Improved manufacturing process for capsules comprising a double matrix shell enclosing a lipophilic core

Abstract

Improved manufacturing method for capsules comprising a double matrix shell containing a lipophilic core. The present invention relates to a method for manufacturing capsules comprising at least one water-insoluble double matrix shell containing at least one lipophilic core. Figure for abstract: None

Description

Title of the invention: Improved manufacturing method for capsules comprising a double matrix shell enclosing a lipophilic core

[0001] The invention relates to a method for manufacturing capsules comprising at least one double matrix envelope enclosing at least one lipophilic nucleus. Technical field

[0002] Capsules with a particle size of less than 3 mm have found wide application, particularly in the fields of pharmaceuticals, cosmetics, diagnostics, food processing, and materials science. Such capsules can be made from an emulsion of monodisperse droplets in a continuous phase. Monodispersity increases stability and allows for precise volume control in numerous chemical or biological reactions. Microfluidics provides a suitable platform for forming such monodisperse droplets.

[0003] For many applications, it is desirable to provide capsules with an oily core, that is, a core comprising at least one oil, enclosed in a suitable coating. This is mainly due to the fact that many compounds of interest, for example, flavorings, perfumes, cosmetic or pharmaceutical active ingredients, or vitamins, are hydrophobic and / or soluble only in an oil phase, but not in water. Previous technique

[0004] There are several known processes, including microfluidic ones, for producing capsules from monodisperse drops, and in particular the one described in patent application WO2022106361.

[0005] The manufacturing process according to WO2022106361 is based on the following steps: - the encapsulation of an inverse emulsion composed of an aqueous phase comprising at least one salt dispersed in a continuous oily phase comprising at least one oil and at least one active agent, the inverse emulsion being stabilized by a first surfactant; - contacting this inverse emulsion with an aqueous solution comprising at least one second surfactant, in particular polyvinyl alcohol (PVA), thereby obtaining a double emulsion; and - the contacting of this double emulsion with an alginate solution comprising a third surfactant and alcohol, in particular an ethoxylated surfactant such as, for example, Tween 20.

[0006] The process described in patent application WO2022106361, however, presents several disadvantages.

[0007] First, the process described in WO2022106361 makes extensive use of surfactants, the use of which is increasingly criticized, particularly in cosmetics, because they are often irritating, petrochemical-based, non-biodegradable, and highly ecotoxic. Furthermore, ethoxylated surfactants are becoming less and less accepted due to their potential carcinogenicity.

[0008] Secondly, the process according to WO2022106361 makes significant use of alcohol, and in particular ethanol, namely approximately 20% in the alginate solution, to improve the diffusion of the gelling agent towards the droplet interface, thereby increasing the thickness of the shell and the stability of the capsule. However, the use of alcohols is also increasingly criticized, particularly in cosmetics (drying and irritation of the skin, disruption of the skin microbiome, comedogenic effect, allergic reactions (redness, itching and / or swelling)). Ethanol also has a negative impact on the environment, notably due to its production, which requires the use of pesticides and fertilizers in the cultivation of the source plants, and its polluting nature due to poor biodegradability.

[0009] Finally, the capsules obtained with this process, although sprayable, have limitations in terms of active agent concentration. When this active agent is a perfumer, the capsules obtained with this process 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). Description of the invention

[0010] It is therefore a general aim to advance the state of the art relating to the manufacture of capsules and in particular to propose an improved alternative to the prior art described above.

[0011] Contrary to all expectations, the inventors observed that it is possible to improve, and in particular to overcome, the disadvantages of the prior art manufacturing process described above, by adapting the latter so as to form double-walled capsules. Summary of the invention

[0012] Thus, the invention relates to a method for manufacturing capsules comprising at least one double matrix envelope containing at least one lipophilic nucleus, the method comprising at least the steps of: a. to have a reverse emulsion comprising a first aqueous phase dispersed in a continuous oily phase, the first aqueous phase comprising water and less one gelling and oil phase-inducing agent comprising at least one active agent, in particular at least one perfumer; b. have a first aqueous envelope forming solution comprising water and at least one first matrix forming agent; c. bring the reverse emulsion of step a. into contact with at least the first aqueous shell-forming solution of step b., thereby obtaining a DI dispersion in the form of a water-in-oil-in-water emulsion, the gelling-inducing agent and the first matrix-forming agent being configured so that they are capable of undergoing a chemical reaction with each other to form a first water-insoluble matrix shell; d. to react the gelling-inducing agent and the first matrix-forming agent, whereby the dispersed phase of the DI dispersion is in the form of capsules comprising a first water-insoluble matrix envelope containing at least one lipophilic nucleus; e. bringing into contact the capsules comprising a first matrix shell obtained in step d, or even the dispersion DI of step d, with at least a second aqueous shell-forming solution comprising water and at least a second matrix-forming agent, identical or different from the first matrix-forming agent, thereby obtaining a dispersion D2, the gelling-inducing agent and the second matrix-forming agent being configured such that they are capable of undergoing a chemical reaction with each other to form a second water-insoluble matrix shell, and f. react the gelling-inducing agent and the second matrix-forming agent, whereby the dispersed phase of the dispersion D2 is in the form of capsules comprising a double water-insoluble matrix envelope containing at least one lipophilic core.

[0013] Unexpectedly, and as can be seen from the example below, the inventors observed that the formation of double-walled capsules allows for reduced use of surfactant(s) and / or alcohol(s), makes it possible to significantly increase the concentration of active agent(s), and in particular of perfumer(s), without altering the sprayability and the ability to precisely control the size of the capsules and the thickness of their wall.

[0014] The maintenance of satisfactory sprayability is particularly unexpected insofar as a double envelope implies greater mechanical resistance than a single envelope, and therefore appears at first glance contradictory with good sprayability.

[0015] With a process according to the invention, the first matrix grows around the nucleus by a chemical reaction between the gelling-inducing agent, present within each The first drop of inverse emulsion, and the first matrix-forming agent, present in the first aqueous envelope-forming solution, are then combined. The second matrix grows around the first matrix through a chemical reaction between the gelling-inducing agent, present in each drop of inverse emulsion, and the second matrix-forming agent, present in the second aqueous envelope-forming solution, and possibly also the first matrix-forming agent. Indeed, steps e and f are carried out consecutively to step d. Therefore, the second aqueous envelope-forming solution is necessarily mixed with the first aqueous envelope-forming solution, thus leading to a mixing of the second matrix-forming agent with at least the portion of the first matrix-forming agent that has not yet reacted with the gelling-inducing agent during the formation of the first matrix.

[0016] The first matrix-forming agent is typically dissolved in the first aqueous envelope-forming solution. The second matrix-forming agent is typically dissolved in the second aqueous envelope-forming solution.

[0017] A manufacturing process according to the invention is further advantageous in that it allows in particular access to capsules whose double matrix envelope and / or lipophilic core is / are transparent.

[0018] Preferably, a process according to the invention does not include an evaporation or removal step of solvent(s), in particular as described in WO2022179982.

[0019] It is understood that a manufacturing process according to the invention does not include a step of dropping drops or capsules by gravity through a volume of air, in particular in a solution in which they are immersed, like the process described in WO2010063937, which can therefore be described as a liquid / air capsule manufacturing process.

[0020] In other words, a process according to the invention can be described as a liquid / liquid method for manufacturing capsules.

[0021] It is understood that steps a and b do not necessarily have to be performed in that order. It may also be possible to perform step b first and then step a, or to perform them simultaneously. It is understood that steps c and d may be performed simultaneously. It is also understood that steps e and f may be performed simultaneously.

[0022] It is understood that the DI dispersion formed in step c comprises a plurality of monodisperse droplets including the inverse emulsion of step a as the dispersed phase in the first aqueous envelope-forming solution of step b as the continuous phase. The DI dispersion formed in step c can be described as a transient water-in-oil-in-water emulsion (or "transient double emulsion"). " in the form of drops dispersed in the first aqueous envelope formation solution of step b., the drops being formed from the first aqueous phase dispersed in the oily phase.

[0023] It is further understood that the composition of the lipophilic core of the capsules obtained at the end of step d is not identical to the composition of the inverse emulsion of step a, which is used to form the core of the capsules, particularly given that the first dispersed aqueous phase and certain reagents react and / or diffuse, in whole or in part, from the core, notably into the aqueous solution used for shell formation. This is particularly the case for the gelling-inducing agent.

[0024] It is also understood that the composition of the lipophilic core of the capsules obtained at the end of step f is not identical to the composition of the lipophilic core of the capsules obtained at the end of step d, particularly given that the first dispersed aqueous phase and certain reagents also react and / or diffuse, in whole or in part, from the core, notably towards the second aqueous shell-forming solution. This is particularly the case for the gelling-inducing agent.

[0025] Nevertheless, the lipophilic core of the capsules obtained at the end of step f 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 f is composed of the fat phase. Typically, the capsules obtained at the end of step f comprise more than 60%, preferably more than 70%, in particular more than 80%, better more than 90%, in particular more than 95%, and especially more than 99%, by weight of fat phase relative to the total weight of the capsule core.

[0026] In step c., each drop of inverse emulsion generated comprises mainly the oily phase from step a., but also the dispersed aqueous phase which includes the gelling-inducing agent from step a. Thus, the DI dispersion formed in step c. is a water-in-oil-in-water dispersion where the continuous aqueous phase is the first aqueous solution for envelope formation.

[0027] The gelling-inducing agent and the first shell-forming agent are configured so that they are capable of undergoing a chemical reaction with each other to form the first water-insoluble matrix shell, and the gelling-inducing agent and the second shell-forming agent are configured so that they are capable of undergoing a chemical reaction with each other to form the second water-insoluble matrix shell, including when the first water-insoluble matrix shell has already been formed. These can, for example, be configured to undergo a complexation reaction, an ion-exchange reaction, or an interphase-limited polymerization reaction.

[0028] For the purposes of this invention, the term "capsule" refers to a substantially spherical macroscopic core / shell element, in which the shell (or "envelope" or "membrane") completely encapsulates the core (or "nucleus") and the core comprises at least one droplet of the oil phase. A capsule comprising a single shell, particularly one obtained in step d of a process according to the invention, may be referred to interchangeably as a "single-shell capsule." A capsule comprising at least two shells, such as those obtained in step f of a process according to the invention, may be referred to interchangeably as a "double-shell capsule."

[0029] In other words, by "double-walled capsule" means, in the context of the present invention, a substantially spherical macroscopic element of the core / shell type, in which the first wall totally encapsulates the core and the core comprises at least one drop of oily phase, and the second wall totally encapsulates (or surrounds) the first wall.

[0030] Within the framework of the present invention and in view of the foregoing, step d. allows access to single-walled capsules and step f. allows access to double-walled capsules.

[0031] The capsules according to the invention are advantageously substantially spherical.

[0032] The capsules according to the invention are advantageously macroscopic and of monodisperse preference.

[0033] By "macroscopic", we mean, for the purposes of the present invention, capsules visible to the naked eye. Preferably, the capsules according to the invention have an average diameter of between 250 µm and 3,000 µm, preferably between 500 µm and 2,000 µm, in particular between 1,000 µm and 1,750 µm, and better between 1,200 µm and 1,500 µm, preferably with a coefficient of variation less than or equal to 10%, preferably less than or equal to 5%, and better less than or equal to 3%.

[0034] Preferably, the capsules according to the invention have a lipophilic core which has an average diameter between 250 µm and 2,500 µm, preferably between 500 µm and 2,000 µm, in particular between 750 µm and 1,500 µm, and better between 1,000 µm and 1,250 µm, preferably with a coefficient of variation less than or equal to 10%, preferably less than or equal to 5%, and better less than or equal to 3%.

[0035] Thus, the capsules according to the invention, when placed in the presence of a physiologically acceptable medium as described below, allow access to dispersions in which the phases constituting them form a macroscopically inhomogeneous mixture.

[0036] In view of the above, the first and second layers are therefore aqueous phases, and more particularly aqueous phases in the form of gels. Preferably, the first and second layers are transparent.

[0037] Advantageously, the first and second shells have a uniform thickness. For the purposes of this invention, "uniform thickness" refers to capsules in which the thickness of the double shell (or total shell), that is, the shell formed by the combination (or superposition) of the first and second shells, varies by a standard deviation of 10% or less, preferably 5% or less. In the expressions "first shell," "second shell," and "double shell," the term "shell" may be referred to interchangeably as "membrane" or "shell."

[0038] Preferably, the capsules according to the invention have a double envelope (or "final envelope") with a thickness of between 50 microns and 600 microns, preferably between 100 microns and 500 microns, better between 150 microns and 400 microns, and particularly between 200 microns and 350 microns.

[0039] Preferably, in the capsules according to the invention, the first shell has a thickness between 10 microns and 300 microns, preferably between 25 microns and 250 microns, better between 50 microns and 200 microns, and particularly between 75 microns and 150 microns.

[0040] Preferably, in the capsules according to the invention, the second layer has a thickness between 75 microns and 600 microns, preferably between 100 microns and 500 microns, better between 150 microns and 400 microns, and particularly between 200 microns and 300 microns.

[0041] For the purposes of this invention, "conduit" means 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 as defined in this invention may be referred to interchangeably as a "micro-conduit," "channel," or "micro-channel." A conduit may be described, in particular, as an elongated and narrow structure, generally circular or rectangular in cross-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, such as the internal conduit 34, external conduit 38, or even the third conduit 72 described below, is distinct from and different from a chamber as described in the "step-emulsification" embodiment below and illustrated in [Fig. 3].In a microfluidic device, a "chamber" refers to a confined space larger than a conduit, often irregularly shaped, used to contain a volume of fluid. Two chambers can be connected by at least one conduit, as illustrated in [Fig. 3]. Also, to avoid any ambiguity, such a conduit is not equivalent to the guide conduit considered in a conditioning and distribution device described below.

[0042] 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 conveyed therein. The material fitting 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, particularly when step c. relies on the co-flow microfluidic process described below.

[0043] Unless otherwise indicated, in all that follows, it is assumed that we are at ambient temperature (for example T=25°C ± 2°C) and atmospheric pressure (760 mm of Hg, i.e. 1.013.105 Pa or 1013 mbar).

[0044] According to the invention, the pH is typically between 3.0 and 8.0, in particular between 4.0 and 7.0. Brief description of the drawings

[0045] The invention described herein will be better understood from the detailed description given below and the accompanying drawings, which should not be considered as limiting the invention described in the attached claims.

[0046] The drawings show:

[0047] [Fig.1] Fig.1 is a schematic representation of the different microfluidic emulsification techniques, namely: A) T-junction, B) flow focusing junction, C) coaxial 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".

[0048] [Fig.2] Fig.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.

[0049] [Fig.3] [Fig.3] is a cross-sectional view of the microfluidic device shown in [Fig.2],

[0050] [Fig. 4] Fig. 4 is a schematic representation of an example of a manufacturing process according to the invention in which step c is carried out with a co-flow type microfluidic device. Arrow 75 indicates the presence of an agitation device in operation in the container 33.

[0051] [Fig.5] The [Fig.5] is a photograph obtained by optical microscopy of single-envelope capsules, similar to those obtained with a process according to WO2022106361.

[0052] [Fig.6] The [Fig.6] is a photograph obtained by optical microscopy of double-envelope capsules according to the invention and corresponding to test C of the example below.

[0053] In figures 1 to 4, with the exception of the aforementioned arrow 75, the arrows indicate the direction of movement of the different fluids used. Detailed description Reverse emulsion

[0054] Step a. consists of having an emulsion comprising an aqueous phase dispersed in a continuous oily phase, the dispersed aqueous phase comprising water and at least one gelling-inducing agent and said oily phase comprising at least one active agent, in particular at least one perfumer.

[0055] Step a. therefore consists of having an inverse emulsion, also referred to interchangeably as "water-in-oil emulsion" or "IF".

[0056] For obvious reasons, the reverse emulsion for carrying out step c is in liquid (or fluid) form. By "liquid" in the context of the present invention, we mean a non-solid reverse emulsion, and in particular one capable of flowing under its own weight and passing through the conduit(s) described below in step c.

[0057] To satisfy this condition, the reverse emulsion can be preheated and / or hot injected in step c.

[0058] For obvious reasons, the dispersed aqueous phase and the continuous oily phase are substantially immiscible.

[0059] By "substantially immiscible" in the context of the present invention, it is understood that the solubility of a first phase in a second phase is advantageously less than 5% by mass, and vice versa. Continuous fat phase

[0060] The fatty phase of step a. may also be designated "IF2". The fatty phase of step a. comprises at least one active agent, also designated as "compound of interest". An active agent can be chosen from among a biological active, a pharmaceutical active and / or a cosmetic active, for example chosen from among moisturizing agents, healing agents, depigmenting agents, UV filters, desquamating agents, antioxidant agents, actives stimulating the synthesis of dermal and / or epidermal macromolecules, dermo-contracting agents, antiperspirant agents, soothing agents, anti-aging agents, perfumer agents, anticoagulants, antithrombogenics, antimitotic agents, antiproliferative agents, antiadhesion, antimigration agents, cell adhesion promoters, growth factors, antiparasitic molecules, anti-inflammatories, angiogenics, angiogenesis inhibitors, vitamins,Hormones, proteins, antifungals, antimicrobial molecules, antiseptics or antibiotics, aromas, antibodies, peptides, enzymes, RNA, DNA, microorganisms, and mixtures thereof.

[0061] The active agent may already be present / mixed in the oil phase or also added only after the aqueous solution formed of the gelling-inducing agent in water is mixed with the oil phase.

[0062] In particular, the oily phase of step a. comprises at least one perfumer. Fragrance agent(s)

[0063] A fragrance agent according to the invention is a lipophilic agent, that is, one capable of being solubilized or dispersed in an organic solvent, in particular an oil. However, for the purposes of this invention, a fragrance agent is not necessarily solubilized or dispersed in an organic solvent. A "fragrance agent," also referred to interchangeably as "perfume," "perfume juice," or "perfume concentrate," for the purposes of this invention, can be chosen from compounds having the INCI name "Parfum" or "Fragrance." Thus, for the purposes of this invention, the term "perfume" does not refer to a mixture comprising a perfume concentrate and alcohol. The fragrance 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 could not, moreover, be exhaustive, as the expert is capable of choosing them based on their general knowledge and according to the desired olfactory effect. These perfume 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 listed in reference texts such as S. Arctander's book, Perfume and Flavor Chemicals, 1969, Montclair, New Jersey, USA, or its more recent editions, or in other works of a similar nature, as well as in scientific literature and more recent patents relating to the art of perfumery.For example, a fragrance agent is a compound or mixture of compounds that is at least partially volatile at room temperature and whose odor can be detected. A fragrance agent composed of essential oils is generally diluted to express its full olfactory potential, meaning a perception that evolves throughout the day after application to the surface to be treated, thanks to the presence of several fragrant organic compounds with varying volatilities. The creation of a perfume includes a step of combining several fragrant raw materials to give the fragrance composition a top note, a middle note, and a base note. A fragrance agent can be prepared from natural or synthetic organic fragrant materials.Examples of natural fragrance materials include extracts of flowers, stems, leaves, fruits, bark, roots, woods, herbs, grasses, resins, balms, and mixtures thereof. These plant-based fragrance materials 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. Examples of synthetic fragrance materials include... 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 ether, linear alkanals of 8 to 18 carbon atoms, citral, citronellal, citronellyl oxyacetaldehyde, cyclamenaldehyde, hydroxycitronellal, ionones such as alpha-isomethyl ionone, methyl cedrylketone, anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, terpineol, terpenes, and mixtures thereof. These compounds often occur as a mixture of two or more of these odoriferous substances.

[0064] Of course, a person skilled in the art will take care to choose any 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 proposed addition. These adjustments fall within the general knowledge of a person skilled in the art.

[0065] The oily phase may advantageously comprise from 20% to 100%, preferably from 40% to 99%, and better from 60% to 95%, by weight of active agent(s), in particular of perfumer agent(s), relative to the total weight of the oily phase.

[0066] Insofar as the oily phase may comprise only one or more active agents, particularly when this agent is a fragrance agent, the core of the capsules is designated by the expression "lipophilic core" and not by the expression "oily core," which would have suggested the presence of at least one oil, which is not mandatory with the present invention. Consequently, in the context of the aforementioned water-in-oil and water-in-oil-in-water emulsions, the term "oil" does not necessarily imply that the corresponding oily phase comprises at least one oil but may, on the contrary, and according to a particular embodiment, designate an oily phase devoid of oil. Surfactant(s)

[0067] According to a first embodiment, the oily phase of step a. does not include a surfactant, in particular as defined below, and in particular a lipophilic surfactant.

[0068] The removal of this surfactant is particularly unexpected as it goes against the teaching of WO2022106361, where this surfactant is described as necessary to ensure adequate stabilization of the aqueous phase droplets dispersed in the emulsion forming the oily core.

[0069] According to a second embodiment, the oily phase of step a. further comprises at least one lipophilic surfactant, in particular at least one surfactant suitable for forming a reverse emulsion, and in particular a surfactant having an HLB < 10, and preferably between 2 and 8, and better between 3 and 5. Preferably, the surfactant may be a nonionic surfactant, in particular selected from polyglycerol polyricinoleate (PGPR), a sorbitan derivative, in particular a sorbitan ester, for example sorbitan monooleate and / or sorbitan trioleate, such as Span 80 or Span 85, and mixtures thereof. In particular, the oil phase of step a. comprises a surfactant selected from POLYGLYCERYL-2 ISOSTEARATE (3,2), POLYGLYCERYL-6 POLYRICINOLEATE (3,3), POLYGLYCERYL-4 POLYRICINOLEATE (3,5), and mixtures thereof.

[0070] According to the invention, the oily phase of step a. can comprise between 0.01% and 2%, preferably between 0.05% and 1.5%, better between 0.1% and 1%, or even between 0.1% and 0.5%, by weight of surfactant(s) relative to the total weight of the oily phase.

[0071] Preferably, the oil phase of step a. does not include a solid particle surfactant, for example, a hydrophilic, hydrophobic, or Janus-type particle. Oil(s)

[0072] According to a first embodiment, the oily phase of step a. does not include oil, in particular as defined below.

[0073] According to a second embodiment, the oil phase of step a. further comprises at least one oil, in particular selected from vegetable hydrocarbon oils; animal hydrocarbon oils; synthetic esters and ethers, particularly of fatty acids; linear or branched hydrocarbons of mineral or synthetic origin; silicone oils, such as polymethylsiloxanes (PDMS); fatty alcohols having from 8 to 26 carbon atoms; and / or partially hydrocarbon and / or silicone fluorinated oils. In particular, the oil phase comprises at least one oil selected from Caprylic / Capric Triglyceride, isopentyldiol, caviar oil, and mixtures thereof.

[0074] Preferably, the oily phase does not include any oil selected from Caprylic / Capric Triglyceride, isopentyldiol, caviar oil, and mixtures thereof. Lipophilic gelling agent(s)

[0075] According to a first embodiment, the fatty phase of step a. does not include a lipophilic gelling agent.

[0076] According to a second embodiment, the oil phase of step a. further comprises at least one lipophilic gelling agent, i.e., soluble or dispersible in the oil phase, preferably chosen from organic or mineral, polymeric or molecular gelling agents; solid fats at ambient temperature and pressure, in particular chosen from waxes, pasty fats, butters; and mixtures thereof, and preferably among polymeric gelling agents. Such lipophilic gelling agents are described in particular in WO2019002308.

[0077] Among lipophilic gelling agents, we can also mention: - the glycerin and hydroxystearic acid triester, such as that marketed under the name THIXCIN® R by Elementis Specialties (INCI: Trihydroxystearin), - polyurethane-79, such as that marketed under the name OILKEMIA™ 5S polymer by the Lubrizol company (INCI: Caprylic / Capric Triglyceride (and) Polyurethane-79), - the crosslinked polymer hexamethylene diisocyanate (HDI) / trimethylol hexyllactone, such as that marketed under the name Oilkemia™ 5S CC polymer (INCI: Caprylic / Capric Triglyceride (and) Hydrogenated Poly(C6-20 Olefin) (and) HDI / Trimethylol Hexyllactone Crosspolymer) or under the name Oilkemia™ Alpha POF polymer (INCI: Hydrogenated Poly(C6-20 Olefin) (and) HDI / Trimethylol Hexyllactone Crosspolymer), - castor oil / isophorone diisocyanate (IPDI) copolymer, such as those marketed under the name Estogel M by the company PolymerExpert (INCI: CASTOR OIL / IPDI COPOLYMER & CAPRYLIC / CAPRIC TRIGLYCERIDE), or under the name EMC30 (INCI: Caprylic / Capric Triglyceride (and) Castor Oil / IPDI Copolymer) or EMI30 (INCI: Isononyl Isononanoate (and) Castor Oil / IPDI Copolymer (and) Caprylic / Capric Triglyceride), - the hydrogenated castor oil / sebacic acid copolymer (INCI name: Hydrogenated Castor Oil / Sebacic Acid Copolymer), as well as its derivatives, notably marketed respectively under the names Estogel Green (or Estogel G) and Estogel Green 40 by PolymerExpert, and - their mixtures.

[0078] Advantageously, a lipophilic gelling agent is a thermosensitive 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.

[0079] Naturally, a person skilled in the art will take care to choose the lipophilic gelling 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, and in particular sprayability. These adjustments fall within the general knowledge of a person skilled in the art.

[0080] According to the invention, an inverse emulsion according to the invention can comprise between 0.1% and 20%, preferably between 0.5% and 10%, or even between 1% and 5%, and better between 2% and 3%, by weight of lipophilic gelling agent(s) relative to the total weight of the oil phase. First dispersed aqueous phase

[0081] The first dispersed aqueous phase of the reverse emulsion of step a., also designated "IF1", comprises at least water and at least one gelling-inducing agent. Water

[0082] 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 notably the case for the first dispersed aqueous phase of the inverse emulsion in step a.

[0083] According to one embodiment, the mass percentage of water in the first dispersed aqueous phase is at least 50%, and preferably at least 60%, in particular between 50% and 98%, preferably between 60% and 95%, and preferably between 70% and 90%, relative to the total mass of the dispersed aqueous phase. Gelling-inducing agent(s)

[0084] A gelling-inducing agent is advantageously a salt of at least one inorganic cation, in particular an inorganic salt selected 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.

[0085] In certain embodiments in which the gelling-inducing agent is an inorganic salt, as indicated above, the reaction in step d between, on the one hand, the gelling-inducing agent and the first matrix-forming agent and, on the other hand, the gelling-inducing agent and the second matrix-forming agent, is an ion-exchange reaction, i.e., ionotropic gelation. Thus, the inorganic salt (and vice versa the first and second matrix-forming agents) is chosen such that its reaction with the first matrix-forming agent, and then with the second matrix-forming agent, gives two reaction products that are insoluble in water. Particularly suitable salts, especially for polysaccharides, can thus be salts of K, Mg, Sr or Ca. Those skilled in the art understand the term "pseudohalide" as polyatomic analogues 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 include acetate, formate, lactate, oxalate, butyrate, succinate, and the like. The gelling agent is typically chosen to be completely soluble in water at room temperature, i.e., to have a water solubility greater than 10 g / 100 mL, preferably greater than 20 g / 100 mL, and especially greater than 50 g / 100 mL. Non-limiting examples include... Appropriate limiting agents of gelling are: CaCl2, CaF2, Calcium Lactate, MgCl2, Sr(OAc)2, and mixtures thereof.

[0086] 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, CaCO3 or MgCO3, particularly in powder form, can be used.

[0087] In some embodiments, the gelling-inducing agent is a composition of an acid photogenerator, 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, in particular an alkali-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 carried out in steps d and / or f, the photoacid generator produces an acid, which then releases strontium ions. These ions, in turn, react with the first and / or second matrix-forming agent(s), for example, sodium alginate, to form a water-insoluble matrix shell.

[0088] In some embodiments, the gelling-inducing agent is CO2 or a CO2 generator. A CO2 generator can release CO2 under specific conditions. For example, bicarbonate can release CO2 in the presence of an acid. In some embodiments, the gelling-inducing agent may be a Brønsted acid, for example, a mineral acid or a carboxylic acid. In this case, the first and / or second matrix-forming agent(s) may be a composition of a polysaccharide, such as an alginate, chitosan, etc., and a suitable alkali metal complex or water-soluble alkaline earth metal complex, such as Ca-Na2-EDTA, Mg-Na2 EDTA, Sr-Na2 EDTA, and the like.

[0089] Advantageously, the reverse emulsion of step a. comprises between 0.5% and 60%, preferably between 1% and 40%, better between 2.5% and 20%, and most particularly between 1% and 10%, by weight of gelling-inducing agent(s) relative to the total weight of the first aqueous phase.

[0090] Preferably, the first dispersed aqueous phase does not include a hydrophilic surfactant.

[0091] First aqueous solution for envelope formation

[0092] Step b. consists of having a first aqueous envelope-forming solution comprising water and at least one first water-soluble matrix-forming agent (or "first matrix agent") as described in more detail below. The first aqueous envelope-forming solution may can be referred to interchangeably as "second aqueous solution" or "OF".

[0093] The gelling-inducing agent and the first matrix-forming agent are configured so that they are capable of undergoing a chemical reaction with each other to form a first water-insoluble matrix shell.

[0094] According to one embodiment, the mass percentage of water in the first aqueous shell-forming solution is at least 50%, in particular at least 60%, preferably at least 70%, in particular between 70% and 99.95%, preferably between 80% and 99%, and preferably between 90% and 95%, relative to the total mass of the first aqueous phase.

[0095] For obvious reasons, the first aqueous envelope-forming solution and the oily phase of the reverse emulsion are immiscible.

[0096] Advantageously, the viscosity of the first aqueous envelope formation solution, particularly during step c., is less than 1000 cP (or mPa.s), preferably less than 500 cP, particularly less than 250 cP, better less than 100 cP, and especially less than 50 cP.

[0097] For obvious reasons, the first aqueous envelope-forming solution, at least in step c, must be in liquid (or fluid) form, i.e., in a non-solid form. If necessary, the liquid character of the first aqueous envelope-forming solution, at least in step c, can be achieved by heating this aqueous solution.

[0098] In particular, the first aqueous envelope formation solution can be heated to a temperature between 50°C and 150°C, preferably between 60°C and 110°C, and better between 70°C and 90°C.

[0099] Second aqueous solution envelope deformation

[0100] The second aqueous envelope-forming solution, also referred to as the "third aqueous solution" or "AF", comprises water and at least one second water-soluble matrix-forming agent (or "second matrix agent") as described in more detail below.

[0101] The gelling-inducing agent and the second matrix-forming agent are configured so that they are capable of undergoing a chemical reaction with each other to form a second water-insoluble matrix envelope, this second matrix envelope totally surrounding the first matrix envelope.

[0102] According to one embodiment, the mass percentage of water in the second aqueous shell-forming solution is at least 50%, in particular at least 60%, preferably at least 70%, in particular between 70% and 99.9%, preferably between 80% and 99%, and better between 90% and 95%, relative to the total mass of the second aqueous solution for envelope formation.

[0103] For obvious reasons, the second aqueous envelope-forming solution and the oily phase of the inverse emulsion are immiscible.

[0104] For obvious reasons, the second aqueous envelope-forming solution and the first aqueous envelope-forming solution are miscible.

[0105] Advantageously, the viscosity of the second aqueous envelope formation solution, particularly during step e., is less than 1000 cP (or mPa.s), preferably less than 500 cP, particularly less than 250 cP, better less than 100 cP, and especially less than 50 cP.

[0106] For obvious reasons, the second aqueous envelope-forming solution, at least in step e, must be in liquid (or fluid) form, i.e., in a non-solid form. If necessary, the liquid character of the second aqueous envelope-forming solution, at least in step e, can be achieved by heating this aqueous solution. In particular, the second aqueous envelope-forming solution can be heated to a temperature between 50°C and 150°C, preferably between 60°C and 110°C, and more preferably between 70°C and 90°C.

[0107] Preferably, the first and / or second aqueous envelope-forming solution does / do not comprise acrylic polymer, in particular carbomer.

[0108] Preferably, the first and / or second aqueous shell-forming solution does / do not include any base, in particular alkali metal hydroxide, and especially NaOH (or sodium hydroxide).

[0109] Water-soluble matrix forming agent(s)

[0110] In some embodiments, the first and second matrix-forming agents, whether identical or different, are polysaccharides or a salt thereof. A suitable salt is a form of salt that can be completely soluble in water. Typically, polysaccharide salts consist of an anionic polysaccharide component and a suitable counter-cation. Preferably, suitable polysaccharides are selected from chitosan, alginate, particularly sodium alginate, carrageenan, particularly kappa and iota carrageenan, pectins, gellan, or a derivative thereof, and mixtures thereof.

[0111] Preferably, the first matrix-forming agent is chosen from gellan, alginate, and mixtures thereof, and preferably gellan, and the second matrix-forming agent is alginate, and in particular sodium alginate.

[0112] The choice of gellan over alginate as the first matrix-forming agent is particularly preferred with regard to its slower reaction kinetics with the gelling-inducing agent, thus allowing for optimization of the proper formation of the DI dispersion and in particular to ensure the formation of a matrix envelope without prejudice to good spherization of the capsules and / or without clogging of the microfluidic conduits.

[0113] In some embodiments, the polysaccharides can be solubilized by adjusting the pH, for example by basifying the pH of the first and / or second aqueous solution(s) of envelope formation.

[0114] Preferably, the first and / or second matrix-forming agent(s) are not selected from cellulose, diutan gum, furcellarane, starch, agar, agarose, or any of their derivatives, or mixtures thereof.

[0115] In certain embodiments, the first and / or second matrix-forming agent(s) and the gelling-inducing agent are selected such that the first and / or second water-insoluble matrix formed breaks and / or melts at a temperature of at least 80°C, in particular at least 90°C. Such embodiments have the advantage that an active agent inside the capsules is released at a specific predetermined temperature. This is, for example, particularly advantageous for capsules used as food additives. Such capsules can be completely odorless when intact but break during cooking, so that the odor of interest is only released during cooking.In some embodiments, the gelling agent may be an alkali-earth metal salt, in particular a calcium salt such as CaCl₂, or an alkali metal salt, such as KCl, and the first and / or second matrix-forming agent(s) may be carrageenan, or a mixture of carrageenan and sodium alginate, or gellan, or a mixture of gellan and sodium alginate, preferably in a ratio of 2:1 to 1:2. Alternatively, gellan, optionally combined with sodium alginate, may be used as the first and / or second matrix-forming agent(s), preferably as the first matrix-forming agent in such embodiments. Alternatively, the matrix-forming agent may be a polycarboxylate. In this case, the gelling-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 gelling-inducing agent can be a polyammonium salt, i.e., a polymer comprising a plurality of polyammonium groups.

[0116] A person skilled in the art will be able to adjust the content of first and second matrix forming agents so as to form stable double-shell capsules without altering the robustness of the process according to the invention, or even the sprayability of the capsules when the latter is sought.

[0117] Indeed, a chemical reaction kinetics that is too rapid between the first gelling-inducing agent and the matrix-forming agent to form the first The introduction of a water-insoluble matrix shell, followed by the formation of a second gelling agent and a matrix-forming agent to form a second water-insoluble matrix shell, can lead to obstruction or even blockage of the duct(s), and / or the formation of insufficiently spherical capsules, which is undesirable for obvious reasons. Advantageously, an aqueous shell-forming solution according to the invention comprises between 0.01% and 5%, preferably between 0.025% and 2.5%, better between 0.05% and 1%, or even between 0.1% and 0.5%, by weight of the first or second matrix-forming agent(s) relative to the total weight of said aqueous shell-forming solution. Advantageously: - the first aqueous envelope-forming solution comprises between 0.01% and 5%, preferably between 0.025% and 2.5%, better between 0.05% and 1%, or even between 0.1% and 0.5%, by weight of the first matrix-forming agent(s) relative to the total weight of said first aqueous envelope-forming solution; and - the second aqueous envelope forming solution comprises between 0.05% and 2.5%, preferably between 0.1% and 1%, and better between 0.2% and 0.5%, by weight of second matrix forming agent(s) relative to the total weight of said second aqueous envelope forming solution. Additional component(s)

[0118] According to the invention, the first aqueous envelope-forming solution and / or the second aqueous envelope-forming solution may further comprise at least one additional compound other than the gelling-inducing agents, active agents, first and second matrix-forming agents, lipophilic surfactants, lipophilic gelling agents and the aforementioned oils.

[0119] According to the invention, the first aqueous envelope-forming solution and / or the second aqueous envelope-forming solution may further comprise powders; coloring agents; blurring / soft-focus fillers, in particular as described in WO2019053236; emulsifying and / or non-emulsifying silicone elastomers, in particular as described in EP2353577; hydrophilic texturizing agents (or hydrophilic gelling agents), in particular as described in FR3041251; preservatives; pearlescent pigments; pigments; humectants; hydrophilic surfactants; stabilizers; pH-stabilizing agents, in particular a pH buffer (e.g., HEPES, PBS); chelating agents; emollients; osmotic regulating agents; structural stabilizing agents; additional biopolymer agents different from the matrix agent; etc... or any usual cosmetic additive; and mixtures thereof.

[0120] The first aqueous envelope-forming solution and / or the second aqueous envelope-forming solution may further comprise at least one hydrophilic active ingredient, in particular biological or cosmetic, preferably chosen from among moisturizing agents, healing agents, depigmenting agents, UV filters, desquamating agents, antioxidant agents, active ingredients stimulating the synthesis of dermal and / or epidermal macromolecular molecules, dermo-contracting agents, anti-perspirant agents, soothing agents, anti-aging agents, perfumer agents, and mixtures thereof.

[0121] Naturally, a person skilled in the art will ensure that any additional compound(s) and / or active ingredient(s) mentioned above, and / or their respective quantities, are chosen in such a way that the advantageous properties of the capsules according to the invention, as well as their manufacturing process, are not or are not substantially altered by the envisaged addition. These adjustments fall within the competence of a person skilled in the art.

[0122] According to a first embodiment, the first and / or second aqueous solution(s) for envelope formation do not include hydrophilic surfactants such as those defined below.

[0123] According to a second embodiment, the first and / or second aqueous envelope-forming solution(s) may further comprise at least one hydrophilic surfactant, in particular selected from a polyglycerol ester, polyvinyl alcohol, polysorbate, in particular Tween or SDS, 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. When present in the first aqueous envelope-forming solution, such a hydrophilic surfactant ensures the DI dispersion formed in step c. sufficient stability when the reverse emulsion is brought into contact with the first aqueous envelope formation solution in step c.

[0124] Advantageously, the first aqueous envelope-forming solution comprises between 0.05% and 5%, preferably between 0.1% and 2.5%, and better between 0.2% and 1%, by weight of hydrophilic surfactant(s) relative to the total weight of the first aqueous envelope-forming solution.

[0125] When present in the second aqueous envelope formation solution, such a hydrophilic surfactant ensures sufficient stability for the dispersion D2 formed in step e. when the dispersion DI is brought into contact with the second aqueous envelope formation solution in step e.

[0126] Advantageously, the second aqueous envelope-forming solution comprises between 0.05% and 5%, preferably between 0.1% and 2.5%, and better between 0.2% and 1%, by weight of hydrophilic surfactant(s) relative to the total weight of the second aqueous envelope formation solution.

[0127] According to a particular embodiment, the first and / or second aqueous solution(s) for forming the shell may further comprise at least one chelating agent capable of delaying the reaction between the gelling-inducing agent and the first and / or second matrix-forming agent(s), preferably the chelating agent being selected from at least one organophosphate, and more preferably from tetrasodium pyrophosphate. Such an embodiment is advantageous in that it prevents the clogging, obstruction, and blockage of the channels described above.

[0128] According to a particular embodiment, the first and / or second aqueous solution(s) for envelope formation is / are devoid of osmosis regulator, and in particular of alcohol, and especially of methanol, ethanol, propanol, and mixtures thereof.

[0129] According to another particular embodiment, the first and / or second aqueous envelope-forming solution(s) may further comprise at least one osmosis regulator, preferably selected from at least one alcohol or at least one sugar. The osmosis regulator is added to the first aqueous envelope-forming solution in step(s) c and / or d and / or is added to the second aqueous envelope-forming solution in step(s) e and / or f. The osmosis regulator may be an alcohol, in particular methanol, ethanol, propanol, glycerol, and mixtures thereof, or a sugar, in particular 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.The osmosis regulator is configured to improve the diffusion of the gelling-inducing agent towards the droplet interface, thereby increasing the thickness of the first and / or second shell(s) and the stability of the capsule.

[0130] 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 solution forming the envelope comprising it.

[0131] In certain embodiments, the first and / or second aqueous solution(s) for shell formation may further comprise at least one structural stabilizer. A structural stabilizer is a compound configured to improve the structural stability of the shell comprising it and may be selected from agarose, xanthan gum, cellulose and its derivatives, for example methylcellulose or microcrystalline cellulose, and the like, and mixtures thereof.

[0132] The structural stabilizer can be added to the first aqueous envelope formation solution in step(s) c. and / or d and to the second aqueous envelope formation solution in step(s) e. and / or f.

[0133] Preferably, the first aqueous envelope-forming solution further comprises at least one structural stabilizer, preferably xanthan gum. The presence of such a structural stabilizer in the first aqueous envelope-forming solution improves step c, in particular by facilitating the formation of the double emulsion, providing viscous strength, and limiting wetting of the inverse emulsion at the conduit(s). The presence of such a structural stabilizer is particularly relevant when steps c and / or e rely on a co-flow microfluidic emulsification technique.

[0134] According to the invention, an aqueous envelope formation solution can comprise between 0.05% and 15%, preferably from 0.1% to 10%, and better from 0.5% to 5%, by weight of structural stabilizer(s) relative to the total weight of the aqueous envelope formation solution comprising them.

[0135] In certain embodiments, the first and / or second aqueous shell-forming solution(s) may further comprise at least one additional biopolymer, different from the matrix agent, as a structural stabilizer, such as pectin (e.g., 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 addition of such an additional biopolymer, and in particular solid biopolymer particles, increases the mechanical strength of the generated capsules.

[0136] Alternatively, during and / or after step d, the formed capsules may be exposed to temperatures above ambient 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, and in particular between 70°C and 80°C. For example, exposure to such temperatures may be carried out for 5 to 60 minutes, in particular from 15 to 30 minutes. Indeed, such an increase in temperature can have a significant effect on the mechanical strength of the capsules. Manufacturing process Step a.

[0137] The preparation of the reverse emulsion in step a. falls within the general knowledge of a person skilled in the art. By way of illustration, the reverse emulsion in step a. can be obtained by means of conventional stirring processes, such as for example by Rayneri stirring, Rotor / stator stirring, for example of the Ultraturrax / Ultrasound type.

[0138] Preferably, step a. includes at least the substeps of: a1. dissolving the gelling agent in water to form the first aqueous phase; and a2. mixing the first aqueous phase formed in step a1. with the oily phase.

[0139] 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.

[0140] 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.

[0141] Dissolving the gelling agent in the water of the first dispersed aqueous phase of step a. advantageously prevents / avoids clogging of the conduit(s) and improves the formation kinetics of the first and second layers. Indeed, carbonates can lead to an accumulation of insoluble salts in the conduit(s).

[0142] The emulsion forming the core supplied in step a can be stable between 2 and 600 minutes, preferably between 5 and 500 minutes, better between 10 and 100 minutes, or even between 15 and 60 minutes, and particularly between 20 and 30 minutes. Such stability ensures that the droplets are not directly destroyed, especially during step c, or even during step e. However, the stability of the droplets is not too high, which would reduce the efficiency of the formation of the first envelope during step d and then of the second envelope during step f, and would limit the transparency of the lipophilic cores.

[0143] Advantageously, the reverse emulsion of step a. comprises a weight ratio "fatty phase / first aqueous phase" of between 1 and 30, preferably between 2 and 20, and better between 4 and 10, and particularly between 2.5 and 4. Step b.

[0144] The preparation of the first aqueous shell-forming solution in step b. falls within the general knowledge of a person skilled in the art. By way of illustration, the first aqueous shell-forming solution in step b. can be obtained using conventional stirring methods, such as, for example, Rayneri stirring, rotor / stator stirring, for example, of the Ultraturrax / Ultrasound type. Step c.

[0145] Preferably, the DI dispersion of step c. comprises a weight ratio of "reverse emulsion / first aqueous envelope-forming solution" included between 0.02 and 0.3, preferably between 0.05 and 0.25, better between 0.07 and 0.20, and especially between 0.10 and 0.15.

[0146] The preparation of the DI dispersion in step c can be based on any microfluidic emulsification technique known to those skilled in the art. The inverse emulsion droplets thus obtained advantageously exhibit a uniform size distribution.

[0147] In particular, the microfluidic emulsification technique can be chosen from the T-junction (see Figure IA); the flow focusing junction (see Figure IB), in which the fluids flow in different, and typically opposite, directions; coaxial capillaries (see Figure IC), in which the fluids flow in the same direction; or 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 filament triggered by an abrupt change in flow confinement. Preferably, the microfluidic emulsification technique is chosen from coaxial capillaries (or co-flow) or step emulsification, and preferably coaxial capillaries.

[0148] Microfluidic process of the "step-emulsification" type

[0149] According to a first embodiment, step c. of the manufacturing process according to the invention is based on a microfluidic emulsification technique of the "step-emulsification" type.

[0150] A microfluidic device particularly suited to this first embodiment is the device described in WO2021037999 and illustrated in [Fig.3], which includes in particular a first chamber and a second chamber fluidically connected by one or more conduits, preferably by micro-conduits.

[0151] Thus, according to this first embodiment, the manufacturing process according to the invention can include at least the steps of: a', supplying in a first chamber at least the reverse emulsion of step a. ; b', supplying in a second chamber at least the first aqueous envelope formation solution of step b. ; the first chamber and the second chamber being fluidly connected by one or more conduits (or channels), preferably by micro-conduits (or microchannels); c'. guide the reverse emulsion from step a' of the first chamber through the conduit(s) into the second chamber; the steps d. to f' being identical to the steps d. to f. defined above.

[0152] To avoid any ambiguity, a chamber is distinct from and different from a conduit. A manufacturing process according to this first embodiment is illustrated in [Fig.2] and described in more detail below.

[0153] When emulsification step c is based on an injection of the inverse emulsion forming the core of step a through at least one first channel, this allows for precise control of the size and ensures a uniform distribution of the size of the DI dispersion formed in step c. In addition, the process allows a production of the order of 100 g / h (i.e. gram(s) per hour) per channel or more, or even up to 500 g / h per channel.

[0154] 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 such as the one used here is configured to be filled with a solution. Typically, the chambers are closed except for the inlets, channels, and outlets. The first chamber typically has a first fluid inlet for the introduction, particularly continuous, of the inverse emulsion forming the core in step a. into the first chamber, and the second chamber has a second inlet for introducing, particularly continuous, the first aqueous envelope-forming solution from step b. into the second chamber. The second chamber also has an outlet for removing, preferably continuously, the DI dispersion formed in step c.

[0155] 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 and second chambers. Typically, the first and second chambers are fluidly connected by several channels, for example, at least 10, 20, 30, 50, or 100 channels. Typically, the channels are arranged essentially parallel to each other.

[0156] In other embodiments, the cross-sectional area of ​​each channel outlet is from 0.12 to 36,000,000 pm2, preferably from 12 to 5,760,000 pm2. In particular, the total open area on the second side of the membrane can be from 300% to 1,500%, preferably from 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.

[0157] In some embodiments, the channel(s) may be contained within 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 opposite the first side and facing the second chamber. Thus, the first side of the membrane may partially delimit the first chamber and the second side of the membrane may partially delimit the second chamber. The channel(s), typically multiple channels, extend from the first side to the second side through the membrane. Each channel includes a channel inlet arranged on the first side, a channel outlet arranged on the second side and a main section being arranged between the channel inlet and the channel outlet.

[0158] The membrane can typically be a single-layer membrane. That is, the membrane is made in one piece. Preferably, such a membrane is made of a solid material and does not contain 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 droplets, since all interfaces and phase transitions are detrimental to droplet formation and stability.

[0159] In some embodiments, the membrane may be exchangeable.

[0160] In some embodiments, the membrane is made of glass or a material polymeric, such as poly(meth)acrylate methyl or PTFE, or metallic material, such as steel.

[0161] 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, particularly 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, particularly during step c. It is understood that these pressure values ​​are relative to absolute pressures, i.e. that a pressure of 1.01 bar is a pressure which constitutes an overpressure of 0.01 bar with respect to atmospheric pressure.

[0162] In certain 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 can 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 can be adjusted by the pressure with which the first aqueous envelope-forming solution of step b is supplied via the second inlet to the second chamber.

[0163] In certain embodiments, the pressure applied to the first chamber is greater than the pressure applied to the second chamber. It is understood that the first pressure can 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 can be adjusted by the pressure with which the first aqueous envelope-forming solution of step b is supplied via the second inlet to the second chamber.

[0164] In some embodiments, step c is carried out with a device comprising a first feed inlet of the inverse emulsion from step a, which opens into the first chamber, a second feed inlet of the first aqueous envelope-forming solution, opening into the second chamber, and an outlet at the level of the second chamber to collect the DI dispersion and The device then ensures contact with the second aqueous solution for envelope formation. Furthermore, the device includes a membrane, specifically a membrane as described above, which separates the first and second chambers and comprises a first side facing the first chamber and a second side facing the second chamber. The membrane includes multiple channels extending from the first side to the second side, thus ensuring a fluidic connection between the first and second chambers. Each channel comprises a channel inlet arranged on the first side and a channel outlet arranged on the second side. The first chamber can typically be configured so that the flow rate of the reverse emulsion through all individual channels is essentially equal.

[0165] In some embodiments, the second chamber may be made of glass or a transparent polymer, such as PTFE, poly(meth)acrylate, or polyoxymethylene, or of metals such as steel, aluminum, or titanium. Generally, the device may include a container, such as a glass container, which 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 of a transparent polymer, such as PTFE, poly(meth)acrylate, or polyoxymethylene.

[0166] The outlet of the second chamber can for example be in fluidic communication with a container comprising the second aqueous solution for envelope formation, so as to carry out steps e. and f.

[0167] In some embodiments, steps e. and f. are carried out under continuous flow of the single-envelope capsules formed in step d.

[0168] In other embodiments, the device includes a membrane support for mounting the membrane. In some embodiments, the device includes a container support for holding the container, which partially forms the second chamber. The container support can be fixedly and removably connected to the membrane support. The container support and / or the membrane support and / or the base can be made of any suitable material such as a plastic material, such as PTFE, poly(meth)acrylate, or polyoxymethylene, or a metal, preferably steel.

[0169] In some embodiments, the device includes 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, include a A heated bath, such as a water bath or an oil bath. Alternatively, the heater can be an IR heater, a heating coil, or any other suitable heater.

[0170] In other embodiments, the device comprises a first reservoir for the reverse 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 fluidly connected to a pressure source, such as a compressor. Alternatively, the reservoirs may be syringes and pressurized by a conventional syringe pump and / or a piston or a peristaltic, gear, or other pumping system.

[0171] Figure 2 schematically illustrates a manufacturing process according to the invention, wherein 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 gelling agent and water with the oil phase 102 (Figure 2a). This can, for example, be done with the stirrer 111. Figure 2a also shows a magnified view of a drop of solution 101 in the emulsion. The straight lines of the droplets represent droplets comprising water and the gelling agent dissolved therein. Thus, each droplet shown in Figure 2a is an aqueous solution of the gelling agent. The emulsion formed from the aqueous solution 101 in the oil phase 102 is then supplied to the first chamber 4 of a suitable device (Figure 2b).The second chamber 5 of the device comprises a first aqueous shell-forming solution 104, consisting of water and at least one first matrix-forming agent. 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 and second chambers are separated by a membrane 7, the first side 8 of which faces the first chamber and the second side 9 of which faces the second chamber. The channels 10 extend from the first side 8 to the second side 9. Generally, appropriate pressure is applied to the core-forming emulsion in the first chamber 4. The emulsion in the first chamber 4 is then guided through the channels 10.Since the emulsion generally comprises the oil phase 102 as its main component, an emulsification step occurs when the emulsion reaches the outlet of the channel opening into the second chamber 5, thus forming the dispersion DI of step c., which can be described as a transient water-in-oil-in-water emulsion (or "transient double emulsion") in the form of monodisperse droplets 113 in the first aqueous envelope-forming solution 104, the monodisperse droplets 113 being formed from the solution 101 dispersed in the oil phase. Then, the gelling-inducing agent contained in the droplets 113 diffuses towards the surface of the droplets, and then... reacts chemically at the interface with the first matrix-forming agent to form a first water-insoluble matrix envelope, which develops completely around each droplet, thus forming capsules 106 comprising a first water-insoluble matrix envelope containing a lipophilic core. Furthermore, the relative size of the droplets 101 compared to the droplets 113 and / or the capsules 106 does not resemble reality. Each monodisperse droplet 113 in the second chamber 5 comprises one or more droplets 101 dispersed in the oily phase 102.

[0172] The DI dispersion comprising capsules 106 then exits the second chamber 6 to be placed in a container 105 containing the second aqueous envelope-forming solution 108, optionally equipped with a stirrer 107 (Figure 2c).Indeed, when the dispersion Dl, and in particular the capsules 106, are mixed with the second aqueous envelope-forming solution 108, the gelling-inducing agent contained in the capsules 106 diffuses towards the surface of said capsules, beyond the first envelope, and then reacts chemically at the interface with the second matrix-forming agent to form a second water-insoluble matrix envelope, which develops entirely around each capsule 106, and in particular around each first envelope of said capsules 106, thus forming capsules 110 comprising a double water-insoluble matrix envelope containing a lipophilic core. It should be noted that the droplet sizes in step 2c of [Fig. 2] are exaggerated for clarity.

[0173] Figure 3 shows a cross-sectional view of the device of Figure 2. The device comprises a base 14 with a first inlet 2 for supplying the core-forming 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 first aqueous envelope-forming solution 104 and a second chamber outlet 6 for collecting the dispersion DL. The second inlet 3 opens into the second chamber 5, which is partially formed by the container 19. The first and second chambers are separated by the membrane 7. As can be seen in Figure 3, the first chamber has a rounded cross-section with respect to the corresponding plane of section along the central longitudinal axis 15 and being perpendicular to the membrane 7.In the particular embodiment shown, the first chamber 4 has a semi-circular cross-section and can thus be shaped like a hemisphere. The first inlet 2 is located at the pole 13 of the hemisphere. The second chamber 5 is conical towards the outlet 6, which is located 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 forms a central axis of the device in the longitudinal direction. In the embodiment shown, the second chamber is arc-shaped towards the outlet of the second chamber 6. Thus, the second chamber 5 has a U-shaped cross-section. The first inlet 2 is arranged at an angle α of approximately 90° with respect to the central axis 15 and 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 this particular case is a foam pad, can be placed between the container 19 and the container holder 21. The membrane holder 20 includes a groove 22 to receive the container 19. "Co-flow" type microfluidic process

[0174] According to a second preferred embodiment, step c. relies on a coaxial capillary microfluidic emulsification technique (or “co-flow”), with phase (or fluid) ejection by dripping or jetting. In the case where phase (or fluid) ejection is by jetting, the process may further include a suitable mechanical device for cutting off the jet, similar to the microfluidic devices and associated processes described in WO2019145424 or WO2020039062.

[0175] Microfluidic devices particularly suited to this second embodiment variant are described in WO2012120043, WO2015148892, WO2019145424 or WO2020039062.

[0176] Thus, step c is advantageously carried out such that the first aqueous envelope-forming solution of step b is circulated in a second conduit, the downstream opening of the first conduit opening into the second conduit, advantageously coaxial with the local axis of the second conduit. Advantageously, step c consists of injecting the inverse emulsion of step a into at least one first conduit opening into the first aqueous envelope-forming solution of step b. For the purposes of the present invention, the terms "upstream" and "downstream" refer to the direction of fluid flow.

[0177] A step c. according to this second embodiment can in particular be carried out using the microfluidic device (or nozzle) described in [Fig.4].

[0178] This [Fig. 4] represents a microfluidic device 30 comprising a single forming nozzle 32 having an internal conduit 34 (i.e., "first conduit") for supplying an internal fluid 36 comprising the reverse emulsion of step a. 14, and a conduit external 38 (i.e. "second conduit") arranged around the internal conduit 34 to bring an external fluid 40 comprising the second aqueous phase of step b. 16.

[0179] 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 from the downstream opening 54 defined by the external conduit 38.

[0180] 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 times the diameter of the external conduit 38.

[0181] The external conduit 38 preferably delimits with the internal conduit 34 an annular space connected upstream to the supply means 48.

[0182] In the external conduit 38 there takes place (i) the mixing between the internal fluid 36 and the external fluid 40 and (ii) the reaction between the gelling-inducing agent and the first matrix-forming agent, thereby obtaining single-shell capsules, i.e. capsules comprising a water-insoluble matrix shell 11 containing the lipophilic core 17.

[0183] According to a first embodiment (not shown in [Fig.4]), the downstream opening 54 of the external conduit 38 is in fluidic connection with a container 33 comprising the second aqueous solution for forming the envelope 44, so as to ensure the performance of steps e. and f.

[0184] According to a second embodiment (not shown in [Fig.4]), the nozzle 32 is adapted so as to bring the second aqueous solution for forming the envelope 44 through a third conduit 72 located in the immediate vicinity of the external conduit 38. In other words, in this second embodiment, the external conduit 38 is not housed (or included) in whole or in part in the third conduit 72. In other words, in this second embodiment, the external conduit 38 is independent of the third conduit 72, and vice versa.

[0185] According to a third embodiment (illustrated in [Fig.4]), the nozzle 32 is adapted so as to bring the second aqueous solution for the formation of the envelope 44 through a third conduit 72 in which the external conduit 38 is included in whole or in part, advantageously coaxial with the local axis of the third conduit 72.

[0186] In this third embodiment, the downstream opening 54 of the external conduit 38 can open before, at the same level or after the downstream opening 56 of the third conduit 72.

[0187] Preferably, the downstream opening 54 of the external conduit 38 opens after the downstream opening 56 of the third conduit. This embodiment is shown in [Fig. 4] and is considered for manufacturing the capsules of Example 1 below.

[0188] In the container 33 there takes place (i) the mixing between the external fluid 40 and the second aqueous solution for forming the shell 44 and (ii) the reaction between the gelling-inducing agent and the second matrix-forming agent, thereby obtaining double-shell capsules, i.e. capsules comprising a water-insoluble matrix shell 11 containing the lipophilic core 17 and a matrix shell 12 containing the matrix shell 11.

[0189] In [Fig.4], the forming nozzle 32 includes 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 second aqueous solution for forming the envelope 44 into the supply conduit 42.

[0190] In the example shown in [Fig.4], the device 30 has been illustrated with a single nozzle 32. In an advantageous embodiment, the device 30 comprises a plurality of nozzles 32 arranged below one or more container(s) 33.

[0191] According to the first and second embodiment variants, all downstream openings 54 of the external conduits 38 are advantageously in fluidic connection with the container 33.

[0192] 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.

[0193] The supply means 46, 48 and 50 each include, for example, a syringe pump, a peristaltic pump or another pressure generating system controlling the flow, such as, for example, a pressure pot coupled with a flow meter and a flow regulation system.

[0194] Each of the supply means 46, 48, 50 is suitable for conveying a respective fluid 36, 40, 44 at a controlled and adjustable flow rate.

[0195] Advantageously, for carrying out steps e and f, 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. In particular, such a stirring device may be represented by the stirring device described in WO2023 / 099530.

[0196] In some embodiments, the device includes 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, include 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.

[0197] According to a first embodiment, all the conduits have an identical diameter, which makes it possible to obtain monodisperse capsules.

[0198] According to a second embodiment, the conduits have different diameters, which makes it possible to obtain polydisperse capsules, with controlled polydispersities.

[0199] Preferably, the maximum diameter of the conduits 34, 38 and 72 is 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, to preserve the microfluidic nature of the process. Under no circumstances may the conduit 34, 38 and / or 72 be considered a chamber. Step d.

[0200] In some embodiments, step d. includes stirring the DI dispersion obtained in step d., in particular to prevent the agglutination of the monodisperse droplets of the DI dispersion formed and / or the capsules formed. This also ensures a uniform size distribution of the capsules and prevents the risk of the capsules clumping together. Typically, a suspended stirrer or a stirring device as described in WO2023 / 099530 can be used. Preferably, the stirring is carried out with a stirrer operating at 10 rpm (revolutions per minute) to 800 rpm, preferably from 25 rpm to 500 rpm, in particular from 50 rpm to 350 rpm, and preferably from 100 rpm to 250 rpm.

[0201] In some embodiments, step d. is carried out between 1 and 30 seconds, preferably between 2 and 20 seconds, and better between 5 and 10 seconds. The reaction time of step d., i.e. the time until the reaction is stopped, for example by separating or isolating the capsules from the first aqueous shell-forming solution, or by placing the DI dispersion in the presence of the second aqueous shell-forming solution, directly influences the size of the capsules and in particular the thickness of the first shell of the capsules.

[0202] It is not excluded that the formation of the first matrix envelope continues during step(s) e and / or f. Step e.

[0203] Thus, according to a first variant, step e is carried out using only the single-shell capsules obtained in step d, that is, capsules devoid of the first aqueous shell-forming solution. This second variant then assumes that the process according to the invention, between steps d and e, further comprises at least one intermediate step of separating the single-shell capsules obtained in step d from the first aqueous shell-forming solution.

[0204] According to a second preferred embodiment, step e is carried out using the DI dispersion obtained in step d. A process according to the invention, between steps d and e, then does not include an intermediate step for separating the simple capsules envelopes obtained in step d. of the first aqueous solution for envelope formation. This second variant is preferred as it is simpler and allows steps d. and e. to be carried out continuously.

[0205] The generation of DI dispersion droplets in the second aqueous envelope formation solution carried out in step e. can be based on any microfluidic emulsification technique known to those skilled in the art, and in particular those described above. According to a preferred embodiment, step e. relies on a coaxial capillary microfluidic emulsification technique (or "co-flow"). According to a preferred embodiment described above, the second aqueous envelope-forming solution of step e. is then circulated in a third conduit, which includes the second conduit, advantageously coaxial 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.

[0206] Preferably, the dispersion D2 of step e. comprises a weight ratio "dispersion DI / second aqueous envelope forming solution" of between 0.5 and 2, and preferably between 1 and 1.5.

[0207] In the process according to the invention, step e is not a soaking step, and in particular is not a contact or immersion step of the capsules formed in step d. Step f.

[0208] In some embodiments, step f. includes stirring the dispersion D2 obtained in step e., in particular to prevent the agglutination of the monodisperse droplets of the dispersion DI formed and / or the capsules formed. This also ensures a uniform size distribution of the capsules and prevents the risk of the capsules clumping together. Typically, a suspended stirrer or a stirring device as described in WO2023 / 099530 can be used. Preferably, the stirring is carried out with a stirrer operating at 10 rpm (revolutions per minute) to 800 rpm, preferably from 25 rpm to 500 rpm, in particular from 50 rpm to 350 rpm, and preferably from 100 rpm to 250 rpm.

[0209] In some embodiments, step f is carried out between 10 seconds and 2 minutes, preferably between 20 seconds and 1 minute, and better between 30 seconds and 45 seconds. 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 second aqueous shell-forming solution, directly influences the size of the capsules and in particular the thickness of the second shell of the capsules.

[0210] Preferably, the capsules of step f. according to the invention comprise between 5% and 40%, preferably between 10% and 35%, and more preferably between 15% and 30%, by weight of active agent(s), in particular fragrance agent(s), relative to the total weight of the capsules. Additional step(s)

[0211] As previously stated, a process according to the invention may further include, between steps d. and e., at least one intermediate step of separating the single-shell capsules obtained in step d. from the first aqueous shell-forming solution.

[0212] Preferably, a process according to the invention does not include an additional coating step by dipping.

[0213] In some embodiments, the process may further comprise, after step f, at least one additional coating step by dipping. In some embodiments, this additional coating step may comprise a step of contacting or immersing the capsules formed in step f in a third aqueous coating-forming solution, identical or different from the first and / or second aqueous coating-forming solution(s) of steps c and e, particularly in terms of the nature and / or content of the matrix-forming agent(s). The third aqueous coating-forming solution comprises water and at least one third matrix-forming agent, identical or different from the first and / or second matrix-forming agent(s) present in the first and / or second aqueous coating-forming solution(s) of steps c and e.

[0214] In some embodiments, the capsules are coated with three or more additional layers. Thus, the dip coating can be repeated with different matrix-forming agents.

[0215] Advantageously, the process according to the invention further comprises at least one step g. of rinsing the capsules obtained at the end of step f. in an aqueous rinsing solution comprising water, preferably reverse osmosis water, and optionally at least one preservative. Typically, step g. can be carried out using a device as described in WO2023099536. Such a rinsing step g. is intended, in particular, to stop the reaction between the gelling-inducing agent and the first and second matrix-forming agents.

[0216] In certain embodiments, particularly after step f. or possibly after step g., the capsules formed are isolated, hardened and / or stored.

[0217] Isolation of the capsules may for example include filtration or sieving to separate the capsules from the aqueous solution of shell formation, and possibly washing of the capsules with water.

[0218] Hardening may, for example, include drying the capsules, for example by an air current or by freeze-drying, in order to evaporate all or at least the majority of the water is unbound. The curing process may also include further agitation of the capsules in an aqueous solution comprising at least one inorganic salt, such as CaCl2 or MgCl2, 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, particularly the outer shell.

[0219] Preservation may be achieved by immersing the capsules in distilled water, in a solution comprising divalent cations, or in an aqueous solution of an inorganic salt, such as CaCl2 or MgCl2.

[0220] In certain embodiments, particularly after step f or possibly after step g, 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 gelling-inducing agent. For example, if the chelating agent is a calcium salt, such as CaCl2, the chelating agent can form a chelating complex with Ca2+. Suitable chelating agents are Lewis bases, such as EDTA, GLDA (N,N-Bis(carboxymethyl)-L-glutamate tetrasodium), MGDA (trisodium dicarboxymethyl alaninate), citrate salts, tartaric acid salts, and the like. The solvent is generally chosen so that the chelating agent is soluble in it, but the capsules formed, or the water-insoluble matrix, are not dissolved. Thus, water can be a suitable solvent.By exposing capsules to such a solution for a predetermined period, the second, or even the first, layer of the capsules can be weakened because the chelating agent forms chelates with a portion of the gelling agent, or its derivatives. For example, if the gelling agent is CaCl2 and the chelating agent is sodium citrate, the resulting calcium citrate weakens the capsule's outer layer. The advantage is that the weakening of the outer layer, and therefore its mechanical strength, can be precisely controlled. This weakening may be desirable for products where the outer layers need to break or disintegrate relatively quickly, such as cosmetic products like skin creams.As an 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 shaken in this solution for 10 to 50 minutes, in particular 20 to 40 minutes. Uses.

[0221] The invention also relates to a set of capsules comprising a plurality of capsules that can be obtained with the manufacturing process according to the invention, optionally in association with at least one physiologically acceptable medium.

[0222] In particular, the invention relates to an assembly of capsules comprising a plurality of capsules obtainable with the manufacturing process according to the invention, optionally in association with at least one physiologically acceptable medium, in which the capsules comprise at least one double matrix envelope containing at least one lipophilic core, the capsules having a double envelope with a thickness of between 50 microns and 600 microns, preferably between 100 microns and 500 microns, better between 150 microns and 400 microns, and most particularly between 200 microns and 350 microns, and preferably: - the first layer has a thickness between 10 microns and 300 microns, preferably between 25 microns and 250 microns, better between 50 microns and 200 microns, and particularly between 75 microns and 150 microns; and - the second layer has a thickness between 75 microns and 600 microns, preferably between 100 microns and 500 microns, better between 150 microns and 400 microns, and especially between 200 microns and 300 microns.

[0223] The invention also relates to a set of capsules comprising a plurality of capsules obtained with the manufacturing process according to the invention, optionally in association with at least one physiologically acceptable medium.

[0224] Preferably, a set of capsules according to the invention is directly usable, at the end of the aforementioned manufacturing process, as a composition, in particular cosmetic, pharmaceutical, nutritional or agri-food, and preferably cosmetic.

[0225] The invention also relates to the use of a set of capsules according to the invention for the preparation of a composition, in particular cosmetic, pharmaceutical, nutritional or agri-food, preferably cosmetic and in particular a skincare and / or makeup and / or perfume composition of a keratinous material, in particular from human beings, in particular from the skin.

[0226] Thus, the present invention also relates to a composition, in particular a cosmetic and in particular a perfumed composition, comprising at least a plurality of capsules that can be obtained with the process or a set of capsules according to the invention, optionally in association with at least one physiologically acceptable medium.

[0227] The present invention also relates to a composition, in particular a cosmetic and in particular a perfumed composition, comprising at least a plurality of capsules obtained with the process according to the invention, optionally in association with at least one physiologically acceptable medium.

[0228] In view of the foregoing, such a composition advantageously comprises less than 10%, preferably less than 5%, in particular less than 2.5%, or even is devoid of alcohol(s), in particular ethanol, relative to the total weight of said composition.

[0229] In the context of the invention, and unless otherwise stated, "physiologically acceptable medium" means a medium suitable for cosmetic applications, and suitable in particular for the application of a composition of the invention on a keratinous material, in particular the skin and / or hair, and more particularly the skin.

[0230] Preferably, the physiologically acceptable medium is a gelled aqueous phase suitable for suspending the capsules. Such a gelled aqueous phase advantageously comprises water, at least one preservative and at least one hydrophilic gelling agent (or hydrophilic texturizing agents), such as those described in FR3041251.

[0231] A composition according to the invention is intended for oral or topical application, preferably topical.

[0232] A set of capsules or cosmetic composition of the invention may be, for example, a cream, a lotion, a serum and a gel for the skin (hands, face, feet, etc.), a foundation (liquid, paste), a preparation for baths and showers (salts, mousses, oils, gels, etc.), a hair care product (hair dyes and bleaching agents), a cleaning product (lotions, powders, shampoos), a hair care product (lotions, creams, oils), a styling product (lotions, hairsprays, brilliantines), a shaving product (soaps, mousses, lotions, etc.), a product intended to be applied to the lips, a sunscreen product, a sunless tanning product, a skin whitening product, an anti-wrinkle product or a perfume composition, preferably a perfume composition.A perfume composition according to the invention may be an eau de toilette, an eau de Cologne, a perfume extract, a perfume spirit, a perfume veil, an eau de parfum or an eau de parfum.

[0233] Thus, a cosmetic composition according to the invention is advantageously a perfumed composition, in particular an alcohol-free perfumed composition, intended to perfume an individual after spraying or application to the skin, hair, and / or clothing. Such a product is not rinsed off after application. A perfumed composition will thus be distinguished from a perfumed composition. Indeed, a cosmetic composition can be perfumed without being perfumed.

[0234] The invention also relates to a packaging and dispensing device in the form of a spray of fluid composition, particularly cosmetic, characterized in that it comprises at least: - a container containing at least one heterogeneous mixture; - a guide tube (or dip tube) placed inside the container; and - a distribution device capable of drawing heterogeneous mixture from the container, transforming the heterogeneous mixture into the fluid composition, and distributing the fluid composition in the form of a spray, the heterogeneous mixture comprising a plurality of capsules capable of being obtained with the process according to the invention, a set of capsules or a composition according to the invention, in association with at least one physiologically acceptable medium.

[0235] Said heterogeneous mixture may advantageously comprise a plurality of capsules obtained with the process according to the invention, in association with at least one physiologically acceptable medium.

[0236] Such a conditioning and distribution device in the form of a spray may also be designated as a "spray device", "spraying device" or "sprayer".

[0237] Preferably, in such a spray device, the capsules represent a volume fraction of between 50% and 70%, preferably between 55% and 65%, and better between 57% and 63%, relative to the total volume of the heterogeneous mixture.

[0238] Preferably, the heterogeneous mixture comprises between 5% and 30%, preferably between 10% and 20%, and better between 12% and 15%, by weight of active agent(s), in particular of perfumer agent(s), relative to the total weight of said heterogeneous mixture.

[0239] 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.

[0240] A packaging and distribution device in the form of a spray may in particular be as described in the patent application filed under No. FR2314016.

[0241] The present invention also relates to a non-therapeutic cosmetic treatment method for keratinous material, in particular skin and / or hair, comprising at least one step of applying to the keratinous material at least one set of capsules or a cosmetic composition as mentioned above.

[0242] Throughout the description, the expression "including one" shall be understood as synonymous with "including at least one", unless otherwise specified. The expressions "between ... and ...", "from ... to ..." and "ranging from ... to ..." shall be understood inclusive, unless otherwise specified. Examples

[0243] Manufacture of double-walled perfume capsules

[0244] From the solutions described in Table 1 below, perfume capsules were manufactured using the microfluidic device illustrated in [Fig.4], with the flow rates described in Table 2.

[0245] [Tables 1] Table 1 Solution Raw materials INCI ABCD CoBip. Comp. Ihv. Inv. Inverse Emulsion (IF) Water QSp* Calcium chloride 50 Total IF1 100 PGPR Polyglyceryl polyricylitol 0.2 0.05 Labraiac CC MB Caprylic / Capric Triglyceride Q*P* Fragrance 60 Total H2 100 Ratio 1F2 / IF1 80 / 20 First Aqueous Shell Deformation Solution (OF) Water QSp* Gellan GUM 0 0.05 Xanthan GUM 0 0.05 0 0.05 Polyvinyl Alcohol (Polyvinyl PVA) 1 0 Total OF 100 Second Aqueous Shell Formation Solution (AF) Water QSp* Sodium alginate 0.3 Tween 20 Polysorbate 20 1 0 Ethanol Ethyl alcohol 20 0 Total AF 100 * : Sufficient Quantity For.

[0246] [Tables2] Table 2 Solution Flow Rates (in ml / hr / nozzle) Emulsion, inverse (IF) Dispersed aqueous phase (IF1) 13 Continuous oil phase (IF2) 30 First aqueous envelope forming solution (OF) 720 Second aqueous envelope forming solution (AF) 700

[0247] Tests A to D make it possible to obtain capsules having a diameter of approximately 1650 microns.

[0248] The capsules from tests A to D were then analyzed according to the evaluation criteria described in Table 3.

[0249] [Tables3] Table 3 Criteria 1 2 3 Capsule Sphericity Presence of multiplets, i.e., at least 3 lipophilic nuclei embedded in the same capsule Presence of doublets, i.e., 2 lipophilic nuclei embedded in the same capsule Spherical capsules without doublets or multiplets Oil Leakage High Moderate Low, even thousands Transparency of the lipophilic nucleus Opaque nucleus Translucent nucleus Transparent nucleus

[0250] Results:

[0251] [Tables4] Table 4 A (comp.) B (comp.) c (inv.) D (ÎBV.) Capsule sphericity 1 1 2 3 Oil leakage .1. 2 3 Lipophilic core transparency 2 3 3

[0252] With tests C and D according to the invention, it is observed that the suppression of surfactants in the OF and the AF as well as the suppression of ethanol in the AF does not have a negative impact on the formation of the capsules and their kinetic stability, which is particularly unexpected.

[0253] Even more unexpectedly, it is observed that the capsules according to tests C and D even exhibit improved performance in terms of sphericity, oil leakage and transparency compared to tests A and B.

[0254] These results are all the more unexpected as they are obtained in the presence of an oily phase comprising a high perfume content.

[0255] Similar results were obtained using a microfluidic device such as that described in Figures 2 and 3.

[0256] The capsules from tests A to D are then mixed at a volume fraction of 70% in a new aqueous phase described in Table 5, thereby obtaining a heterogeneous mixture.

[0257] [Tables5] Table 5 Aqueous Phase Raw Materials (by mass) Water QS* Glycerol 19.0 Propanediol (Zemea, Dupont Tate) 7.0 Microcare PE (Phenoxyethanol) 0.89 Microcare emollient PTG (Pentylene Glycol) Total 100 * Sufficient Quantity For

[0258] These four 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 dispensing mechanism. Release tests are carried out, consisting of pressing the push button four times per hour for eight hours, for five 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 output, and (iv) the sensory output.

[0259] Results:

[0260] The spray devices exhibiting the best properties in terms of capsule aspiration and delivery of a composition in spray form are tests C and D.

[0261] Without wishing to be bound by any theory, the inventors believe that the multiplets present in tests A and B obstruct the dip tube and / or the spray pump.

[0262] On the other hand, the 4 spray devices have satisfactory properties in terms of olfactory rendering.

[0263] Example 1 shows that the present invention makes it possible to produce double-walled capsules with unexpected technical effects, namely a reduced or even complete elimination of alcohol and surfactants, without compromising the robustness of the manufacturing process, the stability of the capsules, or even their sprayability. This last aspect is particularly unexpected since a double wall implies greater mechanical resistance than a single wall, and therefore appears at first glance to be contradictory to good sprayability.

Claims

1. Demands A method for manufacturing capsules comprising at least one double matrix shell enclosing at least one lipophilic core, the method comprising at least the steps of: a. to have an inverse emulsion comprising a first aqueous phase dispersed in a continuous oily phase, the first aqueous phase comprising water and at least one gelling-inducing agent and the oily phase comprising at least one active agent, in particular at least one perfumer; b. have a first aqueous envelope forming solution comprising water and at least one first matrix forming agent; c. bring the reverse emulsion of step a. into contact with at least the first aqueous shell-forming solution of step b., thereby obtaining a DI dispersion in the form of a water-in-oil-in-water emulsion, the gelling-inducing agent and the first matrix-forming agent being configured so that they are capable of undergoing a chemical reaction with each other to form a first water-insoluble matrix shell; d. react the gelling-inducing agent and the first matrix-forming agent, whereby the dispersed phase of the DI dispersion is in the form of capsules comprising a first water-insoluble matrix envelope containing at least one lipophilic nucleus; e. bringing into contact the capsules comprising a first matrix shell obtained in step d, or even the dispersion DI of step d, with at least a second aqueous shell-forming solution comprising water and at least a second matrix-forming agent, identical or different from the first matrix-forming agent, thereby obtaining a dispersion D2, the gelling-inducing agent and the second matrix-forming agent being configured such that they are capable of undergoing a chemical reaction with each other to form a second water-insoluble matrix shell, and f. to cause the gelling-inducing agent and the second matrix-forming agent to react, thereby causing the dispersed phase of the dispersion D2 is in the form of capsules comprising a double matrix envelope insoluble in water containing at least one lipophilic nucleus.

2. A method according to the preceding claim, wherein the reverse emulsion further comprises at least one surfactant, in particular a lipophilic surfactant, and preferably polyglycerol polyricinoleate.

3. A process according to any one of the preceding claims, wherein the gelling-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.

4. A process according to any one of the preceding claims, wherein the reverse emulsion of step a. comprises between 0.5% and 60%, preferably between 1% and 40%, better between 2.5% and 20%, and most particularly between 1% and 10%, by weight of gelling-inducing agent(s) relative to the total weight of the first aqueous phase.

5. A process according to any one of the preceding claims, wherein the oil phase comprises from 20% to 100%, preferably from 40% to 99%, and better from 60% to 95%, by weight of active agent(s), in particular of fragrance agent(s), relative to the total weight of the oil phase.

6. A method according to any one of the preceding claims, wherein the first and second matrix-forming agents are selected from polysaccharides or one of their salts, preferably from chitosan, alginate, in particular sodium alginate, carrageenan, in particular kappa and iota-carrageenan, pectins, gellan, or one of their derivatives, and mixtures thereof.

7. A method according to any one of the preceding claims, wherein the first matrix-forming agent is selected from gellan, alginate, and mixtures thereof, and preferably gellan, and the second matrix-forming agent is alginate, and in particular sodium alginate.

8. A method according to any one of the preceding claims, wherein: - the first aqueous envelope-forming solution comprises between 0.01% and 5%, preferably between 0.025% and 2.5%, better between 0.05% and 1%, or even between 0.1% and 0.5%, by weight of the first(s) matrix forming agent(s) relative to the total weight of said first aqueous envelope forming solution; and - the second aqueous envelope forming solution comprises between 0.05% and 2.5%, preferably between 0.1% and 1%, and better between 0.2% and 0.5%, by weight of second matrix forming agent(s) relative to the total weight of said second aqueous envelope forming solution.

9. A method according to any one of the preceding claims, wherein the first and / or second aqueous solution(s) for envelope formation may further comprise at least one structural stabilizer, preferably selected from agarose, xanthan gum, cellulose and its derivatives, for example methylcellulose or microcrystalline cellulose, and the like, and mixtures thereof, and particularly xanthan gum.

10. A method according to any one of the preceding claims, wherein step c. consists of injecting the reverse emulsion of step a. into at least a first conduit opening into the first aqueous envelope-forming solution of step b.

11. A method according to the preceding claim, wherein step c. is carried out in such a way that the first aqueous envelope-forming solution of step b. is put into circulation in a second conduit, the downstream opening of the first conduit opening into the second conduit, advantageously coaxial with the local axis of the second conduit.

12. A method according to the preceding claim, wherein the second aqueous envelope-forming solution of step e. is circulated in a third conduit in which the second conduit is included, advantageously coaxial 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.

13. A method according to any one of claims 1 to 9, wherein the method comprises at least the steps of: a'. supplying in a first chamber at least the reverse emulsion of step a. ; b', supplying in a second chamber at least the first aqueous envelope-forming solution of step b. ; the first chamber and the second chamber being fluidly connected by one or more conduits, preferably by micro-conduits; c'. guiding the reverse emulsion from step a' of the first chamber through the conduit(s) into the second chamber; steps d' to f' being identical to steps d to f defined according to any one of claims 1 to 9.

14. A method according to any one of the preceding claims, wherein step e is not a soaking step, and in particular is not a contact or immersion step of the capsules formed in step d.

15. A process according to any one of the preceding claims, said process further comprising at least one step g. of rinsing the capsules obtained at the end of step f. in an aqueous rinsing solution comprising water, preferably osmosis water, and optionally at least one preservative.

16. A method according to any one of the preceding claims, wherein the capsules obtained at the end of step f. have an average diameter of between 250 µm and 3,000 µm, preferably between 500 µm and 2,000 µm, in particular between 1,000 µm and 1,750 µm, and better between 1,200 µm and 1,500 µm, preferably with a coefficient of variation less than or equal to 10%, preferably less than or equal to 5%, and better less than or equal to 3%.

17. A process according to any one of the preceding claims, wherein the capsules obtained at the end of step f. comprise between 5% and 40%, preferably between 10% and 35%, and better between 15% and 30%, by weight of active agent(s), in particular of perfumer agent(s), relative to the total weight of the capsules.

18. A set of capsules comprising a plurality of capsules obtained by the process according to any one of the preceding claims, optionally in association with at least one physiologically acceptable medium.

19. An assembly of capsules according to the preceding claim, wherein the capsules comprise at least one double matrix envelope containing at least one lipophilic core, the capsules having a double envelope with a thickness of between 50 microns and 600 microns, preferably between 100 microns and 500 microns, more preferably between 150 microns and 400 microns, and especially between 200 microns and 350 microns, and preferably: - the first layer has a thickness between 10 microns and 300 microns, preferably between 25 microns and 250 microns, better between 50 microns and 200 microns, and especially between 75 microns and 150 microns; and - the second layer has a thickness between 75 microns and 600 microns, preferably between 100 microns and 500 microns, better between 150 microns and 400 microns, and especially between 200 microns and 300 microns.

20. Composition, in particular cosmetic and in particular perfumed, comprising at least a plurality of capsules obtained by the process according to any one of claims 1 to 17 or a set of capsules according to claim 18 or 19, optionally in association with at least one physiologically acceptable medium, preferably said composition comprising less than 10%, preferably less than 5%, in particular less than 2.5%, or even being devoid of alcohol(s), in particular ethanol, relative to the total weight of said composition.

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