FR3153264A1 - Improved method of manufacturing capsules comprising at least one matrix shell enclosing an oily core - Google Patents

Abstract

Improved method for manufacturing capsules comprising at least one matrix shell enclosing an oily core The present invention relates to a method for manufacturing capsules comprising at least one matrix shell enclosing at least one oily core, the method comprising at least the steps of: a. providing in a first chamber an emulsion comprising an aqueous phase dispersed in a continuous fatty phase, the dispersed aqueous phase comprising water and at least one gelling agent; b. providing in a second chamber at least one aqueous shell-forming solution comprising water and at least one water-soluble matrix-forming agent; the first chamber and the second chamber being fluidically connected by one or more channels; c. guiding the emulsion of step a. from the first chamber through the one or more channels into the second chamber to form in the second chamber a dispersion of the emulsion of step a. in the aqueous shell-forming solution of step b.; and d. in the second chamber, reacting the gelation-inducing agent and the matrix-forming agent in the dispersion formed in step c. to form capsules comprising a water-insoluble matrix shell containing at least one oily core. Figure for abstract: None

Description

Improved method of manufacturing capsules comprising at least one matrix shell enclosing an oily core

The invention relates to a method for manufacturing capsules comprising at least one matrix shell enclosing at least one oily core.

Capsules, particularly microcapsules with particle sizes less than 1 mm, have found wide application, notably in the fields of pharmacy, cosmetics, diagnostics, food and materials science. Such capsules can be made from an emulsion of monodisperse drops in a continuous phase. Monodispersity increases stability and allows precise volume control in multiple chemical or biological reactions. Microfluidics offers a suitable platform for forming monodisperse drops. Monodisperse drops can further be adapted to generate capsules for the encapsulation of active ingredients such as drugs, perfumes, flavors, peptides, living materials, such as bacteria or phages, fertilizers, pesticides and other active substances for skincare, makeup and/or well-being.

For many applications, it is desirable to provide capsules with an oily core, i.e., a core (or heart) comprising at least one oil, enveloped by a suitable shell. This is mainly due to the fact that many compounds of interest, for example, flavors, perfumes, cosmetic or pharmaceutical actives, or vitamins, are hydrophobic and/or only soluble in a fatty phase, but not in water. In addition, several oils can enhance the mechanism of action of these compounds. For example, some compounds, such as vitamins, are only absorbed in sufficient quantity by the body in the presence of oil(s). In addition to maintaining the structural integrity of the capsule, the shell enclosing the oily core may further have certain adjustable characteristics. For example, it may be desirable to prevent the shell from breaking down upon contact with saliva, but only in the stomach to release the compound of interest. Also, it may be desirable that a compound of interest, particularly a pharmaceutical active, is released only in the intestine, but not in the mouth or stomach. In addition, it may in some cases be desirable to provide the capsules with mucoadhesive properties for better control of the release of a compound of interest.

There are several known methods, including microfluidic ones, for producing capsules from monodisperse drops. In particular, patent application WO2022106361 describes a microfluidic manufacturing method that makes it possible to manufacture capsules whose shell size and thickness can be precisely controlled.

The method described in WO2022106361, however, has the disadvantage of comprising numerous steps, one of which consists of mixing an inverse emulsion in an aqueous phase comprising at least one hydrophilic surfactant, in particular PVA, Tween or SDS, whereby a water-in-oil-in-water emulsion is obtained and which, in a subsequent non-continuous step, is mixed with an alginate solution to ensure the formation of the shell, and therefore of the capsules. The optimization, in particular the simplification, of manufacturing processes, in particular on an industrial scale, remains a constant objective. In addition, the use of surfactants is increasingly criticized, particularly in cosmetics, because they are often irritants and of petrochemical origin, non-biodegradable and very ecotoxic.

It is therefore a general aim to advance the state of the art relating to the manufacture of capsules having an oily core (or heart) and a shell enclosing the oily core and preferably to propose an improved alternative to the prior art described above.

In particular, the present invention aims to propose a microfluidic manufacturing method which, in particular compared to that described in WO2022106361, is simplified, easily industrializable and furthermore advantageously relies on a reduced use of hydrophilic surfactants, while remaining satisfactory in terms of the capacity for precise control of the size of the capsules and the thickness of their envelope.

Thus, the invention relates to a method for manufacturing capsules comprising at least one matrix envelope containing at least one oily core, the method comprising at least the steps consisting of:

a. providing in a first chamber an emulsion comprising an aqueous phase dispersed in a continuous fatty phase, the dispersed aqueous phase comprising water and at least one gelling-inducing agent, optionally the emulsion further comprising at least one surfactant;

b. providing in a second chamber at least one aqueous shell-forming solution comprising water and at least one water-soluble matrix-forming agent;

the first chamber and the second chamber being fluidically connected by one or more channels, preferably by micro-channels;

c. guiding the emulsion of step a. from the first chamber through the channel(s) into the second chamber to form in the second chamber a dispersion of the emulsion of step a. in the aqueous shell-forming solution of step b.; and

d. in the second chamber, reacting the gelation-inducing agent and the matrix-forming agent in the dispersion formed in step c. to form capsules comprising a water-insoluble matrix shell enclosing at least one oily core.

It is understood that steps a. and b. do not necessarily have to be performed in this 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 understood that the dispersion formed in step c. comprises a plurality of monodisperse drops comprising the emulsion of step a. as a dispersed phase in the aqueous shell-forming solution of step b. as a continuous phase.

It is further understood that the composition of the oily core of the capsules obtained at the end of step d. is not identical to the composition of the emulsion of step a. provided in the first chamber and dedicated to forming the core of the capsules, in particular given the fact that the dispersed aqueous phase and certain reagents react and/or diffuse from the core, in particular towards the aqueous solution for forming the shell. This is particularly the case for the agent inducing gelation.

However, the oily core of the capsules obtained at the end of step d. may contain minor amounts of residual dispersed aqueous phase, i.e. minor amounts of water. However, the majority of the oily core of the capsules obtained at the end of step d. is composed of the fatty phase. Typically, the capsules comprise more than 60%, preferably more than 70%, in particular more than 80%, better still more than 90%, in particular more than 95%, and most particularly more than 99%, by weight of fatty phase relative to the total weight of the capsule core.

Step c. of the method according to the invention is advantageous in that it makes it possible to generate a dispersion of an emulsion directly in the aqueous solution for forming the shell. Thus, in step c., each drop generated comprises mainly the fatty phase from step a., but also the dispersed aqueous phase which comprises the gelling-inducing agent from step a. Thus, the dispersion formed in step c. is a water-in-oil-in-water dispersion where the continuous aqueous phase is the aqueous solution for forming the shell. The use of the emulsification step c., i.e. guiding the emulsion forming the core from step a. through the microchannels, makes it possible to precisely control the size and ensure a uniform distribution of the size of the dispersion formed in step c. In addition, the process allows rapid capsule production, in the order of 100 g/h (i.e. gram(s) per hour) or more, or even up to 500 g/h.

In step c., guiding the emulsion a. to the second chamber comprising the aqueous shell-forming solution is advantageous for at least the following reasons.

A method according to the invention is therefore simplified compared to the method described in WO2022106361. Indeed, in WO2022106361, the second chamber comprises an aqueous solution comprising a hydrophilic surfactant so as to form a sufficiently stable water-in-oil-in-water double emulsion which is then injected into another receptacle comprising an aqueous solution for forming the envelope. In WO2022106361, the second chamber therefore ensures the performance of an intermediate step of forming a transient water-in-oil-in-water double emulsion.

A method according to the invention dispenses with this intermediate step and the formation of the capsules is carried out directly in the second chamber, which also allows the easy formation of capsules continuously, which is particularly advantageous, in particular when seeking to produce large volumes, and even more so on an industrial scale. In addition, the non-use in the second chamber of an aqueous solution comprising a hydrophilic surfactant as described in WO2022106361 mechanically makes it possible, for a method according to the invention, to reduce, or even eliminate, the use of hydrophilic surfactant.

Thus, a method according to the invention does not require a second aqueous solution comprising water and a second surfactant nor the implementation of a non-continuous step of mixing the aforementioned transient water-in-oil-in-water double emulsion in a gelling container containing an aqueous shell-forming solution, as described in WO2022106361.

With a method according to the invention, the matrix grows around the core by a chemical reaction between the gelling-inducing agent, present within each drop of the emulsion, and the matrix-forming agent, present in the aqueous solution for forming the shell, this step being carried out, in whole or in part, in the second chamber.

Preferably, step a. comprises at least the sub-steps consisting of:

a1. dissolving the gelation-inducing agent in water to form a solution; and

a2. mixing the solution formed in step a1. with the fatty phase comprising at least one oil, and optionally at least one lipophilic gelling agent and/or at least one surfactant.

Step a2. can be carried out extemporaneously or simultaneously with the supply of the emulsion into the first chamber.

Dissolving the gel-inducing agent in the water of the dispersed aqueous phase of step a. advantageously prevents/avoids clogging of the channels. Indeed, carbonates can cause an accumulation of insoluble salts in the channels.

The core-forming emulsion provided in step a. may be stable between 60 minutes and 600 minutes, preferably between 100 minutes and 500 minutes. Such stability ensures that the drops are not directly destroyed, especially in step c. However, the stability of the drops is also not too high, which would decrease the efficiency of shell formation in step d.

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

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

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

Preferably, all or part of the capsules are macroscopic, i.e. visible to the naked eye. The capsules are advantageously substantially spherical.

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

Preferably, the capsules obtained with a method according to the invention and included in an assembly according to the invention have an average diameter of between 150 μm and 3,000 μm, preferably between 250 μm and 2,000 μm, in particular between 500 μm and 1,500 μm, and better still between 750 μm and 1,000 μm, preferably with a coefficient of variation of less than or equal to 10%, preferably less than or equal to 5%, and better still less than or equal to 3%.

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

Advantageously, the envelope has a uniform thickness. By “uniform thickness”, for the purposes of the present invention, is meant droplets whose shell thickness varies according to a standard deviation of less than or equal to 10%, preferably less than or equal to 5%.

For the purposes of the present invention, the term "capsule" means a capsule having a size less than 4 mm, preferably between 100 µm and 3 mm, in particular between 200 µm and 2 mm.

For the purposes of the present invention, the term “drop” means a drop having a diameter of less than 4 mm, preferably between 1 µm and 4 mm, and in particular between 1 µm and 1 mm.

For the purposes of the present invention, the term “microchannel” means a channel having an internal diameter of less than 4 mm, preferably between 1 µm and 4 mm, and in particular between 10 µm and 1 mm.

The envelope can be referred to interchangeably by the terms “membrane” or “bark”.

Unless otherwise stated, in all that follows, we consider that we are at room temperature (for example T=25°C ± 2°C) and atmospheric pressure (760 mm Hg, or 1,013.10 ⁵ Pa or 10 ¹³ mbar).

According to the invention, the pH is typically between 4.0 and 8.0, in particular between 5.0 and 7.0.

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

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

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

For example, the channel(s) may have a diameter of between 0.25 and 2000 µm, preferably between 0.5 and 800 µm, more preferably between 1 and 500 µm, or even between 2 and 250 µm. The multiple channels of the membrane are typically microchannels. For example, each channel may have a cross-section of 0.04 µm ² to 4,000,000 µm ² , preferably from 4 µm ² to 640,000 µm ² .

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

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

In other embodiments, the ratio "channel length / minimum diameter" may be between 5 and 1000, preferably between 10 and 500, in particular between 10 and 50. In some embodiments, the channel length may be between 0.05 mm and 20 mm, in particular between 0.1 mm and 20 mm, in particular between 0.1 mm and 5 mm, in particular between 0.5 and 20 mm.

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

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

In other embodiments, the cross-sectional area of each channel outlet is from 0.12 to 36,000,000 µm ² , preferably from 12 to 5,760,000 µm ² . In particular, the total open area of the second side of the membrane may 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.

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

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

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

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

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

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

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

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

Emulsion

Step a. consists of providing in a first chamber an emulsion comprising an aqueous phase dispersed in a continuous fatty phase, the dispersed aqueous phase comprising water and at least one gelling-inducing agent, optionally the emulsion further comprising at least one surfactant.

Step a. therefore consists of providing in a first chamber an inverse emulsion, also referred to interchangeably as “water-in-oil emulsion”.

For obvious reasons, the inverse emulsion injected into the first chamber is in a liquid (or fluid) form. By “liquid” for the purposes of the present invention, we mean a non-solid inverse emulsion and in particular capable of flowing under its own weight and passing through the channels between the first and second chambers.

To satisfy this condition, the inverse emulsion may be preheated. Thus, the first chamber may advantageously comprise a heating member to maintain the inverse emulsion at a temperature above its melting point and thus ensure that this inverse emulsion is liquid in the microfluidic device, in particular for carrying out step c.

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

By “substantially immiscible” within the meaning of the present invention, it is meant that the solubility of a first phase in a second phase is advantageously less than 5% by mass, and vice versa.

Continuous oily phase

The fatty phase of step a. comprises at least one oil and optionally at least one lipophilic gelling agent and/or at least one surfactant.

Oils)

The term "oil" means a fatty substance that is liquid at room temperature.

Examples of oils that can be used according to the invention include:

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

- hydrocarbon oils of animal origin, such as perhydrosqualene and squalane;

- synthetic esters and ethers, in particular of fatty acids, such as oils of formulas R1COOR2 and R1OR2 in which R1 represents the residue of a fatty acid in C8 to C29, and R2 represents a hydrocarbon chain, branched or not, in C3 to C30, such as for example Purcellin oil, isononyl isononanoate, isodecyl neopentanoate, isopropyl myristate, ethyl-2-hexyl palmitate, octyl-2-dodecyl stearate, octyl-2-dodecyl erucate, isostearyl isostearate; hydroxylated esters such as isostearyl lactate, octylhydroxystearate, octyldodecyl hydroxystearate, diisostearyl malate, triisocetyl citrate, fatty alcohol heptanoates, octanoates, decanoates; polyol esters, such as propylene glycol dioctanoate, neopentyl glycol diheptanoate and diethylene glycol diisononanoate; and pentaerythritol esters such as pentaerythrityl tetrabehenate (DUB PTB) or pentaerythrityl tetraisostearate (Prisorine 3631);

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

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

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

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

- and their mixtures.

According to a preferred embodiment, the oil is selected from the group consisting of isononyl isononanoate, dimethicone, isohexadecane, polydimethylsiloxane, octyldodecanol, isodecyl neopentanoate and mixtures thereof.

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

Those skilled in the art will know how to adjust the nature and/or the content of oil(s), in particular to ensure satisfactory stability of the inverse emulsion and the capsules according to the invention and to retain the aforementioned advantageous technical effects.

According to one embodiment, the capsules according to the invention advantageously comprise between 40% and 99%, preferably between 50% and 90%, and better still between 60% and 80%, by weight of oil(s) relative to the total weight of the fatty phase, or even of the core of the capsules.

According to one embodiment, the emulsion advantageously comprises between 50% and 90%, and preferably between 60% and 80%, by weight of oil(s) relative to the total weight of the emulsion.

Lipophilic surfactant(s)

As indicated previously, the fatty phase may further comprise at least one surfactant, and therefore necessarily a lipophilic surfactant.

Preferably, the surfactant is a non-ionic surfactant, such as polyglycerol polyricinoleate (PGPR), a sorbitan derivative, particularly a sorbitan ester, for example sorbitan monooleate, sorbitan trioleate, such as Span 80 or Span 85, and mixtures thereof. Furthermore, the surfactant may be a solid particle, preferably a hydrophilic hydrophobic or Janus-type particle, configured to provide a release emulsion. For example, the solid particle may be colloidal.

Preferably, the lipophilic surfactant, in particular the non-ionic lipophilic surfactant, has a molecular weight of between 600 and 120,000 g/mol, preferably between 800 and 80,000 g/mol.

Such a surfactant, in particular a non-ionic one, is advantageous in that it can ensure sufficient stabilization of the drops of the dispersed aqueous phase in the core-forming emulsion. PGPR is particularly advantageous because it has a satisfactory compromise in terms of stability in such a way that the microdispersed drops of the aqueous dispersed phase are not immediately destroyed, in particular when guiding the emulsion through the channels, but also does not stabilize the drops too much, as this would decrease the efficiency of the diffusion process of the gelation-inducing agent at the droplet interface in step d. so that it can react with the matrix-forming agent.

Advantageously, the emulsion forming the core may comprise between 0.01% and 2%, preferably between 0.05% and 1.5%, and better still between 0.1% and 1%, by weight of lipophilic surfactant(s) relative to the weight of the fatty phase, or even of the emulsion forming the core.

Lipophilic gelling agent(s)

In certain embodiments, the fatty phase of step a. further comprises at least one lipophilic gelling agent. A lipophilic gelling agent, i.e. soluble or dispersible in the fatty phase, may be chosen from organic or mineral, polymeric or molecular gelling agents; fatty substances that are solid at room temperature and pressure, in particular chosen from waxes, pasty fatty substances, butters; and mixtures thereof, and preferably from polymeric gelling agents.

Such lipophilic gelling agents are notably described in WO2019002308.

Among the lipophilic gelling agents that can be used in the present invention, mention may be made of dextrin and fatty acid esters, such as dextrin palmitates. Among the dextrin and fatty acid esters, mention may be made, for example, of dextrin palmitates, dextrin myristates, dextrin palmitates/ethylhexanoates and mixtures thereof. Mention may in particular be made of the dextrin and fatty acid esters marketed under the names Rheopearl® KL2 (INCI name: dextrin palmitate), Rheopearl® TT2 (INCI name: dextrin palmitate ethylhexanoate), and Rheopearl® MKL2 (INCI name: dextrin myristate) by the company Miyoshi Europe, also dextrin palmitate marketed by The Innovation Company.

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

Advantageously, a lipophilic gelling agent is a heat-sensitive gelling agent, that is to say a gelling agent which reacts to heat, and in particular which is solid at room temperature and liquid at a temperature above 50°C, preferably above 60°C.

Advantageously, a lipophilic gelling agent is a thixotropic gelling agent or one capable of giving the fatty phase thixotropic behavior. Such a thixotropic gelling agent is in particular chosen from pyrogenic silicas which may be hydrophobically treated.

According to the invention, a dispersion according to the invention may comprise between 0.5% and 30%, preferably between 1% and 25%, in particular between 1.5% and 20%, better still between 2% and 15%, and very particularly between 5% and 12%, by weight of lipophilic gelling agent(s) relative to the total weight of the fatty phase.

Compound(s) of interest

In certain embodiments, the fatty phase of step a. further comprises at least one compound of interest. A compound of interest may be chosen from a biological active agent, a pharmaceutical active agent and/or a cosmetic active agent, for example chosen from moisturizing agents, healing agents, depigmenting agents, UV filters, desquamating agents, antioxidant agents, active agents stimulating the synthesis of dermal and/or epidermal macromolecular agents, dermo-contracting agents, antiperspirant agents, soothing agents, anti-aging agents, perfuming agents, anticoagulants, anti-thrombogenic agents, anti-mitotic agents, anti-proliferation, anti-adhesion, anti-migration agents, cell adhesion promoters, growth factors, antiparasitic molecules, anti-inflammatories, angiogenic agents, angiogenesis inhibitors, vitamins, hormones, proteins, antifungals, antimicrobial molecules, antiseptics or antibiotics, flavorings, antibodies, peptides, enzymes, RNA, DNA, microorganisms, and mixtures thereof.

In particular, the fatty phase of step a. comprises at least one perfuming agent.

For obvious reasons, a perfuming agent according to the invention is a lipophilic agent, i.e. soluble or dispersible in an organic solvent, in particular an oil. A “perfuming agent”, also indifferently referred to as “perfume”, “perfume juice” or “perfume concentrate”, within the meaning of the present invention, may be chosen from compounds having the INCI name “Perfume” or “Fragrance”. Thus, within the meaning of the present invention, the term “perfume” does not designate a mixture comprising a perfume concentrate and alcohol. The perfuming agents that can be used according to the invention are ingredients commonly used in perfumery. Their nature does not require a more detailed description here, which cannot be exhaustive, as a person skilled in the art is able to choose them based on their general knowledge and according to the desired olfactory effect. These perfuming agents belong to chemical classes as varied as alcohols, aldehydes, ketones, esters, ethers, acetates, nitriles, terpene hydrocarbons, nitrogenous or sulfurous heterocyclic compounds, as well as essential oils of natural or synthetic origin. Many of these ingredients are also listed in reference texts such as the book by S. Arctander, Perfume and Flavor Chemicals, 1969, Montclair, New Jersey, USA, or its more recent versions, or in other works of a similar nature, as well as in the more recent scientific and patent literature relating to the art of perfumery. For example, a perfuming agent is a compound or mixture of compounds at least partially volatile at room temperature and whose odor can be detected. A perfuming agent composed of essential oils is generally diluted in order to express its full olfactory potential, that is to say a perception that evolves during the day after application to the surface to be treated, thanks to the presence of several odorous organic compounds having different volatilities. The development of a perfume includes a step of combining several perfuming raw materials to give a top note, a middle note and a base note to the perfume composition. A perfuming agent can be prepared from natural or synthetic organic perfumed materials. Examples of natural perfumed materials are extracts of flowers, leaf stems, fruits, barks, roots, woods, herbs, grasses, resins, balsams, and mixtures thereof. These plant-based fragrances may be essential oils, such as bergamot, rose, lavender, sandalwood, cardamom, sage, chamomile, clove, lemon balm, mint, cinnamon leaf, juniper, vetiver, olibanum, galbanum, labdanum, and mixtures thereof. Examples of fragrances of synthetic origin are hedione, ethylene brassilate, habanolide, benzyl acetate, benzyl benzoate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, citronellyl acetate, citronellyl formate, geranyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate. , benzyl formate, ethyl methyl phenyl glycinate alkylcyclohexyl propionate, styralyl propionate and benzyl salicylate, benzyl ethyl ether, linear alkanals of 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamenaldehyde, hydroxycitronellal, ionones such as alpha-isomethylionone, methylcedrylketone, anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, terpineol, terpenes, and mixtures thereof.

The fatty phase may advantageously comprise from 0.5% to 60%, preferably from 1% to 50%, and better still from 10% to 40%, by weight of perfuming agent(s) relative to the total weight of the fatty phase.

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

In some embodiments, step a. comprises dissolving the gelation-inducing agent in water to form an aqueous solution and mixing this aqueous solution with the fatty phase and with at least one surfactant, preferably a lipophilic surfactant. The compound of interest may in these embodiments already be mixed in the fatty phase or also added only after the formed aqueous solution of the gelation-inducing agent in water is mixed with the fatty phase.

In some embodiments, mixing the aqueous solution formed of the gelation-inducing agent in water with the fatty phase and the surfactant advantageously comprises stirring with a stirrer at at least 8,000 rpm, preferably between 10,000 rpm and 20,000 rpm, for example between 1,3000 rpm and 1,5000 rpm.

Dispersed aqueous phase

The dispersed aqueous phase comprises at least water and at least one gelation-inducing agent.

Water

An aqueous phase or aqueous solution according to the invention comprises water. In addition to distilled or deionized water, water suitable for the invention may also be natural spring water or floral water.

According to one embodiment, the mass percentage of water in the dispersed aqueous phase is at least 50%, and better still at least 60%, in particular between 70% and 98%, and preferably between 75% and 95%, relative to the total mass of said dispersed aqueous phase.

Gelling-inducing agent(s)

In some embodiments, the gelation-inducing agent is an inorganic salt, particularly an alkaline earth metal salt, particularly an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate, an alkaline earth metal nitrate, and mixtures thereof.

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

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 gel-inducing agent. For example, CaCO ₃ or MgCO ₃ can be used, especially in powder form.

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

In some embodiments, the gelation-inducing agent is CO ₂ or a CO ₂ generator. A CO ₂ generator may release CO ₂ under specific conditions. For example, bicarbonate may release CO ₂ in the presence of an acid. In some embodiments, the gelation-inducing agent may be a Bronsted acid, for example, a mineral acid or a carboxylic acid. In this case, the matrix-forming agent may be a composition of a polysaccharide, such as an alginate, chitosan, etc., and a suitable water-soluble alkali metal complex or alkaline earth metal complex, such as Ca-Na2-EDTA _, Mg-Na2 _- EDTA, Sr-Na2 _- EDTA, and the like.

Advantageously, the emulsion forming the core comprises between 1.5% and 7.0%, preferably between 2.0% and 5.0%, by weight of agent(s) inducing gelling relative to the weight of the dispersed aqueous phase, or even to the weight of the emulsion.

Advantageously, the emulsion forming the core comprises a “dispersed aqueous phase / continuous fatty phase” weight ratio of between 1 and 50, preferably between 2 and 30, better still between 3 and 20, and very particularly between 4 and 15.

Preferably, the dispersed aqueous phase does not comprise a hydrophilic surfactant.

Aqueous envelope-forming solution

Step b. comprises providing in the second chamber an aqueous shell-forming solution which comprises at least water and at least one water-soluble matrix-forming agent (or “matrix agent”).

For obvious reasons, the aqueous solution for forming the envelope in step b. must be in a liquid (or fluid) form, i.e. in a non-solid form and capable of ensuring the formation of drops during step c.

If necessary, the liquid character of the aqueous solution forming the envelope in step b. can be obtained by heating this aqueous solution.

Advantageously, the second chamber may comprise a heating member for maintaining the aqueous solution for forming the envelope at an adjusted temperature to ensure that this aqueous solution for forming the envelope remains fluid in the microfluidic device, in particular for carrying out step c.

According to one embodiment, the mass percentage of water in the aqueous solution for forming the envelope is at least 50%, and better still at least 60%, in particular between 70% and 98%, and preferably between 75% and 95%, relative to the total mass of said aqueous solution for forming the envelope.

For obvious reasons, the aqueous solution forming the envelope and the continuous fatty phase are immiscible.

Water-soluble matrix-forming agent(s)

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

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

Alternatively, the matrix agent may be a monomer soluble in the aqueous phase but not in oil. Such a monomer must be chosen such that it can undergo stepwise polymerization, for example a diamine. In this case, the gelation-inducing agent is a monomer soluble in the oil phase but not in water, such as a diacid chloride, thus allowing interface polymerization during step e of formation of the water-insoluble matrix.

A person skilled in the art will know how to adjust the content of matrix-forming agent(s) so as to form stable capsules without altering the robustness of the process according to the invention.

Indeed, too rapid a chemical reaction kinetics between the gelling-inducing agent and the matrix-forming agent to form a water-insoluble matrix shell can lead to clogging or even blocking the channels, which for obvious reasons is not desirable.

In some embodiments, the aqueous shell-forming solution may comprise between 0.05% and 5%, preferably between 0.1% and 2%, and more preferably between 0.5% and 1.0%, by weight of matrix-forming agent(s) relative to the weight of the aqueous shell-forming solution.

According to a particular embodiment, the aqueous solution for forming the envelope may further comprise at least one chelating agent capable of delaying the reaction between the gelling-inducing agent and the matrix-forming agent, preferably chosen from at least one organophosphate, and better chosen from tetrasodium pyrophosphate. Such an embodiment is advantageous in that it makes it possible to prevent clogging, obstructions and plugging of the channels described above.

Preferably, the aqueous solution for forming the shell does not comprise a hydrophilic surfactant.

In some embodiments, the aqueous shell-forming solution may further comprise at least one hydrophilic surfactant. The presence of such a surfactant in the aqueous shell-forming solution may enhance the gelation reaction.

A hydrophilic surfactant for use in the aqueous shell-forming solution may be selected from polyvinyl alcohol (PVA), polysorbate, such as Tween 20 or Tween 80, 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.

Advantageously, the aqueous solution for forming the envelope may comprise between 0.001% and 5%, preferably between 0.01% and 2.5%, and better still between 0.1% and 1%, by weight of hydrophilic surfactant(s) relative to the weight of the aqueous solution for forming the envelope.

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

Such alcohol may be added to the aqueous shell-forming solution before step d. Alcohol has been found to promote diffusion of the gelation-inducing agent to the droplet interface. The alcohol is typically present in an amount of 5% to 30%, preferably 10% to 20%, by weight of the aqueous shell-forming solution. It has been observed that if the amount of alcohol is between 10% and 20% by weight, the capsule core size, i.e., the core diameter, is larger than if more ethanol is used. For example, a capsule diameter greater than 300 μm can be achieved. If the amount of alcohol is between 20% and 30% by weight (under otherwise identical conditions), the capsule core size, i.e., the core diameter, is smaller.

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

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

In some embodiments, the aqueous shell-forming solution of step d. 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, e.g., starch. The provision of such an additional biopolymer, and in particular solid biopolymer particles, increases the mechanical strength of the capsules generated.

In some embodiments, the aqueous shell-forming solution comprises from 1% to 10%, in particular from 3% to 7%, by weight of additional biopolymer(s), and in particular solid biopolymer particles, relative to the weight of the aqueous shell-forming solution. Particularly suitable solid particles are starch particles, such as corn starch particles.

In some embodiments, the particle size of the solid particles is equal to or less than 20 µm, in particular equal to or less than 1.5 µm.

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

Additionally, or alternatively, after step d., the formed capsules may be exposed to temperatures above room temperature, in particular between 25°C and 95°C, in particular between 40°C and 85°C, in particular between 50°C and 80°C, in particular between 65°C and 80°C, in particular between 70°C and 80°C. For example, exposure to such temperatures may be carried out for 5 min to 60 min, in particular from 1 5 min to 30 min. Indeed, increasing temperatures during or after step d. may have a significant effect on the mechanical strength of the capsules.

In addition, or alternatively, the device may comprise a cooler positioned at the second chamber and/or after the outlet of the second chamber so as to accelerate the cooling kinetics of the drops of fatty phase and thus to optimize their mechanical strength. This is particularly the case when the fatty phase comprises at least one thermosensitive lipophilic gelling agent. This cooling step may therefore be carried out during and/or after step d.

In other embodiments, a pressure of 1.01 bar to 1.15 bar, preferably 1.03 bar to 1.07 bar is applied to the first chamber, in particular during step c., and/or a pressure of 1.02 bar to 1.2 bar, preferably 1.05 bar to 1.1 bar is applied to the second chamber, in particular during step c. It is understood that these pressure values relate to absolute pressures, i.e. a pressure of 1.01 bar is a pressure which constitutes an overpressure of 0.01 bar relative to atmospheric pressure.

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

In some embodiments, step d. comprises stirring in the second chamber, the aqueous shell-forming solution and the dispersion obtained in step d. Preferably, stirring is carried out with a stirrer with stirring speed of 10 rpm (for "revolutions per minute") to 800 rpm, preferably 25 rpm to 500 rpm, in particular 50 rpm to 350 rpm, and more preferably 100 rpm to 150 rpm. Mixing during step d. is beneficial because it prevents agglutination of the monodisperse drops of the formed dispersion and/or the formed capsules. This further ensures a uniform size distribution of the capsules and prevents the risk of agglomerations of the capsules with each other. Typically, an overhead stirrer or a stirring device as described in WO2023/099530 may be used.

In some embodiments, step d. is carried out for 5 min to 25 min, preferably for 8 min to 12 min or for 15 min to 20 min. 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 aqueous shell-forming solution, directly influences the size of the capsules and the size of the capsule core.

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

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

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

Isolation of the capsules may for example comprise filtration or sieving to separate the capsules from the aqueous shell-forming solution, and optionally washing the capsules with water optionally comprising at least one surfactant, such as sodium lauryl sulfate (SDS), a Tween derivative, such as Tween 20 or 80, or PVA.

Curing may for example comprise drying the capsules, for example by an air stream or by freeze-drying, in order to evaporate all or at least the majority of the unbound water. Curing may also comprise further stirring of the capsules in an aqueous solution comprising at least one inorganic salt, such as CaCl ₂ or MgCl ₂ , preferably an aqueous solution of 1% to 10%, preferably 1% to 5%, by weight of inorganic salt(s). This further increases the stability and structural integrity of the capsules, in particular of the shell.

Preservation may be achieved by immersing the capsules in distilled water or in an aqueous solution of inorganic salt, such as CaCl ₂ or MgCl ₂ , preferably a 1 to 10% aqueous solution, more preferably 1 to 5% by weight of the inorganic salt. Such preservation has been found to increase the stability of the capsules.

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

In some embodiments, step c. is performed with a device comprising a first core emulsion feed inlet of step a., which opens into the first chamber, a second aqueous shell-forming solution feed inlet, opening into the second chamber and an outlet at the second chamber for collecting capsules in the aqueous shell-forming solution. Further, the device comprises a membrane, in particular a membrane as described above, which separates the first chamber and the second chamber and which comprises a first side facing the first chamber and a second side facing the second chamber. The membrane comprises multiple channels extending from the first side to the second side, i.e., providing a fluid connection of the first chamber and the second chamber. Each channel comprises a channel inlet arranged on the first side and a channel outlet arranged on the second side. The first chamber may typically be configured such that a flow rate of the core-forming emulsion through all the individual channels is substantially equal. In the prior art, an inhomogeneous pressure distribution, especially of the core emulsion, allows only a small percentage of channels to actively produce drops. An equal pressure distribution on the first side allows for a smooth flow of the core emulsion into the aqueous shell-forming solution and the generation of drops, and capsules, with reproducible quality at a high flow rate of up to 5 liters per hour. The first chamber can typically be configured so that a flow rate of the core emulsion through all individual channels is essentially equal.

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

The outlet of the second chamber may, for example, be in fluid communication with a tank for storing capsules in the aqueous solution for forming the shell.

In some embodiments, the capsules and the aqueous shell-forming solution are recovered from the second chamber via the outlet of the second chamber continuously, thereby increasing production efficiency.

In some embodiments, the storage tank is configured such that at least a portion of the aqueous shell-forming solution is reinjected into the second chamber, so as to limit the consumption of aqueous shell-forming solution. This embodiment is particularly possible due to the ability of the capsules to cream given their density, which is generally lower than that of the aqueous shell-forming solution, and/or by adapting the collection of the dispersion, for example by placing a sieve above the inlet of the storage tank. This embodiment is particularly relevant when the recovery of the capsules in the aqueous shell-forming solution via the outlet of the second chamber is carried out continuously, as described above.

In certain embodiments, step d. is carried out under continuous flow of the dispersion of the emulsion formed in step c. Thus, according to a preferred embodiment, steps c. and d. are carried out simultaneously and continuously, thus making it possible to increase the production yield.

In some embodiments, the first chamber is configured such that in an operative state, the pressure along the first side of the membrane is substantially isobaric. For example, the first inlet may include a nozzle to provide an isobaric pressure distribution across the first side of the membrane. In particular, a spray nozzle may be used. Alternatively, the first chamber may be shaped such that an isobaric pressure distribution across the first side of the membrane is provided.

In other embodiments, the first chamber has a rounded cross-section relative to a cross-sectional plane, which is perpendicular to the membrane and rotationally symmetrical relative to a central longitudinal axis. The term "rounded cross-section" as used herein refers to a continuous curve without increments, in particular to a curve which has in the cross-sectional plane perpendicular to the membrane, a radius of at least 1 mm, in particular at least 5 mm, in particular at least 10 mm. It is understood that the curvature in the cross-sectional view can be described as a part of a circle with said radius. Thus, the side walls of the first chamber can continuously converge towards each other in the upstream direction. The central longitudinal axis is an axis extending in the longitudinal direction of the device, which is arranged at the center of the device and/or at an axis being perpendicular to the membrane and intersecting the center of the membrane. The first chamber may have a U-shaped cross-section or may be concavely rounded or semi-circular. The rounded cross-section is typically rimless and thus excludes edges, which would lead to uneven pressure distribution when the core-forming emulsion is forced through the membrane. Preferably, the first chamber may have the shape of a spherical dome. The shape of the first chamber may generally preferably be substantially rotationally symmetrical about the central longitudinal axis.

In some embodiments, the outlet of the second chamber may be substantially disposed on the central longitudinal axis and/or the axis being perpendicular to the membrane and intersecting the center of the membrane. Preferably, the second chamber is tapered toward the outlet of the second chamber. For example, at least portions of the second chamber may be arc-shaped or cone-shaped toward the outlet of the second chamber. These embodiments ensure that no capsules are trapped and all are directly retrievable via the outlet of the second chamber. In some embodiments, the first chamber is shaped like a hemisphere or a truncated cone. Typically, the hemisphere or truncated cone opens toward the membrane, i.e., the largest radius is typically closest to the membrane. The term "hemispherical" as used herein also includes other spherical segments, such as one-third of a sphere. Thus, in some embodiments, the shape of the first chamber is a spherical dome or a spherical cap. Preferably, if the first chamber has a spherical dome shape, and/or in particular a hemispherical shape, the first inlet may be arranged adjacent to or at a pole of the spherical dome of the first chamber, in particular the hemispherical dome. Such shapes have the advantage that the material flow of the core-forming emulsion is equally distributed on the first side of the membrane, thereby helping to provide an equal pressure distribution adjacent to the individual channel. The first inlet may for example be arranged substantially perpendicular to the central longitudinal axis, i.e., substantially parallel to the first side of the membrane, or also parallel to the central longitudinal axis.

In some embodiments, the first inlet is disposed at an angle of substantially 90° or less relative to the membrane channels. Typically, all of the channels are arranged substantially parallel to one another. This has the beneficial effect that the core-forming emulsion is not directly forced onto the membrane, thereby further providing uniform pressure distribution across each membrane channel. For example, the angle between the first inlet and the membrane channels may be between 60° and 90°, including 75° and 90°. Preferably, the first inlet is substantially transversely, preferably perpendicularly, to the multiple membrane channels. Thus, in such embodiments, the first inlet may be parallel to the first side of the membrane.

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

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

In some embodiments, the membrane holder includes clamping means for mounting the membrane, the membrane holder and/or the clamping means being configured to receive membranes having different thicknesses. Typically, the clamping means may be adjustable. Examples of clamping means include screws, clamps, bolts, locks, etc.

In some embodiments, the device comprises a base, and preferably the first chamber is partially formed by the base.

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

In some embodiments, the base and/or the membrane holder comprises a spacer ring. Such a spacer ring allows membranes of different thicknesses to be used. In some embodiments, the first chamber comprises a gas outlet, in particular a fluidic switch such as for example a valve. The gas outlet and the membrane are arranged such that the gas inside the first chamber is, upon feeding the core-forming emulsion into the first chamber, in particular upon the first initial filling of the first chamber with the core-forming emulsion, directed towards the gas outlet and removed from the first chamber via the gas outlet. In some examples, the membrane is inclined relative to the central longitudinal axis of the device. Thus, the angle in a sectional view along the central longitudinal axis between the central longitudinal axis and the first and/or second side of the membrane is other than 90°. For example, the acute angle between the second side of the membrane and the central longitudinal axis may be between 45° and 89°, preferably between 70° and 88°, more preferably between 78° and 87°. In such embodiments, the gas outlet may be arranged at the upper edge of the first chamber, which is formed by the membrane and another chamber wall. This ensures that any residual gas, in particular air, present in the first chamber, for example before use of the apparatus, rises towards the membrane and, due to the inclined arrangement of the membrane, is directed towards the upper edge and thus towards the gas outlet. Normally, the membrane channels are too narrow for air to pass through them and, therefore, a gas outlet as described in the above embodiments allows for the removal of all remaining gas, which would otherwise negatively influence the uniform drop size and distribution or prevent the first fluid from reaching all micro-channels, thus decreasing the flow rate. Typically, the gas outlet may be in fluid communication with the device environment.

In some embodiments, the device comprises at least one heater for heating the emulsion and/or the aqueous shell-forming solution and/or at least one cooler for cooling the emulsion and/or the aqueous shell-forming solution and/or the capsules. It may be advantageous to heat or cool either phase, since curing of the generated capsules can be easily effected by temperature changes. Typically, the at least one heater may provide sufficient thermal energy to heat the core-forming emulsion and/or the second aqueous solution up to 100°C, up to 125°C or up to 150°C. The heater may for example comprise a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an IR heater, a heating coil or any other suitable heater.

According to one embodiment, the device comprises a cooler positioned after the outlet of the second chamber so as to accelerate the cooling kinetics of the capsules and thus optimize their mechanical resistance.

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

In some embodiments, a flow restrictor is arranged between the second reservoir for the aqueous shell-forming solution and the second chamber. Such a restrictor is advantageous because the second chamber generally does not provide significant flow resistance for the aqueous shell-forming solution. Thus, by using a flow restrictor, the device is more stable because unintentional pressure differences, for example due to fluctuating air pressure, can be avoided.

In other embodiments, the second inlet comprises a feed channel arranged at least partially circumferentially around the central longitudinal axis, respectively the axis being perpendicular to the first and second sides of the membrane and intersecting the center of the membrane. The feed channel comprises one or more openings in the second chamber. "at least partially circumferentially arranged around the axis" mentioned above means that the feed channel may have the outline of a partial circle, such as a semicircle or a third of a circle, etc. Preferably, the feed channel is arranged entirely circumferentially around the central longitudinal axis, respectively the axis being perpendicular to the membrane and intersecting the center of the membrane. In such embodiments, the feed channel forms an annular structure. Preferably, the feed channel comprises multiple openings in the second chamber, which are in particular essentially uniformly distributed along the circumference of the feed channel. Typically, the opening(s) of the feed channel may be arranged in the direction of the outlet of the second chamber, i.e., such that the openings face the outlet of the second chamber. Embodiments comprising a feed channel have the advantage that the aqueous shell-forming solution may be uniformly and smoothly introduced into the second chamber without causing harmful turbulence that negatively influences the uniform shape and size distribution of the drops, and thus of the capsules, generated. In some embodiments, the opening(s) of the feed channel are arranged such that a vortex is generated when the aqueous shell-forming solution is introduced into the second chamber. In particular, the opening(s) may be tubular and the longitudinal axis of each tubular opening may be inclined relative to the central longitudinal axis of the device. Typically, all tubular openings are uniformly inclined. Vortex generation is beneficial because the transport of the generated dispersion towards the outlet of the second chamber is accelerated, which is particularly advantageous if the density of the capsules and the aqueous shell-forming solution is approximately equal.

Typically, the feed channel is arranged at the bottom of the second chamber, i.e. adjacent to the membrane. The feed channel can, for example, also be arranged circumferentially around the membrane. The feed channel can have a diameter of 2 mm to 100 mm, preferably 5 mm to 20 mm.

Alternatively, the second entrance may be a single entrance opening directly into the second chamber, preferably from a lateral side of the second chamber.

In a second aspect, the overall general objective technical problem is achieved by an assembly of capsules produced according to the method of any of the embodiments as described herein. Advantageously, the capsules have an equal particle size distribution with a coefficient of variation less than or equal to 10%, in particular less than or equal to 8%, in particular less than or equal to 6%, in particular less than or equal to 5%, in particular less than or equal to 4%. Determining the coefficient of variation falls within the general skills of a person skilled in the art.

In certain embodiments, the capsules preferably have a particle size of less than 4 mm, preferably between 100 µm and 3 mm, more preferably between 200 µm and 2 mm, in particular between 300 µm and 1 mm, and better still between 500 µm and 800 µm.

In some embodiments, the capsule shell comprises a water-insoluble matrix that ruptures and/or melts at a temperature of at least 80°C, especially at least 90°C, preferably between 80°C and 100°C. °C, preferably between 70°C and 90°C. Such embodiments have the advantage that a compound of interest within the capsules is released at a specific, predetermined temperature. This is, for example, particularly interesting for capsules used as food additives. Such capsules may be completely odorless when intact, but rupture upon cooking, so that the odor of interest is only released during cooking. In some embodiments, the water-insoluble matrix may consist of, or comprise, calcium carrageenan, calcium alginate, potassium alginate, and/or potassium carrageenan.

Brief description of the figures

The invention described herein will be better understood from the detailed description given below and the accompanying drawings which should not be construed as limiting the invention described in the appended claims.

The drawings show:

FIG. 1 There FIG. 1 is a schematic representation of the method according to the invention;

FIG. 2 There FIG. 2 is a schematic view of a device for generating a dispersion of a core-forming emulsion in a second aqueous solution according to a first embodiment of the invention;

FIG. 3 There FIG. 3 is a sectional view of the device shown in the FIG. 2 ;

FIG. 4 There FIG. 4 is a partially cutaway exploded view of the device shown in the FIG. 2 ;

FIG. 5 There FIG. 5 is a schematic view of a device 1 according to another embodiment of the invention;

FIG. 6 There FIG. 6 is a schematic enlarged view of a second side of a membrane according to one embodiment of the invention.

There FIG. 1 schematically illustrates the method according to one embodiment of the invention. In a first step, a core-forming emulsion is generated by mixing a solution 101 comprising at least one gelation-inducing agent and water with the fatty phase 102 (Figure 1a). This can for example be done with the stirrer 103. Figure 1a) also shows an enlarged view of a drop of solution 101 in the emulsion. The straight lines of the drops represent drops comprising water and dissolved therein the gelation-inducing agent. Thus, each drop shown in Figure 1a) is an aqueous solution of the gelation-inducing agent. The emulsion formed of the aqueous solution 101 in the fatty phase 102 is then supplied into the first chamber 4 of a suitable device (Figure 1b). The second chamber 5 of the device comprises an aqueous shell-forming solution 104 comprising water and at least one 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 chamber and the second chamber are separated by a membrane 7 whose first side 8 faces the first chamber and whose second side 9 faces the second chamber. The channels 10 extend from the first side 8 to the second side 9. Typically, 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 typically comprises as its main component the fatty phase 102, an emulsification step takes place when the emulsion reaches the outlet of the channel opening into the second chamber 5, thereby forming a transient water-in-oil-in-water emulsion (or "transient double emulsion") in the form of monodisperse drops 113 in the aqueous shell-forming solution 104, the monodisperse drops 113 being formed of the solution 101 dispersed in the fatty phase. It should be noted that the drop sizes are exaggerated for clarity. In addition, the relative size of the drops 101 compared to the drops 113 and/or the capsules 106 does not resemble reality. Each monodisperse drop 113 in the second chamber 5 now comprises one or more drops 101 dispersed in the fatty phase 102. In the second chamber, the monodisperse drops 113 in contact with the aqueous shell-forming solution 104 will evolve into capsules 106. Indeed, when the dispersion of the core-forming emulsion, i.e. the monodisperse drops 113, are mixed in the second chamber with the aqueous shell-forming solution 104, the gel-inducing agent contained in the drops 113 diffuses towards the surface of the drops, then reacts chemically at the interface with the matrix-forming agent to form a water-insoluble matrix shell, which develops entirely around each drop, thus forming capsules 106 of a water-insoluble matrix shell enclosing an oily core. The mixture between the capsules 106 and the aqueous solution for forming the shell 104 then passes through the outlet of the second chamber 6 to be collected in a storage tank 105, possibly equipped with a stirrer 107 (figure 1c). Note that the reaction between the gelling-inducing agent, contained in the drops 113, and the matrix-forming agent, present in the aqueous solution for forming the shell 104, can continue after leaving the second chamber 6 and therefore in the storage tank. Thus, step d. is carried out in whole or in part in the second chamber.

There FIG. 2 represents the device 1 usable in a method according to the invention. The device 1 comprises a container 19 made of glass and the base 14 (or “base” or “base”) made of metal. The base 14 comprises a first inlet 2 (not shown, see FIG. 3 ) of emulsion feed forming a core, opening into a first chamber. The first chamber may be partially formed by the base 14 and the membrane 7 (see FIG. 3 ). The container 19 comprises a second inlet 3 for supplying the aqueous solution for forming the shell 104, opening into a second chamber and a second chamber outlet 6 for collecting the capsules generated in the aqueous solution for forming the shell 104 inside the second chamber. The second chamber is formed by the container 19 and the membrane 7 (see FIG. 3 ).

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

There FIG. 4 shows an exploded view of the device 1 partially cut from the FIG. 2 . As can be seen, the first chamber is partially formed by the base 14 and has the shape of a hemisphere. The first inlet 2, which is arranged at an angle of essentially 90° to the central axis 15, is arranged on the pole of the hemisphere. The base 14 comprises the spacer ring 16 which allows the use of different membranes of different thicknesses and the membrane holder 20 comprises the sealing ring 17. The membrane 7 is arranged between the rings 16 and 17. The design of the device 1 with adjustable clamping means 18 allows the use of membranes of different thicknesses. The membrane holder 20 further comprises a circumferential groove 22 for receiving the lower end portion of the container 19. Clamping means 18 fixedly and removably connect the membrane holder 20 to the container holder 21.

There FIG. 5 shows a schematic view of a device 1 that can be used according to a preferred embodiment of the invention. The second chamber 5 is formed by the container 19 and the membrane 7 that separates the first chamber 4 from the second chamber 5. The container 19 comprises a second chamber outlet 6, which is in fluid connection with the product container 29 and the waste container 30. In general, the fluid flow rate can be controlled by a valve, such as a three-valve valve. The device 1 further comprises a first reservoir 24 that is in fluid communication with the first chamber 4 that can either only serve as a reservoir for supplying the core-forming emulsion into the first chamber 4 via the first inlet 2, or that can also serve as a mixing container for preparing the core-forming emulsion. Between the first reservoir 24 and the first inlet 2 is arranged a flow meter for measuring the fluid flow rate of the core-forming emulsion. The first reservoir 24 is in fluid communication with the pressure source 32. Furthermore, the pressure regulator 27a is arranged between the first reservoir 24 and the pressure source 32. In addition to the first reservoir 24, the device 1 comprises a rinse reservoir 31 which is also in fluid communication with both the first chamber 4 and the pressure source 32. The rinse reservoir 31 is configured to supply a rinse solution into the first chamber 4 for cleaning the device 1 after its intended use. In general, if a rinse solution is supplied to the first chamber 4, the three-way valve arranged between the product container 29 and the waste container 30 and the second chamber outlet 6 is configured so that the rinse solution can flow into the waste container 30. The product container 29 can for example serve directly as a storage tank. The device 1 further comprises a heater 33 configured to heat the first and second chambers during the production of a dispersed phase. In addition, the second chamber 5 is in fluid communication with the second reservoir 25 to supply the second chamber 5 with the aqueous solution for forming the shell. The flow limiter 26 and the flow meter 28 are arranged between the second chamber 5 and the second reservoir 25. In the embodiment shown, the flow limiter 26 is arranged behind the flow meter 28 in the direction of flow. The second reservoir 25 is further in fluid connection with the pressure source 32.

There FIG. 6 shows a monolayer membrane 7 for generating a dispersion of a core-forming emulsion in an aqueous shell-forming solution, which may be used in a method and/or device as described in any of the embodiments described herein. The membrane 7 has a first side 8 (not shown) and a second side 9 which, in an operative state, face a second chamber. Multiple microchannels 10 extend through the membrane 7. Each channel 10 has an elliptical contour. In addition, the membrane 7 includes a membrane sealing ring 44, which fully circumferentially surrounds the periphery of the membrane.

The following tables illustrate a suitable recipe that can be used in the process according to the invention:

[Table 1]: Generation of the core-forming inverse emulsion comprising an aqueous phase dispersed in a continuous fatty phase Raw materials INCI %* Water Water 5 CaCl ₂ Calcium chloride 5 PGPR Polyglyceryl polyricinoleate 0.04 Labrafac CC MB Caprylic/Capric Triglyceride 36 Scent Fragrance Qsp** Total 100

*: % relative to the total weight of the inverse emulsion.

**: Sufficient Quantity For.

[Table 2]: Generation of the aqueous solution for forming the envelope Raw materials % Water QSP** Sodium alginate 0.3 Ethanol 10 Total 100

The inverse emulsion of Table 1 is injected into the first chamber of a microfluidic device as described in Figures 2 and 3.

The aqueous solution for forming the envelope of Table 2 is injected into the second chamber of a microfluidic device as described in Figures 2 and 3.

This easily and continuously produces a dispersion comprising capsules with a size greater than 270 µm and whose envelope is transparent and of uniform thickness.

A method according to the invention makes it possible to easily modulate the size of the oily core and the thickness of the envelope by varying the injection flow rates in inverse emulsion and in aqueous solution for forming the envelope.

In the case where it is desired to manufacture a cosmetic product, the dispersion obtained above is filtered. The capsules thus isolated are then rinsed and stored/kept in a physiologically acceptable medium, in particular a suspensive aqueous gel such as that described in table 3 below, in a “capsules / aqueous phase” weight ratio, for example 30/70.

[Table 3]: Physiologically acceptable environment Name Supplier INCI name % w/w Osmosis water / Aqua QSP** MICROCARE PE Thor PHENOXYETHANOL, AQUA 0.5 MICROCARE EMOLLIENT PTG Thor PENTYLENE GLYCOL, AQUA 3.00 GLYCERIN CODEX Interchemistry GLYCERIN, AQUA 6.00 ZEMEA PROPANEDIOL Dupont Tate & Lyle PROPANEDIOL, AQUA 4.00 RHODICARE T Rhodia XANTHAN GUM, AQUA 0.46 HEPES-LUV Hopax HYDROXYETHYLPIPERAZINE ETHANE SULFONIC ACID, AQUA 0.50 SODIUM HYDROXIDE PELLETS PRS CODEX Panreac SODIUM HYDROXIDE 0.03 Total 100.00

Claims (18)

Method for manufacturing capsules comprising at least one matrix shell containing at least one oily core, the method comprising at least the steps of:
a. providing in a first chamber an emulsion comprising an aqueous phase dispersed in a continuous fatty phase, the dispersed aqueous phase comprising water and at least one gelling-inducing agent, optionally the emulsion further comprising at least one surfactant;
b. providing in a second chamber at least one aqueous shell-forming solution comprising water and at least one water-soluble matrix-forming agent;
the first chamber and the second chamber being fluidically connected by one or more channels, preferably by micro-channels;
c. guiding the emulsion of step a. from the first chamber through the channel(s) into the second chamber to form in the second chamber a dispersion of the emulsion of step a. in the aqueous shell-forming solution of step b.; and
d. in the second chamber, reacting the gelation-inducing agent and the matrix-forming agent in the dispersion formed in step c. to form capsules comprising a water-insoluble matrix shell enclosing at least one oily core. The method of claim 1, wherein the gelation-inducing agent is an inorganic salt, in particular an alkaline earth metal salt, in particular an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate, an alkaline earth metal nitrate, and mixtures thereof. A method according to any one of the preceding claims, wherein the aqueous shell-forming solution of step b. further comprises at least one surfactant, preferably selected from polyvinyl alcohol, polysorbate, saponins, sapogenins, quillaja extract, gum arabic, beta lactoglobulin, sodium dodecyl sulfate, soy lecithin, sodium cesinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof. Process according to any one of the preceding claims, in which the fatty phase of step a. comprises at least one oil and optionally at least one lipophilic gelling agent and/or at least one surfactant. Method according to any one of the preceding claims, in which the fatty phase of step a. further comprises at least one compound of interest, and in particular at least one perfuming agent. A method according to any preceding claim, wherein step a. comprises at least the sub-steps of:
a1. dissolving the gelation-inducing agent in water to form a solution; and
a2. mixing the solution formed in step a1. with the fatty phase comprising at least one oil, and optionally at least one lipophilic gelling agent and/or at least one surfactant. Method according to the preceding claim, in which step a2. is carried out extemporaneously or simultaneously with the supply of the emulsion in the first chamber. A method according to any preceding claim, further comprising agitating, in the second chamber, the aqueous shell-forming solution and the dispersion in step d. Method according to the preceding claim, in which the stirring is carried out with a stirrer with stirring from 10 rpm to 800 rpm, preferably from 25 rpm to 500 rpm, in particular from 50 rpm to 350 rpm, and better still at 100 rpm to 150 rpm. A method according to any one of the preceding claims, wherein the surfactant present in the emulsion of step a. is a non-ionic surfactant, preferably chosen from polyglycerol polyricinoleate (PGPR), a sorbitan derivative, in particular a sorbitan ester, for example sorbitan monooleate, sorbitan trioleate, and mixtures thereof. A method according to any one of the preceding claims, wherein the matrix-forming agent is a polysaccharide or a salt thereof, preferably is selected from chitosan, cellulose, alginate, in particular sodium alginate, carrageenan, agar, agarose, pectins, gellan, starch, and mixtures thereof. A method according to any one of the preceding claims, wherein the aqueous shell-forming solution further comprises at least one osmosis regulator, preferably selected from at least one alcohol or at least one sugar, the osmosis regulator being added to the aqueous shell-forming solution in step(s) b., c. and/or d. A method according to any one of the preceding claims, wherein the aqueous shell-forming solution further comprises at least one chelating agent capable of delaying the reaction between the gelation-inducing agent and the matrix-forming agent, preferably chosen from at least one organophosphate, and more preferably chosen from tetrasodium pyrophosphate. A method according to any preceding claim, wherein the pressure applied to the first chamber is lower than the pressure applied to the second chamber, and preferably wherein a pressure of 1.01 bar to 1.15 bar, preferably 1.03 bar to 1.07 bar, is applied to the first chamber and/or a pressure of 1.02 bar to 1.2 bar, preferably 1.05 bar to 1.1 bar, is applied to the second chamber. A method according to any preceding claim, wherein step d. is carried out for 5 min to 25 min, preferably for 8 min to 12 min or for 15 min to 20 min. A method according to any preceding claim, wherein after step d., the formed capsules are isolated, hardened and/or preserved. A capsule assembly comprising a plurality of capsules produced according to the method of any one of claims 1 to 16. Set of capsules according to the preceding claim, in which the capsules have an average diameter of between 150 μm and 3,000 μm, preferably between 250 μm and 2,000 μm, in particular between 500 μm and 1,500 μm, and better still between 750 μm and 1,000 μm, preferably with a coefficient of variation of less than or equal to 10%, preferably less than or equal to 5%, and better still less than or equal to 3%.