix ruptures and / or melts at a temperature of at least 80°C, in particular at least 90°C. Such embodiments have the advantage that a compound of interest inside the capsules is released at a specific, predetermined temperature. This is, for example, particularly interesting for capsules used as food additives. Such capsules may be completely odorless when intact, but rupture upon cooking, so that the odor of interest is only released during cooking.In some embodiments, the gelation-inducing agent may be an alkaline earth metal salt, particularly a calcium salt such as CaCh, or an alkali metal salt, such as KCl, and the matrix-forming agent may be carrageenan, or a mixture of carrageenan and sodium alginate, preferably in a ratio of 2:1 to 1:2. Alternatively, agar-agar, optionally combined with sodium alginate, may be used as the matrix-forming agent in such embodiments. Preferably, 0.25 wt% to 2 wt%, particularly 0.5 wt% to 1.5 wt% of carrageenan is used in the aqueous shell-forming solution. For example, if 1.5 wt% of carrageenan in water is used in step d. as an aqueous shell-forming solution, capsules are formed which begin to melt at 80°C.If, on the other hand, 0.75% by weight of carrageenan with 0.5% by weight of sodium alginate in water is used in step d. as the aqueous shell-forming solution, then capsules are formed which are more stable and open at about 80°C, but do not yet melt completely. Alternatively, the matrix agent may be a polycarboxylate. In this case, the gelation-inducing agent may be an inorganic salt as described above which can form a water-insoluble matrix upon ion exchange with the polycarboxylate. Alternatively, the gelation-inducing agent may be a polyammonium salt, i.e., a polymer comprising a plurality of polyammonium groups.

[0160] Those skilled in the art will know how to adjust the content of matrix-forming agent(s) so as to form stable capsules without altering the robustness of the process according to the invention, or even the sprayability of the capsules when the latter is desired.

[0161] Indeed, too rapid a chemical reaction kinetics between the gelling-inducing agent and the matrix-forming agent to form a water-insoluble matrix envelope can lead to obstruction or even blocking of the conduit(s), which for obvious reasons is not desirable.

[0162] Advantageously, the aqueous solution for forming the envelope may comprise between 0.1% and 5%, preferably between 0.15% and 2.5%, and better still between 0.2% and 1%, by weight of matrix-forming agent(s) relative to the total weight of the aqueous solution for forming the envelope.

[0163] Surfactant(s)

[0164] The aqueous shell-forming solution may further comprise at least one surfactant. In particular, the aqueous shell-forming solution may further comprise at least one hydrophilic surfactant selected from a polyglycerol ester, polyvinyl alcohol, polysorbate, saponins, sapogenins, quillaja extract, gum arabic, beta lactoglobulin, sodium dodecyl sulfate, soy lecithin, sodium cesinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

[0165] Of course, the person skilled in the art will take care to choose the possible surfactant(s) in the aqueous solution for forming the envelope and / or their quantity in such a way that the advantageous properties of the invention are not or are not substantially altered by the envisaged addition. These adjustments fall within the general knowledge of the person skilled in the art.

[0166] According to the invention, a dispersion according to the invention may comprise between 0.1% and 30%, preferably between 0.5% and 25%, or even between 1% and 20%, and better still between 2% and 15%, by weight of surfactant(s) relative to the total weight of the aqueous solution for forming the shell. According to a particular embodiment, the aqueous solution for forming the shell may further comprise at least one chelating agent capable of delaying the reaction between the gelling-inducing agent and the matrix-forming agent, preferably chosen from at least one organophosphate, and better still chosen from tetrasodium pyrophosphate. Such an embodiment is advantageous in that it makes it possible to prevent clogging, obstructions and plugging of the channels described above.

[0167] In some embodiments, the aqueous shell-forming solution may further comprise at least one osmosis regulator, preferably selected from at least one alcohol or at least one sugar, the osmosis regulator being added to the aqueous shell-forming solution in step(s) d. and / or e. The osmosis regulator is configured to enhance the diffusion of the gelation-inducing agent toward the droplet interface, thereby increasing the shell thickness and the stability of the capsule. The osmosis regulator may be an alcohol as described above or a sugar, for example a monosaccharide or a disaccharide, i.e., glucose or fructose. Such a sugar derivative may be used alone or in combination with an alcohol as described above.

[0168] According to an advantageous embodiment, the aqueous solution for forming the envelope further comprises at least one alcohol, in particular methanol, ethanol, propanol, and mixtures thereof.

[0169] Alcohol has been found to promote diffusion of the gelation-inducing agent to the droplet interface. The alcohol is typically present in an amount of 5% to 30%, preferably 10% to 20%, by weight relative to the weight of the aqueous shell-forming solution.

[0170] In some embodiments, the aqueous shell-forming solution may further comprise at least one structural stabilizer. A structural stabilizer is a compound configured to improve the structural stability of the shell and may be selected from agarose, xanthan gum, cellulose and its derivatives, e.g., methylcellulose or microcrystalline cellulose, and the like, and mixtures thereof. The structural stabilizer may be added to the aqueous shell-forming solution in step(s) d. and / or e.

[0171] In some embodiments, the aqueous solution for forming the shell of step d. may further comprise at least one additional biopolymer different from the matrix agent, as a structural stabilizer, such as pectin (for example, GENU® pectin type LM-104AS-FG). Preferably, the additional biopolymer may also be capable of forming a matrix shell. In some embodiments, the additional biopolymer may be solid biopolymer particles, for example, starch. The provision of such an additional biopolymer and in particular solid biopolymer particles increases the mechanical strength of the capsules generated.

[0172] In certain embodiments, steps c. and / or d. and / or e. may be carried out at temperatures above room temperature, in particular between 25°C and 95°C, in particular between 40°C and 85°C, in particular between 50°C and 80°C, in particular between 65°C and 80°C, in particular between 70°C and 80°C. This is particularly the case when the inverse emulsion of step a. and / or the second aqueous phase comprises at least one gelling agent, in particular a heat-sensitive agent, so as to guarantee the liquid nature described above and thus ensure satisfactory performance of step c., step d. and / or step e.

[0173] Additionally, or alternatively, after step e., the formed capsules may be exposed to temperatures above room temperature, in particular between 25°C and 95°C, in particular between 40°C and 85°C, in particular between 50°C and 80°C, in particular between 65°C and 80°C, in particular between 70°C and 80°C. For example, exposure to such temperatures may be carried out for 5 min to 60 min, in particular from 15 min to 30 min. Indeed, the increase in temperatures during or after step e. may have a significant effect on the mechanical strength of the capsules.

[0174] Manufacturing process

[0175] Step a.

[0176] The preparation of the inverse emulsion of step a. falls within the general knowledge of a person skilled in the art. By way of illustration, the inverse emulsion of step a. can be obtained by means of conventional stirring methods, such as for example by stirring with a Rayneri, Rotor / stator, for example of the Ultraturrax / Ultrasound type.

[0177] Advantageously, the inverse emulsion of step a. comprises a “fatty phase / first aqueous phase” weight ratio of between 1 and 9, preferably between 1.5 and 5, and better still between 2.5 and 4. Step b.

[0178] The preparation of the second aqueous phase of step b. falls within the general knowledge of a person skilled in the art. By way of illustration, the second aqueous phase of step b. can be obtained using conventional stirring methods, such as for example by stirring with a Rayneri, Rotor / stator, for example of the Ultraturrax / Ultrasound type.

[0179] Step c.

[0180] The preparation of the dispersion of step c. can be obtained by means of any suitable microfluidic method.

[0181] According to this embodiment, the inverse emulsion drops obtained by this microfluidic method advantageously have a uniform size distribution.

[0182] Preferably, the dispersion of step c. comprises a “reverse emulsion / second aqueous phase” weight ratio of between 0.02 and 0.3, preferably between 0.05 and 0.25, better still between 0.07 and 0.20, and very particularly between 0.10 and 0.15.

[0183] In particular, the generation of the inverse emulsion drops in the second aqueous phase carried out in step c. may be based on any microfluidic emulsification technique known to those skilled in the art. In particular, the microfluidic emulsification technique may be chosen from:

[0184] - the T-junction (see figure IA);

[0185] - Flow focusing injunction (see figure IB), in which the fluids used go in different directions, and typically in opposite directions;

[0186] - coaxial capillaries (or “co-flow”; see figure IC), in which the fluids used go in the same direction; or

[0187] - step-emulsification (see Figure 1D); step-emulsification is a variant of the co-flow droplet generation technique, which is based on the instability of a two-phase liquid stream triggered by a sudden change in flow confinement. Preferably, the microfluidic emulsification technique is chosen from coaxial capillaries (or "co-flow") or step-emulsification, and better coaxial capillaries. Step-emulsification microfluidic process

[0188] According to a first embodiment, step c. of the manufacturing method according to the invention is based on a microfluidic emulsification technique of the “step-emulsification” type.

[0189] A microfluidic device particularly suited to this first embodiment is the device described in WO2021037999 and illustrated in figure 3, which notably comprises a first chamber and a second chamber fluidly connected by one or more conduits, preferably by micro-conduits.

[0190] Thus, according to this first embodiment, the manufacturing method according to the invention may comprise at least the steps consisting of: a', providing in a first chamber at least the inverse emulsion of step a.; b', providing in a second chamber at least the second aqueous phase of step b.; the first chamber and the second chamber being fluidically connected by one or more conduits, preferably by micro-conduits; c'. guiding the inverse emulsion of step a' from the first chamber through the conduit(s) into the second chamber; steps d'. and e' being identical to steps d. and e. defined above.

[0191] A manufacturing method according to this first embodiment is illustrated in Figure 2 and described in more detail below.

[0192] By "chamber" is meant a container configured to accommodate and store at least temporarily chemical substances, in fluid form such as a liquid or a gas. Typically, a chamber, in microfluidics, is an enlarged area of ​​the device where the fluid can accumulate. A chamber within the meaning of the present invention therefore designates a confined space larger than a conduit, often of irregular shape, which is used to contain a volume of fluid, two chambers being able to be connected by at least one conduit, like the device illustrated in Figure 3.

[0193] Thus, in the context of the present invention, a chamber is configured for a different operation and has a larger volume compared to a conduit. Therefore, a chamber according to the invention cannot be considered as a conduit. In the context of the present invention, the chambers are independent, i.e. according to the invention, a chamber is not positioned inside another chamber. In addition, the chambers according to the invention are connected only by the conduit(s). According to one embodiment, the method of the invention is of the “step-emulsification” type, in which a first phase and a second phase are located in separate chambers separated by at least one conduit; the mixing of the first phase with the second phase is carried out in the second chamber, after passage of the first phase through the conduit(s).

[0194] The microfluidic process of the "staged emulsification" type is characterized in that the mixing of the first phase with the second phase is carried out in the second chamber. In contrast, the meeting zone of the two phases in a "co-flow" type microfluidic process is always in at least one conduit (or channel). Thus, such a "staged emulsification" type process is different from a "co-flow" type microfluidic process.

[0195] The first chamber and the second chamber are typically separated from each other except for the channel, or channels, connecting the first chamber to the second chamber. A chamber as used herein is configured to be filled with a solution. Typically, the chambers are closed except for the inlets, channels and outlets. The first chamber typically comprises a first fluid inlet for introducing, in particular continuously, the emulsion forming the core in step a. into the first chamber and the second chamber has a second inlet for introducing, in particular continuously, the second aqueous phase of step b. into the second chamber. The second chamber also comprises an outlet for discharging, preferably continuously, the dispersion formed during step c.

[0196] It is understood that the channel(s) each comprise an inlet opening into the first chamber and an outlet opening into the second chamber. Thus, the channel(s) are directly connected to the first chamber and to the second chamber. Typically, the first chamber and the second chamber are fluidically connected by several channels, for example at least 10, at least 20, at least 30, at least 50 or at least 100 channels. Preferably, the first chamber and the second chamber are fluidically connected by 1 to 10,000,000, preferably 20 to 500,000, and more preferably 50 to 200,000 channels. Typically, the channels are arranged essentially parallel to each other.

[0197] For example, the channel(s) may have a diameter of between 0.25 and 2000 pm, preferably between 0.5 and 800 pm, more preferably between 1 and 500 pm, or even between 2 and 250 pm. The multiple channels of the membrane are typically microchannels. For example, each channel may have a cross-sectional area of ​​0.04 pm. 2 at 4,000,000 pm 2 , preferably 4 pm 2 at 640,000 pm 2 .

[0198] In other embodiments, the ratio "duct length / minimum diameter" may be between 5 and 1000, preferably between 10 and 500, in particular between 10 and 50. In certain embodiments, the length of the channel may be between 0.05 mm and 20 mm, in particular between 0.1 mm and 20 mm, in particular between 0.1 mm and 5 mm, in particular between 0.5 and 2 mm.

[0199] In some embodiments, each conduit comprises a channel outlet with a cross-section that is larger than the cross-section of the remaining portion of the respective channel. In the longitudinal direction, i.e., in the flow direction, the channel outlet has a typical length of a few micrometers, e.g., 200 μm to 20 mm, preferably 500 μm to 5 mm. The channel outlet may, for example, be funnel-shaped, V-shaped, or U-shaped, as described in WO2022106361. In some embodiments, the channel outlet may have an elliptical contour. In particular, the channel outlet is not rotationally symmetrical, thus having a length-to-width ratio of 3 and higher. Therefore, the channel outlet may not have a circular or square-shaped cross-section. Such a channel outlet allows the detachment of a droplet without external force.Therefore, the formation of droplets from the core-forming emulsion in the second aqueous phase is decoupled and thus essentially independent of the flow rate. According to the Young-Laplace equation, the pressure at an immiscible liquid interface is higher at the outlet of the channels than in the second reservoir. Thus, a pressure gradient along the flow direction is generated, which causes the fluid thread to detach into individual drops. Thus, a pressure gradient is generated at the end of the channel, which facilitates the detachment of the fluid boundary layer and thus the formation of individual drops. When it reaches the channel outlet, the pressure gradient of the dispersed phase inside and outside the channel of a drop detaches without external force.

[0200] Typically, each conduit is defined by conduit walls. The channel walls may be curved, i.e., the channel walls may have a convex or concave shape toward the channel outlet. Furthermore, each channel may include a constriction with a cross-section that is smaller than the cross-section of the remainder of the channel and wherein the constriction is arranged adjacent to the channel outlet. Thus, the constriction is arranged between the channel outlet and the remainder of the channel.

[0201] In other embodiments, the cross-sectional area of ​​each channel outlet is 0.12 to 36,000,000 pm 2 , preferably from 12 to 5,760,000 pm 2 . In particular, the total open area of ​​the second side of the membrane may be 300% to 1500%, preferably 400% to 900%, greater than the total open area of ​​the channels at any other given position, such as the main section and / or the channel inlets.

[0202] In some embodiments, the one or more channels may be comprised in a membrane separating the first chamber from the second chamber. In such embodiments, the membrane may be flat, for example, disc-shaped. The membrane typically has a first side facing the first chamber and a second side, being opposite the first side and facing the second chamber. Thus, the first side of the membrane may partially limit the first chamber and the second side of the membrane may partially limit the second chamber. The one or more channels, typically multiple channels, extend from the first side to the second side through the membrane. Each channel includes a channel inlet disposed on the first side, a channel outlet disposed on the second side, and a main section being disposed between the channel inlet and the channel outlet.

[0203] The membrane can typically be a single-layer membrane. That is, the membrane is made of a single piece. Preferably, such a membrane is made of a solid material and does not contain any phase interfaces or transition zones in addition to the multiple channels of the membrane. Such a membrane is advantageous for the quality of the generated drops, since all interfaces and phase transitions are detrimental to the formation and stability of the drops.

[0204] In some embodiments, the membrane may be exchangeable. The multiple channels of the membrane are typically microchannels. For example, each channel may have a cross-sectional area of ​​0.04 μm 2 at 4,000,000 pm 2 , preferably 4 pm 2 at 640,000 pm 2 .

[0205] In other embodiments, the channel outlet may be wedge-shaped. In particular, the channel outlet may comprise an elliptical cross-section with respect to a transverse plane perpendicular to the extending channel, i.e., the channel outlet may be larger in a first direction than in a second direction. In other embodiments, the second side of the membrane comprises a total open area that is greater than the total open area of ​​the first side. Such a membrane has the advantage of generating high-quality drops, even at flow rates of up to 5 l / h (or liter(s) per hour). In some embodiments, the flow rate per channel may be between 1 pl / h and 50 ml / h, preferably between 10 pl / h and 25 ml / h, and more preferably between 100 pl / h and 15 ml / h.

[0206] In some embodiments, each channel outlet may have an elliptical contour. Thus, the channel outlet may have an elliptical cross-section with respect to a plane being transverse to the extending channel and being parallel to the first or second side of the membrane. Channel outlets with an elliptical contour have a beneficial effect on the quality of the drops formed, as any edges within the channel may lead to unstable and inhomogeneous drops.

[0207] In some embodiments, the membrane is disc-shaped. Such a membrane may have a circular outline. Alternatively, the membrane may have an angular outline, such as triangular or rectangular.

[0208] In other embodiments, the membrane comprises 0.06 to 600,000 channels / cm 2 , preferably 20 to 30,000 channels / cm 2 .

[0209] In some embodiments, the membrane is made of glass or a polymeric material, such as poly(methyl meth)acrylate or PTFE, or a metallic material, such as steel.

[0210] In other embodiments, a pressure of 1.01 bar to 1.25 bar, preferably 1.03 bar to 1.17 bar is applied to the first chamber, in particular during step c., and / or a pressure of 1.02 bar to 1.3 bar, preferably 1.05 bar to 1.2 bar is applied to the second chamber, in particular during step c. It is understood that these pressure values ​​relate to absolute pressures, i.e. a pressure of 1.01 bar is a pressure which constitutes an overpressure of 0.01 bar relative to atmospheric pressure.

[0211] In some embodiments, the pressure applied to the first chamber is lower than the pressure applied to the second chamber. It is understood that the first pressure may be adjusted by the pressure with which the core-forming emulsion is supplied via the first inlet to the first chamber and / or the second pressure may be adjusted by the pressure with which the second aqueous phase of step b. is supplied via the second inlet to the second chamber. In some embodiments, the pressure applied to the first chamber is higher than the pressure applied to the second chamber. It is understood that the first pressure may be adjusted by the pressure with which the core-forming emulsion is supplied via the first inlet to the first chamber and / or the second pressure may be adjusted by the pressure with which the second aqueous phase of step b. is supplied via the second inlet to the second chamber.

[0212] In some embodiments, step c. is carried out with a device comprising a first inlet for supplying the inverse emulsion of step a., which opens into the first chamber, a second inlet for supplying the second aqueous phase, opening into the second chamber and an outlet at the second chamber to collect the dispersion and ensure its contact in the aqueous solution for forming the shell. In addition, the device comprises a membrane, in particular a membrane as described above, which separates the first chamber and the second chamber and which comprises a first side facing the first chamber and a second side facing the second chamber. The membrane comprises multiple channels extending from the first side to the second side, i.e. ensuring a fluidic connection of the first chamber and the second chamber.Each channel includes a channel inlet arranged on the first side and a channel outlet arranged on the second side. The first chamber may typically be configured such that a flow rate of the reverse emulsion through all individual channels is essentially equal.

[0213] In some embodiments, the second chamber may be made of glass or a transparent polymer, such as PTFE, poly(methyl meth)acrylate, or polyoxymethylene, or metals such as steel, aluminum, or titanium. Generally, the device may include a container, such as a glass container, that partially forms the second chamber. Together with the membrane, the container may form the second chamber. In some embodiments, the first chamber may be made of metal, for example, aluminum or steel, or a transparent polymer, such as PTFE, poly(methyl meth)acrylate, or polyoxymethylene.

[0214] The outlet of the second chamber may for example be in fluid communication with a container comprising the aqueous solution for forming the envelope, so as to carry out steps d. and e. In certain embodiments, steps d. and e. are carried out under a continuous flow of the dispersion formed in step c.

[0215] Preferably, the second chamber is tapered toward the outlet of the second chamber. For example, at least portions of the second chamber may be arc-shaped or cone-shaped toward the outlet of the second chamber. These embodiments ensure that no portion of the dispersion formed in step c. is trapped and is fully recoverable via the outlet of the second chamber.

[0216] In some embodiments, the first chamber has the shape of a hemisphere or a truncated cone. Typically, the hemisphere or truncated cone opens toward the membrane, i.e., the largest radius is typically closest to the membrane. The term "hemispherical" as used herein also includes other spherical segments, such as one-third of a sphere. Thus, in some embodiments, the shape of the first chamber is a spherical dome or a spherical cap. Typically, all of the channels are arranged substantially parallel to one another. Preferably, the first inlet is substantially arranged transversely, preferably perpendicularly, to the multiple channels of the membrane. Thus, in such embodiments, the first inlet may be parallel to the first side of the membrane.

[0217] In other embodiments, the device comprises a membrane holder for mounting the membrane. In some embodiments, the device comprises a container holder for holding the container, which partially forms the second chamber. The container holder may be fixedly and removably connected to the membrane holder. The container holder and / or the membrane holder and / or the base may be made of any suitable material such as a plastic material, such as PTFE, poly(methyl meth)acrylate or polyoxymethylene or a metal, preferably steel.

[0218] Preferably, if the container is a glass container, a shock absorbing pad may be arranged between the glass container and the container holder to prevent damage and seal the glass container.

[0219] In some embodiments, the membrane holder includes clamping means for mounting the membrane, the membrane holder and / or the clamping means being configured to receive membranes having different thicknesses. Typically, the clamping means may be adjustable. Examples of clamping means include screws, clamps, bolts, locks, etc. In some embodiments, the device includes a base, and preferably the first chamber is partially formed by the base.

[0220] In other embodiments, the base and / or the membrane holder includes at least one gasket for sealing the membrane against the base and / or against the membrane holder. The sealing ring may be configured so that it completely circumferentially surrounds the periphery of the membrane. The sealing ring may also include a gas outlet in fluid communication with the first chamber and being configured to vent any gas present in the first chamber out of the first chamber.

[0221] In some embodiments, the base and / or the membrane holder comprises a spacer ring. Such a spacer ring allows membranes of different thicknesses to be used.

[0222] In some embodiments, the device comprises at least one heater for heating the inverse emulsion and / or the second aqueous phase and / or at least the dispersion and / or a cooler for cooling the inverse emulsion and / or the second aqueous phase and / or the dispersion. The heater may for example comprise a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an IR heater, a heating coil or any other suitable heater.

[0223] In other embodiments, the device comprises a first reservoir for the inverse emulsion and / or a second reservoir for the second aqueous phase. Both the first and second reservoirs may be pressurized. For example, the reservoirs may be fluidically connected to a pressure source, such as a compressor. Alternatively, the reservoirs may be syringes and pressurized by a common syringe pump and / or a piston or peristaltic, gear, or other pumping system.

[0224] Co-flow microfluidic process

[0225] According to a second embodiment variant, step c. is based on a microfluidic emulsification technique of the coaxial capillary type (or "co-flow"). Thus, step c. is advantageously carried out in such a way that the second aqueous phase of step b. is circulated in a second conduit, the downstream opening of the first conduit opening into the second conduit, advantageously coaxially with the local axis of the second conduit. For the purposes of the present invention, the expressions "upstream" and "downstream" are understood to refer to the direction of movement of the fluids.

[0226] A step c. according to this second embodiment variant can in particular be carried out by means of the microfluidic device (or nozzle) described in figure 4.

[0227] This figure 4 represents a microfluidic device 30 comprising a single formation nozzle 32 comprising an internal conduit 34 (i.e. “first conduit”) for supplying an internal fluid 36 comprising the inverse emulsion of step a. 14, and an external conduit 38 (i.e. “second conduit”) arranged around the internal conduit 34 to supply an external fluid 40 comprising the second aqueous phase of step b. 16.

[0228] The internal conduit 34 is advantageously arranged coaxially in the external conduit 38. It is connected upstream to the supply means 46. It opens downstream through a downstream opening 52 arranged in the external conduit 38, set back relative to the downstream opening 54 defined by the external conduit 38.

[0229] The distance separating the downstream opening 52 of the internal conduit 34 and the downstream opening 54 of the external conduit 38 may preferably be greater than 1 time the diameter of the external conduit 38.

[0230] The external conduit 38 preferably delimits with the internal conduit 34 an annular space connected upstream to the supply means 48.

[0231] According to a first variant embodiment (not shown in the figure), the downstream opening 54 of the external conduit 38 is in fluid connection with a container 33 comprising the aqueous solution for forming the envelope 44, so as to ensure that steps d. and e. are carried out.

[0232] According to a second variant embodiment (not shown in the figure), the nozzle 32 is adapted so as to bring the aqueous solution for forming the envelope 44 through a third conduit 72 located in the immediate vicinity of the conduit of the external conduit 38.

[0233] According to a third variant embodiment (illustrated in figure 4), the nozzle 32 is adapted so as to bring the aqueous solution for forming the envelope 44 through a third conduit 72 in which the external conduit 38 is included, advantageously coaxially with the local axis of the third conduit 72.

[0234] In this third embodiment, the downstream opening 54 of the external conduit 38 can open before or after the downstream opening 56 of the third conduit 72. Preferably, the downstream opening 54 of the external conduit 38 opens after the downstream opening 56 of the third conduit. It is this embodiment which is shown in Figure 4 and considered for manufacturing the capsules of Examples 1 and 2 below.

[0235] The present invention also relates to a method in which the aqueous solution for forming the envelope of step d. can be circulated in a third conduit in which the second conduit is included, advantageously coaxially with the local axis of the third conduit, and preferably the downstream opening of the second conduit opens after the downstream opening of the third conduit.

[0236] In the container 33, (i) the mixing between the external fluid 40 and the aqueous shell-forming solution 44 and (ii) the reaction between the gelling-inducing agent and the matrix-forming agent takes place, whereby capsules are obtained comprising a water-insoluble matrix shell 12 enclosing the lipophilic core 17.

[0237] In Figure 4, the forming nozzle 32 comprises means 46 for supplying internal fluid 36 into the internal conduit 34, means 48 for supplying external fluid 40 into the external conduit 38, and in particular into the annular space delimited between the internal conduit 34 and the external conduit 38 and means 50 for supplying the aqueous solution for forming the envelope 44 into the supply conduit 42.

[0238] In the example shown in Figure 4, the device 30 has been illustrated with a single nozzle 32. In an advantageous variant, the device 30 comprises a plurality of nozzles 32 arranged below one or more containers 33.

[0239] According to the first and second embodiments, all the downstream openings 54 of the external conduits 38 are in fluid connection with the container 33 comprising the aqueous solution for forming the envelope 44.

[0240] According to the third embodiment, each third conduit 72 comprises an external conduit 38, advantageously coaxial with the local axis of the third conduit 72 associated with it.

[0241] The supply means 46, 48 and 50 each comprise, for example, a syringe pump, a peristaltic pump or another pressure generating system controlling the flow rate, such as, for example, a pressure pot coupled with a flow meter and a flow rate regulation system. Each of the supply means 46, 48, 50 is capable of conveying a respective fluid 36, 40, 44 at a controlled and adjustable flow rate. Advantageously, for carrying out steps e. and d., the container 33 further comprises a stirring device 75. Such a stirring device may be represented by any stirring device known to those skilled in the art. Such a stirring device may in particular be represented by the stirring device described in WO2023 / 099530.

[0242] In some embodiments, the device comprises at least one heater for heating the inverse emulsion and / or the second aqueous phase and / or at least the dispersion and / or a cooler for cooling the inverse emulsion and / or the second aqueous phase and / or the dispersion. The heater may for example comprise a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an IR heater, a heating coil or any other suitable heater.

[0243] According to a first embodiment, all the conduits have an identical diameter, which makes it possible to obtain monodisperse capsules.

[0244] According to a second embodiment, the conduits have different diameters, which makes it possible to obtain polydisperse capsules, with controlled polydispersity.

[0245] Steps d. and e.

[0246] In some embodiments, step d. and / or e. comprises stirring the aqueous shell-forming solution and the dispersion obtained in step d. Preferably, stirring is carried out with a stirrer with stirring speed of 10 rpm (for "revolutions per minute") to 800 rpm, preferably 25 rpm to 500 rpm, in particular 50 rpm to 350 rpm, and more preferably 100 rpm to 250 rpm. Mixing during step d. and step e. is beneficial because it prevents agglutination of the monodisperse drops of the formed dispersion and / or the formed capsules. This further ensures a uniform size distribution of the capsules and prevents the risk of agglomerations of the capsules with each other. Typically, an overhead stirrer or a stirring device as described in WO2023 / 099530 may be used.

[0247] In some embodiments, step e. is carried out between 30 seconds and 10 minutes, preferably between 45 seconds and 5 minutes, and more preferably between 1 minute and 2 minutes. The reaction time of step e., i.e. the time until the reaction is stopped, for example by separating or isolating the capsules from the aqueous shell-forming solution, directly influences the size of the capsules and the size of the capsule core. Preferably, the dispersion of step d. comprises a weight ratio of "inverse emulsion / (second aqueous phase + aqueous shell-forming solution)" of between 0.005 and 0.15, preferably between 0.01 and 0.12, in particular between 0.025 and 0.10, and more preferably between 0.05 and 0.075.

[0248] In some embodiments, the method may further comprise, after step e., at least one additional coating step by dipping. The additional coating step may in some embodiments comprise a step of contacting or immersing the capsules formed in step e. in a second aqueous shell-forming solution, identical or different from the shell-forming solution of step d., in particular in terms of nature and / or contents of matrix-forming agent(s). The second shell-forming solution comprises water and at least one matrix-forming agent, identical or different from the matrix-forming agent present in the shell-forming solution of step d.

[0249] In some embodiments, the capsules are coated with two or more additional layers. Thus, the dip coating can be repeated with different matrix-forming agents.

[0250] In certain embodiments, the method according to the invention further comprises at least one step f. of rinsing the capsules obtained at the end of step e. in a third aqueous solution comprising water, preferably osmosis water, and optionally at least one preservative. Typically, step f. can be carried out using a device as described in WO2023099536.

[0251] In certain embodiments, in particular after step e. or optionally after step f., the capsules formed are isolated, hardened and / or preserved.

[0252] Capsule isolation may, for example, include filtration or sieving to separate the capsules from the aqueous shell-forming solution, and possibly washing the capsules with water.

[0253] Curing may for example comprise drying the capsules, for example by an air stream or by freeze-drying, in order to evaporate all or at least the majority of the unbound water. Curing may also comprise further stirring of the capsules in an aqueous solution comprising at least one inorganic salt, such as CaCh or MgCh, preferably an aqueous solution of 1% to 10%, preferably 1% to 5%, by weight of inorganic salt(s). This further increases the stability and structural integrity of the capsules, in particular of the shell.

[0254] Preservation can be achieved by immersing the capsules in distilled water, in a solution comprising divalent cations or in an aqueous solution of inorganic salt, such as CaCh or MgCh.

[0255] In some embodiments, in particular after step e. or optionally after step f., the capsules are exposed to a solution comprising at least one chelating agent. The chelating agent is configured such that it can form a chelating complex with the gelation-inducing agent. For example, if the chelation-inducing agent is a calcium salt, such as CaCh, the chelating agent can form a chelating complex with Ca 2+. Suitable chelating agents are Lewis bases, such as EDTA, GLDA (tetrasodium N,N-Bis(carboxymethyl)-L-glutamate), MGDA (trisodium dicarboxymethyl alaninate), citrate acid salts, tartaric acid salts and the like. The solvent is usually chosen such that the chelating agent is soluble in it and the formed capsules, respectively the water-insoluble matrix, are not dissolved. Thus, a suitable solvent can be water. By exposing the capsules to such a solution for a predetermined time, the capsule shell is weakened, because the chelating agent forms chelates with a part of the gelation-inducing agent, respectively its derivatives. For example, if the gelling agent is CaCh and the chelation agent is sodium citrate, in the form of calcium citrate, which weakens the shell of the formed capsules.The advantage is that the embrittlement of the shell and thus the mechanical strength can be precisely controlled. Weakening may be desired for products in which the shells must break, or disintegrate, relatively quickly, for example in cosmetic products, such as skin creams. For example, 0.001 to 0.4% by weight, in particular 0.01 to 0.1% by weight, of sodium citrate and possibly NaCl in 0.6 times the amount of sodium citrate can be dissolved in water. The capsules are stirred in this solution for 10 min to 50 min, in particular 20 min to 40 min.

[0256] Brief Description of the Drawings The invention described herein will be better understood from the detailed description given below and the accompanying drawings which should not be construed as limiting the present invention.

[0257] The drawings show:

[0258] [Figl] Figure 1 is a schematic representation of the different microfluidic emulsification techniques, namely: A) T-junction, B) flow focusing junction, C) co-flow capillaries, and D) step-emulsification, where “Ud” means “linear flow velocity of the dispersed phase” and “Uc” means “linear flow velocity of the continuous phase”;

[0259] [Fig2] Figure 2 is a schematic representation of an example of a manufacturing process according to the invention in which step c. is carried out with a microfluidic device of the “step emulsification” type;

[0260] [Fig3] Figure 3 is a sectional view of the device shown in Figure 2;

[0261] [Fig4] Figure 4 is a schematic representation of an example of a manufacturing method according to the invention in which step c. is carried out with a microfluidic device of the “co-flow” type; Arrow 75 designates the presence of a stirring device in action in the container 33.

[0262] In Figures 1 to 4, with the exception of the aforementioned arrow 75, the arrows designate the direction of movement of the different fluids used.

[0263] Description of the embodiments

[0264] Figure 2 schematically illustrates a manufacturing method according to the invention in which step c. is carried out with a microfluidic device of the “step emulsification” type. In a first step, an inverse emulsion is generated by mixing a solution 101 comprising at least one gelation-inducing agent and water with the fatty phase 102 (Figure 2a). This can for example be done with the stirrer 103. Figure 2a) also shows an enlarged view of a drop of solution 101 in the emulsion. The straight lines of the drops represent drops comprising water and dissolved therein the gelation-inducing agent. Thus, each drop shown in Figure 2a) is an aqueous solution of the gelation-inducing agent. The emulsion formed from the aqueous solution 101 in the fatty phase 102 is then supplied into the first chamber 4 of a suitable device (Figure 2b).The second chamber 5 of the device comprises a second aqueous phase 104 comprising water and at least one surfactant. As can be seen, the first chamber 4 and the second chamber 5 are fluidically connected by several channels 10. In the embodiment shown, the first chamber and the second chamber are separated by a membrane 7 whose first side 8 faces the first chamber and whose second side 9 faces the second chamber. The channels 10 extend from the first side 8 to the second side 9. In general, an appropriate pressure is applied to the emulsion forming the core in the first chamber 4. The emulsion in the first chamber 4 is then guided through the channels 10. Since the emulsion generally comprises as its main component the fatty phase 102, an emulsification step takes place when the emulsion reaches the outlet of the channel opening into the second chamber 5, thus forming the dispersion of step c.which can be referred to as a water-in-oil-in-water transient emulsion (or “transient double emulsion”) in the form of monodispersed drops 113 in the second aqueous phase 104, the monodispersed drops 113 being formed from the solution 101 dispersed in the fatty phase. It should be noted that the sizes of the drops are exaggerated for clarity. In addition, the relative size of the drops 101 compared to the drops 113 and / or the capsules 106 does not resemble reality. Each monodispersed drop 113 in the second chamber 5 now comprises one or more drops 101 dispersed in the fatty phase 102. The transient emulsion then passes through the outlet of the second chamber 6 to be placed in a container 105 comprising the aqueous solution for forming the shell 104, optionally equipped with a stirrer 107 (Figure 2c).Indeed, when the dispersion, i.e. the monodispersed drops 113, are mixed with the aqueous shell-forming solution 104, the gelation-inducing agent contained in the drops 113 diffuses towards the surface of the drops, then reacts chemically at the interface with the matrix-forming agent to form a water-insoluble matrix shell, which develops entirely around each drop, thus forming capsules 106 of a water-insoluble matrix shell enclosing a lipophilic core.

[0265] Figure 3 shows a sectional view of the device of Figure 2. The device comprises a base 14 with a first inlet 2 for supplying the core emulsion. The inlet 2 opens into the first chamber 4, which is partially formed by the base 14. The device 1 further contains a container 19 with a second inlet 3 for supplying the second aqueous phase 104 and a second chamber outlet 6 for collecting the transient emulsion 104. The second inlet 3 opens into the second chamber 5, which is partially formed by the container 19. The first chamber and the second chamber are separated by the membrane 7. As can be seen in Figure 3, the first chamber has a rounded cross-section relative to the corresponding section plane along the central longitudinal axis 15 and being perpendicular to the membrane 7.In the particular embodiment shown, the first chamber 4 has a semicircular section and can thus have the shape of a hemisphere. The first inlet 2 is arranged at the pole 13 of the hemisphere. The second chamber 5 is conical towards the outlet 6, which is arranged on the longitudinal axis 15 extending along the longitudinal direction of the device, intersecting the center of the first and second chambers, being perpendicular to the membrane 7 and intersecting the center of the membrane. As can be seen, the longitudinal axis 15 constitutes a central axis of the device in the longitudinal direction. In the embodiment shown, the second chamber is arc-shaped towards the second chamber outlet 6. Thus, the second chamber 5 has a U-shaped section. The first inlet 2 is arranged at an angle α of substantially 90° relative to the central axis 15 and to the membrane channels, which are generally parallel to the axis 15.The device 1 comprises a membrane holder 20 and a container holder 21, which are fixedly connected to each other via removable clamping means 18. The membrane 7 is mounted on the membrane holder 20 by clamping the membrane between the membrane holder 20 and the base 14. The membrane holder 20 is fixedly connected to the base 14 via clamping means 18. To securely fix a glass container 19 between the membrane holder 20 and the container holder 21, the pad 23, which in the particular case is a foam pad, can be arranged between the container 19 and the container holder 21. The membrane holder 20 comprises a groove 22 for receiving the container 19.

[0266] Throughout the description, the expression "comprising a" shall be understood as being synonymous with "comprising at least one", unless otherwise specified. The expressions "between ... and ...", "from ... to ..." and "ranging from ... to ..." shall be understood inclusively, unless otherwise specified. Example

[0267] Example 1: Manufacturing of skincare capsules

[0268] From the solutions described in Table 1 below, perfume capsules were manufactured using the microfluidic device illustrated in Figure 4, with the flow rates described in Table 2. These capsules were then analyzed according to the assessment criteria described in Table 3.

[0269] [Table 1]

[0270] *: Sufficient Quantity For.

[0271] [Table 2]

[0272] [Table 3]

[0273] Results :

[0274] [Table 4]

[0275]

[0276] With test B, we observe that the removal of PVA in F OF is not detrimental to the proper formation of capsules. Against all expectations, test B even allows access to capsules with improved transparency compared to the Control.

[0277] With test C, it is observed that the removal of the surfactant in the inverse emulsion is not detrimental to the good formation of the capsules, with however a slight alteration of the homogeneity of the envelope. Test C is however advantageous due to the transparency of the lipophilic core which is obtained more quickly than with test B, undoubtedly due to a faster kinetics of destabilization of the inverse emulsion (*).

[0278] With test D, we observe that replacing the surfactant in AF with alcohol allows access to capsules with properties similar to those of test B.

[0279] With test E, we observe that the removal of the surfactant in the AF is not detrimental to the good formation of the capsules, with however an alteration of the sphericity of the capsules and the homogeneity of the envelope.

[0280] Test F is the one that allows access to capsules with improved properties compared to those of the Witness.

[0281] Similar results, although slightly less qualitative at the capsule level, were obtained using a microfluidic device such as that described in Figure 3. Example 2: Production of perfume capsules

[0282] From the solutions and flow rates described in Tables 5 and 6 below, perfume capsules were manufactured using the microfluidic device illustrated in Figure 4.

[0283] The assessment criteria used to evaluate these perfume capsules are identical to those of example 1.

[0284] [Table 5]

[0285] *: Sufficient Quantity For. [Table 6]

[0286] Results: [Table 7]

[0287] Example 2 shows that the invention works with an inverse emulsion in which the continuous fatty phase includes perfume, or even is composed of 100% perfume. Example 2 shows that the invention works with percentages of raw materials and an IF2 / IF1 weight ratio different from those described in Example 1.

[0288] Example 2 thus demonstrates the robustness and stability of the invention.

[0289] Similar results were obtained by adding 0.1% xanthan gum in the second aqueous phase (OF).

[0290] Similar results, although slightly less qualitative at the level of the perfume capsules, were obtained using a microfluidic device such as that described in Figure 2. The capsules of tests G, H and I are then mixed at a volume fraction of 70% in a new aqueous phase described in Table 8, whereby a heterogeneous mixture is obtained.

[0291] [Table 8]

[0292] * Sufficient Quantity For

[0293] These 3 heterogeneous mixtures are then packaged in devices with a capacity of 50 ml and comprising a dip tube with an internal diameter of 1.66 mm and a spray pump type dispensing member. Restitution tests are carried out, consisting of actuating the push button 4 times per hour for 8 hours and this, for 5 days, and observing during this use (i) the aspiration of the capsules, (ii) the delivery of a composition in the form of a spray, (iii) the olfactory rendering and (iv) the sensory rendering.

[0294] Results :

[0295] All 3 spray devices have satisfactory properties in terms of capsule suction and delivery of a composition in the form of a spray.

[0296] On the other hand, the 3 spray devices present differences in terms of olfactory and sensory rendering, as summarized in the table below.

[0297] [Table 9] [Table 10] It is noted that the absence of oil in Test I helps prevent the greasy effect. Without wishing to be bound by any theory, the inventors believe that the absence of oil in Test I is at least partly responsible for the significantly improved properties in terms of olfactory rendering, which is again particularly unexpected and advantageous when seeking to manufacture a perfume composition.

[0298] Similar results, although slightly less qualitative at the level of the perfume capsules, were obtained using a microfluidic device such as that described in Figure 2.

Claims

Claims 1. A method for manufacturing capsules comprising at least one matrix shell containing at least one lipophilic core, the method comprising at least the steps of: a. providing an inverse emulsion comprising a first aqueous phase dispersed in a continuous fatty phase, said first aqueous phase comprising water and at least one gelling-inducing agent; b. providing a second aqueous phase comprising water, said second aqueous phase being free of surfactant, and in particular free of polyvinyl alcohol and / or polysorbate; c. injecting the inverse emulsion of step a. into at least one first conduit opening into the second aqueous phase of step b., whereby a dispersion is obtained comprising drops of inverse emulsion of step a. dispersed in the second aqueous phase of step b.; d. bringing the dispersion of step c. into contact.with at least one aqueous shell-forming solution comprising water and at least one matrix-forming agent, the gelation-inducing agent and the matrix-forming agent being configured such that they are capable of undergoing a chemical reaction with each other to form a water-insoluble matrix shell; and e. reacting the gelation-inducing agent and the matrix-forming agent, whereby capsules comprising a water-insoluble matrix shell enclosing at least one lipophilic core are obtained.

2. The method of claim 1, wherein the gelation-inducing agent is an inorganic salt, in particular an alkaline earth metal salt, in particular an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate, an alkaline earth metal nitrate, and mixtures thereof.

3. Process according to claim 1 or 2, in which the first aqueous phase of the inverse emulsion of step a. comprises between 2.5% and 60%, preferably between 5% and 50%, better still between 10% and 40%, by weight of gelling-inducing agent(s) relative to the total weight of the first aqueous phase.

4. Method according to any one of the preceding claims, in which the inverse emulsion may further comprise at least one oil and / or at least one surfactant, preferably a non-ionic surfactant, and better still a surfactant chosen from polyglycerol polyricinoleate (PGPR), a sorbitan derivative, in particular a sorbitan ester, for example sorbitan monooleate, sorbitan trioleate, and mixtures thereof.

5. Method according to any one of the preceding claims, in which the fatty phase comprises between 0.01% and 2%, preferably between 0.05% and 1.5%, and better still between 0.1% and 1%, by weight of surfactant(s) relative to the total weight of the fatty phase.

6. Method according to any one of the preceding claims, in which the fatty phase further comprises at least one active agent, in particular at least one perfuming agent.

7. Method according to claim 6, in which the fatty phase comprises from 20% to 100%, preferably from 30% to 90%, and better still from 40% to 80%, by weight of active agent(s), in particular perfuming agent(s), relative to the total weight of the fatty phase.

8. Method according to any one of the preceding claims, in which the inverse emulsion comprises a “fatty phase / first aqueous phase” weight ratio of between 1 and 9, preferably between 1.5 and 5, and better still between 2.5 and 4.

9. Method according to any one of the preceding claims, in which the second aqueous phase of step b. further comprises at least one hydrophilic gelling agent, preferably chosen from agarose, xanthan gum, cellulose and its derivatives, methylcellulose, microcrystalline cellulose, and mixtures thereof, and preferably xanthan gum.

10. Process according to the preceding claim, in which the second aqueous phase of step b. comprises from 0.1% to 15%, preferably from 0.5% to 10%, and better still from 1% to 5%, by weight of hydrophilic gelling agent(s) relative to the total weight of the second aqueous phase.

11. Method according to any one of the preceding claims, in which the dispersion of step c. comprises a “reverse emulsion / second aqueous phase” weight ratio of between 0.02 and 0.3, preferably between 0.05 and 0.25, better still between 0.07 and 0.20, and very particularly between 0.10 and 0.

15.

12. A method according to any preceding claim, wherein the matrix-forming agent present in the aqueous shell-forming solution of step d. is a polysaccharide or one of its salts, preferably is chosen from chitosan, cellulose, alginate, in particular sodium alginate, carrageenan, agar, agarose, pectins, gellan, starch, and mixtures thereof.

13. A method according to any one of the preceding claims, wherein the aqueous shell-forming solution of step d. comprises between 0.1% and 5%, preferably between 0.15% and 2.5%, and more preferably between 0.2% and 1%, by weight of matrix-forming agent(s) relative to the total weight of said aqueous shell-forming solution.

14. A method according to any one of the preceding claims, wherein the aqueous shell-forming solution further comprises at least one surfactant, preferably selected from a polyglycerol ester, polyvinyl alcohol, polysorbate, saponins, sapogenins, quillaja extract, gum arabic, beta lactoglobulin, sodium dodecyl sulfate, soy lecithin, sodium cesinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

15. A method according to any one of the preceding claims, wherein the aqueous solution for forming the envelope further comprises at least one alcohol, in particular methanol, ethanol, propanol, and mixtures thereof.

16. A method according to any one of the preceding claims, wherein step a. comprises at least the substeps of: a1. dissolving the gelling-inducing agent in water to form the first aqueous phase; and a2. mixing the first aqueous phase formed in step a1. with the fatty phase.

17. A method according to any one of the preceding claims, wherein steps d. and e. are carried out with stirring, preferably with stirring from 10 rpm to 800 rpm, preferably from 25 rpm to 500 rpm, in particular from 50 rpm to 350 rpm, and more preferably at 100 rpm to 250 rpm.

18. Method according to any one of the preceding claims, wherein step e. is carried out between 30 seconds to 10 minutes, preferably between 45 seconds to 5 minutes, and more preferably between 1 minute to 2 minutes.

19. A method according to any preceding claim, wherein the matrix shell and the lipophilic core of the capsules are transparent.

20. Method according to any one of the preceding claims, in which step c. is carried out in such a way that the second aqueous phase of step b. is circulated in a second conduit, the downstream opening of the first conduit opening into the second conduit, advantageously coaxially with the local axis of the second conduit.

21. Method according to the preceding claim, in which the aqueous solution for forming the envelope of step d. is circulated in a third conduit in which the second conduit is included, advantageously coaxially with the local axis of the third conduit, and preferably the downstream opening of the second conduit opens after the downstream opening of the third conduit.

22. A method according to any one of claims 1 to 19, wherein the method comprises at least the steps of: a', providing in a first chamber at least the inverse emulsion of step a.; b', providing in a second chamber at least the second aqueous phase of step b.; the first chamber and the second chamber being fluidically connected by one or more conduits, preferably by micro-conduits; c'. guiding the inverse emulsion of step a' from the first chamber through the conduit(s) into the second chamber; steps d'. and e' being identical to steps d. and e. defined according to any one of claims 1 to 19.

23. Method according to any one of the preceding claims, said method further comprising at least one step f. of rinsing the capsules obtained at the end of step e. in a third aqueous solution comprising water, preferably osmosis water, and optionally at least one preservative.

24. A set of capsules comprising a plurality of capsules produced according to the method according to any one of the preceding claims, wherein the capsules preferably have an average diameter of between 250 pm and 3,000 pm, preferably between 500 pm and 2,000 pm, in particular between 1,000 pm and 1,750 pm, and better still between 1,200 pm and 1,500 pm, preferably with a coefficient of variation of less than or equal to 10%, preferably less than or equal to 5%, and better still less than or equal to 3%.

25. Set of capsules according to the preceding claim, in which the capsules comprising between 5% and 30%, preferably between 10% and 20%, and better still between 12 % and 15%, by weight of active agent(s), in particular perfuming agent(s), relative to the total weight of the capsules.

26. Capsule set according to claim 24 or 25, wherein the capsule set comprises less than 10%, preferably less than 5%, in particular less than 2.5%, or even is free of alcohol(s), in particular ethanol, relative to the total weight of said set.

27. Packaging and distribution device in the form of a spray of fluid composition, in particular cosmetic, characterized in that it comprises at least: - a container comprising at least one heterogeneous mixture; - a guide conduit arranged in the container; and - a dispensing member capable of sucking up heterogeneous mixture from the container, transforming the heterogeneous mixture into the fluid composition and dispensing the fluid composition in the form of a spray, the heterogeneous mixture comprising a set of capsules as defined in claims 24 to 26 dispersed in a continuous phase.

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