Microcapsules encapsulating an oil core

Abstract

A method for producing capsules having a matrix shell encapsulating an oil core is disclosed, the method comprising the steps of: providing a nucleation emulsion of an aqueous dispersed phase in an oil phase in a first chamber, the aqueous dispersed phase comprising water and a dissolved gelation inducing agent, the emulsion further comprising a first surfactant; providing a second aqueous solution in a second chamber, the aqueous solution comprising water and a second surfactant; wherein the first chamber and the second chamber are fluidically connected by one or more channels, preferably by microchannels; directing the nucleation emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleation emulsion in the aqueous solution of step; mixing the formed dispersion with an aqueous shell forming solution, the aqueous shell forming solution comprising water and a water soluble matrix forming agent; wherein the gelation inducing agent and the matrix forming agent are configured such that they are capable of chemically reacting with each other to form a water insoluble matrix shell; allowing the gelation inducing agent and the matrix forming agent to react in the formed dispersion to form capsules of a water insoluble matrix shell encapsulating an oil core.

Description

Technical Field

[0001] The present invention relates to a method for producing capsules, particularly microcapsules, with shells containing encapsulated oil cores, as well as dispersions of microdroplets. Background Technology

[0002] Capsules, especially microcapsules with a particle size of less than 1 mm, have been widely used in pharmaceuticals, cosmetics, diagnostics, food, and materials science. These capsules can be produced from emulsions of monodisperse droplets in a continuous phase. Monodispersity increases stability, allows for precise control of volume in multiple chemical or biological reactions, and enables the creation of periodic structures. Microfluidics provides a sophisticated platform for the precise formation of monodisperse droplets. Monodisperse droplets can be solidified to produce microcapsules for encapsulating active ingredients such as pharmaceuticals, fragrances, flavorings, peptides, live substances (such as bacteria or bacteriophages), fertilizers, pesticides, and other active substances for health purposes.

[0003] For many applications, there is a desire to provide capsules with an oil core encapsulated in a suitable shell. This is primarily due to the fact that many target compounds (e.g., flavorings, fragrances, active pharmaceutical ingredients, vitamins, etc.) are hydrophobic and / or readily soluble only in the oil phase rather than in water. This makes the oil core an excellent carrier for such target compounds. Furthermore, several oils enhance the mechanism of action of these compounds. For example, some compounds (such as vitamins) are absorbed by the body in sufficient quantities only in the presence of oil.

[0004] In addition to maintaining the structural integrity of the capsule, the shell encapsulating the core of such capsules can also possess certain adjustable properties. For example, it may be desirable to prevent the shell from breaking down upon contact with saliva, and instead allow it to break down only in the stomach to release the target compound (if interest). Alternatively, it is conceivable that certain target compounds (especially active pharmaceutical ingredients) are released only in the intestines, and not in the mouth or stomach. Furthermore, in some cases, it may be desirable to provide capsules with mucosal adhesion properties to better control the release of the target compound. Summary of the Invention

[0005] To date, known methods for producing capsules from monodisperse droplets have exhibited significant limitations. These methods are plagued by severely limited overall operational capability and / or poor reproducibility and dimensional control. However, controlling capsule size is crucial for a wide range of applications, particularly in the pharmaceutical, flavoring, and taste-enhancing industries. Furthermore, accurate control of the shell thickness is also important, as it directly affects the release characteristics of the target compound encapsulated in the oil core. Therefore, not only is controlling the overall shell thickness important, but ensuring a uniform distribution of shell thickness across the capsule is also essential.

[0006] Therefore, the general objective is to improve the existing technology for producing capsules, particularly microcapsules, with an oil core and a shell encapsulating the oil core, and preferably to completely or partially overcome the disadvantages of the prior art. In an advantageous embodiment, a method for producing such capsules is provided, which allows for precise control of capsule size and size distribution. In a further advantageous embodiment, a method for producing such capsules is provided, which allows for control of shell thickness.

[0007] In a first aspect, a general objective is achieved by a method for producing a capsule having a matrix shell encapsulating an oil core, the method comprising the following steps:

[0008] a. A nucleating emulsion of an aqueous dispersion phase in an oil phase is provided in a first chamber, the aqueous dispersion phase comprising water and a gelation inducing agent, the emulsion further comprising a first surfactant;

[0009] b. A second aqueous solution is provided in the second chamber, the aqueous solution comprising water and a second surfactant.

[0010] The first chamber and the second chamber are fluidly connected via one or more channels, preferably via microchannels. The method further includes the following steps:

[0011] c. The nucleating emulsion from step a. is guided from the first chamber through one or more channels into the second chamber to form a dispersion of the nucleating emulsion from step a. in the second aqueous solution of step b.

[0012] d. Mix the dispersion formed in step c. with an aqueous shell-forming solution, the aqueous shell-forming solution comprising water and a water-soluble matrix forming agent.

[0013] The gelling inducer and the matrix forming agent are configured such that they can chemically react with each other to form a water-insoluble matrix shell. The method further includes the following steps:

[0014] e. React the gelation inducer and the matrix forming agent in the dispersion formed in step c. to form a capsule encapsulating an oil core in a water-insoluble matrix shell.

[0015] It should be understood that steps a and b do not necessarily have to be performed in this order. Step b can be performed first, followed by step a, or they can be performed simultaneously.

[0016] It should be understood that the dispersion formed in step c. comprises a plurality of monodisperse droplets, which are contained in the nucleating emulsion of step a. within a second aqueous solution that is a continuous phase.

[0017] It should also be understood that the oil core formed by encapsulation of a water-insoluble matrix shell may contain a small amount of residual aqueous dispersed phase, i.e., a small amount of water. However, the majority of the core consists of the oil phase. Typically, this is greater than 60 wt%, particularly greater than 70 wt%, particularly greater than 80 wt%, particularly greater than 90 wt%, particularly greater than 95 wt%, and particularly greater than 99 wt%.

[0018] Furthermore, the nucleating emulsion is not an emulsion of the nucleus itself that forms the final capsule, but rather a delivery agent that reacts and / or diffuses from the nucleus. Therefore, the nucleating emulsion in step a. need not be exactly the same, especially in terms of its composition, it need not be exactly the same as the oil core of the final product.

[0019] An advantage of the method according to the invention is that step c. produces a micro-dispersion of the emulsion in water. Therefore, in step c., each droplet produced primarily contains the oil phase of step a., and also contains an aqueous dispersion phase containing the gelation inducing agent of step a. Thus, the dispersion formed in step c is a water-in-oil-in-water dispersion. Using stepwise emulsification, i.e., guiding the nucleating emulsion of step a. through microchannels, allows for precise control of size and ensures a uniform size distribution of the dispersion formed in step c. Furthermore, the method allows for capsule production much faster than methods known in the prior art. The method disclosed herein allows for capsule production at 100 g / h or more, or even up to 500 g / h. The formed droplets are stabilized by a second surfactant, and therefore their size remains substantially constant when the dispersion is mixed with the aqueous shell-forming solution that induces the formation of a water-insoluble matrix in step d. Thus, the matrix grows around a stable nucleus through a chemical reaction between the gelation inducing agent present in each droplet and the matrix-forming agent present in the aqueous shell-forming solution.

[0020] In some embodiments, the gelling inducer is dissolved in the water of the aqueous dispersion phase in step a. The advantage of dissolving the gelling inducer is that it avoids clogging of the channels. In particular, carbonates can cause insoluble salts to accumulate within the channels.

[0021] The nucleating emulsion provided in step a. can be stable for 60 to 600 minutes, preferably 100 to 500 minutes. This stability ensures that the droplets are not directly destroyed, especially during step c. However, the droplet stability is not too high, otherwise it would reduce the efficiency of shell formation (i.e., step e).

[0022] The matrix forming agent in step d is typically dissolved in an aqueous shell-forming solution.

[0023] The gelation inducer and the matrix forming agent are configured such that they can chemically react with each other to form a water-insoluble matrix shell. These can be configured, for example, to undergo complexation reactions, ion exchange reactions, or interphase-limited polymerization reactions.

[0024] As used herein, the term "microcapsule" generally refers to a capsule having a particle size of less than 4 mm, preferably between 1 μm and < 4 mm, and more preferably between 1 μm and < 1 mm. Meanwhile, microdroplets have a droplet size (i.e., diameter) of less than 4 mm, preferably between 1 μm and < 4 mm, and more preferably between 1 μm and < 1 mm, and microchannels typically have a diameter of less than 4 mm, preferably between 1 μm and < 4 mm, and more preferably between 1 μm and < 1 mm.

[0025] Apart from one or more channels connecting the first chamber and the second chamber, the first and second chambers are typically separate from each other. As used herein, the chambers are configured to be filled with a solution. Typically, the chambers are closed except for an inlet, channel, and outlet.

[0026] The first chamber typically has a first fluid inlet for introducing (particularly continuously) the nucleating emulsion from step a. into the first chamber, and the second chamber has a second inlet for introducing (particularly continuously) the second aqueous solution into the second chamber in step b. The second chamber also has a dispersion outlet for removing (preferably continuously) the dispersion formed during step c. from the second chamber.

[0027] It should be understood that each of the one or more channels includes an inlet leading to the first chamber and an outlet leading to the second chamber. Therefore, the one or more channels are directly connected to the first and second chambers. Typically, the first and second chambers are fluidly connected by a plurality of channels (i.e., 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 connected by 1 to 10,000,000, preferably 20 to 500,000 channels. Typically, the channels are arranged substantially parallel to each other.

[0028] For example, the one or more channels may have a diameter in the range of 0.25 to 2000 μm, preferably 2 to 800 μm. Multiple channels in the membrane are typically microchannels. For example, each channel may have a diameter of 0.04 μm. 2 Up to 4,000,000 μm 2 4μm is preferred 2 Up to 640,000 μm 2 The cross-sectional area.

[0029] In other embodiments, the aspect ratio (defined as channel length / minimum diameter) of each channel is 5 to 1000, particularly 10 to 500, and even more particularly 10 to 50. In some embodiments, the channel length can be in the range of 0.05 mm to 20 mm, particularly between 0.1 mm and 20 mm, particularly between 0.1 mm and 5 mm, and particularly between 0.5 mm and 20 mm.

[0030] In some embodiments, each channel 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., in the flow direction, the channel outlet has a typical length of several micrometers, for example, 200 μm to 20 mm, preferably 500 μm to 5 mm. The channel outlet can be, for example, funnel-shaped, V-shaped, or U-shaped. In some embodiments, the channel outlet can have an elliptical profile. In particular, the channel outlet is not rotationally symmetric and therefore has an aspect ratio of 3 or higher. Therefore, the channel outlet may not have a circular or square cross-section. This channel outlet allows droplets to separate without external forces. As a result, droplet formation of the nucleating emulsion in the second aqueous solution is decoupled and therefore substantially independent of flow rate. According to Young's Laplace equation, the pressure at the immiscible fluid interface is higher at the channel outlet than in the second reservoir. Therefore, a pressure gradient is generated along the flow direction, which promotes the separation of the fluid lines into individual droplets. Thus, a pressure gradient is generated at the end of the channel, which facilitates the separation of the fluid boundary layer and thus contributes to the formation of individual droplets. Upon reaching the channel outlet, the droplets separate without external force due to the pressure gradient of the dispersed phase inside and outside the channel. This type of nozzle is advantageous because it decouples the flow rate from the emulsification process.

[0031] Typically, each channel is defined by a channel wall. The channel wall may be curved, meaning it may be convex or concave towards the channel outlet. Furthermore, each channel may include a constriction section with a cross-section smaller than the cross-section of the remainder of the channel, and the constriction section is arranged adjacent to the channel outlet. Therefore, the constriction section is arranged between the channel outlet and the remainder of the channel.

[0032] In another embodiment, the cross-sectional area of ​​each channel outlet is 0.12 to 36,000,000 μm. 2 Preferably 12 to 5,760,000 μm 2 In particular, the total opening area on the second side of the membrane can be 300% to 1500% larger than the total opening area of ​​the channel at any other given location (such as the main segment and / or the channel inlet), preferably 400% to 900%.

[0033] In some embodiments, the one or more channels may be included in a membrane separating a first chamber and a second chamber. In such embodiments, the membrane may be flat, for example, disc-shaped. The membrane typically has a first side facing the first chamber and a second side opposite the first side and facing the second chamber. Thus, the first side of the membrane may partially limit the first chamber, and the second side of the membrane may partially limit the second chamber. The one or more channels (typically multiple channels) extend from the first side through the membrane to the second side. Each channel includes a channel inlet disposed on the first side, a channel outlet disposed on the second side, and a main segment disposed between the channel inlet and the channel outlet, wherein the channel outlet includes a shape that deviates from the shape of the main segment.

[0034] The membrane can typically be a monolayer membrane. That is, the membrane is made from a single piece. Preferably, such a membrane is made of a bulk material and does not include any phase interfaces or transition regions other than the multiple channels of the membrane. Such a membrane is advantageous for the quality of the resulting droplets because any phase interfaces and transitions are detrimental to droplet formation and droplet stability.

[0035] In some embodiments, the membrane may be replaceable. The multiple channels of the membrane are typically microchannels. For example, each channel may have a diameter of 0.04 μm. 2 Up to 4,000,000 μm 2 4μm is preferred 2 Up to 640,000 μm 2 The cross-sectional area.

[0036] In another embodiment, the channel outlet may be wedge-shaped. In particular, the channel outlet may include an elliptical cross-section with respect to a cross-sectional plane perpendicular to the extending channel, i.e., the channel outlet may be larger in a first direction than in a second direction.

[0037] In another embodiment, the second side of the membrane has a larger total opening area than the first side. The advantage of this membrane is that it can produce high-quality droplets even at flow rates up to 5 L / h. In some embodiments, the flow rate per channel can be between 1 μL / h and 50 ml / h, preferably between 10 μL / h and 5 ml / h.

[0038] In some embodiments, each channel outlet may have an elliptical profile. Therefore, the channel outlet may have an elliptical cross-section with respect to a plane that crosses the extended channel and is parallel to a first or second side of the membrane. Channel outlets with elliptical profiles have a beneficial effect on the quality of the formed droplets, as any edges within the channel can lead to unstable and non-uniform droplets.

[0039] In some embodiments, the membrane is disc-shaped. Such a membrane may have a circular profile. Alternatively, the membrane may have an angular profile, particularly a triangular or rectangular profile.

[0040] In another embodiment, the membrane contains 0.06 to 600,000 channels / cm². 2 Preferred channel density: 20 to 30,000 channels / cm 2 .

[0041] In some embodiments, the membrane is made of glass or polymeric materials (such as poly(methyl methacrylate) or PTFE), or of metallic materials (such as steel).

[0042] In some embodiments, the oil phase in step a. further comprises at least one target compound. The target compound may be selected from proteins, small molecules, particularly flavorings or tasters, active pharmaceutical ingredients such as cannabinoids, cannabis extracts, caffeine, melatonin, or hyaluronic acid; antibodies, peptides, enzymes, RNA, DNA, vitamins, and microorganisms. For example, the target compound may be mixed into the oil phase at a suitable concentration.

[0043] In some embodiments, step a. includes dissolving the gelation inducing agent in water to form a solution, and mixing the formed solution with an oil phase and a first surfactant. In these embodiments, the at least one target compound may have already been mixed into the oil phase, or it may be added only after the solution of the gelation inducing agent in water has been mixed with the oil phase. In some embodiments, mixing the solution of the gelation inducing agent in water with the oil phase and the first surfactant includes stirring with a stirrer at at least 8,000 rpm, preferably between 10,000 rpm and 20,000 rpm, for example, between 13,000 rpm and 15,000 rpm.

[0044] In specific embodiments, particularly in nucleating emulsions in an oil phase or an aqueous dispersion phase, the at least one target compound is a living organism, particularly a microorganism, such as bacteria, viruses, including bacteriophages, or single cells. In some embodiments, a dormant living organism may be provided to the nucleating emulsion, particularly in an oil phase or an aqueous dispersion phase. It should be understood that the dormant state of the living organism refers to an inactive state.

[0045] The method according to the invention is particularly suitable for encapsulating living organisms because, compared to prior art methods, it applies only edge shear forces. Furthermore, the encapsulation efficiency is significantly higher than that of methods known in the prior art. Encapsulation efficiencies of up to 90% or even up to 95% can be achieved relative to living organisms.

[0046] In some implementations, the method is carried out at room temperature, which is highly beneficial for encapsulating living organisms because of the increased vitality.

[0047] Furthermore, by guiding the nucleating emulsion through one or more channels, the channel size (specifically the channel diameter) determines the amount of living organisms in each droplet, and thus the amount of organisms in each formed capsule. Therefore, by selecting a predetermined channel size, the amount of organisms loaded in each capsule can be precisely controlled.

[0048] In some embodiments where at least one target compound is a living organism (such as cells or bacteria), the living organism is provided by culture and then added to a nucleating emulsion, particularly in an oil phase or an aqueous dispersion phase. For example, the culture can be carried out on a suitable nutrient medium (such as agar). In some embodiments, the viability of the living organism is monitored during culture, and when the viability reaches its maximum, the living organism is freeze-dried and subsequently added to a nucleating emulsion, particularly in an oil phase or an aqueous dispersion phase.

[0049] In some embodiments, it is advantageous to deoxygenate the nucleating emulsion or its components (such as the oil phase or aqueous dispersion) and / or a second aqueous solution. Deoxygenation can be achieved by common laboratory techniques, such as degassing with an inert gas (such as argon or nitrogen), or by a freeze-pump-thaw technique. This deoxygenation is advantageous because it preserves the living organism in its dormant state.

[0050] In some implementations, particularly nucleating emulsions in the oil phase or in the aqueous dispersion phase, the emulsions additionally contain nutrient components for live microorganisms, such as sugars, electrolyte solutions, etc.

[0051] In some embodiments, particularly nucleating emulsions in the oil phase or in the aqueous dispersion phase, a buffer solution is additionally contained in a buffer solution configured to maintain a pH suitable for the respective living organism.

[0052] In some embodiments, the dispersion formed in step c. is delivered to a gelling vessel containing the aqueous shell-forming solution from step d after step c. Therefore, the second chamber may include an outlet fluidly connected to the gelling vessel. Specifically, the dispersion formed in step c. is continuously delivered from the second chamber to the gelling vessel. Alternatively, the dispersion formed in step c. is continuously delivered from the second chamber to an intermediate storage vessel, where it can be stored and a predetermined amount of dispersion can be collected before being delivered to the gelling vessel. It should be understood that in these embodiments, the outlet of the second chamber may be fluidly connected to the intermediate storage vessel. The intermediate storage vessel may be fluidly connected to the gelling vessel.

[0053] It should be understood that in embodiments with gelling vessels, the gelling vessel typically contains the aqueous shell-forming solution of step d. prior to delivering the dispersion formed in step c. to the gelling vessel.

[0054] In a particular embodiment, the nucleating emulsion from step a. in step b., in the delivery dispersion and aqueous shell-forming solution in the second aqueous solution, is stirred in a gelling vessel using a stirrer, preferably a mechanical stirrer. During step e., stirring can preferably be carried out at 50 rpm to 150 rpm, more preferably 100 rpm to 120 rpm. This stirring speed has been found to be optimal because it avoids agglomeration of the formed capsules and further ensures a uniform size distribution of the capsules, while being low enough that the growing capsules or the resulting capsules are not destroyed.

[0055] In some implementations, the oil phase may contain or consist of medium-chain triglycerides (MCT), menthol, sunflower oil, etc.

[0056] In some embodiments, the first surfactant is a nonionic surfactant, such as polyglycerol polyricinoleate (PGPR) or a spanish derivative, such as spanish 80 or spanish 85, or a combination thereof. Alternatively, the first surfactant may be solid particles, preferably hydrophobic-hydrophilic or Janus-type particles, configured to provide a pickingling emulsion, depending on the application. For example, the solid particles may be colloidal silica.

[0057] Preferably, the first surfactant (especially a nonionic surfactant) has a molecular weight between 600 g / mol and 120,000 g / mol, more preferably between 800 g / mol and 80,000 g / mol.

[0058] Nonionic surfactants have been found suitable for providing sufficient stability to droplets of the aqueous dispersed phase in nucleating emulsions. PGPR has been found advantageous because it adequately stabilizes the nucleating emulsion, preventing the microdispersed droplets of the aqueous dispersed phase from being immediately disrupted, particularly during the guiding of the emulsion through channels, without overstabilizing the droplets, as this reduces the diffusion process of the gelation inducer to the droplet interface in step e, thus hindering its efficient reaction with the matrix forming agent. Stability is important, as droplets are exposed to significant shear forces during step c, which could potentially disrupt the aqueous dispersed phase in the nucleating emulsion.

[0059] In some embodiments, the amount of the first surfactant in the nucleating emulsion is between 0.01 wt% and 0.80 wt%, preferably between 0.05 wt% and 0.12 wt%.

[0060] In some embodiments, the amount of the second surfactant in the second aqueous solution is between 0.5 wt% and 5 wt%, particularly between 1 wt% and 2 wt%.

[0061] In some embodiments, the second surfactant has a molecular weight between 600 g / mol and 120,000 g / mol, preferably between 800 g / mol and 80,000 g / mol.

[0062] Typically, the first surfactant is different from the second surfactant, and therefore they are not identical.

[0063] In some embodiments, the second surfactant is selected from polyvinyl alcohol (PVA); polysorbate, such as Tween 20 or Tween 80; saponins; aglycones, i.e., soap tree extracts; gum arabic; β-lactoglobulin; sodium lauryl sulfate; soybean lecithin; sodium caseinate; potato protein isolate (e.g., Solanic 300); ); whey protein isolate; octenyl succinate starch ester; or combinations thereof. Preferably selected from polyvinyl alcohol, polysorbate esters such as Tween 20 or Tween 80, β-lactoglobulin, and octenyl succinate starch ester. Compared to other second surfactants, polyvinyl alcohol, polysorbate esters such as Tween 20 or Tween 80, β-lactoglobulin, and octenyl succinate starch ester have yielded relatively thick and stable shells. Polyvinyl alcohol further provides excellent monodispersity of nucleating emulsion droplets in a second aqueous solution. Furthermore, the second surfactant can be solid particles, preferably hydrophobic-hydrophilic or Janus-type particles, configured to provide a Pickering emulsion, depending on the application. For example, the solid particles can be colloidal silica. If PVA should be avoided, gum arabic, Tween 20, potato protein, pectin, or mixtures thereof can be used as the second surfactant as PVA substitutes. Particularly suitable examples include the use of 1wt%-5wt%, especially 2wt% to 4wt% of gum arabic (e.g., Agri-Spray Acacia RE). ) and 0.25 wt% to 4 wt%, particularly 1 wt% to 2 wt% of Tween 20 as a second surfactant in the second aqueous solution; or 0.5 wt% to 5 wt%, particularly 1 wt% to 3 wt% of potato protein isolate (e.g., Solanic 300, ) as a second surfactant in the second aqueous solution; or use 0.5 wt% to 5 wt%, particularly 0.5 wt% to 2 wt% of pectin (e.g., beet pectin: Swiss Beta Pectin, Schweizer Zucker). The second aqueous solution contains 0.25 wt% to 4 wt%, particularly 1 wt% to 2 wt% of Tween 20 as a second surfactant. When using these examples as the second surfactant, a size distribution with a coefficient of variation of less than 10% can be readily achieved. In some embodiments where potato protein isolate is used as the second surfactant, the pH of the second aqueous solution is adjusted to pH 9-11, preferably to pH 10.

[0064] In some embodiments, the matrix forming agent is a polysaccharide or a suitable salt thereof. A suitable salt is a salt form that is completely soluble in water. Typically, the polysaccharide salt consists of an anionic polysaccharide component and a suitable countercation. Suitable polysaccharides are selected from chitosan, cellulose, alginate (especially sodium alginate), carrageenan, agar, agarose, pectin, gellan gum, starch, etc. Preferred polysaccharides are alginate (preferably sodium alginate), chitosan, carrageenan, and cellulose, more preferably alginate (preferably sodium alginate) and chitosan. In some embodiments, the polysaccharide can be dissolved by adjusting the pH, for example, by alkalizing the pH of the aqueous shell-forming solution.

[0065] In some embodiments, the matrix forming agent and gelation inducing agent are selected such that the formed water-insoluble matrix ruptures and / or melts at a temperature of at least 80°C, particularly at least 90°C. Such embodiments have the advantage of releasing the target compound within the capsule at a specific predetermined temperature. This is particularly important, for example, for capsules used as food additives. Such capsules may be completely odorless when intact, but they rupture when cooked, so that the target odor is released only during cooking. In some embodiments, the gelation inducing agent may be an alkaline earth metal salt, particularly a calcium salt such as CaCl2, or an alkali metal salt such as KCl, and the matrix forming agent may be carrageenan, or a mixture of carrageenan and sodium alginate, preferably in a ratio of 2:1 to 1:2. Alternatively, in such embodiments, agar, optionally combined with sodium alginate, may be used as the matrix forming agent. Preferably, 0.25 wt% to 2 wt%, particularly 0.5 wt% to 1.5 wt%, of carrageenan is used in the aqueous shell-forming solution. For example, if 1.5 wt% carrageenan in water is used as an aqueous shell-forming solution in step d., a capsule is formed that begins to melt at 80°C. On the other hand, if 0.75 wt% carrageenan and 0.5 wt% sodium alginate in water are used as an aqueous shell-forming solution in step d., a capsule is formed that is more stable and breaks open at about 80°C, but has not yet completely melted.

[0066] Alternatively, the matrix forming 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.

[0067] As an alternative, the matrix forming agent can be a monomer that is soluble in the aqueous phase but insoluble in the oil. This monomer must be selected so that it can undergo stepwise growth polymerization, such as a diamine. In this case, the gelation inducing agent is a monomer soluble in the oil phase but insoluble in water, such as a diacyl chloride, thereby enabling interfacial polymerization during step e to form a water-insoluble matrix.

[0068] In some embodiments, the amount of matrix forming agent in the aqueous shell-forming solution is between 0.1 wt% and 2 wt%, preferably between 0.5 wt% and 1.0 wt%.

[0069] In some embodiments, prior to step d., a third surfactant (e.g., polysorbate, such as Tween 20) may be present in or added to the aqueous shell-forming solution. This third surfactant has been found to improve the gelation reaction.

[0070] In some embodiments, the gelation inducing agent is an inorganic salt, particularly an alkaline earth metal salt, especially an alkaline earth metal halide, alkaline earth metal pseudohalide, alkaline earth metal carboxylate, or alkaline earth metal nitrate, or an alkali metal halide, alkali metal pseudohalide, alkali metal carboxylate, or alkali metal nitrate. In some embodiments outlined above where 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., ionotropic gelation. Therefore, the inorganic salt (and conversely, the matrix forming agent) is chosen such that its reaction with the matrix forming agent produces a water-insoluble reaction product. Particularly suitable salts (especially for polysaccharides) can therefore be K, Mg, Sr, or Ca salts. Those skilled in the art understand that the term "pseudohalide" (also known as "pseudohalogenide") refers to a polyatomic analog of a halogen that has chemical properties similar to a true halogen. Non-limiting examples include cyanides, isocyanates, cyanate esters, isocyanates, methanesulfonyl groups, and trifluoromethanesulfonyl groups. Non-limiting examples of carboxylates are acetates, formates, lactates, oxalates, butyrates, succinates, etc. Gelation inducing agents are typically selected such that they are completely soluble in water at room temperature, i.e., a solubility in water >10 g / 100 mL, preferably >20 / 100 mL, and particularly >50 g / 100 mL. Suitable non-limiting examples of gelation inducing agents are: CaCl2, CaF2, calcium lactate, MgCl2, and Sr(OAc)2.

[0071] Inorganic salts are typically water-soluble. However, it is also conceivable to use powdered water-insoluble salts as gelation inducers. For example, CaCO3 or MgCO3 could be used, especially in powder form.

[0072] In some embodiments, the gelation inducing agent is a composition of: a photoacid generator, i.e., a compound configured to produce acid upon irradiation (preferably UV irradiation), such as diphenyliodonium nitrate, and a chelate of an inorganic salt (particularly an alkaline earth metal salt or an alkali metal salt). The chelate may be, for example, a carboxylic acid chelate. A suitable example is a chelate of strontium and ethylene glycol tetraacetic acid. Upon irradiation with UV light (which may be carried out in step e.), the photoacid generator produces acid and then releases strontium ions, which subsequently react with a matrix-forming agent, such as sodium alginate, to form a water-insoluble matrix shell.

[0073] In some implementations, the gelation inducer is a CO2 or CO2 generator. A CO2 generator can release CO2 under certain conditions. For example, bicarbonates can release CO2 in the presence of an acid.

[0074] In some embodiments, the gelation inducing agent may be a Brønsted acid, such as an inorganic acid or a carboxylic acid. In this case, the matrix forming agent may be a combination of a polysaccharide (such as alginate, chitosan, etc.) and a suitable water-soluble alkali metal complex or alkaline earth metal complex (such as Ca-Na2-EDTA, Mg-Na2-EDTA, Sr-Na2-EDTA, etc.).

[0075] In some embodiments, the amount of gelation inducing agent in the nucleating emulsion is between 1.5 wt% and 7.0 wt%, preferably between 2.0 wt% and 5.0 wt%.

[0076] In some embodiments, an alcohol (particularly methanol, ethanol, or propanol) is added to the aqueous shell-forming solution prior to step d. Alcohols have been found to enhance the diffusion of the gelation inducing agent to the microdroplet interface. The alcohol is typically present in an amount of 10 wt% to 30 wt% of the aqueous shell-forming solution. It has been observed that when the amount of alcohol is between 10 wt% and 20 wt%, preferably 13 wt% to 17 wt%, the core size (i.e., core diameter) of the capsule is larger than if more ethanol is used. For example, microcapsule diameters greater than 300 μm can be achieved. If the amount of alcohol is between 20 wt% and 30 wt%, preferably 23 wt% to 27 wt%, (all other things being equal), the core size (i.e., core diameter) of the capsule is smaller. For example, microcapsule diameters less than 300 μm can be achieved.

[0077] In some embodiments, prior to step d, a permeation regulator is added to the aqueous shell-forming solution. The permeation regulator is configured to enhance the diffusion of the gelation inducer to the microdroplet interface, thereby increasing shell thickness and capsule stability. The permeation regulator can be an alcohol as described above, or a sugar, such as a monosaccharide or disaccharide, i.e., glucose or fructose. This sugar derivative can be used alone or in combination with an alcohol as described above.

[0078] In some embodiments, prior to step d, a structural stabilizer may be added to or present in the aqueous shell-forming solution. A structural stabilizer is a compound configured to enhance the structural stability of the shell. Examples include agarose, as well as xanthan gum or cellulose and its derivatives, such as methylcellulose or microcrystalline cellulose. These may typically be present in the shell-forming solution and then incorporated into the growing shell during step e.

[0079] In some embodiments, the aqueous shell-forming solution of step d. contains, in addition to the matrix forming agent, another biopolymer as a structural stabilizer, such as pectin (e.g. (Pectin-based LM-104AS-FG). Preferably, the additional biopolymer can also form a matrix shell.

[0080] In some embodiments, the additional biopolymer may be solid biopolymer particles, such as starch. Providing such additional biopolymer, and particularly solid biopolymer particles, increases the mechanical strength of the resulting capsule.

[0081] In some embodiments, the concentration of the additional biopolymer, and particularly the solid biopolymer particles in the aqueous shell-forming solution, is 1 wt% to 10 wt%, particularly 3 wt% to 7 wt%. Particularly suitable solid particles are starch particles, such as corn starch particles.

[0082] In some embodiments, the particle size of the solid particles is equal to or less than 20 μm, particularly equal to or less than 15 μm.

[0083] In some embodiments, the ratio of the oil core diameter of the resulting microcapsules to the particle size of the solid biopolymer particles is between 10:1 and 100:1, preferably between 20:1 and 60:1.

[0084] In some embodiments, step e. is performed at temperatures above room temperature, particularly between 25°C and 95°C, particularly between 40°C and 85°C, particularly between 50°C and 80°C, particularly between 65°C and 80°C, and particularly between 70°C and 80°C. Alternatively or additionally, after step e., the formed capsules are exposed to temperatures above room temperature, particularly between 25°C and 95°C, particularly between 40°C and 85°C, particularly between 50°C and 80°C, particularly between 65°C and 80°C, and particularly between 70°C and 80°C. For example, exposure to such temperatures can be carried out for 5 to 60 minutes, particularly 15 to 30 minutes. It has been found that increasing the temperature during or after step e. has a significant effect on the mechanical strength of the particles. Without being bound by theory, it is assumed that biopolymers (e.g., like solid starch granules) form a wider network after gelation at high temperatures, which confers higher mechanical strength to the capsules.

[0085] In some embodiments, the capsule may be exposed to a solution of another polysaccharide after step e. Typically, this polysaccharide may be different from the matrix forming agent of step d. Suitable polysaccharides are selected from chitosan, cellulose, alginate (especially sodium alginate), carrageenan, agar, agarose, pectin, gellan gum, starch, etc., with chitosan being preferred.

[0086] In another embodiment, particularly during step c., a pressure of 1.01 bar to 1.15 bar, preferably 1.03 bar to 1.07 bar, is applied to the first chamber, and / or particularly during step c., a pressure of 1.02 bar to 1.2 bar, preferably 1.05 bar to 1.1 bar, is applied to the second chamber. It should be understood that these pressure values ​​refer to absolute pressure, i.e., a pressure of 1.01 bar is a pressure constituting an overpressure relative to atmospheric pressure of 0.01 bar.

[0087] In some embodiments, the pressure applied to the first chamber is less than the pressure applied to the second chamber. It should be understood that the first pressure can be adjusted by the pressure at which the nucleating emulsion is supplied to the first chamber via the first fluid inlet of the first chamber, and / or the second pressure can be adjusted by the pressure at which the second aqueous solution of step b. is supplied to the second chamber via the second fluid inlet of the second chamber.

[0088] In some embodiments, the mixing in step d. is carried out using a stirrer at 10 rpm to 800 rpm, preferably 50 rpm to 700 rpm. Mixing during step d. is beneficial because it further prevents the aggregation of monodisperse droplets of the dispersion formed in step c. and / or the formation of capsules. Therefore, this further ensures a uniform size distribution of the capsules. Typically, a top-mounted stirrer can be used.

[0089] In some embodiments, prior to step d, the aqueous shell-forming solution is stirred with a stirrer at 500 rpm to 800 rpm, and during step d, the aqueous shell-forming solution is stirred at 50 rpm to 150 rpm, preferably 100 rpm to 120 rpm. Therefore, the aqueous shell-forming solution is stirred more vigorously to ensure its homogeneity before the dispersion formed in step c is mixed with it. During addition, the stirring speed is reduced so that the stirring speed is low enough that the growing capsules or the resulting capsules are not destroyed.

[0090] In some embodiments, step e. is carried out for 5 to 25 minutes, preferably 8 to 12 minutes, or 15 to 20 minutes. The reaction time of step e. (i.e., the time until the reaction is interrupted, for example, by separating or separating the capsule from the aqueous shell-forming solution) directly affects the particle size and core size of the capsule. For example, if step e. is carried out for 8 to 12 minutes, oil cores with an average diameter of less than 600 μm can be obtained, and if step e. is carried out for 15 to 20 minutes, oil cores with an average diameter of greater than 600 μm can be obtained. Those skilled in the art are familiar with several methods for determining particle size, such as sieving with sieves of different mesh sizes.

[0091] In some embodiments, the method further includes an encapsulation step after step e, which may in particular include dip coating. In some embodiments, the additional encapsulation step may include the following steps:

[0092] f. Immerse the capsule formed in step e. in a separate aqueous shell-forming solution, which is typically different from the shell-forming solution in step d. The separate shell-forming solution contains water, a pH-dependent matrix-forming agent, and optionally an inorganic salt, preferably an alkaline earth metal salt or an alkali metal salt;

[0093] g. Adjust the pH so that the matrix forming agent (i.e., the pH-dependent matrix forming agent of step f.) is converted into a water-insoluble matrix coating, preferably a complete coating, wherein the capsule has an additional shell. Thus, the resulting capsule may contain an oil core directly encapsulated by the matrix formed in step e., which is then encapsulated by a matrix of a different material, preferably formed in step g, thereby forming a multilayered capsule.

[0094] The matrix forming agent may be a polysaccharide. Typically, it may be a different polysaccharide than the matrix forming agent in step d. Suitable polysaccharides are selected from chitosan, cellulose, alginate (especially sodium alginate), carrageenan, agar, agarose, pectin, gellan gum, starch, etc. Preferred polysaccharides are alginate (preferably sodium alginate), chitosan, carrageenan, and cellulose, more preferably alginate (preferably sodium alginate) and chitosan. Preferably, the matrix forming agent in step d. may be sodium alginate, and the matrix forming agent in step f. may be chitosan or microcrystalline carboxymethyl cellulose.

[0095] Typically, pH adjustment involves acidification, i.e., lowering the pH. For example, the pH can be lowered from 7 or higher to 5 or lower, preferably to pH 4-5.

[0096] In some embodiments, the capsule is coated with two or more additional layers. Therefore, the dip-coating can be repeated with different matrix-forming agents. Specifically, steps f. and g. can be repeated at least once, using the same matrix-forming agent or different matrix-forming agents, such as different polysaccharides, or with pH-protective coatings, such as… or

[0097] In some embodiments, particularly after step e. or optionally after step g., the formed capsules are separated, solidified, and / or preserved. Separation of the capsules may, for example, include filtration or sieving to separate the capsules from the aqueous shell-forming solution, and optionally washing the capsules with water containing surfactants such as sodium lauryl sulfate (SDS), Tween derivatives such as Tween 20 or 80, or PVA. Solidification may, for example, include drying the capsules by airflow or by freeze-drying to evaporate all or at least most of the unbound water. Solidification may also include further stirring the capsules in an aqueous inorganic salt solution, such as a CaCl2 or MgCl2 solution, preferably 1 wt% to 10 wt%, more preferably 1 wt% to 5 wt%. This further increases the stability and structural integrity of the capsules (particularly the shell). Preservation can be achieved by immersing the capsules in distilled water or an aqueous inorganic salt solution, such as a CaCl2 or MgCl2 solution, preferably 1 wt% to 10 wt%, more preferably 1 wt% to 5 wt%. This preservation method has been found to increase the capsule's bench stability.

[0098] In some embodiments, particularly after step e. or optionally after step g., the capsule is exposed to a solution of the chelating agent in a solvent. The chelating agent is configured such that it can form a chelating complex with the gelation inducing agent. For example, if the chelation inducing agent is a calcium salt, such as CaCl2, then the chelating agent can react with Ca... 2+A chelating complex is formed. Suitable chelating agents are Lewis bases, such as EDTA, GLDA (N,N-bis(carboxymethyl)-L-glutamate tetrasodium salt), MGDA (trisodium dicarboxymethylalanine), citrate, tartrate, etc. The solvent is typically chosen such that the chelating agent is soluble therein, and the formed capsule, and correspondingly the water-insoluble matrix, is insoluble. Therefore, a suitable solvent can be water. By exposing the capsule to this solution for a predetermined duration, the capsule shell is weakened because the chelating agent forms a chelate with some gelation inducing agent, and correspondingly its derivatives. For example, if the gelation inducing agent is CaCl2 and the chelating inducing agent is sodium citrate, calcium citrate is formed, which weakens the shell of the formed capsule. The advantage is that the weakening of the shell can be precisely controlled, and thus the mechanical strength can be precisely controlled. For products in which the shell should break and disintegrate relatively quickly, such as in cosmetic products (e.g., skin creams), weakening may be desirable. As an example, 0.001 wt% to 0.4 wt%, particularly 0.01 wt% to 0.1 wt%, of sodium citrate and optionally NaCl (in an amount 0.6 times that of sodium citrate) can be dissolved in water. The capsules are stirred in this solution for 10 to 50 minutes, particularly 20 to 40 minutes. The addition of NaCl has the effect of causing a more uniform softening effect between the capsules and resulting in fewer capsule breakages.

[0099] In some embodiments, step c. is carried out using a device for generating a dispersion of the nucleating emulsion in a second aqueous solution, i.e., the device includes a first inlet for supplying the nucleating emulsion from step a., leading to a first chamber; a second inlet for supplying the second aqueous solution, leading to a second chamber; and a dispersion outlet for collecting the dispersion. Furthermore, the device includes a membrane, particularly the membrane described above, separating the first and second chambers, and including 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, i.e., providing fluid connection between the first and second chambers. Each channel includes a channel inlet disposed on the first side and a channel outlet disposed on the second side. The first chamber can typically be configured such that the flow rate of the nucleating emulsion through all individual channels is substantially equal. In the prior art, non-uniform pressure distribution (particularly non-uniform pressure distribution of the nucleating emulsion) results in only a small percentage of channels being able to actively generate droplets. However, the isobaric distribution on the first side allows the nucleating emulsion to flow stably into the second aqueous solution and allows for the production of droplets with reproducible quality at a high throughput of up to 5 liters per hour.

[0100] In some embodiments, the second chamber may be made of glass or a transparent polymer (such as PTFE, poly(meth)acrylate, or polyoxymethylene), or of a metal (such as steel, aluminum, or titanium). Typically, the device may include a container, such as a glass container, that partially forms the second chamber. The container may form the second chamber together with the membrane. In some embodiments, the first chamber may be made of a metal (e.g., aluminum or steel) or of a transparent polymer (such as PTFE, poly(meth)acrylate, or polyoxymethylene).

[0101] The dispersion outlet may be in fluid communication with, for example, a gelling vessel or an intermediate storage vessel.

[0102] In some embodiments, the first chamber is configured such that, in the operating state, the pressure along a first side of the membrane is substantially isobaric. For example, the first inlet may include a nozzle for providing an isobaric pressure distribution on the first side of the membrane. In particular, a spray nozzle may be used. Alternatively, the first chamber may be shaped to provide an isobaric pressure distribution on the first side of the membrane.

[0103] In another embodiment, the first chamber has a circular cross-section relative to a cross-sectional plane perpendicular to the membrane and rotationally symmetric about a central longitudinal axis. As used herein, the term "circular cross-section" refers to a continuous curve without increments, particularly a curve having a radius of at least 1 mm, especially at least 5 mm, and especially at least 10 mm in a cross-sectional plane perpendicular to the membrane. It should be understood that the curvature in the cross-sectional view can be described as part of a circle having said radius. Therefore, the sidewalls of the first chamber can converge continuously towards each other in the upstream direction. The central longitudinal axis is an axis extending in the longitudinal direction of the device, which is arranged at the center of the device and / or perpendicular to and intersects the center of the membrane. For example, the first chamber can have a U-shaped cross-section or can be a concave circle or a semicircle. The circular cross-section is typically edgeless and therefore does not include edges, which would result in uneven pressure distribution when the nucleating emulsion is forced through the membrane. Preferably, the first chamber can have a spherical dome shape. The shape of the first chamber can generally preferably be substantially rotationally symmetric about the central longitudinal axis.

[0104] In some embodiments, the dispersion outlet may be substantially arranged on the central longitudinal axis and / or on an axis perpendicular to the membrane and intersecting the center of the membrane. Preferably, the second chamber gradually narrows towards the dispersion outlet. For example, at least a portion of the second chamber may be arched or conical towards the dispersion outlet. These embodiments ensure that no droplets are trapped and all droplets can be collected directly via the dispersion outlet.

[0105] In some embodiments, the first chamber has a hemispherical or truncated cone shape. Typically, the hemisphere or truncated cone faces the membrane opening, i.e., the maximum radius is typically closest to the membrane. The term "hemispherical" as used herein also includes other spherical segments, such as one-third of a sphere. Thus, in some embodiments, the first chamber is shaped like a spherical dome or cap. Preferably, if the first chamber has a spherical dome shape, and / or particularly a hemispherical shape, the first inlet can be arranged adjacent to the pole of the spherical dome (particularly the hemispherical first chamber) of the first chamber or in the region of the pole of the spherical dome (particularly the hemispherical first chamber). An advantage of this shape is that the material flow of the nucleating emulsion is evenly distributed on the first side of the membrane, thereby contributing to isobaric distribution in adjacent individual channels. The first inlet can be arranged, for example, substantially perpendicular to the central longitudinal axis, i.e., substantially parallel to the first side of the membrane, or it can be parallel to the central longitudinal axis, i.e., perpendicular to the first side of the membrane.

[0106] In some embodiments, the first inlet is arranged at an angle of substantially 90° or less relative to the membrane channels. Typically, all channels are arranged substantially parallel to each other. This has the advantageous effect that the nucleating emulsion is not directly pressed onto the membrane, thereby further enabling a uniform pressure distribution across each channel of the membrane. For example, the angle between the first inlet and the membrane channels can be between 60° and 90°, particularly between 75° and 90°. Preferably, the first inlet is arranged substantially transversely (preferably perpendicularly) to the plurality of channels of the membrane. Thus, in such an embodiment, the first inlet can be parallel to a first side of the membrane.

[0107] In another embodiment, the device includes a membrane retainer for mounting the membrane.

[0108] In some embodiments, the device includes a container retainer for holding a container that partially forms a second chamber. The container retainer may be fixedly and releasably connected to the membrane retainer. The container retainer and / or the membrane retainer and / or the base may be made of any suitable material, such as plastic materials (e.g., PTFE, poly(meth)acrylate, or polyoxymethylene) or metal (preferably steel).

[0109] Preferably, if the container is a glass container, a damping liner can be placed between the glass container and the container holder to avoid damage to the glass container and to seal the glass container.

[0110] In some embodiments, the membrane retainer includes a clamping device for mounting the membrane, and the membrane retainer and / or clamping device are configured to accommodate membranes of various thicknesses. Typically, the clamping device can be adjustable. Examples of clamping devices include screws, clamps, bolts, locks, etc.

[0111] In some embodiments, the device includes a base, and preferably, the first chamber is partially formed by the base.

[0112] In another embodiment, the base and / or the membrane retainer includes at least one seal to seal the membrane against the base and / or the membrane retainer. A sealing ring may be configured such that it circumferentially and completely surrounds the periphery of the membrane. The sealing ring may also include a gas outlet in fluid communication with the first chamber and configured to discharge any gas present in the first chamber.

[0113] In some embodiments, the base and / or the membrane retainer includes a spacer ring. This spacer ring allows for the use of membranes of different thicknesses.

[0114] In some embodiments, the first chamber includes a gas outlet, particularly a fluid switch, such as a valve. The gas outlet and the membrane are arranged such that during the supply of the nucleating emulsion to the first chamber, particularly during the initial / initial filling of the first chamber with the nucleating emulsion, the gas within the first chamber is directed to the gas outlet and removed from the first chamber via the gas outlet. In some instances, the membrane is inclined relative to the central longitudinal axis of the device. Therefore, in a cross-sectional view along the central longitudinal axis, the angle between the central longitudinal axis and the first and / or second side of the membrane is different from 90°. For example, the acute angle between the second side of the membrane and the central longitudinal axis can be between 45° and 89°, preferably between 70° and 88°, more preferably between 78° and 87°. In such embodiments, the gas outlet can be located at the top edge of the first chamber, formed by the membrane and additional chamber walls. This ensures that any residual gas (particularly air) present in the first chamber prior to the use of the device rises to the membrane and is guided to the top edge due to the inclined arrangement of the membrane, and thus to the gas outlet. Typically, the membrane channels are too narrow for air to pass through, and therefore the gas outlet, as described in the above embodiments, allows for the removal of all remaining gas, which would otherwise adversely affect the uniformity of droplet size and distribution or impede the first fluid from reaching all microchannels, thus reducing flux. Typically, the gas outlet may be in fluid communication with the ambient environment of the device.

[0115] In some embodiments, the apparatus includes at least one heater to heat the nucleating emulsion and / or the second aqueous solution, and / or at least one cooler to cool the nucleating emulsion and / or the second aqueous solution. Heating or cooling either phase may be advantageous because the solidification of the resulting dispersed droplets can be readily affected by temperature changes, for example, by allowing the dispersion to cool. Typically, the at least one heater can provide sufficient thermal energy to heat the nucleating emulsion and / or the second aqueous solution to 100°C, 125°C, or 150°C. The heater may, for example, comprise a heating bath, such as a water bath or an oil bath. Alternatively, the heater may be an IR radiator, a heating coil, or any other suitable heater.

[0116] In another embodiment, the apparatus includes a first reservoir for the nucleating emulsion and / or a second reservoir for the second aqueous solution. Both the first and second reservoirs can be pressurized. For example, the reservoirs can be fluidly connected to a pressure source, such as a compressor. Alternatively, the reservoirs can be syringes and pressurized by a conventional syringe pump and / or a plunger or peristaltic pump, gear pump, or any other pumping system.

[0117] In some embodiments, a flow restrictor is arranged between the second reservoir and the second chamber for the second aqueous solution. This restrictor is advantageous because the second chamber typically does not provide significant flow resistance to the second aqueous solution. Therefore, by using the flow restrictor, the device is more stable because unintentional pressure differences, such as those caused by fluctuations in air pressure, can be avoided.

[0118] In another embodiment, the second inlet includes a supply channel that is at least partially circumferentially arranged around a central longitudinal axis, and correspondingly, at least partially circumferentially arranged around an axis perpendicular to the first and second sides of the membrane and intersecting the center of the membrane. The supply channel includes one or more openings leading to the second chamber. Being at least partially circumferentially arranged around the aforementioned axis means that the supply channel can have a partially circular profile, such as a semicircle or a third of a circle. Preferably, the supply channel is fully circumferentially arranged around the central longitudinal axis, and correspondingly, fully circumferentially arranged around an axis perpendicular to the membrane and intersecting the center of the membrane. In such an embodiment, the supply channel forms a ring-like structure. Preferably, the supply channel includes a plurality of openings leading to the second chamber, the openings being distributed substantially uniformly along the circumference of the supply channel. Typically, one or more openings of the supply channel can be arranged in the direction of the dispersion outlet, i.e., such that the openings face the dispersion outlet. An advantage of including a supply channel is that the second aqueous solution can be introduced into the second chamber uniformly and smoothly without causing harmful turbulence that adversely affects the uniform shape and size distribution of the generated droplets. In some embodiments, one or more openings of the supply channel are arranged such that eddies are generated when the second aqueous solution is supplied to the second chamber. Specifically, the one or more openings may be tubular, and the longitudinal axis of each tubular opening may be inclined relative to the central longitudinal axis of the device. Typically, all tubular openings are uniformly inclined. The generation of eddies is advantageous because, firstly, surface stabilizers, which can typically be included in the first and / or second aqueous solutions, can be distributed more uniformly, which will therefore enhance the stability of the formed dispersion; and secondly, because the resulting dispersion is transported toward the dispersion outlet, this is particularly advantageous if the densities of the first and second aqueous solutions are substantially equal.

[0119] Typically, the supply channel is arranged at the bottom of the second chamber, i.e., adjacent to the membrane. The supply channel may also be arranged circumferentially around the membrane, for example. The supply channel may have a diameter of 2 mm to 100 mm, preferably 5 mm to 20 mm.

[0120] Alternatively, the second inlet may be a single inlet that preferably leads directly from the lateral side of the second chamber to the second chamber.

[0121] In the second aspect, the general objective technical problem is solved by a component of capsules (especially microcapsules) comprising a plurality of capsules produced according to any of the embodiments described herein.

[0122] In some embodiments of the capsule assembly, the capsules have an iso-size distribution and a coefficient of variation of 10% or less, particularly 8% or less, particularly 6% or less, particularly 5% or less, particularly 4% or less.

[0123] Technicians understand that the coefficient of variation can be calculated as the ratio of the standard deviation σ to the mean μ (i.e., the average capsule size of the component's capsules).

[0124] In some embodiments, the capsule assembly comprises more than 50 capsules, particularly more than 100 capsules, particularly more than 500 capsules, particularly more than 1,000 capsules, and particularly more than 10,000 capsules, produced by the method according to any embodiment described herein.

[0125] In some embodiments, each capsule of the capsule assembly has a particle size of less than 4 mm, preferably between 1 μm and <4 mm, and more preferably between 1 μm and <1 mm.

[0126] In some embodiments, the capsules of the component (in particular, all capsules of the component) have a maximum difference of 1% relative to a perfect sphere. Specifically, the surface of the capsule has a maximum difference of 5% or even a maximum of 1% relative to a perfect sphere.

[0127] In some embodiments, the capsule of the component comprises a water-insoluble matrix that ruptures and / or melts at a temperature of at least 80°C, particularly at least 90°C, preferably between 80°C and 100°C, and more preferably between 70°C and 90°C. Such embodiments have the advantage that the target compound within the capsule is released at a specific predetermined temperature. This is particularly important, for example, for capsules used as food additives. Such capsules may be completely odorless when intact, but they rupture when cooked, so that the target odor is released only during cooking. In some embodiments, the water-insoluble matrix may consist of or contain calcium carrageenan, calcium alginate, potassium alginate, and / or potassium carrageenan.

[0128] In a third aspect, the general objective technical problem is solved by a dispersion of microdroplets. The dispersion comprises microdroplets of an aqueous continuous phase and a dispersed phase. Typically, the dispersion can be formed by steps a. to c. of the method according to any embodiment of the first aspect of the invention. Each microdroplet of the dispersed phase is a microemulsion of the aqueous dispersed phase in an oil phase. Thus, the majority of the material of each microdroplet is formed by the oil phase. Typically, the oil phase can constitute at least 50 wt%, or at least 60 wt%, or at least 70 wt% of the nucleating emulsion. The aqueous dispersed phase of each microdroplet comprises water and a dissolved gelation inducing agent. Furthermore, each microdroplet also contains a first surfactant. The aqueous dispersed phase can typically be the aqueous dispersed phase provided in step a. of the method according to any embodiment of the first aspect of the invention. The dispersion of the microdroplets also contains a second surfactant.

[0129] In some embodiments, the oil phase comprises at least one target compound. The target compound may be selected from proteins, small molecules, particularly flavorings or tasters, active pharmaceutical ingredients such as cannabinoids, cannabis extracts, caffeine, melatonin, or hyaluronic acid; antibodies, peptides, enzymes, RNA, DNA, vitamins, and microorganisms.

[0130] In some embodiments, the first surfactant is a nonionic surfactant, such as polyglycerol polyricinoleate (PGPR) or a spade derivative, such as spade 80 or spade 85, or a combination thereof. Alternatively, the first surfactant may be solid particles, preferably hydrophobic-hydrophilic or Janus-type particles, configured to provide a Pickering emulsion, depending on the application. For example, the solid particles may be colloidal silica.

[0131] Preferably, the first surfactant (especially a nonionic surfactant) has a molecular weight between 600 g / mol and 120,000 g / mol, more preferably between 800 g / mol and 80,000 g / mol.

[0132] Nonionic surfactants have been found to be suitable for providing sufficient stability to droplets of the aqueous dispersed phase in nucleating emulsions. PGPR has been found advantageous because it adequately stabilizes the nucleating emulsion, preventing the microdispersed droplets of the aqueous dispersed phase from being immediately disrupted, particularly during the guiding of the emulsion through channels, without over-stabilizing the droplets, as this reduces the diffusion process of the gelling inducer to the droplet interface in step e, thus hindering its efficient reaction with the matrix forming agent.

[0133] In some embodiments, the amount of the first surfactant in the nucleating emulsion is between 0.03 wt% and 0.15 wt%, preferably between 0.05 wt% and 0.10 wt%.

[0134] In some embodiments, the second surfactant has a molecular weight between 600 g / mol and 120,000 g / mol, preferably between 800 g / mol and 80,000 g / mol.

[0135] Typically, the first surfactant is different from the second surfactant, and therefore they are not identical.

[0136] In some embodiments, the second surfactant is selected from polyvinyl alcohol (PVA); polysorbate, such as Tween 20 or Tween 80; saponins; aglycones, i.e., soap tree extracts; gum arabic; β-lactoglobulin; sodium lauryl sulfate; soybean lecithin; potato protein (e.g., Solanic 300). Sodium caseinate; potato protein isolate; whey protein isolate; octenyl succinate starch ester; or combinations thereof. Preferably selected from polyvinyl alcohol, polysorbate esters such as Tween 20 or Tween 80, β-lactoglobulin, and octenyl succinate starch ester. Compared with other second surfactants, polyvinyl alcohol, polysorbate esters such as Tween 20 or Tween 80, β-lactoglobulin, and octenyl succinate starch ester have yielded relatively thick and stable shells. Polyvinyl alcohol further provides excellent monodispersity of nucleating emulsion droplets in the second aqueous solution. Furthermore, the second surfactant may be solid particles, preferably hydrophobic-hydrophilic or Janus-type particles, configured to provide a Pickering emulsion, depending on the application. For example, the solid particles may be colloidal silica.

[0137] In some embodiments, the gelation inducing agent is a reagent as disclosed with respect to the first aspect of the invention. Therefore, in some embodiments, the gelation inducing agent is an inorganic salt, particularly an alkaline earth metal salt, especially an alkaline earth metal halide, alkaline earth metal pseudohalide, alkaline earth metal carboxylate, or alkaline earth metal nitrate, as disclosed in the first aspect of the invention.

[0138] In a fourth aspect, the present invention includes an apparatus for producing capsules with a matrix shell encapsulating an oil core, the apparatus comprising:

[0139] a. A first inlet (2) for supplying a nucleating emulsion of an aqueous dispersion phase in an oil phase, the aqueous dispersion phase comprising water and a dissolved gelation inducer, the emulsion further comprising a first surfactant, the first inlet (2) leading to a first chamber (4);

[0140] b. A second inlet (3) for supplying a second aqueous solution, the aqueous solution comprising water and a second surfactant, the second inlet (3) leading to a second chamber (5);

[0141] c. A dispersion outlet (6) for collecting dispersions or droplets from the second chamber (5);

[0142] d. One or more channels (10), preferably microchannels, wherein the one or more channels (10) fluidly connect the first chamber (4) and the second chamber (5);

[0143] e. A gelling vessel (105), preferably fluidly connected to the dispersion outlet (6), the gelling vessel containing an aqueous shell-forming solution containing water and a water-soluble matrix forming agent.

[0144] It should be understood that the apparatus of the fourth aspect of the present invention may also include embodiments of the apparatus described with respect to the first aspect of the present invention, i.e., apparatus that can be used in the method according to the first aspect of the present invention.

[0145] In some embodiments, the apparatus may include a mixing vessel, preferably comprising a stirrer for mixing an aqueous dispersion of a nucleating emulsion in an oil phase, the aqueous dispersion comprising water and a dissolved gelation inducing agent, the emulsion further comprising a first surfactant. The mixing vessel may be fluidly connected to a first inlet leading to a first chamber of the apparatus. Preferably, the mixing vessel comprises at least an oil phase and optionally already contains an aqueous dispersion of a nucleating emulsion in the oil phase.

[0146] In a fifth aspect, the overall objective technical problem is solved by a capsule produced by any embodiment of the method of the first aspect of the invention.

[0147] In a sixth aspect, the general objective is achieved by a method for producing a capsule with a matrix shell encapsulating an oil core, the method comprising the following steps:

[0148] a. A nucleating emulsion of an aqueous dispersion phase in an oil phase is provided in a first chamber, the aqueous dispersion phase comprising water and a dissolved matrix forming agent, the emulsion further comprising a first surfactant;

[0149] b. A second aqueous solution is provided in the second chamber, the aqueous solution comprising water and a second surfactant.

[0150] The first chamber and the second chamber are fluidly connected via one or more channels, preferably via microchannels. The method further includes the following steps:

[0151] c. The nucleating emulsion from step a. is guided from the first chamber through one or more channels into the second chamber to form a dispersion of the nucleating emulsion from step a. in the second aqueous solution of step b.

[0152] d. Mix the dispersion formed in step c. with an aqueous shell-forming solution, the aqueous shell-forming solution comprising water and a water-soluble gelation inducer.

[0153] The gelling inducer and the matrix forming agent are configured such that they can chemically react with each other to form a water-insoluble matrix shell. The method further includes the following steps:

[0154] e. React the gelation inducer and the matrix forming agent in the dispersion formed in step c. to form a capsule encapsulating an oil core in a water-insoluble matrix shell.

[0155] It should be understood that the method according to the sixth aspect of the present invention may also include the embodiments described with respect to the first aspect of the present invention. Attached Figure Description

[0156] The invention described herein will be more fully understood from the detailed description and accompanying drawings given below, which should not be considered as limiting the invention as described in the appended claims. The drawings show:

[0157] Figure 1 A schematic diagram of the method according to the present invention;

[0158] Figure 2 A schematic diagram of an apparatus for generating a dispersion of a nucleating emulsion in a second aqueous solution according to a first embodiment of the present invention;

[0159] Figure 3 Figure 2 Cross-sectional view of the device shown;

[0160] Figure 4 Figure 2 An exploded partial cross-sectional view of the device shown;

[0161] Figure 5 A schematic diagram of device 1' according to another embodiment of the present invention;

[0162] Figure 6 A schematic enlarged view of the second side of the membrane according to an embodiment of the present invention;

[0163] Figure 7 A partial cross-section of the device according to another embodiment of the present invention;

[0164] Figure 8 A cross-section of the device according to another embodiment of the invention;

[0165] Figure 9 Another apparatus that can be used in the method according to an embodiment of the invention is shown;

[0166] Figure 10 shows a microscopic image of the capsule produced by the method according to the present invention;

[0167] Figure 11 The size distribution of the capsule assembly according to an embodiment of the present invention is shown;

[0168] Figure 12 A comparison of the mechanical properties of capsules in which solid starch granules have been added to an aqueous shell-forming solution and capsules without such granules is shown.

[0169] Figure 13 A comparison of the mechanical properties of capsules in which pectin has been added to an aqueous shell-forming solution and capsules without such addition is shown. Detailed Implementation

[0170] Figure 1The method according to an embodiment of the present invention is illustrated schematically. In a first step, a nucleating emulsion is generated by mixing a solution 101 containing a gelling inducer and water with an oil phase 102. Figure 1 a). This can be done, for example, with a mixer 103. Figure 1 a) A magnified view of the droplets of solution 101 in the emulsion is also shown. The straight lines of the droplets indicate that the droplets contain water and gelling inducers dissolved therein (e.g., inorganic salt A). + B – ).therefore, Figure 1 Each droplet shown in a) is an aqueous solution of a gelation inducing agent. The emulsion formed by the aqueous solution 101 of the gelation inducing agent in the oil phase 102 is then provided to the first chamber 4 of a suitable apparatus. Figure 1 (b) The second chamber 5 of the device contains a second aqueous solution 104 containing water and a first surfactant. As can be seen, 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 toward the second side 9. Typically, a suitable pressure is applied to the nucleating emulsion in the first chamber 4. The emulsion in the first chamber 4 is then guided through the channels 10. Since the emulsion typically contains an oil phase 102 as the main component, stepwise emulsification occurs when the emulsion reaches the channel outlet leading to the second chamber 5, thereby forming a dispersion of the nucleating emulsion, i.e., monodisperse droplets 103 in the second aqueous phase 104. It should be noted that the droplet size is exaggerated for clarity. Furthermore, the relative size of droplet 101 with respect to droplets 103 and / or 106 does not conform to reality. Each monodisperse droplet 103 in the second chamber 5 now contains one or more droplets 101 dispersed in the oil phase 102, as shown in the enlarged view of the droplets. Therefore, the dispersion in the second chamber 5 can be considered a “water-in-oil-in-water emulsion (W / O / W emulsion)”. This dispersion is then mixed with an aqueous shell-forming solution 108 containing water and a water-soluble and dissolved matrix-forming agent. The aqueous shell-forming solution 108 is contained in a gelling vessel 105 equipped with a stirrer 107. When the dispersion of the nucleating emulsion in the second aqueous phase 104 (i.e., monodisperse droplets 103) is mixed with the shell-forming aqueous solution 108, the gelling inducing agent within the droplets 103 diffuses to the droplet surface and then chemically reacts with the matrix-forming agent at the interface to form a water-insoluble matrix shell, which grows sufficiently around each droplet to form a capsule 106 encapsulating the oil core within the water-insoluble matrix shell.

[0171] Figure 2An apparatus 1 is depicted, which can be used in the method according to the invention, particularly for producing a dispersion of a nucleating emulsion in a second aqueous solution. Apparatus 1 includes a container 19 made of glass and a base 14 made of metal. The base 14 includes a first inlet (not shown, see [link to first chamber]) for supplying the nucleating emulsion to a first chamber. Figure 2 The first chamber may be partially formed by the base 14 and the membrane 7 (see...). Figure 3 The container 19 includes a second inlet 3 leading to a second chamber for supplying a second aqueous solution 104 and a dispersion outlet 6 for collecting a dispersion generated within the second chamber. The second chamber is formed by the container 19 and the membrane 7 (see [link to container 19]). Figure 3 The device 1 also includes a membrane holding structure 20 fixedly connected to the base 14. Furthermore, the device includes a container holding structure 21 fixedly connected to the membrane holding structure 20 via a clamping device 18. As a result, the container 19 is fixedly connected to the base 14.

[0172] Figure 3 It shows Figure 2 A cross-sectional view of device 1. Device 1 includes a base 14 having a first inlet 2 for supplying a nucleating emulsion. Inlet 2 leads to a first chamber 4 partially formed by the base 14. Device 1 also includes a container 19 having a second inlet 3 for supplying a second aqueous solution 104 and a dispersion outlet 6 for collecting a dispersion of the nucleating emulsion in the second aqueous solution. The second inlet 3 leads to a second chamber 5 partially formed by the container 19. The first chamber and the second chamber are separated by a membrane 7. Figure 2As can be readily seen, the first chamber has a circular cross-section relative to a corresponding cross-sectional plane along the central longitudinal axis 15 and perpendicular to the membrane 7. In the particular embodiment shown, the first chamber 4 has a semi-circular cross-section and can therefore have a hemispherical shape. The first inlet 2 is arranged in the region of the pole 13 of the hemisphere. The second chamber 5 tapers toward the dispersion outlet 6, which is arranged on the longitudinal axis 15, which extends in the longitudinal direction of the device, intersects the center of the first and second chambers, is perpendicular to the membrane 7, and intersects the center of the membrane. As can be seen, the longitudinal axis 15 constitutes the central axis of the device in the longitudinal direction. In the embodiment shown, the second chamber is arched toward the dispersion outlet 6. Therefore, the second chamber 6 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 retainer 20 and a container retainer 21, which are fixedly connected to each other via a releasable clamping device 18. The membrane 7 is mounted onto the membrane holder 20 by clamping it between the membrane holder 7 and the base 14. The membrane holder 20 is securely connected to the base 14 via a clamping device 18. To securely fasten the glass container 19 between the membrane holder 20 and the container holder 21, a gasket 23, which may be a foam gasket in certain cases, may be arranged between the container 19 and the container holder 21. The membrane holder 20 includes a groove 22 for receiving the container 19.

[0173] Figure 4 It shows Figure 2 An exploded view of the partially cut device 1. As can be seen, the first chamber is partially formed by the base 14 and has a hemispherical shape. The first inlet 2 is arranged at the pole of the hemisphere, at an angle of approximately 90° to the central axis 15. The base 14 includes spacer rings 16 that allow the use of different membranes of different thicknesses, and the membrane holder 20 includes a sealing ring 17. The membrane 7 is arranged between the rings 16 and 17. The design of the device 1 with an adjustable clamping device 18 allows for the use of membranes of various thicknesses. The membrane holder 20 also includes a circumferential groove 22 for receiving the lower end of the container 19. The clamping device 18 securely and releasably connects the membrane holder 20 to the container holder 21.

[0174] Figure 5A schematic diagram of an apparatus 1 that can be used according to a preferred embodiment of the invention is shown. The second chamber 5 is formed by a container 19 and a membrane 7 separating the first chamber 4 from the second chamber 5. The container 19 includes a dispersion outlet 6 in fluid communication with a product vessel 29 and a waste vessel 30. Typically, fluid flow can be controlled by a valve (such as a three-way valve). The apparatus 1 also includes a first reservoir 24 in fluid communication with the first chamber 4, which can be used solely as a reservoir for supplying the nucleating emulsion to the first chamber 4 via a first inlet 2, or it can also be used as a mixing vessel for preparing the nucleating emulsion. A flow meter for measuring the flow rate of the nucleating emulsion is arranged between the first reservoir 24 and the first inlet 2. The first reservoir 24 is in fluid communication with a pressure source 32. Furthermore, a pressure regulator 27a is arranged between the first reservoir 24 and the pressure source 32. In addition to the first reservoir 24, the apparatus 1 also includes a flushing reservoir 31, which is also in fluid communication with both the first chamber 4 and the pressure source 32. The flushing reservoir 31 is configured to provide flushing solution to the first chamber 4 for cleaning the device 1 after its intended use. Typically, if flushing solution is provided to the first chamber 4, a three-way valve arranged between the product vessel 29 and the waste vessel 30, and the dispersion outlet 6, is configured to allow flushing solution to flow into the waste vessel 30. The product vessel 29 can be used, for example, directly as a gelling vessel. Alternatively, it can be used as an intermediate storage vessel, and the resulting dispersion is then mixed with an aqueous shell-forming solution. The device 1 also includes a heater 33 configured to heat the first and second chambers during dispersion generation. Furthermore, the second chamber 5 is in fluid communication with a second reservoir 25, which supplies a second aqueous solution to the second chamber 5. A flow restrictor 26 and a flow meter 28 are arranged between the second chamber 5 and the second reservoir 25. In the illustrated embodiment, the flow restrictor 26 is arranged downstream of the flow meter 28 in the flow direction. The second reservoir 25 is also in fluid connection to a pressure source 32. In addition, the second pressure regulator 27b is arranged between the second reservoir 25 and the pressure regulator 27a.

[0175] Figure 6 A monolayer membrane 7 for generating a dispersion of a nucleating emulsion in a second aqueous solution is shown. This monolayer membrane can be used in any of the methods and / or apparatuses disclosed herein. The membrane 7 has a first side 8 (not shown) and a second side 9, the second side facing a second chamber in the operating state. A plurality of microchannels 10 extend through the membrane 7. Each channel 10 has an elliptical profile. Furthermore, the membrane 7 includes a membrane sealing ring 44 that circumferentially and completely surrounds the periphery of the membrane.

[0176] Figure 7A partial cross-sectional view of an apparatus that can be used in an embodiment of the invention is shown. The apparatus 1 has a first inlet 2 for supplying the nucleating emulsion, the first inlet leading to a first chamber 4 having a circular cross-section. In the illustrated embodiment, the first chamber 4 has a spherical dome shape, the radius at the base of the dome being smaller than the radius of a corresponding imaginary perfect sphere. A second chamber 5 is at least partially defined by a container 19. The apparatus also includes a dispersion outlet 6 for collecting a dispersion generated from the nucleating emulsion in a second aqueous solution. For better visualization, the corresponding membrane is not shown. In the illustrated embodiment, the second inlet leading to the second chamber 5 includes a supply channel 34 circumferentially arranged around a central longitudinal axis 15 and / or an axis perpendicular to the first and second sides of the membrane and intersecting the center of the membrane. The supply channel 34 includes a plurality of openings 35 leading to the second chamber 5. The openings 35 are evenly distributed along the circumference of the supply channel and are arranged in the direction of the dispersion outlet 7. In the illustrated embodiment, the supply channel 34 forms a ring-like structure arranged at the bottom of the second chamber 5, i.e., at the edge of the membrane and container 19. In the illustrated embodiment, the supply channel has an angular cross-section. Alternatively, the supply channel can have a rounded, in particular a circular, cross-section.

[0177] Figure 8 It shows Figure 7 A cross-sectional view of another embodiment of the device shown. Device 1 has a first inlet 2 for supplying nucleating emulsion, the first inlet leading to a first chamber 4 having a circular cross-section. In the illustrated embodiment, the first chamber 4 has a spherical dome shape. A membrane 7 separates the first chamber 4 from a second chamber 5. Figure 2The embodiment shown forms a contrast, with the membrane inclined relative to the central longitudinal axis 15 of device 1. In a cross-sectional view along the central longitudinal axis, the acute angle β between the central longitudinal axis and the second side of the membrane is between 45° and 89°, preferably between 70° and 88°, and more preferably between 78° and 87°. Device 1 further includes a gas outlet 36. The gas outlet and the membrane are arranged such that during the supply of nucleating emulsion to the first chamber, particularly during the initial filling, the gas in the first chamber is directed to the gas outlet and removed from the first chamber 4 via the gas outlet 36. As can be seen, the gas outlet 36 is located at the top edge of the first chamber 4, which is formed by the membrane 7 and the chamber wall, which is part of the base 14. Before the first chamber 4 is initially filled with the nucleating emulsion, gas (particularly air) is present in the first chamber. During the filling of the first chamber 4 with the nucleating emulsion, the air is expelled through the gas outlet 36. Due to the arrangement of the membrane 7 and the gas outlet 36, substantially all the gas can be removed from the first chamber 4. Because the residual gas (especially bubbles) has a detrimental effect on the pressure distribution, the size and particle distribution become more uniform.

[0178] Figure 9 A cross-sectional view of another device that can be used in the method according to the invention is shown (see Figure 1 (b) The apparatus includes a first chamber 4 fluidly connected to a second chamber 5 via a microchannel 10. Thus, a nucleating emulsion of an aqueous dispersion in an oil phase, comprising water and a dissolved gelation inducing agent, can be provided in the first chamber, the emulsion also comprising a first surfactant. This emulsion is then introduced from the first chamber into the second chamber 5 containing a second aqueous solution comprising water and a second surfactant via the microchannel 10. The emulsion is then transported from there to a gelling vessel (not shown) containing an aqueous shell-forming solution.

[0179] Figure 10a Microscopic images of capsules produced by the method according to the invention are shown, the capsules having a uniform size distribution and an average core diameter of 270 μm. Figure 10b Microscopic images of capsules produced by the method according to the invention are shown, the capsules having a uniform size distribution and an average core diameter of 550 μm.

[0180] Figure 11The size distribution of an alginate capsule assembly with an MCT oil core according to an embodiment of the present invention is shown. The size distribution on the left shows the distribution of the capsule shell thickness. The average shell thickness of the capsules in the assembly is 94 μm. The central plot shows that the average diameter of the oil core in each capsule is 265 μm and the coefficient of variation is 2.4%. The right plot shows the overall size distribution of the capsules in the assembly, i.e., twice the shell thickness and oil core diameter. The average particle size of the capsules is 453 μm and the coefficient of variation is 3.9%.

[0181] Figure 12 The following capsules are shown to have measured elasticity (◆), retention (●), and peak force (▲): (a) a capsule prepared in step d. using an aqueous shell-forming solution containing only 1 wt% sodium alginate, providing a shell essentially composed of calcium alginate; (b) a capsule prepared in step d. using an aqueous shell-forming solution containing 1 wt% sodium alginate and 5 wt% corn starch solid particles with a particle size equal to or less than 15 μm; (c) a capsule prepared in step d. using an aqueous shell-forming solution containing 1 wt% sodium alginate and 5 wt% corn starch solid particles with a particle size equal to or less than 15 μm, wherein the heat treatment of the capsule is performed at 75°C; (d) the capsule according to (c) after 28 days. As can be seen, the use of an additional biopolymer (such as starch) provides a significant increase compared to using only alginate as a shell-forming agent (compare (a) with (b)). Furthermore, heating the capsule provides additional mechanical strength because the starch itself produces a more pronounced network (compare (a) / (b) with (c)). Furthermore, the observed effects are stable over time, as demonstrated by (d).

[0182] To measure these parameters, the capsule was compressed to 25% strain (points 1 to 2) using a compression element with a flat geometry having a diameter larger than the particle, at a constant compression rate of 0.5 mm / s, and then returned to its initial position (points 2 to 3) at the same constant recoil rate of 0.5 mm / s. The elasticity (i.e., the elasticity of the capsule) is the ratio of the area under the force-moment curves of recoil and compression (2 to 3 and 1 to 2). The peak force is equal to the maximum force at 25% strain (point 2).

[0183] To measure the retained energy, the capsule was compressed to 25% strain using a compression element with a flat geometry having a diameter larger than the particle, at a constant compression rate of 0.5 mm / s. This position was held for 15 seconds, and then the compression element was allowed to retract at a rate >0.5 mm / s. The retained energy (i.e., retention) is the ratio between the force at the end of 25% strain compression and the force at the beginning of 25% strain compression.

[0184] Figure 13The following capsules are shown to have measured elasticity (◆), retention (■), and peak force (▲): (a) a capsule prepared in step d. using an aqueous shell-forming solution containing only 1 wt% sodium alginate, providing a shell substantially composed of calcium alginate; (b) a capsule prepared in step d. using an aqueous shell-forming solution containing 0.67 wt% sodium alginate and 1.33 wt% pectin; (c) a capsule prepared in step d. using an aqueous shell-forming solution containing 0.67 wt% sodium alginate and 1.33 wt% pectin, wherein the capsule is further coated with chitosan by immersion in an aqueous chitosan solution (2 wt%) for 10 to 30 minutes; (d) a capsule prepared in step d. using an aqueous shell-forming solution containing 0.67 wt% sodium alginate and 1.33 wt% pectin, wherein the capsule is further coated with chitosan by immersion in an aqueous chitosan solution (2 wt%) for 10 to 30 minutes, and wherein the heat treatment of the capsule is performed at 90°C.

[0185] The following table shows suitable formulations that can be used in the method according to the present invention:

[0186] Table 1: Formation of nucleation emulsions of aqueous dispersed phase in oil phase

[0187] Components Concentration (wt%) water 20-30 <![CDATA[CaCl2]]> 2-5 PGPR 0.03-0.15 Sunflower oil 64.85-77.97

[0188] Table 2: Generation of aqueous shell-forming solutions that produce capsules with a core size >270 μm

[0189] Components Concentration (wt%) Sodium alginate 0.1-2 ethanol 10-20 water 78-89.9

[0190] Table 3: Generation of aqueous shell-forming solutions that produce capsules with a core size of <270 μm

[0191] Components Concentration (wt%) Sodium alginate 0.1-2 ethanol 21-30 water 68-78.9

[0192] The second aqueous phase is a 1 wt% solution of PVA in water.

Claims

1. A method for producing capsules having a matrix shell encapsulating an oil core, the method comprising the steps of: a. providing a nucleation emulsion of an aqueous dispersed phase in an oil phase in a first chamber, the aqueous dispersed phase comprising water and a gelation inducing agent, the emulsion further comprising a first surfactant; b. providing a second aqueous solution in a second chamber, the aqueous solution comprising water and a second surfactant; wherein the first chamber and the second chamber are fluidly connected by one or more channels; the method further comprising: c. directing the nucleation emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleation emulsion of step a. in the second aqueous solution of step b.; d. mixing the dispersion formed in step c. with an aqueous shell forming solution, the aqueous shell forming solution comprising water and a water soluble matrix forming agent; wherein the gelation inducing agent and the matrix forming agent are configured such that they are capable of chemically reacting with each other to form a water insoluble matrix shell; the method further comprising: e. allowing the gelation inducing agent and the matrix forming agent to react in the dispersion formed in step c. to form capsules of a water insoluble matrix shell encapsulating an oil core.

2. The method according to claim 1, wherein the first chamber and the second chamber are fluidly connected by microchannels.

3. The method according to claim 1, wherein the oil phase in step a. additionally comprises at least one target compound.

4. The method according to any one of claims 1-3, wherein step a. comprises the substeps al. dissolving the gelation inducing agent in water to form a solution, and a2. mixing the formed solution with the oil phase and the first surfactant.

5. The method according to any one of claims 1-3, wherein after step c. the dispersion formed in step c. is delivered into a gelation vessel containing the aqueous shell forming solution of step d.

6. The method according to claim 5, further comprising stirring the delivered dispersion of the nucleation emulsion of step a. in the aqueous solution of step b. and the aqueous shell forming solution within the gelation vessel.

7. The method according to any one of claims 1-3, wherein the first surfactant is a non-ionic surfactant, such as polyglycerol polyricinoleate (PGPR) or a Span derivative, such as Span 80 or Span 85.

8. The method according to any one of claims 1-3, wherein the second surfactant is selected from the group consisting of polyvinyl alcohol (PVA); polysorbate; saponin; sapogenin, i.e. Quillaja extract; gum arabic; beta lactoglobulin; sodium dodecyl sulfate; soy lecithin; sodium caseinate; potato protein isolate; whey protein isolate; octenyl succinyl starch.

9. The method according to claim 8, wherein the polysorbate is selected from the group consisting of Tween 20 or Tween 80.

10. The method according to claim 8, wherein the second surfactant is selected from the group consisting of polyvinyl alcohol, polysorbate, beta-lactoglobulin and octenyl succinyl starch. ​ ​ ​ ​ ​ ​ ​ 11. The method according to any one of claims 1-3, wherein the matrix forming agent is a polysaccharide or a salt thereof.

12. The method according to any one of claims 1-3, wherein the gelation inducing agent is an inorganic salt.

13. The method according to claim 12, wherein the gelation inducing agent is an alkaline earth metal salt.

14. The method according to claim 12, wherein the gelation inducing agent is an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate or an alkaline earth metal nitrate, or an alkali metal halide, an alkali metal pseudohalide, an alkali metal carboxylate or an alkali metal nitrate.

15. The method according to any one of claims 1-3, wherein a permeability adjusting agent such as an alcohol or a sugar is added to the aqueous shell forming solution prior to step d.

16. The method according to any one of claims 1-3, wherein a pressure of 1.01 bar to 1.15 bar is applied to the first chamber, and / or wherein a pressure of 1.02 bar to 1.2 bar is applied to the second chamber.

17. The method according to claim 16, wherein a pressure of 1.03 bar to 1.07 bar is applied to the first chamber.

18. The method according to claim 16, wherein a pressure of 1.05 bar to 1.1 bar is applied to the second chamber.

19. The method according to claim 16, wherein the pressure applied to the first chamber is less than the pressure applied to the second chamber.

20. The method according to any one of claims 1-3, wherein the mixing in step d. is performed with an agitator stirring at 10 rpm to 800 rpm.

21. The method according to claim 20, wherein the mixing in step d. is performed with an agitator stirring at 50 rpm to 700 rpm.

22. The method according to claim 20, wherein the aqueous shell forming solution is stirred with an agitator at 500 rpm to 800 rpm prior to step d., and wherein the stirring is at 50 rpm to 150 rpm during step d.

23. The method according to claim 22, wherein the aqueous shell forming solution is stirred at 100 rpm to 120 rpm during step d.

24. The method according to any one of claims 1-3, wherein step e. is performed for 5 min to 25 min.

25. The method according to claim 24, wherein step e. is performed for 8 min to 12 min.

26. The method according to claim 24, wherein step e. is performed for 15 min to 20 min.

27. The method according to any one of claims 1-3, wherein after step e. the capsules are coated with additional layers by dip coating.

28. The method according to claim 27, wherein the capsules are coated with two or more additional layers.

29. The method according to any one of claims 1-3, wherein after step e. the formed capsules are separated, solidified and / or stored.

30. An assembly of capsules comprising a plurality of capsules produced according to the method of any one of claims 1 to 29, wherein the capsules have an equal size distribution with a coefficient of variation of 10% or less.

31. The assembly of capsules of claim 30, wherein the capsules are microcapsules.

32. The assembly of capsules of claim 30 or 31, wherein the capsules have an equal size distribution with a coefficient of variation of 4% or less.

33. A dispersion of microdroplets, the dispersion comprising an aqueous continuous phase and microdroplets of a dispersed phase; wherein each microdroplet of the dispersed phase is a microemulsion of an aqueous dispersed phase in an oil phase, wherein the aqueous dispersed phase comprises water and a dissolved gelation inducing agent, wherein each microdroplet further comprises a first surfactant; and wherein the dispersion of microdroplets further comprises a second surfactant.

34. The dispersion of claim 33, wherein the oil phase comprises at least one target compound.

35. The dispersion of claim 33 or 34, wherein the first surfactant is a non-ionic surfactant, and / or wherein the second surfactant is selected from the group consisting of polyvinyl alcohol (PVA); polysorbate; saponin; sapogenin, i.e. Quillaja extract; gum arabic; beta lactoglobulin; sodium dodecyl sulfate; soy lecithin; sodium caseinate; potato protein isolate; whey protein isolate; octenyl succinyl starch.

36. The dispersion of claim 35, wherein the non-ionic surfactant is selected from the group consisting of polyglycerol polyricinoleate (PGPR) or Span derivatives.

37. The dispersion of claim 35, wherein the second surfactant is selected from the group consisting of polyvinyl alcohol, polysorbate, beta-lactoglobulin and octenyl succinyl starch.

38. The dispersion of any one of claims 33 to 34, wherein the gelation inducing agent is an inorganic salt.

39. The dispersion of claim 38, wherein the gelation inducing agent is an alkaline earth metal salt.

40. The dispersion of claim 38, wherein the gelation inducing agent is an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate or an alkaline earth metal nitrate.

41. An apparatus for producing capsules having a matrix shell encapsulating an oil core, the apparatus comprising: a. a first inlet (2) for supplying a nucleated emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase comprising water and a dissolved gelation inducing agent, the emulsion further comprising a first surfactant, the first inlet (2) leading to a first chamber (4); b. a second inlet (3) for supplying a second aqueous solution, the aqueous solution comprising water and a second surfactant, the second inlet (3) leading to a second chamber (5); c. a dispersion outlet (6) for collecting a dispersion or microdroplets from the second chamber (5); d. a membrane separating the first chamber (4) from the second chamber (5) and having one or more channels (10) therein, wherein the one or more channels (10) fluidly connect the first chamber (4) with the second chamber (5). e. a gelation vessel (105) fluidly connected to the dispersion outlet (6), the gelation vessel comprising an aqueous shell-forming solution, the aqueous shell-forming solution comprising water and a water-soluble matrix-forming agent.

42. The device of claim 41, wherein the channel (10) is a microchannel.

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