An improved method of manufacturing a capsule comprising at least one matrix shell and a lipophilic core encapsulated therein

Abstract

This invention relates to a method for manufacturing a capsule comprising a matrix shell and an encapsulated lipophilic core, the method comprising the following steps: a. providing a reverse emulsion comprising a first aqueous phase dispersed in a continuous oil phase, the first aqueous phase comprising water and at least one gelling inducing agent; b. providing a second aqueous phase comprising water; c. injecting the reverse emulsion into a first conduit leading to the second aqueous phase; d. contacting the dispersion obtained in step c with an aqueous solution for forming the shell, the aqueous solution comprising water and a matrix forming agent; and e. reacting the gelling inducing agent with the matrix forming agent.

Description

[0001] This invention relates to a method for manufacturing a perfume capsule comprising at least one matrix shell and at least one lipophilic core encapsulated therein. Technical Field

[0002] Capsules with a particle size of less than 3 mm have been widely used, particularly in pharmaceuticals, cosmetics, diagnostics, food, and materials science. These capsules can be manufactured by producing monodisperse droplet emulsions in a continuous phase. Monodispersity improves stability and enables precise volume control in a variety of chemical or biological reactions. Microfluidic technology provides a suitable platform for forming such monodisperse droplets.

[0003] For many applications, it is preferable to provide microcapsules with an oily core, i.e., the core (or core) contains at least one oil and is encapsulated by a suitable shell. This is primarily because many target compounds (e.g., fragrances, aromatics, active ingredients in cosmetics or pharmaceuticals, and vitamins) are hydrophobic and / or soluble only in the oil phase and insoluble in water. Background Technology

[0004] Various methods for manufacturing capsules using monodisperse droplets are known, particularly microfluidic methods, with particular attention paid to the method described in patent application WO2022106361. This method is suitable for manufacturing capsules having an oily core containing at least one fragrance agent; such capsules are also known as "fragrance capsules," "perfume capsules," or "fragrance capsules."

[0005] The method for manufacturing fragrance capsules according to patent application WO2022106361 is mainly based on the following steps:

[0006] - An inverse emulsion consisting of an aqueous phase (containing at least one salt) dispersed in a continuous oil phase (containing at least one oil and at least one fragrance) is encapsulated, the inverse emulsion being stabilized by a first surfactant;

[0007] - The reverse emulsion is contacted with an aqueous solution containing at least one second surfactant (specifically polyvinyl alcohol (PVA)) to obtain a biphase emulsion; and

[0008] - The biphase emulsion is contacted with an alginate solution containing a third surfactant, specifically a solution containing an ethoxylated surfactant (e.g., Tween 20). However, the method described in patent application WO2022106361 has several drawbacks.

[0009] First, the method consumes a large amount of surfactant. However, the use of surfactants is facing increasing criticism, particularly in the cosmetics industry, because they are often irritating, derived from petrochemical products, non-biodegradable, and highly ecotoxic. Furthermore, ethoxylated surfactants are becoming increasingly unacceptable due to their potential carcinogenicity.

[0010] Furthermore, while capsules produced by this method can be sprayed, there are limitations in the concentration of active ingredients (especially fragrances). When fragrances are present, capsules produced by this method also have limitations in terms of scent and sensory performance, which limits the application of this technology in the perfume industry (especially in the high-end perfume industry, also known as "Fine Fragrance"). Summary of the Invention

[0011] Therefore, the overall objective of this invention is to promote the development of fragrance capsule manufacturing technology and preferably to provide an improved alternative to the aforementioned prior art.

[0012] Surprisingly, the inventors observed that capsules, especially fragrance capsules, could still be manufactured by removing surfactants from the second aqueous solution. Even more surprisingly, the inventors observed that this removal was accompanied by unexpected technical effects. In fact, as described in Example 1 below, removing surfactants from the second aqueous solution of the above-mentioned prior art method can achieve the removal of the first surfactant and even oil components, and / or the removal of the third surfactant from the alginate solution.

[0013] Therefore, this invention enables the production of capsules using a simplified manufacturing method, and most importantly, reduces the amount of surfactant used. Furthermore, this invention can produce capsules with higher concentrations of active ingredients while maintaining similar or even better performance in terms of sphericity and transparency of the lipophilic core. Regarding fragrance capsules, the manufacturing method of this invention can produce capsules with superior odor and sensory performance, thereby expanding the application of this technology in the perfume industry.

[0014] Furthermore, the capsules produced in this way can still be sprayable.

[0015] In other words, the present invention can eliminate the need for at least one surfactant required in the method described in patent application WO2022106361. The present invention can even eliminate the need for at least two, or even all three, surfactants required in WO2022106361.

[0016] Furthermore, this invention allows for the manufacture of a reverse emulsion in which the oil phase can be entirely composed of fragrances.

[0017] Therefore, the present invention is based on a microfluidic manufacturing method, which is simpler, easier to industrialize and has significant advantages than the method described in WO2022106361: it can reduce the amount of surfactant used, significantly increase the concentration of active ingredients, and still maintain good performance in terms of spray performance and precise control of capsule size and shell thickness. Summary of the Invention

[0018] Therefore, the present invention relates to a method for manufacturing a capsule comprising at least one matrix shell and at least one lipophilic core encapsulated therein, the method comprising at least the following steps:

[0019] a. A reverse emulsion comprising a first aqueous phase dispersed in a continuous oil phase, the first aqueous phase comprising water and at least one gelation inducing agent;

[0020] b. Provide a second aqueous phase comprising water, wherein the second aqueous phase is free of surfactants, specifically, free of polyvinyl alcohol and / or polysorbate;

[0021] c. Inject the reverse emulsion described in step a into at least one first conduit leading to the second aqueous phase in step b, thereby obtaining a dispersion wherein droplets of the reverse emulsion described in step a are dispersed in the second aqueous phase in step b;

[0022] d. Contact the dispersion obtained in step c with at least one aqueous solution for forming a capsule, the aqueous solution comprising water and at least one matrix forming agent, wherein the gelation inducing agent and the matrix forming agent are configured to chemically react with each other to form a water-insoluble matrix capsule; and

[0023] e. Reacting a gelling inducing agent with a matrix forming agent to obtain a capsule comprising a water-insoluble matrix shell and at least one lipophilic core encapsulated therein.

[0024] The advantage of the manufacturing method described in this invention is that it can produce capsules with both a transparent matrix shell and a lipophilic core. Please note that steps a and b do not necessarily need to be performed in this order. Step b can be performed first, followed by step a, or both steps can be performed simultaneously. Please note that steps d and e can be performed simultaneously.

[0025] Please note that the dispersion formed in step c contains multiple monodisperse droplets, wherein the reverse emulsion described in step a serves as the dispersed phase, and the second aqueous phase in step b serves as the continuous phase. Therefore, the dispersion described in step c can be referred to as a water-in-oil-in-water transition emulsion (or "two-phase transition emulsion"), which consists of droplets dispersed in the second aqueous phase, which are formed from the first aqueous phase dispersed in the oil phase.

[0026] Furthermore, note that the composition of the lipophilic capsule core finally obtained in step e is not the same as that of the reverse emulsion in step a, and the phase is specifically designed to form the capsule core, especially considering that the first aqueous dispersion and certain reactants may react and / or diffuse from the core, particularly into the aqueous solution forming the capsule shell. This is especially true for gelling inducing agents.

[0027] Nevertheless, the lipophilic capsule core obtained after step e may contain trace amounts of residual aqueous phase, i.e., trace amounts of water. However, the lipophilic capsule core obtained after step e is mostly composed of an oil phase. Typically, the oil phase accounts for 60% or more, preferably 70% or more, particularly preferably 80% or more, more preferably 90% or more, particularly preferably 95% or more, and even more preferably 99% or more of the total weight of the capsule core.

[0028] In step c, each drop of the reverse emulsion generated mainly consists of the oil phase described in step a, but also contains a dispersed aqueous phase, which includes the gelation inducing agent described in step a. Therefore, the dispersion formed in step c is a water-in-oil-in-water emulsion, wherein the continuous aqueous phase is the second aqueous phase. Using the emulsification method described in step c, i.e., injecting the reverse emulsion constituting the capsule core described in step a through at least one first conduit, allows for precise control of particle size and ensures a uniform particle size distribution in the dispersion formed in step c. Furthermore, this method enables rapid capsule production, with yields reaching 100 g / h (grams per hour) or higher per conduit, and even up to 500 g / h per conduit.

[0029] According to the method of the present invention, the matrix grows around the core through a chemical reaction between a gelling inducing agent in each drop of the reverse emulsion and a matrix forming agent present in the aqueous solution used to form the shell.

[0030] Preferably, step a includes at least the following sub-steps:

[0031] a1. Dissolve the gelation inducing agent in water to form a first aqueous phase; and

[0032] a2. Mix the first aqueous phase formed in step a1 with the oil phase.

[0033] Step a2 can be performed before or simultaneously with step c.

[0034] According to implementation scheme 1, steps a1 and a2 can be performed simultaneously. In this case, step a2 cannot be performed before or simultaneously with step c.

[0035] According to implementation scheme 2, step a2 can be performed before or simultaneously with step c. In this case, steps a1 and a2 cannot be performed at the same time.

[0036] In step a, dissolving the gelation inducing agent in the first aqueous dispersion helps to effectively prevent pipe blockage and improve the formation kinetics of the capsule. In fact, carbonates may cause insoluble salts to accumulate inside the pipe.

[0037] The emulsion provided in step a for forming the core has a stability between 2 minutes and 600 minutes, preferably between 5 minutes and 500 minutes, more preferably between 10 minutes and 100 minutes, even between 15 minutes and 60 minutes, and particularly preferably between 20 minutes and 30 minutes. This stability ensures that the oil droplets are not directly destroyed, especially in step c. However, the stability of the oil droplets cannot be too high, otherwise it will reduce the efficiency of shell formation in step e and limit the transparency of the lipophilic core.

[0038] Matrix forming agents are typically dissolved in an aqueous solution used to form the capsule shell.

[0039] The gelation inducing agent and shell-forming agent are designed to react chemically with each other to form a water-insoluble matrix shell. For example, the gelation inducing agent and shell-forming agent can be designed to undergo complexation reactions, ion exchange reactions, or interface-confined polymerization reactions.

[0040] The present invention also relates to a capsule assembly comprising a plurality of capsules manufactured according to the method of the present invention.

[0041] The manufacturing method of the present invention also has a particularly significant advantage: the method can manufacture capsule combinations in which, based on the total weight of the capsule combinations, the alcohol (specifically ethanol) content of the capsule combinations is less than 10%, preferably less than 5%, particularly preferably less than 2.5%, or even contains no alcohol.

[0042] The present invention also relates to a capsule combination, wherein, based on the total weight of the capsules, the capsules contain 5% to 30%, preferably 10% to 20%, more preferably 12% to 15% of an active ingredient, specifically a fragrance.

[0043] The present invention also relates to an apparatus for packaging and dispensing fluid compositions such as cosmetics in the form of a spray, characterized in that the apparatus comprises at least:

[0044] - A container, the container containing at least one non-homogeneous mixture;

[0045] - A conduit (or immersion tube) installed inside the container; and

[0046] - A dispensing mechanism capable of drawing a non-homogeneous mixture from a container, converting the non-homogeneous mixture into a fluid composition, and dispensing the fluid composition in the form of a spray.

[0047] The non-uniform mixture comprises the capsule group of the present invention dispersed in a continuous phase.

[0048] Such packaging and dispensing devices that exist in spray form can also be called "spraying devices", "spraying equipment" or "sprayers".

[0049] Preferably, in the spraying device, the volume fraction of the capsule is 50% to 70%, more preferably 55% to 65%, and more preferably 57% to 63%, based on the total volume of the non-uniform mixture.

[0050] Preferably, in the spray device, the ratio of "inner diameter of the conduit to diameter of the capsule" is between 1 and 1.25, more preferably between 1.1 and 1.2.

[0051] The spray-type packaging and dispensing device may specifically employ a structure as described in patent application number FR2314016.

[0052] In this invention, a “capsule” refers to a substantially spherical “core / shell” type macroscopic element, wherein the shell completely encapsulates the core (or “core”) and the core contains at least one drop of oil phase.

[0053] In this invention, "macroscopic" refers to capsules that are visible to the naked eye. These capsules are preferably approximately spherical.

[0054] Preferably, the average diameter of the capsules manufactured using the method described in this invention and included in the capsule assembly described in this invention is preferably between 250 μm and 3,000 μm, more preferably between 500 μm and 2,000 μm, particularly preferably between 1,000 μm and 1,750 μm, and most preferably between 1,200 μm and 1,500 μm; and the coefficient of variation of the capsules is preferably less than or equal to 10%, more preferably less than or equal to 5%, and most preferably less than or equal to 3%.

[0055] Preferably, the average diameter of the capsules manufactured using the method described in this invention and included in the capsule assembly described in this invention is preferably between 250 μm and 2,500 μm, more preferably between 500 μm and 2,000 μm, particularly preferably between 750 μm and 1,500 μm, and most preferably between 1,000 μm and 1,250 μm; and the coefficient of variation of the capsules is preferably less than or equal to 10%, more preferably less than or equal to 5%, and most preferably less than or equal to 3%.

[0056] Therefore, according to the method of the present invention, a dispersion can be produced in which the phases constituting the dispersion form a macroscopically non-uniform mixture.

[0057] Given the above, the capsule shell is the aqueous phase. Preferably, the capsule shell is transparent.

[0058] Advantageously, the capsule shell has a uniform thickness. In this invention, "uniform thickness" means a capsule with a standard deviation of less than or equal to 10%, preferably less than or equal to 5%, of the range of variation in capsule shell thickness. The capsule shell may be collectively referred to as a "membrane" or "shell".

[0059] In this invention, "channel" refers to a channel with an inner diameter of less than 4 mm, preferably between 1 µm and 3 mm, particularly preferably between 10 µm and 1 mm, and more preferably between 100 µm and 0.5 mm. The catheters in this invention can be collectively referred to as "microcatheters," "channels," "microchannels," or "tubes."

[0060] Pipes are primarily used to transport chemical substances, such as liquids or gases, in fluid form. A pipe can be described as an elongated structure, typically with a circular or rectangular cross-section, used to guide fluid flow from one point to another in a microfluidic device. For the avoidance of ambiguity, pipes are distinguished from the chambers described in WO2021037999 or the "stepped emulsification" type microfluidic devices described in this invention (such as...). Figure 3 The material shown is quite different. The conduit can be made of any material suitable for the purpose described in this invention, particularly suitable for the nature of the fluid being transported. Material selection is within the scope of common knowledge for those skilled in the art. Preferably, the conduit is made of stainless steel, glass, polyetheretherketone (PEEK), or Teflon, especially when step c is based on the conjugated focused microfluidic method described below.

[0061] Unless otherwise stated, all descriptions below are based on room temperature (e.g., T = 25°C ± 2°C) and atmospheric pressure (760 mmHg, i.e., 1,013.10). 5 Pa or 10 13 (mbar) is the condition.

[0062] According to the present invention, the pH value is generally between 3.0 and 8.0, specifically between 4.0 and 7.0.

[0063] Preferably, the method of the present invention does not include the solvent evaporation or removal step, specifically the steps described in WO2022179982.

[0064] Please note that the manufacturing method described in this invention does not include the step of passing droplets or capsules through an air layer (specifically, a solution immersed therein) by gravity, which is different from the method described in WO2010063937, which can therefore be referred to as a liquid-gas capsule manufacturing method.

[0065] That is to say, the method described in this invention can be called a liquid-liquid capsule manufacturing method. Detailed Implementation

[0066] Inverse emulsion

[0067] Step a provides an emulsion comprising an aqueous phase dispersed in a continuous oil phase, the dispersed aqueous phase comprising water and at least one gelling inducer.

[0068] Therefore, step a involves manufacturing an inverted emulsion, which may also be referred to as an "oil-in-water emulsion" or "IF".

[0069] For obvious reasons, the reverse emulsion used to carry out step c is in a liquid (or fluid) state. The term "liquid" as used in this invention refers to a non-solid reverse emulsion, particularly an emulsion capable of flowing under its own weight and passing through the conduit in step c.

[0070] To meet this condition, the reverse emulsion may be preheated and / or injected in a hot state in step c.

[0071] For obvious reasons, the dispersed aqueous phase and the continuous oil phase are essentially immiscible.

[0072] In this invention, "substantially immiscible" means that the solubility of the first phase in the second phase is preferably less than 5% (mass fraction), and vice versa.

[0073] Reverse emulsions can be manufactured using either batch or continuous methods. Batch manufacturing of reverse emulsions refers to manufacturing in fixed and defined quantities, i.e., batch manufacturing.

[0074] Continuous oil phase

[0075] The oil phase (also referred to as "IF2") in step a may contain at least one active ingredient (specifically a fragrance), at least one oil, and mixtures thereof.

[0076] Active ingredients

[0077] The oil phase described in step a may contain at least one active ingredient. The active ingredient may be selected from bioactive ingredients, pharmaceutical active ingredients, and / or cosmetic active ingredients, such as fragrances, moisturizers, healing agents, spot-fading agents, ultraviolet filters, exfoliants, antioxidants, active ingredients that stimulate the synthesis of macromolecules in the dermis and / or epidermis, skin relaxants, antiperspirants, soothing agents, anti-aging agents, anticoagulants, antithrombotic agents, antimitotic agents, antiproliferative agents, antiadhesion agents, antimigration agents, cell adhesion promoters, growth factors, antiparasitic molecules, anti-inflammatory agents, pro-angiogenic agents, anti-angiogenic inhibitors, vitamins, hormones, proteins, antifungal agents, antimicrobial molecules, disinfectants or antibiotics, fragrances, antibodies, peptides, enzymes, RNA, DNA, microorganisms, and mixtures thereof. Preferably, the active ingredient is a fragrance, particularly of the type described below.

[0078] Of course, those skilled in the art will take care in selecting possible active ingredients and / or their amounts to ensure that the beneficial properties of the invention are not, or substantially not, affected by the additions considered. These adjustments fall within the scope of common knowledge for those skilled in the art.

[0079] Based on the total weight of the oil phase, the oil phase may contain 1% to 100%, preferably 5% to 90%, particularly preferably 10% to 80%, and most preferably 20% to 70% of one or more active ingredients.

[0080] The present invention also relates to a method in which, based on the total weight of the oil phase, the oil phase may contain 20% to 100%, preferably 30% to 90%, more preferably 40% to 80% of an active ingredient, specifically one or more fragrances.

[0081] The active ingredient can be pre-mixed with the oil phase, or it can be added after the aqueous solution formed by the gelation inducer in water is mixed with the oil phase.

[0082] Fragrance

[0083] The fragrance in this invention is a lipophilic substance, meaning it can be dissolved or dispersed in an organic solvent (specifically, an oil). However, in the definition of this invention, the fragrance does not necessarily have to be dissolved or dispersed in an organic solvent.

[0084] In this invention, "fragrance agent" may also be collectively referred to as "fragrance essence," "fragrance liquid," or "fragrance concentrate," and may be selected from compounds with the INCI names "Parfum" or "Fragrance." Therefore, in this invention, the term "fragrance agent" does not refer to a mixture containing fragrance concentrate and alcohol.

[0085] The fragrance ingredients used in this invention are commonly used raw materials in the perfume industry. Given their nature, further detailed explanation is unnecessary here—moreover, any explanation is unlikely to be comprehensive, and professionals are fully capable of selecting these fragrances based on their expertise and the desired odor effect. These fragrances belong to a wide variety of chemical categories, including alcohols, aldehydes, ketones, esters, ethers, acetates, cyanides, terpenes, nitrogen- or sulfur-containing heterocyclic compounds, and natural or synthetic essential oils. Furthermore, many of these ingredients are listed in references such as S. Arctander's *Perfume and Flavor Chemicals* (1969, Montclair, New Jersey, USA) and its latest editions, or other similar works, as well as the latest scientific and patent literature related to the art of perfumery.

[0086] For example, a fragrance is a compound or mixture of compounds that is at least partially volatile at room temperature and whose odor is perceptible. Fragrances composed of essential oils typically require dilution to fully realize their odor potential—that is, their perceived odor changes gradually throughout the day after being applied to a surface, thanks to the presence of various organic aromatic compounds with different volatile properties. The process of fragrance formulation involves combining multiple fragrance ingredients to give the fragrance top, middle, and base notes.

[0087] Fragrances can be made from natural or synthetic organic flavorings.

[0088] Examples of natural fragrances include extracts of flowers, stems and leaves, fruits, bark, roots and rhizomes, wood, herbs, grasses, resins, balsams and mixtures thereof.

[0089] These plant-based fragrances can be essential oils, such as bergamot, rose, lavender, sandalwood, cardamom, sage, chamomile, clove, lemon balm, peppermint, cinnamon leaf, juniper, vetiver, frankincense, galbanum, rock rose, and mixtures thereof.

[0090] For the purposes of this invention, essential oils are considered aromatherapy agents and therefore cannot be considered organic oils or organic solvents, specifically lipophilic organic solvents.

[0091] Examples of synthetically derived fragrances include: vanillin, ethylene glycol brassinate, halbanoyl ester, benzyl benzoate, benzyl benzoate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, citronellol acetate, citronellol formate, geraniol acetate, linaloyl acetate, dimethylbenzyl carboxyl acetate, phenethyl acetate, linaloyl benzoate, benzyl benzoate, ethyl methyl phenyl glycine ester, alkylcyclohexyl propionate, styrene propionate and benzyl salicylate, phenethyl ether, straight-chain alkanes with 8 to 18 carbon atoms, citral, citronellol, citronelloloxyacetaldehyde, cyclamenaldehyde, hydroxycitronellol, ionic ketones (such as α-isomethyl ionic ketones), methyl cedrolone, anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenethyl alcohol, terpineol, terpenes and mixtures thereof.

[0092] These compounds typically exist as mixtures of two or more of the aforementioned aroma substances.

[0093] Based on the total weight of the oil phase, the oil phase may contain 20% to 100%, preferably 30% to 90%, more preferably 40% to 80% of one or more fragrances.

[0094] Preferably, based on the total weight of the capsule, the capsule of the present invention may contain 5% to 30%, preferably 10% to 20%, more preferably 12% to 15% of one or more fragrances.

[0095] Since the oil phase may contain only one or more fragrances, the capsule core is referred to as a "lipophilic core" rather than an "oily core"—the latter implying that it must contain at least one oil, which is not mandatory according to the present invention.

[0096] Oil

[0097] According to embodiment 1, the oil phase described in step a is oil-free. Specifically, the oil phase does not contain oils selected from the following categories: hydrocarbon oils of vegetable origin; hydrocarbon oils of animal origin; synthetic esters and ethers (especially fatty acid esters and ethers); straight-chain or branched hydrocarbons of mineral or synthetic origin; silicone oils, such as polymethylsiloxane (PDMS); fatty alcohols having 8 to 26 carbon atoms; and / or fluorinated oils containing hydrocarbon groups and / or silicon groups.

[0098] Specifically, the oil phase does not contain oils selected from caprylic / capric triglycerides, isopentyl glycol, caviar sauce, and mixtures thereof.

[0099] According to another preferred embodiment, the oil phase does not contain silicone oil, and preferably does not contain polymethylsiloxane (PDMS).

[0100] In another embodiment, the oil phase in step a may also contain at least one oil.

[0101] "Oil" refers to a lipoid or fat-like substance that is liquid at room temperature and atmospheric pressure. Oils that can be used in the dispersions of this invention include, for example:

[0102] - Hydrocarbon oils derived from plants, such as hydrogenated jojoba oil, hydrogenated sunflower seed oil, hydrogenated castor oil, and hydrogenated coconut oil;

[0103] - Animal-derived hydrocarbon oils, such as perhydrosqualene and squalane;

[0104] - Synthetic esters and ethers, particularly fatty acid esters and ethers, such as oils conforming to the chemical formulas R1COOR2 and R1OR2, where R1 represents a fatty acid residue from C8 to C29 and R2 represents a hydrocarbon chain from C3 to C30 (whether branched or not), such as purcelyl oil, isononyl isononanoate, neopentyl isodecanoate, isopropyl myristate, 2-ethylhexyl palmitate, 2-octyl dodecyl stearate, 2-octyl dodecyl erucic acid, isostearate isostearate; hydroxylated esters, such as isostearate lactate, F-octyl hydroxystearate, F-octyl dodecyl hydroxystearate, diisostearate malate, triisostearate citrate, fatty alcohol heptanoate, caprylate, decanoate; polyol esters, such as propylene glycol dicaprylate, neopentyl glycol diheptanoate, and diethylene glycol diisonononate; and pentaerythritol esters, such as pentaerythritol tetrabenzyl ester (DUB). PTB or pentaerythritol tetraisostearate (Prisorine 3631);

[0105] - Linear or branched hydrocarbons, whether mineral or synthetic, such as paraffin oil (whether volatile or not) and its derivatives, petrolatum, polydecene, hydrogenated polyisobutylene (such as paramecium oil).

[0106] - Silicone oils, such as volatile or non-volatile polymethylsiloxanes (PDMS) having linear or cyclic silicon chains, which are liquid or paste at room temperature, especially cyclic polydimethylsiloxanes (cyclomethyl silicone oils), such as cyclohexylsiloxane and cyclopentylsiloxane; polydimethylsiloxanes (or dimethyl silicone oils) having alkyl, alkoxy, or phenyl groups on their siloxane chains, which are side chains or located at the ends of the siloxane chains, having 2 to 24 carbon atoms; phenyl silicones, such as phenyltrimethylsiloxane, phenyldimethylsiloxane, phenyltrimethylsiloxydiphenylsiloxane, diphenyldimethylsiloxane, diphenylmethyldiphenyltrisiloxane, 2-phenylethyltrimethylsiloxysilicate, and polymethylphenylsiloxane;

[0107] - Fatty alcohols containing 8 to 26 carbon atoms, such as cetyl alcohol, stearyl alcohol and mixtures thereof (cetearyl alcohol), or octyldodecyl alcohol;

[0108] - Some fluorinated oils containing hydrocarbons and / or silicon, such as the oil described in Japanese Patent Publication JP-A-2-295912;

[0109] - and its mixtures.

[0110] Preferably, in the oil phase described in step a, the weight of oil accounts for less than 40% of the total weight of the oil phase, more preferably less than 30%, most preferably less than 20%, specifically less than 10%, or even less than 5%.

[0111] Of course, those skilled in the art will take care in selecting the oils that may be used and their amounts to ensure that the beneficial properties of the invention are not, or substantially not, affected by the additions considered. These adjustments fall within the scope of common knowledge for those skilled in the art.

[0112] surfactants

[0113] The reverse emulsion may also contain at least one surfactant, specifically at least one surfactant capable of forming a reverse emulsion, especially a surfactant with an HLB value of less than 10, preferably between 2 and 8, more preferably between 3 and 5.

[0114] Specifically, the reverse emulsion may also contain at least one nonionic surfactant, preferably selected from polyglycerol ricinoleate (PGPR), sorbitol derivatives (specifically sorbitol esters, such as sorbitol monooleate), sorbitol trioleate, and mixtures thereof.

[0115] Specifically, the reverse emulsion may contain a surfactant selected from polyglycerol-2 isostearate (3,2), polyglycerol-6 polyricinoleate (3,3), polyglycerol-4 polyricinoleate (3,5) and mixtures thereof.

[0116] Of course, those skilled in the art will take care in selecting the surfactants and their amounts in the reverse emulsion (specifically the oil phase) to ensure that the beneficial properties of the invention are not, or substantially not, affected by the considered additions. These adjustments fall within the scope of common knowledge for those skilled in the art.

[0117] In this invention, based on the total weight of the oil phase, the oil phase may contain 0.01% to 2%, preferably 0.05% to 1.5%, and more preferably 0.1% to 1% of surfactant.

[0118] According to one specific embodiment, the reverse emulsion does not contain the surfactant described above. The removal of the surfactant is particularly surprising because it contradicts the disclosure in WO2022106361—which does state that the surfactant is necessary to ensure adequate stability of the aqueous droplets dispersed in the emulsion forming the oil phase core.

[0119] Lipophilic gelling agents

[0120] According to implementation scheme 1, the oil phase in step a does not contain lipophilic gelling agents.

[0121] According to embodiment 2, the oil phase in step a may further comprise at least one lipophilic gelling agent. The lipophilic gelling agent is a gelling agent that is soluble or dispersible in the oil phase, and may be selected from organic or inorganic, polymeric or molecular gelling agents; it is a solid fat or grease at room temperature and pressure, specifically selected from waxes, paste-like fats, butter; and mixtures thereof, and preferably selected from polymeric gelling agents. Such lipophilic gelling agents are described in detail in WO2019002308.

[0122] Specifically, THIXCIN from Elements Specialties can be cited as an example. ® R (INCI: Trihydroxystearin) Lubrizol's OILKEMIA ™5S polymer (INCI: Caprylic / CapricTriglyceride (and) Polyurethane-79), Estogel M (INCI: CASTOROIL / IPDI COPOLYMER & CAPRYLIC / CAPRIC TRIGLYCERIDE) from PolymerExpert, hydrogenated castor oil / sebacic acid copolymer and its derivatives (of which PolymerExpert sells them under the trade names Estogel Green (or Estogel G) and Estogel Green 40, respectively), and mixtures thereof.

[0123] Preferably, the lipophilic gelling agent is a heat-sensitive gelling agent, that is, a heat-sensitive gelling agent, specifically, it is solid at room temperature and liquid at temperatures above 50°C, preferably above 60°C.

[0124] In this invention, based on the total weight of the oil phase, the dispersion of this invention may contain 0.1% to 30%, preferably 0.5% to 25%, more preferably 1% to 20%, and most preferably 2% to 15% of a hydrophilic gelling agent.

[0125] Preferably, the oil phase in step a is free of surfactants and oil, specifically when the oil phase contains at least one fragrance.

[0126] Preferably, the oil phase in step a further comprises at least one oil, and may even further comprise at least one surfactant, specifically when the active ingredient present in the oil phase is different from the fragrance.

[0127] The present invention also relates to a method wherein the reverse emulsion may further comprise at least one oil and / or at least one surfactant, preferably a nonionic surfactant, more preferably a surfactant selected from polyglycerol ricinoleate (PGPR), sorbitol derivatives (specifically sorbitol esters, such as sorbitol monooleate), sorbitol trioleate, and mixtures thereof.

[0128] First Dispersion Aqueous Phase

[0129] The first aqueous dispersion phase (also referred to as "IF1") of the reverse emulsion in step a contains at least water and at least one gelling inducer.

[0130] water

[0131] For the purposes of this invention, the aqueous phase or aqueous solution contains water. Besides distilled or deionized water, the water suitable for this invention can also be natural spring water or floral water. The first aqueous dispersed phase of the reverse emulsion in step a falls into this category.

[0132] In one embodiment, based on the total mass of the dispersed aqueous phase, the mass percentage of water in the first dispersed aqueous phase is at least 50%, more preferably at least 60%, specifically between 50% and 98%, preferably between 60% and 95%, and more preferably between 70% and 90%.

[0133] Gelation inducer

[0134] The gelation inducing agent is preferably a salt of at least one inorganic cation, specifically an inorganic salt selected from the following substances: alkaline earth metal salts, specifically alkaline earth metal halides, alkaline earth metal pseudohalides, alkaline earth metal carboxylates, alkaline earth metal nitrates, and mixtures thereof.

[0135] In some embodiments, as described above, when the gelation inducing agent is an inorganic salt, the reaction between the gelation inducing agent and the matrix forming agent in step e is an ion exchange reaction, i.e., ionic gelation. Therefore, the inorganic salt (and conversely, the matrix forming agent) should be chosen to ensure that it reacts with the matrix forming agent to form a reaction product insoluble in water. Particularly suitable salts (especially for polysaccharides) can be salts of potassium, magnesium, strontium, or calcium. Those skilled in the art will understand "pseudohalides" as polyatomic analogs of halogens whose chemical properties are similar to those of true halogens. Non-limiting examples include cyanides, isocyanates, cyanate esters, isocyanates, methanesulfonyl groups, and trifluoromethane. Non-limiting examples of carboxylates include acetates, formates, lactates, oxalates, butyrates, succinates, and the like. Gelation inducing agents that are completely water-soluble at room temperature are typically chosen, i.e., their solubility in water is greater than 10 g / 100 mL, preferably greater than 20 g / 100 mL, specifically greater than 50 g / 100 mL. Non-exhaustive examples of suitable gelation inducing agents include: CaCl2, CaF2, calcium lactate, MgCl2, Sr(OAc)2 and mixtures thereof.

[0136] Inorganic salts are typically water-soluble. However, it is also feasible to use powdered water-insoluble salts as gelation inducing agents. For example, CaCO3 or MgCO3, specifically in powder form, can be used.

[0137] In some embodiments, the gelation inducing agent is a composition of a photoacid generator (i.e., a compound that produces acid upon exposure to radiation (preferably ultraviolet radiation), such as diphenyliodonium nitrate) and a chelate of an inorganic salt (specifically 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 is a chelate of strontium and ethylene glycol tetraacetic acid. During ultraviolet irradiation (which may be performed in step d), the photoacid generator produces an acid that subsequently releases strontium ions, which then react with a matrix forming agent (e.g., sodium alginate) to form a water-insoluble matrix shell.

[0138] In some embodiments, the gelation inducing agent is carbon dioxide or a carbon dioxide generator. The carbon dioxide generator can release carbon dioxide under specific conditions. For example, bicarbonates can release carbon dioxide in the presence of an acid. In some embodiments, the gelation inducing agent can be a Brensteinic acid, such as a mineral acid or carboxylic acid. In this case, the matrix forming agent can be a composition of polysaccharides (such as alginates, chitosan, etc.) and suitable water-soluble alkali metal or alkaline earth metal complexes (such as Ca-Na2-EDTA, Mg-Na2-EDTA, Sr-Na2-EDTA, etc.).

[0139] Advantageously, based on the total weight of the first aqueous phase, the first aqueous phase of the reverse emulsion described in step a contains 2.5% to 60%, preferably 5% to 50%, more preferably 10% to 40% of a gelling inducing agent.

[0140] The present invention also relates to a method wherein, based on the total weight of the first aqueous phase, the first aqueous phase of the reverse emulsion in step a may contain 2.5% to 60%, preferably 5% to 50%, more preferably 10% to 40% of a gelling inducing agent.

[0141] Preferably, the dispersed first aqueous phase does not contain hydrophilic surfactants.

[0142] Second aqueous phase

[0143] Step b provides a second aqueous phase containing water, but the second aqueous phase does not contain surfactants, specifically, it does not contain polyvinyl alcohol and / or polysorbate; the second aqueous phase may be collectively referred to as "second aqueous solution" or "OF".

[0144] In one embodiment, based on the total mass of the second aqueous phase, the mass percentage of water in the second aqueous phase is at least 50%, specifically at least 60%, more preferably at least 70%, specifically between 70% and 100%, preferably between 80% and 99%, and more preferably between 90% and 95%.

[0145] For obvious reasons, the second aqueous phase in a reverse emulsion is immiscible with the oil.

[0146] hydrophilic surfactants

[0147] The second aqueous phase does not contain hydrophilic surfactants.

[0148] Specifically, the second aqueous phase is free of hydrophilic surfactants selected from polyglycerol esters, polyvinyl alcohol (or PVA), polysorbate, saponins, saponins, soapberry extracts, gum arabic, β-lactoglobulin, sodium lauryl sulfate, soybean lecithin, sodium caseinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

[0149] Preferably, the second aqueous phase does not contain a surfactant selected from polyvinyl alcohol (or PVA) and / or polysorbate, specifically Tween or SDS.

[0150] The removal of the surfactant is particularly surprising because it contradicts the disclosure of WO2022106361, which does state that the surfactant has sufficient stability to ensure that the "oil-in-water" bilayer emulsion formed in step c comes into contact with the aqueous solution forming the capsule in step d.

[0151] hydrophilic gelling agent

[0152] Step b: The second aqueous phase may further include at least one hydrophilic gelling agent, specifically selected from agarose, xanthan gum, carrageenan, cellulose and its derivatives (preferably methylcellulose or microcrystalline cellulose) and the like, and mixtures thereof, wherein xanthan gum is preferred.

[0153] Preferably, such hydrophilic gelling agents are selected from non-surfactant natural thickeners.

[0154] Adding such hydrophilic gelling agents helps to further optimize the emulsification process described in step c, specifically by limiting the wetting of the reverse emulsion in the pipeline. The presence of such hydrophilic gelling agents is particularly important when step c is based on conjugate focusing microfluidic emulsification technology.

[0155] Of course, those skilled in the art will take care in selecting the hydrophilic gelling agents that may be used and their amounts to ensure that the beneficial properties of the invention are not, or substantially not, affected by the additions considered. These adjustments fall within the scope of common knowledge for those skilled in the art.

[0156] Preferably, based on the total weight of the second aqueous phase, step b, the second aqueous phase contains 0.1% to 15%, preferably 0.5% to 10%, more preferably 1% to 5% of a hydrophilic gelling agent.

[0157] Preferably, the second aqueous phase does not contain carbomer (or acrylic polymer).

[0158] Preferably, the second aqueous phase does not contain an alkali, specifically an alkali metal hydroxide, especially NaOH (or caustic soda).

[0159] In step b, the viscosity of the second aqueous phase is preferably less than 1,000 cP (or mPa·s), more preferably less than 500 cP, specifically less than 250 cP, even more preferably less than 100 cP, and especially preferably less than 50 cP.

[0160] If necessary, the liquid properties of the aqueous phase can be obtained by heating the second aqueous phase in step b to a temperature above its melting point, specifically to a temperature above the temperature corresponding to the highest melting point of the thermosensitive hydrophilic gelling agent contained therein.

[0161] Specifically, the second aqueous phase can be heated to a temperature range of 50°C to 150°C, preferably 60°C to 110°C, and more preferably 70°C to 90°C.

[0162] Aqueous solution used to form capsule shell

[0163] The aqueous solution of the capsule formation (also known as "AF") contains water and at least one water-soluble matrix forming agent (or "matrix agent").

[0164] The formulation of gelation inducing agents and matrix forming agents enables them to react chemically with each other, thereby forming a water-insoluble matrix shell.

[0165] In one embodiment, based on the total mass of the aqueous solution used to form the capsule shell, the mass percentage of water in the aqueous solution used to form the capsule shell is at least 50%, specifically at least 60%, more preferably at least 70%, specifically between 70% and 99.9%, preferably between 80% and 99%, and more preferably between 90% and 95%.

[0166] For obvious reasons, the second aqueous phase is miscible with the aqueous solution used to form the capsule.

[0167] For obvious reasons, the aqueous solution used to form the capsule shell is immiscible with the continuous oil phase of the reverse emulsion.

[0168] For obvious reasons, the aqueous solution used to form the capsule in step d must be in a liquid (or fluid) state, i.e., not solid. If necessary, the aqueous solution used to form the capsule in step d can be kept liquid by heating.

[0169] Water-soluble matrix forming agent

[0170] In some embodiments, the matrix forming agent is a polysaccharide or a salt thereof. A suitable salt is one that is completely soluble in water. Typically, the polysaccharide salt consists of an anionic polysaccharide component and a suitable counterion. Suitable polysaccharides are selected from chitosan, cellulose, alginate (specifically sodium alginate), carrageenan, agar, agarose, pectin, gellan gum, starch, and mixtures thereof. Preferred polysaccharides include alginate (preferably sodium alginate), chitosan, carrageenan, and cellulose, with alginate (preferably sodium alginate) and chitosan being more preferred. In some embodiments, the polysaccharide can be dissolved by adjusting the pH, for example, by using an aqueous solution used to form the capsule to be alkaline.

[0171] In some embodiments, the choice of matrix forming agent and gelation inducing agent is such that the formed hydrophilic matrix ruptures and / or melts at a temperature of at least 80°C, specifically at least 90°C. An advantage of such embodiments is that the target compound within the capsule can be released at a predetermined specific temperature. This is particularly important, for example, for capsules used as food additives. Such capsules may be completely tasteless when intact, but rupture during cooking, thus releasing the target odor only during cooking. In some embodiments, the gelation inducing agent may be an alkaline earth metal salt, specifically a calcium salt (such as CaCl2), or an alkali metal salt (such as KCl), while 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 (optionally used in combination with sodium alginate) may be used as the matrix forming agent in such embodiments. Preferably, 0.25% (by weight) to 2% (by weight), specifically 0.5% (by weight) to 1.5% (by weight), of carrageenan is used in the aqueous solution of the capsule shell formation. For example, if a 1.5% (by weight) aqueous solution of carrageenan is used as the aqueous solution for forming the capsule shell in step d, the formed capsule begins to melt at 80°C. On the other hand, if an aqueous solution of 0.75% (by weight) carrageenan and 0.5% (by weight) sodium alginate is used as the aqueous solution for forming the capsule shell in step d, the formed capsule is more stable and ruptures at approximately 80°C, but has not yet completely melted. Alternatively, the matrix agent can be a polycarboxylate. In this case, the gelation inducing agent can 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 can be a polyammonium salt, i.e., a polymer containing multiple polyammonium groups.

[0172] Those skilled in the art can adjust the content of the matrix forming agent to manufacture stable capsules without affecting the reliability of the method of the present invention, or even the sprayability of the capsules when necessary.

[0173] In fact, if the reaction rate between the gelation inducer and the matrix forming agent is too fast, resulting in the formation of a matrix shell that is insoluble in water, it may cause blockage or even complete blockage of the channel, which is obviously undesirable.

[0174] Advantageously, based on the total weight of the aqueous solution used to form the capsule shell, the aqueous solution used to form the capsule shell in step d may contain 0.1% to 5%, preferably 0.15% to 2.5%, more preferably 0.2% to 1% of a matrix forming agent.

[0175] surfactants

[0176] The aqueous solution used to form the capsule shell may also contain at least one surfactant. Specifically, the aqueous solution used to form the capsule shell may also contain at least one hydrophilic surfactant selected from polyglycerol esters, polyvinyl alcohol, polysorbate, saponins, aglycones, soapberry extracts, gum arabic, β-lactoglobulin, sodium lauryl sulfate, soybean lecithin, sodium caseinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

[0177] Of course, those skilled in the art will take care in selecting the surfactant (if any) and its amount in the aqueous solution used to form the capsule shell to ensure that the beneficial properties of the invention are not, or substantially not, affected by the considered additions. These adjustments are within the scope of common knowledge for those skilled in the art.

[0178] In this invention, the dispersion may contain 0.1% to 30%, preferably 0.5% to 25%, more preferably 1% to 20%, and most preferably 2% to 15% surfactant, based on the total weight of the aqueous solution used to form the capsule.

[0179] According to a specific embodiment, the aqueous solution used to form the capsule shell may further contain at least one chelating agent, which can delay the reaction between the gelation inducing agent and the matrix forming agent, preferably selected from at least one organophosphate, more preferably selected from tetrasodium pyrophosphate. The advantage of this embodiment is that it can prevent the aforementioned channels from becoming stagnant, blocked, or obstructed.

[0180] In some embodiments, the aqueous solution used to form the capsule shell may further contain at least one osmosis regulator, preferably selected from at least one alcohol or at least one sugar, and the osmosis regulator is added to the aqueous solution used to form the capsule shell in steps d and / or e. The role of the osmosis regulator is to promote the diffusion of the gelation inducing agent to the droplet interface, thereby increasing the capsule shell thickness and improving the stability of the capsule. The osmosis regulator can be an alcohol as described above, or it can be a sugar, such as a monosaccharide or disaccharide, i.e., glucose or fructose. Such sugar derivatives can be used alone or in combination with an alcohol as described above.

[0181] In a preferred embodiment, the aqueous solution used to form the capsule further comprises at least one alcohol, specifically methanol, ethanol, propanol, and mixtures thereof.

[0182] Studies have found that alcohol helps the gelling inducing agent diffuse to the droplet interface. The alcohol content is typically 5% to 30%, preferably 10% to 20%, representing a percentage of the total weight of the coating aqueous solution.

[0183] In some embodiments, the aqueous solution of the capsule formation may further contain at least one structural stabilizer. The structural stabilizer is a compound designed to improve the structural stability of the capsule and may be selected from agarose, xanthan gum, cellulose and its derivatives (e.g., methylcellulose or microcrystalline cellulose), and mixtures thereof. The structural stabilizer may be added to the aqueous solution of the capsule formation in steps d and / or e.

[0184] In some embodiments, the aqueous solution used to form the capsule in step d may further contain at least one additional biopolymer, different from the matrix agent, as a structural stabilizer, such as pectin (e.g., GENU). ® (LM-104AS-FG type pectin). Preferably, the additional biopolymer can also form a matrix shell. In some embodiments, the additional biopolymer can be biopolymer solid particles, such as starch. Adding such additional biopolymers, specifically biopolymer solid particles, can improve the mechanical strength of the manufactured capsules.

[0185] In some embodiments, steps c and / or d and / or e can be carried out at temperatures above room temperature, specifically between 25°C and 95°C, between 40°C and 85°C, between 50°C and 80°C, between 65°C and 80°C, or between 70°C and 80°C. Specifically, when the reverse emulsion and / or the second aqueous phase of step a contains at least one gelling agent (especially a heat-sensitive gelling agent), the aforementioned liquid properties are ensured, thereby guaranteeing the smooth implementation of steps c, d, and / or e.

[0186] Alternatively, after step e, the formed capsules may be exposed to temperatures above room temperature, specifically between 25°C and 95°C, particularly between 40°C and 85°C, specifically between 50°C and 80°C, specifically between 65°C and 80°C, particularly between 70°C and 80°C. For example, exposure treatment at the above temperatures may be performed for 5 to 60 minutes, specifically 15 to 30 minutes. In fact, increasing the temperature during or after step e may have a significant impact on the mechanical strength of the capsules.

[0187] Manufacturing method

[0188] Step a

[0189] The manufacture of the reverse emulsion in step a is conventional knowledge for those skilled in the art. For example, the reverse emulsion described in step a can be manufactured by conventional stirring methods, such as using a Rayneri stirrer or a rotor / stator stirrer (e.g., Ultraturrax / Ultrasound type).

[0190] Advantageously, the weight ratio of the "oil phase / first aqueous phase" of the reverse emulsion in step a is between 1 and 9, preferably between 1.5 and 5, and more preferably between 2.5 and 4.

[0191] Step b

[0192] The production of the second aqueous phase in step b is common knowledge to those skilled in the art. For example, the second aqueous phase in step b can be produced by conventional stirring methods, such as using a Rayner stirrer, rotor / stator (e.g., Ultraturrax / Ultrasound type).

[0193] Step c

[0194] The dispersion in step c can be prepared by any suitable microfluidic method.

[0195] According to the aforementioned implementation scheme, the reverse emulsion droplets obtained by the microfluidic method have the advantage of uniform particle size distribution.

[0196] Advantageously, the weight ratio of the "reverse emulsion / second aqueous phase" of the dispersion in step c is between 0.02 and 0.3, preferably between 0.05 and 0.25, more preferably between 0.07 and 0.20, and particularly preferably between 0.10 and 0.15.

[0197] Specifically, in step c, reverse emulsion droplets are generated in the second aqueous phase, which can be based on any microfluidic emulsification technique known to those skilled in the art. Specifically, the microfluidic emulsification technique can be selected from the following options:

[0198] -T-junction (or "T-junction"; see below) Figure 1 A);

[0199] - Flowfocusing connector (or "flowfocusing"; see below) Figure 1 B), in which the fluids used flow in different directions, usually in opposite directions;

[0200] - Coaxial capillary (or "conjugate focusing"; see...) Figure 1 C), wherein the fluid used flows in the same direction; or

[0201] - Stepwise emulsification (see...) Figure 1 D); “Stepped emulsification” is an alternative to conjugate focusing droplet generation technology. Its principle is to utilize the sudden change in fluid constraint conditions to induce instability in the two-phase flow. Preferably, the microfluidic emulsification technology is selected from coaxial capillary (or “conjugate focusing”) or stepped emulsification, with coaxial capillary being more preferred.

[0202] "Stepped emulsification" type microfluidic method

[0203] According to embodiment 1, step c of the manufacturing method of the present invention is based on a "stepped emulsification" type microfluidic emulsification technology. The microfluidic device particularly suitable for embodiment 1 is described in WO2021037999 and is as follows... Figure 3 The device shown in particular includes a first chamber and a second chamber fluidly connected by one or more conduits (preferably microchannels).

[0204] Therefore, according to embodiment 1, the manufacturing method of the present invention may include at least the following steps:

[0205] a'. At least the reverse emulsion described in step a is introduced into the first chamber;

[0206] b'. At least the second aqueous phase from step b is introduced into the second chamber; the first chamber and the second chamber are fluidly connected by one or more pipes (preferably micropipes);

[0207] c'. The reverse emulsion described in step a' is introduced from the first chamber into the second chamber through the pipe;

[0208] Steps d' and e' are the same as steps d and e as defined above.

[0209] Figure 2 A manufacturing method according to embodiment 1 is shown and described in more detail below.

[0210] A "chamber" is a container configured to hold and at least temporarily store chemical substances (such as liquids or gases). Typically, in microfluidics, a chamber refers to a widened area within a device where fluid can accumulate. Therefore, the "chamber" referred to in this invention is a larger enclosed space than a pipe, usually irregularly shaped, used to hold a certain volume of fluid; two chambers can be connected by at least one pipe, such as... Figure 3 The apparatus shown.

[0211] Therefore, in this invention, the chambers are designed for different operating modes, and their volume is larger than that of pipes. Therefore, the chambers in this invention cannot be considered pipes. In this invention, each chamber is independent; that is, according to this invention, a chamber is not located inside another chamber. Furthermore, the chambers in this invention are interconnected only by pipes.

[0212] In one embodiment, the method of the present invention belongs to the "step-emulsification" type, wherein the first phase and the second phase are located in separate chambers separated by at least one conduit; after the first phase passes through the conduit(s), the first phase and the second phase are mixed in the second chamber.

[0213] The "stepwise emulsification" microfluidic method is characterized in that the mixing of the first and second phases takes place in a second chamber. In contrast, in the "conjugate focusing" microfluidic method, the confluence zone of the two phases is always located within at least one channel (or conduit). Therefore, this type of "stepwise emulsification" method differs from the "conjugate focusing" microfluidic method.

[0214] The first and second chambers are typically isolated from each other and connected only by channels (or multiple channels). The chambers used here are designed to be solution-injectable. Generally, the chambers are closed structures except for the inlet, channels, and outlet. The first chamber typically has a first fluid inlet for introducing (particularly continuously) the emulsion used to form the core in step a; the second chamber has a second inlet for introducing (particularly continuously) the second aqueous phase from step b. The second chamber also has an outlet for discharging the dispersion formed in step c, preferably continuously.

[0215] Please note that each channel includes an inlet leading to the first chamber and an outlet leading to the second chamber. Therefore, the channels, or these channels, are directly connected to the first and second chambers. Typically, the first and second chambers are fluidly connected by a plurality of channels (e.g., at least 10, at least 20, at least 30, at least 50, or at least 100 channels). Preferably, the first and second chambers are fluidly interconnected by 1 to 10,000,000, preferably 20 to 500,000, more preferably 50 to 200,000 channels. Typically, these channels are arranged substantially parallel to each other.

[0216] For example, the diameter of the channels can be between 0.25 and 2,000 µm, preferably between 0.5 and 800 µm, more preferably between 1 and 500 µm, and even between 2 and 250 µm. Multiple channels on the membrane are typically microchannels. For example, the cross-sectional area of ​​each channel can be 0.04 µm. 2 Up to 4,000,000µm 2Preferably 4µm 2 Up to 640,000µm 2 .

[0217] In other embodiments, the ratio of "pipe length / minimum diameter" can be between 5 and 1,000, preferably between 10 and 500, specifically between 10 and 50. In some embodiments, the length of the channel can be between 0.05 mm and 20 mm, specifically between 0.1 mm and 20 mm, particularly between 0.1 mm and 5 mm, and more specifically between 0.5 mm and 2 mm.

[0218] In some embodiments, each conduit includes a channel outlet with a cross-sectional area larger than that of the remainder of the corresponding channel. In the longitudinal direction (i.e., the flow direction), the length of the channel outlet is typically a few micrometers, for example, 200 µm to 20 mm, preferably 500 µm to 5 mm. The channel outlet can be funnel-shaped, V-shaped, or U-shaped, as illustrated in WO2022106361. In some embodiments, the channel outlet may have an elliptical profile. Specifically, the channel outlet is not rotationally symmetric, and therefore its aspect ratio is 3 or greater. Thus, the cross-section of the channel outlet may not be circular or square. Such channel outlets allow droplet detachment without external force. Therefore, the formation process of the emulsion droplets forming the core in the second aqueous phase is decoupled and thus essentially rate-independent. According to the Yang-Laplace equation, at the interface of the immiscible fluids, the pressure at the channel outlet is higher than the pressure in the second reservoir. This creates a pressure gradient along the flow direction, causing the fluid filaments to separate into individual droplets. Therefore, a pressure gradient is generated at the end of the channel, which facilitates the detachment of the fluid boundary layer, thereby promoting the formation of individual droplets. When the fluid reaches the channel outlet, the droplets detach without external force due to the pressure gradient between the dispersed phases inside and outside the channel.

[0219] Typically, each conduit is defined by a conduit wall. The conduit wall can be curved, meaning it is convex or concave towards the conduit outlet. Furthermore, each conduit may include a narrow section with a smaller cross-sectional area than the rest of the conduit, and this narrow section is located near the conduit outlet. Therefore, the narrow section lies between the conduit outlet and the rest of the conduit.

[0220] In other embodiments, the cross-sectional area of ​​each channel outlet is from 0.12 to 36,000,000 µm. 2 Preferably 12 to 5,760,000 µm 2 Specifically, the total opening area on the second side of the membrane can be 300% to 1,500% larger than the total opening area of ​​the channel at any other given location (e.g., the main cross-section and / or the channel inlet), preferably 400% to 900%.

[0221] In some embodiments, the channel may be contained within a membrane separating the first chamber and the second chamber. In these embodiments, the membrane may be planar, for example, disk-shaped. The membrane typically has one side facing the first chamber and another side opposite the first side and facing the second chamber. Thus, the first side of the membrane may partially define the first chamber, and the second side of the membrane may partially define the second chamber. The channel (typically multiple channels) extends through the membrane from the first side to the second side. Each channel includes a channel inlet located on the first side, a channel outlet located on the second side, and a body segment located between the channel inlet and the channel outlet.

[0222] The membrane is typically a single-layer membrane. That is, the membrane consists of a single component. Preferably, such membranes are made of dense materials and do not contain phase interfaces or transition regions other than multiple channels on the membrane. Such membranes have an advantage over the quality of the generated droplets because all interfaces and phase transitions can adversely affect droplet formation and stability.

[0223] In some embodiments, the membrane may be replaceable. The multiple channels on the membrane are typically microchannels. For example, the cross-sectional area of ​​each channel may be 0.04 µm. 2 Up to 4,000,000µm 2 Preferably 4µm 2 Up to 640,000µm 2 .

[0224] In other embodiments, the channel outlet may be wedge-shaped. Specifically, the channel outlet may have an elliptical cross-section relative to a cross-sectional plane perpendicular to the extending channel, meaning the dimension of the channel outlet in the first direction may be larger than its dimension in the second direction. In other embodiments, the second side of the membrane has a total opening area greater than the total opening area of ​​the first side. The advantage of such membranes is that they can generate high-quality droplets even at rates up to 5 L / h (or liters per hour). In some embodiments, the 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.

[0225] In some implementations, each channel outlet may have an elliptical profile. Therefore, the channel outlet may have an elliptical cross-section relative to a plane that spans the extended channel and is parallel to the first or second side of the membrane. Channel outlets with elliptical profiles have a positive impact on the quality of the formed droplets, as any edges within the channel can lead to unstable and non-uniform droplets.

[0226] In some embodiments, the membrane is disc-shaped. Such membranes may have a circular profile. Alternatively, the membrane may have a polygonal profile, specifically a triangle or a rectangle.

[0227] In other embodiments, the membrane contains 0.06 to 600,000 channels / cm². 2 Preferably, there are 20 to 30,000 channels / cm. 2 .

[0228] In some embodiments, the membrane is made of glass or polymeric materials (such as polymethyl methacrylate or PTFE), or of metallic materials (such as steel).

[0229] In other embodiments, specifically in step c, a pressure of 1.01 bar to 1.25 bar, preferably 1.03 bar to 1.17 bar, is applied to the first chamber, and / or 1.02 bar to 1.3 bar, preferably 1.05 bar to 1.2 bar, is applied to the second chamber, specifically in step c. Note that these pressure values ​​are all absolute pressures, i.e., 1.01 bar of pressure has 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. Note that the first pressure can be adjusted by the pressure at which the emulsion forming the core is delivered to the first chamber via the first inlet, and / or the second pressure can be adjusted by the pressure at which the second aqueous phase of step b is delivered to the second chamber via the second inlet.

[0230] In some embodiments, the pressure applied to the first chamber is higher than the pressure applied to the second chamber. Note that the first pressure can be adjusted by the pressure at which the emulsion forming the core is delivered to the first chamber via the first inlet, and / or the second pressure can be adjusted by the pressure at which the second aqueous phase in step b is delivered to the second chamber via the second inlet.

[0231] In some embodiments, step c is implemented by a device comprising: a first emulsion inlet, opposite to step a, leading to a first chamber; a second aqueous phase inlet, leading to a second chamber; and an outlet located in the second chamber for collecting the dispersion and ensuring its contact with the aqueous solution formed by the capsule shell. Furthermore, the device includes a membrane, specifically the membrane described above, separating the first and second chambers, and having a first side facing the first chamber and a second side facing the second chamber. The membrane includes a plurality of channels extending from the first side to the second side, thus ensuring fluid connection between the first and second chambers. Each channel includes a channel inlet on the first side and a channel outlet on the second side. Typically, the first chamber may be configured such that the reverse rate of the emulsion is substantially equal in all individual channels.

[0232] In some embodiments, the second chamber may be made of glass or a transparent polymer (such as polytetrafluoroethylene, polymethyl methacrylate, or polyoxymethylene), or it may be made of a metal (such as steel, aluminum, or titanium). Generally, the device may include a container (e.g., a glass container) that partially forms the second chamber. The container, together with the membrane, forms the second chamber. In some embodiments, the first chamber may be made of a metal (e.g., aluminum or steel) or a transparent polymer (such as PTFE, polymethyl methacrylate, or polyoxymethylene).

[0233] For example, the outlet of the second chamber can be fluidly connected to a container containing an aqueous solution for forming the capsule, thereby achieving steps d and e.

[0234] In some implementations, steps d and e are carried out under a continuous flow of the dispersion formed in step c.

[0235] Preferably, the second chamber is conical in the direction of its outlet. For example, at least a portion of the second chamber may be arc-shaped or conical, with the shape facing the outlet of the second chamber. These embodiments ensure that no portion of the dispersion formed in step c is retained and can be completely recovered through the outlet of the second chamber.

[0236] In some embodiments, the first chamber is hemispherical or truncated cone-shaped. Typically, the hemisphere or truncated cone faces the membrane opening, meaning the largest radius is usually closest to the membrane. The term "hemispherical" as used herein also includes other spherical segments, such as one-third of a sphere. Therefore, in some embodiments, the first chamber is shaped like a spherical dome or spherical cover. Typically, all channels are arranged substantially parallel to each other. Preferably, the first inlet is arranged substantially transversely, and more preferably perpendicular to the membrane of the multiple channels. Thus, in these embodiments, the first inlet may be parallel to a first side of the membrane.

[0237] In other embodiments, the device includes a membrane support for mounting the membrane sheet. In some embodiments, the device includes a container support for securing a container portion that forms a second chamber. The container support may be fixedly connected to or detachably connected to the membrane support. The container support and / or membrane support and / or base may be made of any suitable material, such as plastic materials like polytetrafluoroethylene (PTFE), polymethyl methacrylate, or polyoxymethylene, or metal, preferably steel.

[0238] Preferably, if the container is a glass container, a cushioning pad can be placed between the glass container and the container support to avoid damaging the glass container and to ensure its seal.

[0239] In some embodiments, the membrane support includes clamping devices for mounting membrane sheets, and the membrane support and / or clamping devices are configured to accommodate membrane sheets of different thicknesses. Typically, the clamping devices can be adjustable. Examples of clamping devices include screws, clips, bolts, latches, etc.

[0240] In some embodiments, the device includes a base, and preferably, the first chamber portion is formed by the base.

[0241] In other embodiments, the base and / or membrane support includes at least one seal for sealing the membrane to the base and / or membrane support. The sealing ring may be configured to completely surround the periphery of the membrane circumferentially. The sealing ring may also include an vent in fluid communication with the first chamber, the vent being configured to expel any gas within the first chamber.

[0242] In some embodiments, the base and / or membrane support includes spacer rings. These spacer rings allow for the use of membranes of varying thicknesses.

[0243] In some embodiments, the apparatus includes at least one heater for heating the reverse emulsion and / or the second aqueous phase and / or at least the dispersion; and / or a cooler for cooling the reverse emulsion and / or the second aqueous phase and / or the dispersion. For example, the heater may include a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an infrared heater, a heating coil, or any other suitable heater.

[0244] In other embodiments, the apparatus includes a first tank for the reverse emulsion and / or a second tank for the second aqueous phase. Both the first and second tanks can be pressurized. For example, the tanks can be connected to a pressure source, such as a compressor, via fluid channels. Alternatively, the tanks can be syringes and pressurized by conventional syringe plungers and / or pistons, peristaltic pumps, gear pumps, or any other pumping system.

[0245] Conjugate Focusing Microfluidic Method

[0246] According to embodiment 2, step c is based on a coaxial capillary (or "conjugate focusing") type microfluidic emulsification technique. Therefore, step c is preferably performed as follows: the second aqueous phase from step b is circulated in a second conduit, the downstream opening of the first conduit connecting to the second conduit and preferably coaxial with a local axis of the second conduit. In this invention, "upstream" and "downstream" refer to the direction of fluid flow.

[0247] According to the aforementioned implementation scheme 2, step c can be specifically achieved through... Figure 4 This is achieved using the microfluidic device (or nozzle) described in the text.

[0248] Figure 4 The microfluidic device 30 shown includes a single shaped nozzle 32 having an inner tube 34 (i.e., a "first conduit") for conveying an internal fluid 36 containing the reverse emulsion 14 described in step a) and an outer tube 38 (i.e., a "second conduit") arranged around the inner tube 34 for conveying an external fluid 40 containing the second aqueous phase 16 described in step b1.

[0249] The inner tube 34 is preferably coaxially disposed within the outer tube 38. Its upstream end is connected to the conveying device 46. Its downstream end is opened through a downstream opening 52 disposed within the outer tube 38, the opening being arranged in a recessed manner relative to the downstream opening 54 defined by the outer tube 38.

[0250] The distance between the downstream opening 52 of the inner tube 34 and the downstream opening 54 of the outer tube 38 is preferably greater than 1 times the diameter of the outer tube 38.

[0251] The outer tube 38 and the inner tube 34 preferably define an annular space together, and the space is connected to the conveying device 48 at the upstream end.

[0252] According to Implementation Plan 1 (not in Figure 4 As shown in the figure, the downstream opening 54 of the outer tube 38 is in fluid communication with the container 33 containing an aqueous solution for forming the capsule 44, to ensure the implementation of steps d and e.

[0253] According to the second alternative implementation plan (not in Figure 4 (As shown in the figure), nozzle 32 is designed to deliver an aqueous solution 44 for forming a capsule through a third conduit 72 located immediately adjacent to the outer tube 38.

[0254] According to implementation plan 3 (e.g.) Figure 4 As shown), nozzle 32 is designed to deliver an aqueous solution 44 for forming a capsule through a third conduit 72, wherein an outer tube 38 is contained within the third conduit and is preferably coaxial with a local axis of the third conduit 72.

[0255] In this implementation scheme 3, the downstream opening 54 of the outer pipe 38 may be located before or after the downstream opening 56 of the third pipe 72.

[0256] Preferably, the downstream opening 54 of the outer pipe 38 is located after the downstream opening 56 of the third pipe. Figure 4 The above is the implementation scheme. The capsules in Examples 1 and 2 below are manufactured in the manner described.

[0257] The present invention also relates to a method in which, in step d, the aqueous solution for forming the capsule can be circulated in a third conduit, the third conduit comprising a second conduit preferably being coaxial with a local axis of the third conduit, and the downstream opening of the second conduit preferably leading to the downstream opening of the third conduit.

[0258] In container 33, (i) mixing of external fluid 40 with aqueous solution 44 for forming capsule shell and (ii) reaction between gelation inducer and matrix forming agent occur to obtain a capsule containing a water-insoluble matrix capsule shell 12, which encapsulates a lipophilic capsule core 17.

[0259] exist Figure 4 In the process, the forming nozzle 32 includes a conveying device 46 for conveying internal fluid 36 to inner tube 34, a device 48 for conveying external fluid 40 to outer tube 38, specifically conveying to an annular space defined between inner tube 34 and outer tube 38, and a device 50 for conveying the encapsulated aqueous solution 44 to the conveying pipe 42.

[0260] exist Figure 4 In the example shown, device 30 is depicted as having only nozzle 32. In a preferred alternative, device 30 includes a plurality of nozzles 32 arranged below one or more containers 33.

[0261] According to Implementation Scheme 1 and Implementation Scheme 2, all downstream openings 54 of the outer tube 38 are in fluid communication with the container 33 containing the aqueous solution for forming the capsule 44.

[0262] According to implementation scheme 3, each third pipe 72 includes an outer pipe 38, which is preferably coaxial with the local axis of the third pipe 72 associated with it.

[0263] Delivery devices 46, 48, and 50 each include, for example, a syringe plunger, a peristaltic pump, or another rate-controlled pressure-generating system, such as a pressure tank connected to a rate meter and rate control system. Each delivery device 46, 48, and 50 is capable of delivering the corresponding fluid 36, 40, and 44 at a controlled and adjustable rate.

[0264] Preferably, for implementing steps e and d, container 33 further includes a stirring device 75. The stirring device can be any stirring device well known to those skilled in the art. Such a stirring device may specifically be embodied in the stirring device described in WO2023 / 099530.

[0265] In some embodiments, the apparatus includes at least one heater for heating the reverse emulsion and / or the second aqueous phase and / or at least the dispersion; and / or a cooler for cooling the reverse emulsion and / or the second aqueous phase and / or the dispersion. For example, the heater may include a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an infrared heater, a heating coil, or any other suitable heater.

[0266] According to implementation scheme 1, all pipes have the same diameter, thus obtaining monodisperse capsules.

[0267] According to implementation scheme 2, the pipes have different diameters, thereby obtaining polydisperse capsules and controlling their polydispersity.

[0268] Steps d and e.

[0269] In some embodiments, steps d and / or e include stirring the aqueous solution formed for coating and the dispersion obtained in step d. Preferably, stirring should be performed using a stirrer at a speed of 10 rpm to 800 rpm, more preferably 25 rpm to 500 rpm, specifically 50 rpm to 350 rpm, and more preferably 100 rpm to 250 rpm. Mixing in steps d and e is advantageous because it prevents the aggregation of monodisperse droplets in the formed dispersion and / or the formed capsules. Furthermore, this ensures a uniform capsule size distribution and prevents aggregation between capsules. Typically, a suspended stirrer or a stirring device as described in WO2023 / 099530 can be used.

[0270] In some embodiments, step e is performed within 30 seconds to 10 minutes, preferably within 45 seconds to 5 minutes, and more preferably within 1 minute to 2 minutes. The reaction time of step e, i.e., the time required until the reaction terminates (e.g., by separating or isolating the capsule from the aqueous solution used to form the capsule shell), directly affects the size of the capsule and the size of the capsule core.

[0271] Preferably, the weight ratio of the dispersion in step d, consisting of "reverse emulsion / second aqueous phase + aqueous solution for forming the capsule", is between 0.005 and 0.15, more preferably between 0.01 and 0.12, particularly preferably between 0.025 and 0.10, and most preferably between 0.05 and 0.075.

[0272] Supplementary steps

[0273] In some embodiments, the method may further include at least one additional impregnation-coating step after step e. In some embodiments, the additional capsule formation step may include contacting or immersing the capsule formed in step e with or into a second aqueous solution for forming the capsule, said solution being the same as or different from the aqueous solution for forming the capsule in step d, specifically in terms of the nature and / or content of the matrix forming agent. The second solution for forming the capsule comprises water and at least one matrix forming agent, said matrix forming agent being the same as or different from the matrix forming agent contained in the aqueous solution for forming the capsule in step d.

[0274] In some embodiments, the capsule is coated with two or more additional coatings. Therefore, the impregnation coating process can be repeated using different matrix forming agents.

[0275] In some embodiments, the method of the present invention further includes at least one step f, namely: rinsing the capsule obtained at the end of step e with a third aqueous solution; said third aqueous solution comprises water, preferably reverse osmosis water, and optionally at least one preservative. Typically, step f can be implemented using the apparatus described in WO2023099536.

[0276] In some implementations, specifically after step e or optionally after step f, the formed capsule is separated, solidified, and / or preserved.

[0277] Capsule separation may include, for example, filtration or sieving to separate the capsule from the aqueous solution that forms the capsule shell, and optionally washing the capsule with water.

[0278] Curing may include drying the capsule, for example by airflow or freeze-drying, to evaporate all or at least most of the free water. The curing process may also include additional stirring of the capsule in an aqueous solution containing at least one inorganic salt (such as CaCl2 or MgCl2) at a concentration of 1% to 10% (by weight), preferably 1% to 5%. This further improves the stability and structural integrity of the capsule, especially the shell.

[0279] Preservation is achieved by immersing the capsules in distilled water, a solution containing divalent cations, or an aqueous solution containing inorganic salts (such as CaCl2 or MgCl2).

[0280] In some embodiments, after step e or possibly after step f, the capsule is placed in a solution containing at least one chelating agent. The chelating agent is designed to form a chelating complex with a gelling inducing agent. For example, if the chelating inducing agent is a calcium salt (such as CaCl2), the chelating agent can react with Ca... 2+A chelating complex is formed. Suitable chelating agents are Lewis bases, such as EDTA, GLDA (tetrasodium N,N-bis(carboxymethyl)-L-glutamic acid), MGDA (trisodium dicarboxymethyl alanine), citrate, tartrate, etc. The choice of solvent should generally ensure that the chelating agent is soluble in it and that the formed capsule (i.e., the water-insoluble matrix) does not dissolve. Therefore, water is a suitable solvent. After the capsule is placed in such a solution for a predetermined time, the capsule shell becomes brittle because the chelating agent forms a chelate with part of the gelling inducing agent (or its derivative). For example, if the gelling inducing agent is CaCl2 and the chelating agent is sodium citrate in the form of calcium citrate, the strength of the formed capsule shell can be weakened. The advantage is that the degree of brittleness of the shell (i.e., mechanical strength) can be precisely controlled. For products that require rapid shell rupture or decomposition, such as cosmetics like skin creams, it may be necessary to reduce its strength. For example, 0.001% to 0.4% (by weight), specifically 0.01% to 0.1% (by weight), of sodium citrate, and possibly sodium chloride (in an amount 0.6 times that of sodium citrate), can be dissolved in water. The capsules are stirred in the solution for 10 to 50 minutes, specifically 20 to 40 minutes. Attached Figure Description

[0281] The invention will be better understood through the following detailed description and the accompanying drawings, but the drawings should not be regarded as limiting the invention.

[0282] The attached diagram is described below:

[0283] [ Figure 1 ] Figure 1 These are schematic diagrams of various microfluidic emulsification technologies, namely: A) T-junction, B) flow focusing, C) co-flow, and D) step emulsification, where "Ud" represents the "linear velocity of the dispersed phase" and "Uc" represents the "linear velocity of the continuous phase".

[0284] [ Figure 2 ] Figure 2 This is a schematic diagram of an example of the manufacturing method described in this invention, wherein step c is performed using a "step emulsification" type microfluidic device;

[0285] [ Figure 3 ] Figure 3 yes Figure 2 Cross-sectional view of the device shown;

[0286] [ Figure 4 ] Figure 4 This is a schematic diagram of an example of the manufacturing method described in this invention, wherein step c is performed using a "conjugate focusing" type microfluidic device; arrow 75 indicates that there is a stirring device in operation inside container 33.

[0287] exist Figures 1 to 4 In the diagram, except for arrow 75 mentioned above, all arrows indicate the flow direction of the various fluids used. Detailed Implementation

[0288] Figure 2 A manufacturing method according to the present invention is illustrated schematically, wherein step c is performed using a microfluidic device of the "step emulsification" type. In the first step, an inverse emulsion is generated by mixing a solution 101 containing at least one gelling inducer and water with an oil phase 102. Figure 2 a). For example, this can be done using a mixer 103. Figure 2 a) An enlarged view of a single drop of solution 101 in the emulsion is also shown. The droplet represented by the straight line in the figure contains water and dissolved gelling inducing agent. Therefore, Figure 2 Each droplet shown in a) is an aqueous solution of a gelling inducing agent. Subsequently, the emulsion formed by the aqueous phase 101 and the oil phase 102 is conveyed to the first chamber 4 of a suitable device ( Figure 2 (b) The second chamber 5 of the device contains a second aqueous phase 104, which is composed of water and at least one surfactant. As shown, the first chamber 4 and the second chamber 5 are fluidly connected by a plurality of channels 10. In the illustrated embodiment, the first chamber and the second chamber are separated by a membrane 7, with a first side 8 facing the first chamber and a second side 9 facing the second chamber. The channels 10 extend from the first side 8 to the second side 9. Typically, appropriate pressure is applied to the emulsion that forms the core in the first chamber 4. The emulsion in the first chamber 4 is then guided through the channels 10. Since the emulsion is typically composed mainly of the oil phase 102, an emulsification step occurs when the emulsion reaches the channel outlet leading to the second chamber 5, thereby forming the dispersion described in step c, which may be referred to as a water-in-oil-in-water transition emulsion (or "two-phase transition emulsion"), characterized by monodisperse droplets 113 dispersed in the second aqueous phase 104, these monodisperse droplets 113 being formed from a solution 101 dispersed in the oil phase. Please note that the droplet sizes in the figure have been enlarged for clarity. Furthermore, the relative sizes of droplet 101 with respect to droplet 113 and / or capsule 106 do not reflect reality. Each monodisperse droplet 113 in the second chamber 5 now comprises one or more droplets 101 dispersed in the oil phase 102. Subsequently, the transition emulsion flows through the outlet of the second chamber 6 into a container 105 containing an aqueous solution 104 for forming capsules, optionally equipped with a stirrer 107. Figure 2c). In fact, when the dispersion (i.e., monodisperse droplets 113) is mixed with the aqueous solution 104 used to form the capsule shell, the gelation inducing agent contained in the droplets 113 diffuses to the surface of the droplets and then reacts chemically with the matrix forming agent at the interface to form a water-insoluble matrix capsule shell that completely encapsulates each droplet, thereby forming a capsule 106 with a lipophilic core encapsulated by a water-insoluble matrix capsule shell.

[0289] Figure 3 It shows Figure 2 A cross-sectional view of the device is shown. The device includes a base 14 with a first inlet 2 for conveying an emulsion used to form a core. Inlet 2 leads to a first chamber 4, which is partially formed by the base 14. The device also includes a container 19 with a second inlet 3 for supplying a second aqueous phase 104 and an outlet for collecting a transition emulsion 104 in a second chamber 6. The second inlet 3 leads to a second chamber 5, which is partially formed by the container 19. The first and second chambers are separated by a diaphragm 7. Figure 3 As shown, the first chamber has an arc-shaped cross-section, which is perpendicular to the diaphragm 7 along the central longitudinal axis 15. In the specific embodiment shown, the first chamber 4 has a semi-circular cross-section, and therefore can be hemispherical. The first inlet 2 is located at the pole 13 of the hemisphere. The second chamber 5 is conical towards the outlet 6, which is located on the longitudinal axis 15 extending longitudinally along the device, passing through the center of the first and second chambers, perpendicular to the diaphragm 7, and passing through the center of the diaphragm. As shown, the longitudinal axis 15 forms the 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. Therefore, the second chamber 5 has a U-shaped cross-section. The first inlet 2 is arranged at an angle α of approximately 90° relative to the central axis 15 and the membrane channel, which is generally parallel to the axis 15. The device 1 includes a membrane support 20 and a container support 21, which are fixedly connected by a detachable clamping device 18. The diaphragm 7 is mounted on the membrane support 20 and fixed by clamping the diaphragm between the membrane support 20 and the base 14. The membrane support 20 is fixedly connected to the base 14 via a clamping device 18. To securely fix the glass container 19 between the membrane support 20 and the container holder 21, a gasket 23, in this specific example, is provided between the container 19 and the container holder 21. The membrane support 20 is provided with a groove 22 for receiving the container 19.

[0290] Throughout this specification, unless otherwise stated, “comprising” shall be understood as a synonym for “comprising at least one”. Unless otherwise stated, expressions such as “between… and…”, “from… to…”, and “ranging from… to…” shall be understood to include both ends.

[0291] Example

[0292] Example 1 Skincare capsules are manufactured using the solutions described in Table 1 below, utilizing... Figure 4 The microfluidic device shown was used to manufacture fragrance capsules at the rates described in Table 2. These capsules were then analyzed according to the evaluation criteria described in Table 3.

[0293] [Table 1]

[0294]

[0295] *: Sufficient quantity

[0296] [Table 2]

[0297]

[0298] [Table 3]

[0299]

[0300] result :

[0301] [Table 4]

[0302]

[0303] Experiment B showed that removing polyvinyl alcohol (PVA) from F0O did not affect normal capsule formation. Surprisingly, Experiment B even produced capsules with higher transparency compared to the control.

[0304] Experiment C showed that removing the surfactant from the reverse emulsion did not affect good capsule formation, but the uniformity of the capsule shell decreased slightly. However, the advantage of Experiment C was that the transparency of its lipophilic core was more readily obtained than that of Experiment B, which is undoubtedly due to the faster destabilization kinetics of the reverse emulsion (*).

[0305] Experiment D showed that when the surfactant in AF was replaced with an alcohol, the properties of the resulting capsule were similar to those of the capsule in Experiment B.

[0306] Experiment E showed that removing the surfactant from the reverse emulsion (AF) did not affect good capsule formation, but it did lead to a decrease in capsule sphericity and shell uniformity.

[0307] The capsules obtained in experiment F performed better than the control.

[0308] Use such as Figure 3 The microfluidic device shown also achieved similar results, although the quality of the capsule was slightly inferior.

[0309] Example 2 Fragrance capsule manufacturing

[0310] Based on the solutions and rates described in Tables 5 and 6 below, using Figure 4 The microfluidic device shown manufactures fragrance capsules.

[0311] The evaluation criteria used to assess these fragrance capsules are completely consistent with those in Example 1.

[0312] [Table 5]

[0313]

[0314] [Table 6]

[0315]

[0316] result :

[0317] [Table 7]

[0318]

[0319] Example 2 demonstrates that the present invention is applicable to continuous reverse emulsions containing fragrance, or even composed of 100% fragrance. Example 2 also demonstrates that the present invention is equally effective when the percentage of raw materials and the IF2 / IF1 mass ratio differ from those described in Example 1.

[0320] Therefore, Example 2 demonstrates the robustness and stability of the present invention.

[0321] Similar results were obtained after adding 0.1% xanthan gum to the second aqueous phase (OF).

[0322] Use such as Figure 2 The microfluidic device shown also yielded similar results, although the quality of the fragrance capsules was slightly inferior.

[0323] Subsequently, the capsules from experiments G, H, and I were mixed with the new aqueous phase described in Table 8 at a volume fraction of 70% to obtain a non-homogeneous mixture.

[0324] [Table 8]

[0325]

[0326] Subsequently, the three non-homogeneous mixtures were packaged into 50 mL containers containing a 1.66 mm inner diameter dip tube and a spray pump dispensing device. Release tests were then conducted as follows: for 5 consecutive days, 8 hours per day, with the button pressed 4 times per hour, and during use, (i) inhalation of the capsules, (ii) release of the spray formulation, (iii) odor characteristics, and (iv) sensory characteristics were observed.

[0327] result :

[0328] All three spray devices performed well in both capsule inhalation and spray-dispensing formulations.

[0329] However, these three spray devices differ in terms of odor and sensory performance, as shown in the table below.

[0330] [Table 9]

[0331]

[0332] [Table 10]

[0333]

[0334] Please note that no oil was added in Experiment I, thus avoiding an oily feel. While the inventors do not wish to be bound by any theory, they believe that the absence of oil in Experiment I at least partially contributed to the significant improvement in its scent performance, a particularly unexpected and advantageous aspect in developing fragrance formulations.

[0335] Use such as Figure 2 The microfluidic device shown also yielded similar results, although the quality of the fragrance capsules was slightly inferior.

Claims

1. A method of manufacturing a capsule, said capsule comprising at least one matrix shell and at least one lipophilic core encapsulated therein, said method comprising at least the following steps: a. A reverse emulsion comprising a first aqueous phase dispersed in a continuous oil phase, the first aqueous phase comprising water and at least one gelation inducing agent; b. Provide a second aqueous phase comprising water, wherein the second aqueous phase is free of surfactants, specifically, free of polyvinyl alcohol and / or polysorbate; c. Inject the reverse emulsion described in step a into at least one first conduit leading to the second aqueous phase in step b, thereby obtaining a dispersion wherein droplets of the reverse emulsion described in step a are dispersed in the second aqueous phase in step b; d. Contact the dispersion obtained in step c with at least one aqueous solution for forming a capsule, the aqueous solution comprising water and at least one matrix forming agent, wherein the gelation inducing agent and the matrix forming agent are configured to chemically react with each other to form a water-insoluble matrix capsule; and e. Reacting a gelling inducing agent with a matrix forming agent to obtain a capsule comprising a water-insoluble matrix shell and at least one lipophilic core encapsulated therein.

2. The method of claim 1, wherein, The gelation inducing agent is an inorganic salt, specifically an alkaline earth metal salt, specifically an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate, an alkaline earth metal nitrate, or a mixture thereof.

3. The method of claim 1 or 2, wherein, Based on the total weight of the first aqueous phase, the first aqueous phase of the reverse emulsion in step a contains 2.5% to 60%, preferably 5% to 50%, more preferably 10% to 40% of a gelling inducing agent.

4. The method according to any one of the preceding claims, wherein, The reverse emulsion may also contain at least one oil and / or at least one surfactant, preferably a nonionic surfactant, more preferably a surfactant selected from polyglycerol ricinoleate (PGPR) and sorbitol derivatives, specifically sorbitol esters, such as sorbitol monooleate, sorbitol trioleate and mixtures thereof.

5. The method according to any one of the preceding claims, wherein, Based on the total weight of the oil phase, the oil phase contains 0.01% to 2%, preferably 0.05% to 1.5%, and more preferably 0.1% to 1% of surfactant.

6. The method according to any one of the preceding claims, wherein, The oil phase also contains at least one active ingredient, specifically at least one fragrance.

7. The method of claim 6, wherein, Based on the total weight of the oil phase, the oil phase contains 20% to 100%, preferably 30% to 90%, more preferably 40% to 80% of active ingredients, specifically one or more fragrances.

8. The method of any of the preceding claims, wherein, The weight ratio of the "oil phase / first aqueous phase" of the reverse emulsion is between 1 and 9, preferably between 1.5 and 5, and more preferably between 2.5 and 4.

9. The method of any of the preceding claims, wherein, Step b: The second aqueous phase further comprises at least one hydrophilic gelling agent, preferably selected from agarose, xanthan gum, cellulose and its derivatives, methylcellulose, microcrystalline cellulose and mixtures thereof, and preferably xanthan gum.

10. The method according to the preceding claim, wherein, Based on the total weight of the second aqueous phase, step b describes the second aqueous phase as containing 0.1% to 15%, preferably 0.5% to 10%, and more preferably 1% to 5% of a hydrophilic gelling agent.

11. The method according to any one of the preceding claims, wherein, The weight ratio of the "reverse emulsion / second aqueous phase" of the dispersion in step c is between 0.02 and 0.3, preferably between 0.05 and 0.25, more preferably between 0.07 and 0.20, and particularly preferably between 0.10 and 0.

15.

12. The method of any of the preceding claims, wherein, In step d, the matrix forming agent contained in the aqueous solution used to form the capsule is a polysaccharide or its salt, preferably selected from chitosan, cellulose, alginate, specifically sodium alginate, carrageenan, agar, agarose, pectin, gellan gum, starch and mixtures thereof.

13. The method of any of the preceding claims, wherein, Based on the total weight of the aqueous solution used to form the capsule shell, the aqueous solution used to form the capsule shell in step d contains 0.1% to 5%, preferably 0.15% to 2.5%, more preferably 0.2% to 1% of a matrix forming agent.

14. The method of any of the preceding claims, wherein, The aqueous solution used to form the capsule shell further comprises at least one surfactant, preferably selected from polyglycerol esters, polyvinyl alcohol, polysorbate, saponins, saponins, soapberry extracts, gum arabic, β-lactoglobulin, sodium lauryl sulfate, soybean lecithin, sodium caseinate, potato protein isolate, whey protein isolate, starch octenyl succinate, and mixtures thereof.

15. The method of any of the preceding claims, wherein, The aqueous solution used to form the capsule also contains at least one alcohol, specifically methanol, ethanol, propanol, and mixtures thereof.

16. The method of any of the preceding claims, wherein, Step a includes at least the following sub-steps: a1. Dissolve the gelation inducing agent in water to form a first aqueous phase; and a2. Mix the first aqueous phase formed in step a1 with the oil phase.

17. The method according to any one of the preceding claims, wherein, Steps d and e are carried out under stirring, preferably at a speed of 10 rpm to 800 rpm, more preferably at a speed of 25 rpm to 500 rpm, particularly preferably at a speed of 50 rpm to 350 rpm, and most preferably at a speed of 100 rpm to 250 rpm.

18. The method of any of the preceding claims, wherein, Step e is performed within 30 seconds to 10 minutes, preferably within 45 seconds to 5 minutes, and more preferably within 1 minute to 2 minutes.

19. The method of any of the preceding claims, wherein, The capsule's matrix shell and lipophilic core are transparent.

20. The method of any of the preceding claims, wherein, The implementation of step c is as follows: the second aqueous phase from step b is circulated in the second pipe, the downstream opening of the first pipe leads to the second pipe, and preferably is coaxial with the local axis of the second pipe.

21. The method according to the preceding claim, wherein, In step d, the aqueous solution used to form the capsule is circulated in a third conduit, the third conduit comprising a second conduit, the second conduit preferably being coaxial with a local axis of the third conduit, and the downstream opening of the second conduit preferably leading to the downstream opening of the third conduit.

22. The method of any one of claims 1 to 19, wherein, The method includes at least the following steps: a'. At least the reverse emulsion described in step a is introduced into the first chamber; b'. At least the second aqueous phase from step b is introduced into the second chamber; the first chamber and the second chamber are fluidly connected by one or more pipes (preferably micropipes); c'. The reverse emulsion described in step a' is introduced from the first chamber into the second chamber through the pipe; Steps d' and e' are the same as steps d and e according to any one of claims 1 to 19.

23. The method according to any one of the preceding claims, further comprising at least one step f, namely: rinsing the capsule obtained at the end of step e with a third aqueous solution; said third aqueous solution comprising water, preferably reverse osmosis water, and optionally comprising at least one preservative.

24. A capsule combination comprising a plurality of capsules manufactured according to the method of any one of the preceding claims, wherein, The average diameter of the capsule is preferably between 250 μm and 3,000 μm, more preferably between 500 μm and 2,000 μm, particularly preferably between 1,000 μm and 1,750 μm, and most preferably between 1,200 μm and 1,500 μm; and the coefficient of variation of the capsule is preferably less than or equal to 10%, more preferably less than or equal to 5%, and most preferably less than or equal to 3%.

25. The capsule combination according to the preceding claim, wherein, Based on the total weight of the capsule, the capsule contains 5% to 30%, preferably 10% to 20%, more preferably 12% to 15% of an active ingredient, specifically a fragrance.

26. The capsule combination according to claim 24 or 25, wherein, Based on the total weight of the capsule assembly, the alcohol content of the capsule assembly is specifically less than 10% ethanol, preferably less than 5%, particularly preferably less than 2.5%, or even no alcohol at all.

27. An apparatus for packaging and dispensing fluid compositions such as cosmetics in spray form, characterized in that, The device includes at least: - A container, the container containing at least one non-homogeneous mixture; - A conduit installed inside the container; and - A dispensing mechanism capable of drawing a non-homogeneous mixture from a container, converting the non-homogeneous mixture into a fluid composition, and dispensing the fluid composition in the form of a spray. The non-homogeneous mixture comprises the capsule assembly according to claims 24 to 26, the capsule assembly being dispersed in a continuous phase.

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