CH718106A1 - Process for the production of capsules with a matrix shell - Google Patents

Abstract

A method for producing capsules with a matrix shell that encloses an oil core is described, the method comprising the following steps: a. providing in a first chamber a nucleating emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase comprising water and a gelation inducing agent, the emulsion also containing a first surfactant; b. providing an aqueous solution in a second chamber, the aqueous solution containing water and a second surfactant; wherein the first chamber and the second chamber are fluidly connected by one or more channels, preferably by microchannels; the method further comprising c. passing the nucleating emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleating emulsion of step a. in the aqueous solution from step b. to build; i.e. mixing the in step c. formed dispersion with an aqueous shell-forming solution, the aqueous shell-forming solution containing 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 undergoing a chemical reaction with one another to form a water-insoluble matrix shell; the method further comprising: e. reacting the gelation-inducing agent and the matrix-forming agent in the step c. formed dispersion to form capsules of a water-insoluble matrix shell enclosing an oil core.

Description

technical field

The invention relates to a method for producing capsules, in particular microcapsules, with a shell that encloses an oil core, and a dispersion of microdroplets.

background, prior art

Capsules, in particular microcapsules with a particle size of less than 1 mm, are widely used in pharmacy, cosmetics, diagnostics, food science and materials science. Such capsules can be made from an emulsion of monodisperse droplets in a continuous phase. The monodispersity increases stability, allows precise volume control in multiple chemical or biological reactions, and enables the fabrication of periodic structures. Microfluidics provides an excellent platform for the precise formation of monodisperse droplets. The monodisperse droplets can be hardened to produce microcapsules for encapsulation of active ingredients such as drugs, fragrances, flavors, peptides, living matter such as bacteria or phages, etc., fertilizers, pesticides and other wellness active substances.

For many applications it is desirable to provide capsules with an oil core surrounded by a suitable shell. This is mainly due to the fact that many interesting compounds, e.g. flavors, fragrances, active pharmaceutical ingredients, vitamins, etc., are hydrophobic and/or only soluble in an oil phase but not readily soluble in water. This makes the oil core an excellent carrier for such compounds of interest. In addition, various oils enhance the mechanism of action of these compounds. Some connections, such as Vitamins, for example, are only absorbed by the body in sufficient quantities in the presence of oil.

In addition to maintaining the structural integrity of the capsule, the shell that encases the core of such capsules can also have certain tunable properties. For example, it may be desirable that the shell does not decompose when it comes into contact with saliva, but only in the stomach in order to release the desired active ingredient. Alternatively, it is conceivable that a particular compound of interest, in particular a pharmaceutically active substance, is only released in the intestine and not in the mouth or stomach. In addition, in some cases it can be desirable to equip the capsules with mucoadhesive properties in order to be able to better control the release of an active ingredient.

Presentation of the invention

Previously known methods for producing capsules from monodisperse droplets have significant limitations. Known methods suffer from severely limited overall operational capacity and/or poor reproducibility and size control. However, controlling the size of the capsules is of paramount importance for various applications, particularly for applications in the pharmaceutical, fragrance and flavoring industries. In addition, it is also important to be able to precisely control the thickness of the shell, since the thickness of the shell directly affects the release profile of a compound of interest entrapped in the oil core. Therefore, it is important not only to control the overall shell thickness, but also to ensure an even distribution of shell thickness across the capsules.

It is therefore the general task to improve the prior art in the production of capsules, in particular microcapsules, with an oil core and a shell enveloping the oil core and preferably to overcome the disadvantages of the prior art in whole or in part. In advantageous embodiments, a method for producing such capsules is provided, which enables the capsule size and the size distribution to be precisely controlled. In further advantageous embodiments, a method for the production of such capsules is provided which enables the shell thickness to be controlled.

In a first aspect, the general object is achieved by a method for producing capsules with a matrix shell enclosing an oil core, the method comprising the following steps: a. providing in a first chamber a nucleating emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase comprising water and a gelation inducing agent, the emulsion also containing a first surfactant; b. providing a second aqueous solution in a second chamber, the aqueous solution containing water and a second surfactant.

The first chamber and the second chamber are fluidically connected by one or more channels, preferably by microchannels. The method further includes steps c. passing the nucleating emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleating emulsion of step a. in the second aqueous solution from step b. to build; i.e. mixing the in step c. formed dispersion with an aqueous, shell-forming solution, wherein the aqueous, shell-forming solution contains water and a water-soluble matrix-forming agent.

The gelation-inducing agent and the matrix-forming agent are configured such that they are capable of undergoing a chemical reaction with one another to form a water-insoluble matrix shell. The method further includes the step e. reacting the gelation-inducing agent and the matrix-forming agent in the step c. formed dispersion to form capsules of a water-insoluble matrix shell enclosing an oil core.

It is understood that steps a. and b. do not necessarily have to be performed in this order. It is also possible to start step b. and then step a. or do both at the same time.

It is understood that in step c. the dispersion formed comprises a plurality of monodisperse droplets containing the nucleating emulsion of step a. contained in the second aqueous solution as a continuous phase.

It is also understood that the formed oil core, which is enclosed by the water-insoluble matrix shell, contains small amounts of residual aqueous dispersed phase, i. H. small amounts of water. However, most of the core consists of the oil phase, typically more than 60% by weight, in particular more than 70% by weight, in particular more than 80% by weight, in particular more than 90% by weight, in particular more than 95% by weight, in particular more than 99% by weight.

In addition, the core-forming emulsion is not the emulsion which as such forms the core of the endcapsule, but also provides reagents which react and/or diffuse out of the core. The nucleating emulsion in step a. is therefore not necessarily completely identical, especially not in its composition, with the oil core of the end product.

The advantage of the inventive method is that in step c. creating a microdispersion of an emulsion in water. Thus, each in step c. produced droplets predominantly from oil of the oil phase from step a., but also from the aqueous dispersed phase with the gelation-inducing agent from step a. Thus, in step c. dispersion formed is a water-in-oil-in-water dispersion. The use of staged emulsification, i. H. passing the nucleating emulsion of step a. through the microchannels, enables precise control of the size and ensures an even size distribution of the in step c. formed dispersion. The process described here also enables capsule production of 100 g/h or more, or even up to 500 g/h. The droplets formed are stabilized by the second surfactant, so that their size when mixing the dispersion in step d. remains essentially constant with the aqueous shell-forming solution inducing the formation of the water-insoluble matrix. The matrix thus grows around the stable core by a chemical reaction between the gelation-inducing agent present in each droplet and the matrix-forming agent present in the aqueous shell-forming solution.

In some embodiments, the gelation inducing agent is dissolved in the water of the aqueous dispersed phase of step a. The advantage of a dissolved gelation inducing agent is that clogging of the channels is avoided. Carbonates in particular can lead to an accumulation of insoluble salts in the canals.

The in step a. provided nucleating emulsion may be stable for 60 minutes to 600 minutes, preferably 100 minutes to 500 minutes. Such stability ensures that the droplets are not destroyed directly, especially during step c. However, the droplet stability is not too high either, which affects the efficiency of shell formation, i. H. step e, would decrease.

The matrix-forming agent in step d. is usually dissolved in the aqueous shell-forming solution.

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

[0019] 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, more preferably between 1 µm and <1 mm. Correspondingly, a microdroplet has a droplet size, i. H. a diameter of less than 4 mm, preferably between 1 µm and <4 mm, more preferably between 1 µm and <1 mm, and a microchannel has a diameter of typically less than 4 mm, preferably between 1 µm and <4 mm, especially preferably between 1 µm and <1 mm.

The first chamber and the second chamber are typically separate from each other except for the one or more channels connecting the first chamber to the second chamber. A chamber as used herein is configured to be filled with a solution. Typically, the chambers are closed except for the inlets, channels and outlets.

The first chamber typically has a first fluid inlet for introducing, in particular continuously introducing, the core-forming emulsion in step a. into the first chamber and the second chamber has a second inlet for introducing, in particular continuously introducing, the second aqueous solution in step b. into the second chamber. The second chamber further comprises a dispersion outlet for removal, preferably continuous removal, used in step c. formed dispersion from the second chamber.

It is understood that the one or more channels each have an inlet opening into the first chamber and an outlet opening into the second chamber. Thus, the one or more channels are directly connected to the first chamber and the second chamber. Typically, the first chamber and the second chamber are fluidly connected by a plurality of channels, i. H. through at least 10, at least 20, at least 30, at least 50 or at least 100 channels. The first chamber and the second chamber are preferably fluidically connected to one another by 1 to 10,000,000, preferably 20 to 500,000 channels. Typically, the channels are arranged essentially parallel to one another.

For example, the one or more channels can have a diameter in the range from 0.25 to 2000 μm, preferably from 2 to 800 μm. The multiple channels of the membrane are typically microchannels. For example, each channel can have a cross-sectional area of 0.04 μm 2 to 4,000,000 μm 2 , preferably 4 μm 2 to 640 000 μm 2 .

In further embodiments, the aspect ratio of each channel, which is defined as channel length/minimum diameter, is 5 to 1000, especially 10 to 500, especially 10 to 50. In some embodiments, the length of the channel can be in the range of 0.05 mm to 20 mm are, in particular between 0.1 mm and 20 mm, especially 0.1 mm to 5 mm, in particular 0.5 to 20 mm.

In certain embodiments, each channel comprises a channel exit with a cross-sectional area that is larger than the cross-sectional area of the remaining part of the respective channel. In the longitudinal direction, i. H. in flow direction, the channel outlet has a typical length of a few microns, e.g. B. 200 microns to 20 mm, preferably 500 microns to 5 mm. For example, the duct outlet may be funnel-shaped, V-shaped, or U-shaped. In some embodiments, the duct outlet may have an elliptical contour. In particular, the duct outlet is not rotationally symmetrical, i. H. it has a length/width ratio of 3 and more. Therefore, the duct outlet cannot have a circular or square cross-section. Such a channel outlet enables a drop to be detached without external force. As a result, the formation of droplets of the core-forming emulsion in the second aqueous solution is decoupled and thus essentially independent of the flow rate. According to the Young-Laplace equation, the pressure at an immiscible liquid interface is higher at the channel exits than in the second reservoir. This creates a pressure gradient along the direction of flow, which causes the liquid thread to separate into individual droplets. This creates a pressure gradient at the end of the channel, which promotes the detachment of the liquid boundary layer and thus the formation of the individual droplets. When the channel exit is reached, a droplet detaches without external force due to the pressure drop of the disperse phase inside and outside the channel. Such a nozzle is advantageous because it decouples the flow rates from the emulsification process.

As a rule, each channel is delimited by channel walls. The channel walls can be curved, e.g. H. the channel walls can be convex or concave towards the channel exit. In addition, each duct may have a constriction which is smaller in cross-section than the cross-section of the remainder of the duct and the constriction is located adjacent to the duct outlet. The constriction is thus arranged between the duct outlet and the rest of the duct.

In further embodiments, 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 open area of the second side of the membrane may be 300% to 1500%, preferably 400% to 900% greater than the total open area of the channels at any other given location such as the main portion and/or the channel inlets.

In some embodiments, the one or more channels may be contained within a membrane separating the first chamber from the second chamber. In such embodiments the membrane may be flat, e.g. B. 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 can partially define the first chamber and the second side of the membrane can partially define the second chamber. The one or more channels, typically multiple channels, extend through the membrane from the first side to the second side. Each duct includes a duct inlet located on the first side, a duct outlet located on the second side, and a main portion located between the duct inlet and the duct outlet, the duct outlet having a different shape than the shape of the main portion.

The membrane may typically be a single layer membrane. This means that the membrane is made from a single piece. Such a membrane is preferably made of a solid material and, in addition to the numerous channels of the membrane, contains no phase interfaces or transition regions. Such a membrane is advantageous for the quality of the droplets produced, since any phase interfaces and transitions are detrimental to droplet formation and stability.

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

In further embodiments, the channel outlet can be wedge-shaped. In particular, the duct outlet may have an elliptical cross-section with respect to a transverse plane perpendicular to the extending duct, i. H. the channel outlet can be larger in a first direction than in a second direction.

In other embodiments, the second side of the membrane has a total open area that is greater than the total open area of the first side. Such a membrane has the advantage that droplets of high quality are produced even at flow rates of 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.

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

In some embodiments, the membrane is disc-shaped. Such a membrane can have a circular contour. Alternatively, the membrane can also have an angular, in particular triangular or rectangular, contour.

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

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

In some embodiments, the oil phase in step a. additionally at least one connection of interest. The compound of interest may be selected from a protein, a small molecule, particularly a fragrance or flavor, a pharmaceutical agent such as cannabinoids, hemp extracts, caffeine, melatonin or hyaluronic acid, an antibody, peptide, enzyme, RNA, DNA, vitamin and microorganisms. For example, the compound of interest can be mixed into the oil phase at a suitable concentration.

In some embodiments, step a. dissolving the gelation inducing agent in water to form a solution and mixing the formed solution with the oil phase and with the first surfactant. In these embodiments, the at least one compound of interest can already be mixed into the oil phase or can also be added only after the formed solution of the gelation-promoting agent in water has been mixed with the oil phase. In some embodiments, mixing the formed solution of gelation-inducing agent in water with the oil phase and the first surfactant comprises stirring with a stirrer at at least 8,000 rpm, preferably at 10,000 to 20,000 rpm, e.g. B. at 13,000 to 15,000 rpm.

In certain embodiments, the at least one compound of interest in the nucleating emulsion, particularly in the oil phase or in the aqueous dispersed phase, is a living organism, particularly a microorganism such as a bacterium, a virus, including one phage, or a single cell. In some embodiments, the living organism can be introduced into the nucleating emulsion, particularly the oil phase or the aqueous dispersed phase, in a quiescent state. The quiescent state of a living organism is considered to refer to an inactive state.

The method according to the invention is particularly suitable for the encapsulation of living organisms, since the method only exerts low shearing forces in comparison to the methods of the prior art. In addition, the encapsulation efficiency is significantly higher than in the methods known from the prior art. Encapsulation efficiencies of up to 90% or even up to 95% relative to the living organism can be achieved.

In some embodiments, the method is carried out at room temperature, which is very advantageous for the encapsulation of living organisms since viability is increased.

Since the core-forming emulsion is passed through one or more channels, the channel size, in particular the channel diameter, determines the amount of living organisms per drop and thus the amount of organisms per capsule formed. Precise control of the amount of organisms per capsule is therefore possible by choosing predefined channel dimensions.

In some embodiments where the at least one compound of interest is a living organism, the living organism, e.g. B. cells or bacteria, provided by cultivation before it is introduced into the nucleating emulsion, in particular in the oil phase or in the aqueous dispersed phase. The cultivation can be carried out, for example, on a suitable nutrient medium such as agar-agar. In certain embodiments, the viability of the living organism is monitored during cultivation and, when the viability has reached its maximum, the living organism is lyophilized and then added to the nucleating emulsion, particularly in the oil phase or in the aqueous dispersed phase.

In certain embodiments it is advantageous to deoxygenate the nucleating emulsion or its components such as the oil phase or the aqueous dispersed phase and/or the second aqueous solution. Deoxygenation can be accomplished by standard laboratory techniques, e.g. B. by degassing with inert gases such as argon or nitrogen or by the freeze-pump-thaw technique. Such deoxygenation is advantageous because the living organism can be kept in its dormant state.

In some embodiments, the nucleating emulsion, particularly in the oil phase or in the aqueous dispersed phase, additionally contains nutritional components for the living microorganism, such as sugars, electrolyte solutions and the like.

In certain embodiments, the nucleating emulsion, particularly in the oil phase or in the aqueous dispersed phase, additionally contains buffer solutions configured to maintain a pH appropriate for the living organism of interest.

In some embodiments, the step c. dispersion formed after step c. passed into a gelling vessel, which contains the aqueous shell-forming solution from step d. contains. The second chamber can thus have an outlet which is fluidically connected to the gelling vessel. In particular, in step c. formed dispersion continuously passed from the second chamber into the gelling vessel. Alternatively, in step c. dispersion formed is continuously conveyed from the second chamber to an intermediate storage vessel where it can be stored and a predetermined amount of the dispersion can be collected before being introduced into the gelling vessel. It goes without saying that in these embodiments the outlet of the second chamber can be fluidically connected to the intermediate storage vessel. The intermediate storage vessel can be fluidically connected to the gelling vessel.

It is understood that in embodiments with a gelling vessel, the gelling vessel typically contains the aqueous shell-forming solution of step d. contains before the in step c. formed dispersion is added to the gelling vessel.

In particular embodiments, the delivered dispersion of the core-forming emulsion from step a. in the second aqueous solution from step b. and stirring the aqueous shell-forming solution with a stirrer, preferably a mechanical stirrer, in the gelling vessel. During step e. the agitation can preferably be at 50 to 150 rpm, preferably at 100 to 120 rpm. Such a stirring speed has proved to be optimal since it prevents agglutination of the capsules formed and also ensures a uniform size distribution of the capsules, but is low enough so that the growing capsules or the formed capsules are not destroyed.

In some embodiments, the oil phase may include or consist of medium chain triglycerides (MCT), menthol, sunflower oil, and the like.

In some embodiments, the first surfactant is a nonionic surfactant, such as polyglycerol polyricinoleate (PGPR) or Span derivatives, such as Span 80 or Span 85. Additionally, the first surfactant can be a solid particle, preferably hydrophobic, hydrophilic, depending on the application or Janus-type particle configured to give a Pickering emulsion. The solid particle can be, for example, colloidal silica.

The first surfactant, in particular the nonionic surfactant, preferably has a molecular weight of between 600 and 120,000 g/mol, preferably between 800 and 80,000 g/mol.

[0053] Nonionic surfactants have proven to be suitable for sufficiently stabilizing the microdroplets of the aqueous dispersed phase in the core-forming emulsion. PGPR has been found to be advantageous as it stabilizes the nucleating emulsion sufficiently that the microdisperse droplets of the aqueous dispersed phase are not immediately destroyed, particularly not during the passage of the emulsion through the channels, but also not overly stabilized as this Efficiency of the diffusion process of the gelation inducing agent to the interface of the droplet in step e. reduced so that it can react with the matrix-forming agent. Stabilization is important because the microdroplets in step c. are subjected to significant shear forces which can disrupt the microdroplets of the aqueous dispersed phase in the nucleating emulsion.

In some embodiments, the amount of the first surfactant in the nucleating emulsion is between 0.01% and 0.80% by weight, preferably between 0.05% and 0.12% by weight.

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

Typically, the first surfactant and the second surfactant are different and thus not identical.

In some embodiments, the second surfactant is selected from polyvinyl alcohol (PVA), a polysorbate such as Tween 20 or Tween 80, saponins, sapogenins, i. H. Quillaja Extract, Gum Arabic, Beta-Lactoglobulin, Sodium Lauryl Sulfate, Soy Lecithin, Sodium Cesinate, Potato Protein Isolate, Whey Protein Isolate and Starch Octenyl Succinate. Preferably polyvinyl alcohol, a polysorbate such as Tween 20 or Tween 80, beta-lactoglobulin and starch octenyl succinate. A relatively thick and stable shell was obtained with polyvinyl alcohol, a polysorbate such as Tween 20 or Tween 80, beta-lactoglobulin and starch octenyl succinate compared to other second surfactants. Additionally, polyvinyl alcohol provided excellent monodispersity of the nucleating emulsion droplets in the second aqueous solution. Additionally, the second surfactant can be a solid particle, preferably a hydrophobic, hydrophilic, or Janus-type particle, depending on the application, configured to provide a Pickering emulsion. The solid particle can be, for example, colloidal silica.

In some cases the matrix-forming agent is a polysaccharide or a suitable salt thereof. A suitable salt is a salt form that can be completely dissolved in water. Polysaccharide salts usually consist of an anionic polysaccharide component and a suitable counter cation. Suitable polysaccharides are selected from chitosan, cellulose, alginate, especially sodium alginate, carrageenan, agar, agarose, pectins, gellan, starch and the like. Preferred polysaccharides are alginate, preferably sodium alginate, chitosan, carrageenan and cellulose, more preferably alginate, preferably sodium alginate, chitosan. In some embodiments, the polysaccharides can be modified by adjusting the pH, e.g. by making the pH of the aqueous shell-forming solution alkaline.

Alternatively, the matrix-forming agent can also 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 by ion exchange with the polycarboxylate. Alternatively, the gelation inducing agent can be a polyammonium salt, i. H. a polymer with a multiplicity of polyammonium groups.

Alternatively, the matrix-forming agent can be a monomer that is soluble in the water phase but not in the oil. Such a monomer must be chosen so that it can be subjected to a step polymerisation, for example a diamine. In this case the gelation-inducing agent is a monomer which is soluble in the oil phase but not in water, e.g. a diacid chloride, thereby allowing interfacial polymerization during step e to form the water-insoluble matrix.

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

In some embodiments, a third surfactant, e.g. B. a polysorbate such as Tween 20, be present in the aqueous shell-forming solution or her prior to step d. be added. It has been shown that such a third surfactant improves the gelation reaction.

In some embodiments, the gel-inducing agent is an inorganic salt, especially an alkaline earth metal salt, especially an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate or an alkaline earth nitrate, or an alkali metal halide, an alkali metal pseudohalide, an alkali metal carboxylate or an alkali metal nitrate. In some embodiments where the gelation initiating agent is an inorganic salt, the reaction in step e. an ion exchange reaction, or ionotropic gelation, occurs between the gelation-initiating agent and the matrix-forming agent. Therefore, the inorganic salt (and vice versa, the matrix forming agent) is selected such that its reaction with the matrix forming agent results in a water-insoluble reaction product. Particularly suitable salts, in particular for polysaccharides, can therefore be K, Mg, Sr or Ca salts. The term "pseudohalide", also referred to as "pseudohalide", is understood by those skilled in the art to mean polyatomic analogues of halogens whose chemistry is similar to that of true halogens. Non-limiting examples are cyanide, isocyanide, cyanate, isocyanate, methylsulfonyl, and triflyl. Non-limiting examples of carboxylates are acetate, formate, lactate, oxalate, butyrate, succinate and the like. The gelation-inducing agent is typically selected so that it is completely water-soluble at room temperature, i. H. has a solubility in water of >10g/100mL, preferably >20g/100mL, in particular >50g/100mL. Non-limiting examples of suitable gelation inducing agents are: CaCl 2 , CaF 2 , calcium lactate, MgCl 2 , Sr(OAc) 2 .

The inorganic salt is typically a water soluble salt. However, it is also conceivable to use a powder of a water-insoluble salt as the gelation-inducing agent. For example, it is possible to use CaCO3 or MgCO3, in particular as a powder.

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

In some cases the gelation inducing agent is CO 2 or a CO 2 generator. A CO2 generator can release CO2 under certain conditions. For example, bicarbonate can release CO2 in the presence of an acid.

In some embodiments, the gelation initiating agent may be a Brønsted acid, e.g. B. a mineral acid or a carboxylic acid. In this case, the matrix-forming agent can be a composition of a polysaccharide such as alginate, chitosan, etc. and a suitable water-soluble alkali or alkaline earth metal complex such as Ca-Na2-EDTA, Mg-Na2-EDTA, Sr-Na2-EDTA and the like.

In some embodiments, the amount of gelation inducing agent in the nucleating emulsion is between 1.5% and 7.0% by weight, preferably between 2.0% and 5.0% by weight.

In some embodiments, prior to step d. an alcohol, in particular methanol, ethanol or propanol, is added. The alcohol has been shown to enhance the diffusion of the gelation initiating agent towards the microdroplet interface. The alcohol is typically present in an amount from 10% to 30% by weight of the aqueous shell-forming solution. It has been observed that at an alcohol level of between 10 and 20% by weight, preferably at 13 to 17% by weight, the core size of the capsule, ie. H. the core diameter, is larger than when using more ethanol. For example, a microcapsule diameter of more than 300 μm can be achieved. If the amount of alcohol is between 20 and 30% by weight, preferably 23 to 27% by weight, the core size of the capsule, i.e. the core diameter, is smaller (other things being equal). For example, a microcapsule diameter of less than 300 µm can be achieved.

In some embodiments, prior to step d. added an osmosis regulator. The osmotic regulator is configured to enhance diffusion of the gelation inducing agent to the microdroplet interface, thereby increasing the shell thickness and stability of the capsule. The osmotic regulator can be an alcohol as described above or a sugar, e.g. B. a monosaccharide or a disaccharide, i. H. glucose or fructose. Such a sugar derivative can be used alone or in combination with an alcohol as described above.

In some embodiments, prior to step d. a structure stabilizer may be added or present in it. A structural stabilizer is a compound that improves the structural stability of the hull. Examples are agarose, xanthan gum or cellulose and derivatives such as methyl cellulose or microcrystalline cellulose and the like. These can typically be present in the shell-forming solution and are then integrated into the growing shell in step e.

In further embodiments, the first chamber, in particular during step c. , with a pressure of 1.01 bar to 1.15 bar, preferably from 1.03 bar to 1.07 bar, and/or the second chamber, in particular during step c., with a pressure of 1.02 bar to 1.2 bar, preferably from 1.05 bar to 1.1 bar , applied.

In some embodiments, the pressure in the first chamber is less than the pressure in the second chamber. It will be appreciated that the first pressure may be set by the pressure at which the nucleating emulsion is introduced into the first chamber via the first fluid inlet of the first chamber and/or the second pressure may be set by the pressure at which the second aqueous solution from step b. is directed into the second chamber via the second fluid inlet of the second chamber.

In some embodiments, the mixing in step d. carried out with a stirrer stirring at 10 to 800 rpm, preferably at 50 to 700 rpm. The mixing in step d. is advantageous because there is agglutination of the monodisperse droplets of the in step c. dispersion formed and/or the capsules formed prevented. This also ensures a uniform size distribution of the capsules. Typically, an overhead stirrer can be used.

In certain embodiments, prior to step d. stirred with a stirrer at 500 rpm to 800 rpm and during step d. stirred at 50 rpm to 150 rpm, preferably at 100 to 120 rpm. So before the step c. dispersion formed is mixed with the aqueous shell-forming solution, the aqueous shell-forming solution is more stirred to ensure the uniformity of the aqueous shell-forming solution. During the addition, the agitation speed is reduced, low enough not to destroy the growing or formed capsules.

In some embodiments, step e. for 5 minutes to 25 minutes, preferably for 8 minutes to 12 minutes or for 15 minutes to 20 minutes. The reaction time of step e., i. H. the time to stop the reaction, e.g. B. by separating or isolating the capsules from the aqueous shell-forming solution, directly influences the particle size and the core size of the capsules. For example, an oil core with an average diameter of less than 600 µm can be achieved if step e. 8 min to 12 min and an oil core with an average diameter of more than 600 µm when step e. 15 min to 20 min is carried out. Several methods for determining particle size are known to those skilled in the art, e.g. B. Screening with screens of different mesh sizes.

In some embodiments, the method further comprises, after step e. an additional coating step, which can in particular comprise a dip coating. The additional enrobing step may, in some embodiments, include the following steps f. immersing the in step e. formed capsules into a further aqueous shell-forming solution, the further shell-forming solution typically differing from the shell-forming solution in step d. differs. The further shell-forming solution comprises water and a pH-dependent matrix-forming agent and optionally an inorganic salt, preferably an alkaline earth metal salt or an alkali metal salt; G. Adjusting the pH so that the matrix-forming agent is converted into a water-insoluble matrix which coats, preferably completely coats, the capsules with an additional shell. In this way, the resulting capsules can form an oil core that is directly from the in step e. formed matrix is surrounded, in turn, by a step g. formed matrix, preferably of a different material, resulting in a multi-layered capsule.

The matrix-forming agent can be a polysaccharide. Typically, it may be a different polysaccharide than the matrix-forming agent of step d. Suitable polysaccharides are selected from chitosan, cellulose, alginate, especially sodium alginate, carrageenan, agar, agarose, pectins, gellan, starch and the like. Preferred polysaccharides are alginate, preferably sodium alginate, chitosan, carrageenan and cellulose, particularly preferably alginate, preferably sodium alginate, chitosan. Preferably, the matrix-forming agent of step d. Sodium alginate and the matrix forming agent of step f. Chitosan or microcrystalline carboxymethyl cellulose.

Typically, the pH adjustment is an acidification, i.e. a lowering of the pH. For example, the pH can be lowered from 7 or more to 5 or less, preferably pH 4-5.

In some embodiments, the capsules are coated with two or more additional layers. Thus, dip coating can be repeated with different matrix-forming agents. In particular, steps f. and g. can be repeated at least once, either with the same matrix-forming agent or with different matrix-forming agents, e.g. B. different polysaccharides or with a pH protective layer such as Eudragit<®> or Eudraguard<®>.

In some embodiments, particularly after step e. or optionally after step g., the capsules formed are isolated, hardened and/or preserved. Isolation of the capsules may involve, for example, filtering or sieving to separate the capsules from the aqueous shell-forming solution, and optionally washing the capsules with water optionally containing a surfactant such as sodium lauryl sulfate (SDS), a Tween derivative such as Tween 20 or 80, or PVA contains. The curing can, for. B. drying the capsules, z. by air flow or by freeze drying, to evaporate all or at least most of the unbound water. Curing can also involve further stirring of the capsules in an aqueous inorganic salt solution, such as e.g. a CaCl2 or MgCl2 solution, preferably a 1-10, more preferably a 1-5 wt% aqueous solution of the inorganic salt. This further increases the stability and structural integrity of the capsules, particularly the shell. The preservation can be done by immersing the capsules in distilled water or in an aqueous inorganic salt solution such as e.g. B. a CaCl2 or MgCl2 solution, preferably a 1-10 percent, preferably a 1-5 percent aqueous solution of the inorganic salt. It has been shown that such a preservation increases the storage stability of the capsules.

In some embodiments, step c. carried out with or in a device for generating a dispersion of a nucleating emulsion in a second aqueous solution, the device having a first inlet for feeding the nucleating emulsion from step a., which opens into the first chamber, a second inlet for feeding a second aqueous solution opening into the second chamber and a dispersion outlet for collecting the dispersion. Furthermore, the device comprises a membrane, in particular a membrane as described above, which separates the first chamber and the second chamber and which has 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. establishing fluid communication between the first chamber and the second chamber. Each channel includes a channel inlet located on the first side and a channel outlet located on the second side. The first chamber can typically be designed such that a flow rate of the core-forming emulsion through all of the individual channels is essentially the same. In the prior art, an inhomogeneous pressure distribution, in particular of the core-forming emulsion, means that only a small percentage of the channels can actively produce droplets. An even pressure distribution over the first side, on the other hand, enables an even flow of the core-forming emulsion into the second aqueous solution and the generation of droplets with reproducible quality at a high throughput of up to 5 liters per hour.

In certain embodiments, the second chamber can be made of glass or a transparent polymer such as PTFE, polymethyl (meth)acrylate or polyoxymethylene, or metals such as steel, aluminum or titanium. In general, the device may comprise a container, e.g. B. a glass container, which partially forms the second chamber. Together with the membrane, the container can form the second chamber. In some embodiments, the first chamber can be made of metal, e.g. B. aluminum or steel, or made of a transparent polymer such as PTFE, polymethyl (meth) acrylate or polyoxymethylene.

The dispersion outlet can e.g. B. are in fluid communication with the gelling vessel or the intermediate storage vessel.

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

In further embodiments, the first chamber has a rounded cross-section with respect to a cross-sectional plane that is perpendicular to the membrane and rotationally symmetrical with respect to a central longitudinal axis. The term “rounded cross section” used here refers to a continuous curvature without gradations, in particular to a curvature which has a radius of at least 1 mm, in particular at least 5 mm, in particular at least 10 mm, in the cross-sectional plane running perpendicular to the membrane. It will be appreciated that the curvature in cross-sectional view can be described as part of a circle of this radius. Thus, the side walls of the first chamber can continuously converge toward each other in the upstream direction. The central longitudinal axis is an axis extending longitudinally of the device, located at the center of the device and/or an axis perpendicular to the membrane and intersecting the center of the membrane. For example, the first chamber may have a U-shaped cross-section, or be concavely rounded or semi-circular. The rounded cross section is typically edgeless, thus eliminating edges that would lead to uneven pressure distribution when the nucleating emulsion is forced through the membrane. The first chamber can preferably have the shape of a spherical segment. The shape of the first chamber can generally be preferably substantially rotationally symmetrical to the central longitudinal axis.

In certain embodiments, the dispersion outlet may be located substantially on the central longitudinal axis and/or on the axis perpendicular to the membrane and intersecting the center of the membrane. Preferably, the second chamber tapers towards the dispersion outlet. For example, at least parts of the second chamber towards the dispersion outlet can be arcuate or conical. These embodiments ensure that no droplets are trapped and all can be collected directly via the dispersion outlet.

In some embodiments, the first chamber has the shape of a hemisphere or a truncated cone. Typically, the hemisphere or truncated cone opens towards the membrane, i. H. the largest radius is typically closest to the membrane. The term "hemispherical" as used herein also includes other spherical segments, such as. B. a third of a sphere. Thus, in some embodiments, the shape of the first chamber is a spherical dome or segment of a sphere. If the first chamber has the shape of a spherical segment and/or in particular a hemispherical shape, the first inlet can preferably be arranged adjacent to or in the region of a pole of the spherical segment of the first chamber, in particular the hemispherical first chamber. Shapes of this type have the advantage that the material flow of the core-forming emulsion is distributed evenly over the first side of the membrane and thus contributes to an even pressure distribution in the vicinity of the individual channels. The first inlet can e.g. B. substantially perpendicular to the central longitudinal axis, i. H. essentially parallel to the first side of the membrane, or also parallel to the central longitudinal axis, i. H. perpendicular to the first side of the membrane.

In some embodiments, the first inlet is at an angle of substantially 90° or less to the channels of the membrane. As a rule, all of the channels are arranged essentially parallel to one another. This has the beneficial effect of not directing the nucleating emulsion directly onto the membrane, further allowing for an even pressure distribution across each channel of the membrane. The angle between the first inlet and the channels of the membrane can e.g. B. between 60 ° and 90 °, in particular between 75 ° and 90 °. Preferably, the first inlet is substantially transverse, preferably perpendicular, to the plurality of channels of the membrane. In such embodiments, the first inlet can thus run parallel to the first side of the membrane.

In further embodiments, the device comprises a membrane holder for fastening the membrane.

In certain embodiments, the device comprises a container holder for holding the container, which partially forms the second chamber. The container holder can be firmly and detachably connected to the membrane holder. The container holder and/or the membrane holder and/or the base can be made of any suitable material, e.g. B. from a plastic such as PTFE, polymethyl (meth) acrylate or polyoxymethylene, or from a metal, preferably steel.

When the container is a glass container, a cushioning pad may preferably be interposed between the glass container and the container holder to prevent the glass container from being damaged and to seal the same.

In some embodiments, the membrane holder comprises clamping means for fastening the membrane, the membrane holder and/or the clamping means being configured to accommodate membranes of different thicknesses. Typically the clamping means may be adjustable. Examples of clamping means are screws, clamps, bolts, locks, etc.

In some embodiments, the device includes a base, and preferably the first chamber is formed in part by the base.

In further embodiments, the base and/or the membrane holder comprises at least one seal for sealing the membrane against the base and/or the membrane holder. The sealing ring can be designed in such a way that it completely encloses the circumference of the membrane. The seal ring may also include a gas outlet in fluid communication with the first chamber and configured to vent any gas present in the first chamber from the first chamber.

In some embodiments, the base and/or membrane holder includes a spacer ring. Such a spacer ring allows the use of membranes of different thicknesses.

In some embodiments, the first chamber comprises a gas outlet, in particular a fluidic switch such as. B. a valve. The gas outlet and the membrane are arranged in such a way that the gas in the first chamber is conducted to the gas outlet during the feeding of the core-forming emulsion into the first chamber, in particular during the first/first filling of the first chamber with the core-forming emulsion, and out via the gas outlet the first chamber is discharged. In some examples, the membrane is tilted with respect to the central longitudinal axis of the device. Thus, 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 other than 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 arranged at the upper edge of the first chamber, which is formed by the membrane and another chamber wall. This ensures that residual gas, in particular air, that is in the first chamber, for example before the device is used, rises to the membrane and, due to the inclined arrangement of the membrane, is guided to the upper edge and thus to the gas outlet. Normally, the channels of the membrane are too narrow to allow air to pass, and therefore a gas vent as described in the foregoing allows removal of all remaining gas which would otherwise adversely affect uniform droplet size and distribution or the first liquid thereon would prevent reaching all microchannels, thereby reducing throughput. Typically, the gas outlet may be in fluid communication with the environment of the device.

In some embodiments, the device comprises at least one heater for heating the nucleating emulsion and/or the second aqueous solution and/or at least one cooler for cooling the nucleating emulsion and/or the second aqueous solution. It can be advantageous to heat or cool one of the two phases, since the hardening of the dispersed droplets produced can easily be effected by a change in temperature, e.g. B. 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 up to 100°C, up to 125°C or up to 150°C. For example, the heater may be a heating bath such as a water bath or an oil bath. Alternatively, the heater can also be an IR radiator, a heating coil or another suitable heating device.

In further embodiments, the device comprises a first reservoir for the nucleating emulsion and/or a second reservoir for the second aqueous solution. Both the first and the second container can be pressurized. For example, the containers may be connected to a pressure source such as a compressor. Alternatively, the containers may be syringes and pressurized by a conventional syringe pump and/or plunger or peristaltic pump, gear pump or other pumping system.

In some embodiments, a flow restrictor is positioned between the second reservoir for the second aqueous solution and the second chamber. Such a flow limiter is advantageous since the second chamber generally does not offer any significant flow resistance for the second aqueous solution. By using a flow restrictor, the device becomes more stable, since unwanted pressure differences, e.g. B. by fluctuating air pressure can be avoided.

In further embodiments, the second inlet comprises a supply channel which is arranged at least partially in the circumferential direction around the central longitudinal axis, or around the axis which is arranged perpendicularly to the first and second sides of the membrane and which intersects the center of the membrane. The delivery channel includes one or more openings into the second chamber. Arranged at least partially in the circumferential direction around the above-mentioned axis means that the supply channel has the contour of a pitch circle, e.g. B. a semicircle or a third of a circle, etc. may have. Preferably, the supply channel is disposed entirely circumferentially about the central longitudinal axis, which axis is perpendicular to the membrane and intersects the center of the membrane. In such embodiments, the supply channel forms an annular structure. The supply channel preferably has a plurality of openings into the second chamber, which in particular are distributed essentially uniformly along the circumference of the supply channel. Typically, the one or more openings of the feed channel may be arranged towards the dispersion outlet, i.e. such that the openings face the dispersion outlet. Embodiments with a feed channel have the advantage that the second aqueous solution can be introduced into the second chamber evenly and gently without causing harmful turbulence that negatively affects the uniform shape and size distribution of the microdroplets produced. In some embodiments, the one or more openings of the feed channel are arranged such that a vortex is created when the second aqueous solution is introduced into the second chamber. In particular, the one or more openings may be tubular and the longitudinal axis of each tubular opening may be inclined with respect to the central longitudinal axis of the device. Typically, all tubular openings are equally inclined. The creation of a vortex is advantageous because, firstly, a surface stabilizer, which can generally be contained in the first and/or second aqueous solution, can be distributed more evenly, which increases the stability of the dispersion formed, and secondly, the transport of the dispersion produced in the direction of the dispersion outlet is accelerated, which is particularly advantageous when the densities of the first and second aqueous solutions are substantially the same.

Typically, the supply channel is at the bottom of the second chamber, i. H. next to the membrane. The supply channel can, for. B. also be arranged in surrounding around the membrane. The supply channel can have a diameter of 2 mm to 100 mm, preferably 5 mm to 20 mm.

Alternatively, the second inlet can also be a single inlet opening directly into the second chamber, preferably from one side of the second chamber.

In a second aspect, the general technical task is achieved by an assembly of capsules, in particular microcapsules, comprising a plurality of capsules produced according to the method of any of the embodiments described herein.

In some embodiments of the capsule arrangement, the capsules have a uniform size distribution with a coefficient of variation of 10% or less, in particular 8% or less, in particular 6% or less, in particular 5% or less, in particular 4% or less .

Those skilled in the art will understand that the coefficient of variation can be calculated by the ratio of the standard deviation to the mean µ, i.e. the average capsule size, of the capsules of the unit.

In some embodiments, the totality of the capsules comprises more than 50 capsules, in particular more than 100 capsules, in particular more than 500 capsules, in particular more than 1000 capsules, in particular more than 10,000 capsules, according to the method according to one of those described here embodiments were made.

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

In some embodiments, the array capsules, in particular all array capsules, have a maximum difference of 1% with respect to a perfect sphere. In particular, the surface of the capsules has a maximum difference of 5% or even a maximum of 1% with respect to a perfect sphere.

In a third aspect, the general technical problem is solved by a dispersion of microdroplets. The dispersion comprises an aqueous continuous phase and microdroplets of a dispersed phase. Typically, the dispersion can be carried out by steps a. to c. of the method according to one of the embodiments of the first aspect of the invention. Each microdroplet of the dispersed phase is a microemulsion of an aqueous dispersed phase in an oil phase. Thus, most of the material of each microdroplet is made up of the oil phase. In general, the oil phase may constitute at least 50%, at least 60% or at least 70% by weight of the nucleating emulsion. The aqueous dispersed phase of each microdroplet comprises water and a dissolved gelation inducing agent. In addition, each microdroplet also contains a first surfactant. The aqueous dispersed phase can typically be the aqueous dispersed phase obtained in step a. of the method according to one of the embodiments of the first aspect of the invention. The dispersion of micro-droplets also includes a second surfactant.

In some embodiments, the oil phase contains at least one compound of interest. The compound of interest can be selected from a protein, a small molecule, particularly a fragrance or flavor, a pharmaceutical agent such as cannabinoids, hemp extracts, caffeine, melatonin or hyaluronic acid, antibodies, peptides, enzymes, RNA, DNA, vitamins and microorganisms.

In some embodiments, the first surfactant is a nonionic surfactant, such as polyglycerol polyricinoleate (PGPR) or Span derivatives, such as Span 80 or Span 85. Additionally, the first surfactant can be a solid particle, preferably hydrophobic, hydrophilic, depending on the application or Janus-type particle configured to give a Pickering emulsion. The solid particle can be, for example, colloidal silica.

The first surfactant, in particular the nonionic surfactant, preferably has a molecular weight of between 600 and 120,000 g/mol, preferably between 800 and 80,000 g/mol.

[0115] Nonionic surfactants have proven to be suitable for sufficiently stabilizing the microdroplets of the aqueous dispersed phase in the core-forming emulsion. PGPR has been found to be advantageous as it sufficiently stabilizes the nucleating emulsion that the microdisperse droplets of the aqueous dispersed phase are not immediately destroyed, particularly during passage of the emulsion through the channels, but also does not stabilize the microdroplets too much as this the efficiency of the diffusion process of the gelation inducing agent to the interface of the droplet in step e. reduced so that it can react with the matrix-forming agent.

In some embodiments, the amount of the first surfactant in the nucleating emulsion is between 0.03% and 0.15% by weight, preferably between 0.05% and 0.10% by weight.

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

Typically, the first surfactant and the second surfactant are different and thus not identical.

In some embodiments, the second surfactant is selected from polyvinyl alcohol (PVA), a polysorbate such as Tween 20 or Tween 80, saponins, sapogenins, i. H. Quillaja Extract, Gum Arabic, Beta-Lactoglobulin, Sodium Lauryl Sulfate, Soy Lecithin, Sodium Cesinate, Potato Protein Isolate, Whey Protein Isolate and Starch Octenyl Succinate. Preferably polyvinyl alcohol, a polysorbate such as Tween 20 or Tween 80, beta-lactoglobulin and starch octenyl succinate. A relatively thick and stable shell was obtained with polyvinyl alcohol, a polysorbate such as Tween 20 or Tween 80, beta-lactoglobulin and starch octenyl succinate compared to other second surfactants. Additionally, polyvinyl alcohol provided excellent monodispersity of the nucleating emulsion droplets in the second aqueous solution. Additionally, the second surfactant can be a solid particle, preferably a hydrophobic, hydrophilic, or Janus-type particle, depending on the application, configured to provide a Pickering emulsion. The solid particle can be, for example, colloidal silica.

In some embodiments, the gelation-inducing agent is an agent as disclosed in relation to the first aspect of the invention. In some embodiments the gelation-inducing agent is thus an inorganic salt as disclosed in relation to the first aspect of the invention, in particular an alkaline earth metal salt, in particular an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate or an alkaline earth nitrate.

In a fourth aspect, the invention comprises a device for producing capsules with a matrix shell enclosing an oil core, the device comprising: a. A first inlet (2) for feeding a nucleating 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) opens; b. a second inlet (3) for supplying a second aqueous solution, the aqueous solution comprising water and a second surfactant, the second inlet (3) opening into a second chamber (5); c. a dispersion outlet (6) for collecting the dispersion or micro-droplets from the second chamber (5); i.e. One or more channels (10), preferably microchannels, the one or more channels (10) fluidly connecting the first chamber (4) to the second chamber (5); e. A gelling vessel (105), preferably fluidly connected to the dispersion outlet (6), the gelling vessel comprising an aqueous shell-forming solution, the aqueous shell-forming solution comprising water and a water-soluble matrix-forming agent.

It is to be understood that the device of the fourth aspect of the invention may also include the embodiments for the device described in relation to the first aspect of the invention, i.e. the device used in the method according to the first aspect of the invention can be used.

In some embodiments, the device may comprise a mixing vessel, preferably with a stirrer, for mixing a nucleating emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase containing water and a dissolved gelation inducing agent and the emulsion also containing a first contains surfactant. The mixing vessel can be fluidically connected to the first inlet of the device, which is open into the first chamber. Preferably the mixing vessel comprises at least one oil phase and optionally already the nucleating emulsion of the aqueous dispersed phase in the oil phase.

In a fifth aspect, the general objective technical problem is solved by a capsule produced by any of the embodiments of the method of the first aspect of the invention.

In a sixth aspect, the general object is achieved by a method for producing capsules with a matrix shell enclosing an oil core, the method comprising the steps of: a. providing in a first chamber a nucleating emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase comprising water and a dissolved matrix-forming agent, the emulsion also containing a first surfactant; b. providing a second aqueous solution in a second chamber, the aqueous solution containing water and a second surfactant.

The first chamber and the second chamber are fluidly connected by one or more channels, preferably microchannels. The method further includes steps c. passing the nucleating emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleating emulsion of step a. in the second aqueous solution of step b. to build; i.e. mixing the in step c. formed dispersion with an aqueous shell-forming solution, the aqueous shell-forming solution containing water and a water-soluble gel-inducing agent.

The gelation-inducing agent and the matrix-forming agent are configured such that they are capable of chemically reacting with one another to form a water-insoluble matrix shell. The method further includes the step e. reacting the gelation-inducing agent and the matrix-forming agent in the step c. formed dispersion to form capsules of a water-insoluble matrix shell enclosing an oil core.

It goes without saying that the method according to the sixth aspect of the invention can also comprise the embodiments described in relation to the first aspect of the invention.

Brief description of the figures

The invention described herein will be better understood from the following detailed description and the accompanying drawings, which should not be taken as limiting the invention described in the appended claims. The drawings show: FIG. 1 A schematic representation of the method according to the invention; 2 shows a schematic view of an apparatus for producing a dispersion of a nucleating emulsion in a second aqueous solution according to a first embodiment of the invention; Figure 3 is a cross-sectional view of the device shown in Figure 2; Fig. 4 is an exploded view of the device shown in Fig. 2, partially cut away; 5 shows a schematic view of a device 1' according to another embodiment of the invention; 6 shows a schematic enlarged view of a second side of a membrane according to an embodiment of the invention; Fig. 7 is a partial cross section of a device according to another embodiment of the invention; 8 shows a cross section through a device according to another embodiment of the invention; Figure 9 shows another device that can be used in the method according to an embodiment of the invention; Fig. 10 shows microscopic images of capsules produced by the method of the invention; Figure 11 shows the size distribution of an array of capsules according to an embodiment of the invention.

DESCRIPTION OF THE EMBODIMENTS

The method according to an embodiment of the invention is shown schematically in FIG. In a first step, a nucleating emulsion is created by mixing a solution 101 containing a gelation inducing agent and water with the oil phase 102 (Figure 1a). This can be done with a stirrer 103, for example. Figure 1a) also shows an enlarged view of a droplet of solution 101 in the emulsion. The straight lines of the droplets represent droplets containing water and the gelation-inducing agent, e.g. B. an inorganic salt A<+>B<-> included. Each droplet shown in Figure 1a) is thus an aqueous solution of the gel-inducing agent. The formed emulsion of the aqueous solution 101 of the gel-inducing agent in the oil phase 102 is then introduced into the first chamber 4 of a suitable device (Figure 1b). 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 fluidically connected by a plurality of channels 10 . In the embodiment shown, the first and second chambers are separated by a membrane 7, the first side 8 of which faces the first chamber and the second side 9 of which faces the second chamber. The channels 10 extend from the first side 8 to the second side 9. In general, an appropriate pressure is applied to the nucleating emulsion in the first chamber 4. The emulsion in the first chamber 4 is then passed through the channels 10. Since the emulsion generally contains the oil phase 102 as a main component, gradual emulsification takes place when the emulsion reaches the channel outlet opening into the second chamber 5, resulting in a dispersion of the core-forming emulsion, i. H. monodisperse droplets 103 in the second aqueous phase 104 is formed. Note that the size of the droplets is exaggerated for clarity. In addition, the relative size of the droplets 101 in relation to the droplets 103 and/or 106 does not correspond to reality. Each monodisperse droplet 103 in the second chamber 5 now comprises one or more droplets 101 dispersed in the oil phase 102, as illustrated in the enlarged view of a droplet. Thus, the dispersion in the second chamber 5 can be viewed as a "water-in-oil-in-water 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 in the gelling vessel 105, which is equipped with a stirrer 107. When the dispersion of the nucleating emulsion, i. H. the monodisperse droplets 103 in the second aqueous phase 104, is mixed with the aqueous shell-forming solution 108, the gelation-inducing agent in the droplets 103 diffuses to the droplet surface and then chemically reacts at the interface with the matrix-forming agent to form a water-insoluble matrix shell that grows completely around each droplet, forming capsules 106 from a water-insoluble matrix shell enclosing an oil core.

FIG. 2 shows a device 1 which can be used in a method according to the invention, in particular for producing a dispersion of the core-forming emulsion in the second aqueous solution. The device 1 comprises a container 19 made of glass and a base 14 made of metal. The base 14 includes a first inlet (not shown, see Figure 2) for the supply of a nucleating emulsion, which opens into a first chamber. The first chamber may be formed in part by the base 14 and the membrane 7 (see Figure 3). The tank 19 comprises a second inlet 3 for feeding the second aqueous solution 104, which opens into a second chamber, and a dispersion outlet 6 for collecting the dispersion produced in the second chamber. The second chamber is formed by the container 19 and the membrane 7 (see Figure 3). The device 1 also comprises a membrane holder 20 which is firmly connected to the base 14 . In addition, the device contains a container holding structure 21 which is fixedly connected to the membrane holder 20 via clamping means 18 . As a result, the container 19 is firmly connected to the base 14.

FIG. 3 shows a cross-sectional view of the device 1 from FIG. 2. The device 1 comprises a base 14 with a first inlet 2 for the supply of the core-forming emulsion. The inlet 2 opens into the first chamber 4, which is partially formed by the base 14. The apparatus 1 further includes a tank 19 having a second inlet 3 for feeding the second aqueous solution 104 and a dispersion outlet 6 for collecting the dispersion of the nucleating emulsion in the second aqueous solution. The second inlet 3 opens into the second chamber 5, which is partially formed by the container 19. The first chamber and the second chamber are separated by a membrane 7. As can be seen from Figure 2, the first chamber has a rounded cross-section with respect to the corresponding cross-sectional plane along the central longitudinal axis 15 and perpendicular to the membrane 7. In the illustrated embodiment, the first chamber 4 has a semi-circular cross-section and can thus have the shape of a hemisphere. The first inlet 2 is arranged in the area of the pole 13 of the hemisphere. The second chamber 5 tapers towards the dispersion outlet 6, which is arranged on a longitudinal axis 15, which extends longitudinally of the device and intersects the center of the first and second chambers, and is perpendicular to the membrane 7 and intersects the center of the membrane. As can be seen, the longitudinal axis 15 forms a central longitudinal axis of the device. In the embodiment shown, the second chamber is arcuate towards the dispersion outlet 6 . The second chamber 6 thus has a U-shaped cross section. The first inlet 2 is arranged at an angle α of substantially 90° to the central axis 15 and the channels of the membrane which are generally parallel to the axis 15 . The device 1 comprises a membrane holder 20 and a container holder 21 which are firmly connected to one another via detachable clamping means 18 . The membrane 7 is attached to the membrane holder 20 by clamping the membrane between the membrane holder 7 and the base 14 . The membrane holder 20 is firmly connected to the base 14 via the clamping means 18 . To securely fix the glass container 19 between the membrane holder 20 and the container holder 21, a pad 23, in the present case a foam pad, can be arranged between the container 19 and the container holder 21. The membrane holder 20 has a groove 22 for receiving the container 19 .

FIG. 4 shows an exploded view of the partially sectioned device 1 from FIG. 2. As can be seen, the first chamber is partially formed by the bottom 14 and has the shape of a hemisphere. The first inlet 2 is arranged at the pole of the hemisphere and is arranged at an angle of essentially 90° to the central axis 15 . The base 14 includes a spacer ring 16 allowing the use of different membranes with different thicknesses and the membrane holder 20 includes a sealing ring 17. The membrane 7 is placed between the rings 16 and 17. The construction of the device 1 with adjustable clamping means 18 enables the use of membranes of different thicknesses. The membrane holder 20 further comprises a peripheral groove 22 for receiving the lower end portion of the container 19. The clamping means 18 firmly and releasably connect the membrane holder 20 to the container holder 21.

FIG. 5 shows a schematic view of a device 1 which can be used according to a preferred embodiment of the invention. The second chamber 5 is formed by the container 19 and the membrane 7 separating the first chamber 4 from the second chamber 5 . The tank 19 includes a dispersion outlet 6 in fluid communication with the product tank 29 and the waste tank 30 . In general, the liquid flow can be controlled by a valve, such as a valve. B. a three-way valve can be controlled. The device 1 further comprises a first reservoir 24 which is in fluid communication with the first chamber 4, which can be used either only as a reservoir for the supply of the nucleating emulsion into the first chamber 4 via the first inlet 2 or also as a mixing vessel for the preparation of the nucleating Emulsion can serve. A flow meter for measuring the liquid flow of the core-forming emulsion is arranged between the first reservoir 24 and the first inlet 2 . The first reservoir 24 is in fluid communication with the pressure source 32. A pressure regulator 27a is also arranged between the first container 24 and the pressure source 32. In addition to the first reservoir 24, the device 1 comprises a flushing reservoir 31 which is also in fluid communication with the first chamber 4 and the pressure source 32. The rinsing tank 31 is configured to supply a rinsing solution to the first chamber 4 to clean the device 1 after use. If a rinsing solution is supplied to the first chamber 4, the three-way valve arranged between the product container 29 and the waste container 30 and the dispersion outlet 6 is generally designed in such a way that the rinsing solution can flow into the waste container 30. The product container 29 can, for example, serve directly as a gelling vessel. Alternatively, it can serve as an intermediate store before the dispersion formed is mixed with the aqueous shell-forming solution. The device 1 further comprises a heating device 33, which is used to heat the first and second chambers during the production of a dispersed phase. In addition, the second chamber 5 is in fluid communication with the second reservoir 25 for supplying the second chamber 5 with the second aqueous solution. Flow limiter 26 and flow meter 28 are arranged between the second chamber 5 and the second reservoir 25 . In the embodiment shown, the flow restrictor 26 is arranged behind the flow meter 28 in the direction of flow. The second reservoir 25 is also in fluid communication with the pressure source 32. In addition, a second pressure regulator 27b is positioned between the second reservoir 25 and the pressure regulator 27a.

FIG. 6 shows a single-layer membrane 7 for producing a dispersion of a nucleating emulsion in a second aqueous solution, which can be used in a method and/or a device as described in one of the embodiments disclosed herein. The membrane 7 has a first side 8 (not shown) and a second side 9 which, in an operative state, faces a second chamber. A plurality of microchannels 10 extend through the membrane 7. Each channel 10 has an elliptical contour. In addition, the membrane 7 comprises a membrane sealing ring 44 which completely surrounds the periphery of the membrane.

FIG. 7 shows a partial cross-sectional view of a device that can be used in an embodiment of the invention. The device 1 has a first inlet 2 for feeding a nucleating emulsion, which opens into a first chamber 4 with a rounded cross-section. In the embodiment shown, the first chamber 4 has the shape of a spherical segment with a radius at the base of the dome that is smaller than the radius of the corresponding hypothetical solid sphere. The second chamber 5 is at least partially delimited by the container 19 . The device further comprises a dispersion outlet 6 for collecting the generated dispersion of the nucleating emulsion in the second aqueous solution. The corresponding membrane is not shown for better illustration. In the illustrated embodiment, the second inlet opening to the second chamber 5 comprises a supply channel 34 which is arranged circumferentially around the central longitudinal axis 15 and/or around the axis which runs perpendicular to the first and second sides of the membrane and intersects the center of the membrane. The feed channel 34 comprises a large number of openings 35 into the second chamber 5. The openings 35 are distributed evenly over the circumference of the feed channel and are arranged in the direction of the dispersion outlet 6. In the illustrated embodiment, the supply channel 34 forms an annular structure located at the bottom of the second chamber 5, i. H. at the edge of the membrane and the container 19, is arranged. In the embodiment shown, the supply channel has an angular cross-section. Alternatively, the supply channel can also have a rounded, in particular circular, cross section.

FIG. 8 shows a cross-sectional view of another embodiment of the device shown in FIG. The device 1 has a first inlet 2 for the supply of a nucleating emulsion, which opens into a first chamber 4 with a rounded cross-section. In the illustrated embodiment, the first chamber 4 has the shape of a segment of a sphere. A membrane 7 separates the first chamber 4 from the second chamber 5. In contrast to the embodiment shown in FIG. The acute angle in a cross-sectional view along the central longitudinal axis between the central longitudinal axis and the second side of the membrane is between 45° and 89°, preferably between 70° and 88°, more preferably between 78° and 87°. The device 1 additionally comprises a gas outlet 36. The gas outlet and the membrane are arranged in such a way that gas within the first chamber is conducted to the gas outlet during the feeding of the core-forming emulsion into the first chamber, in particular during the first filling, and out via the gas outlet 36 the first chamber 4 is discharged. As can be seen, the gas outlet 36 is arranged at the upper edge of the first chamber 4, which is formed by the membrane 7 and the chamber wall, which is part of the bottom 14. Before the first chamber 4 is filled with the core-forming emulsion, there is gas, in particular air, in the first chamber. After the first chamber 4 has been filled with the core-forming emulsion, the air is forced out of the gas outlet 36 . Due to the arrangement of the membrane 7 and the gas outlet 36, essentially all of the gas can be removed from the first chamber 4. Since the remaining gas, in particular the gas bubbles, affect the pressure distribution, the size and particle distribution becomes more uniform.

FIG. 9 shows a sectional illustration of a further device which can be used in the method according to the invention (cf. FIG. 1b). The device comprises a first chamber 4 which is in fluid communication with a second chamber 5 via microchannels 10 . Thus, a nucleating emulsion of an aqueous dispersed phase in an oil phase can be provided in the first chamber, the aqueous dispersed phase comprising water and a dissolved gelation inducing agent, the emulsion further containing a first surfactant. This emulsion is then passed via microchannels 10 from the first chamber to the second chamber 5 containing a second aqueous solution, the aqueous solution containing water and a second surfactant.

Figure 10a shows a microscopic photograph of capsules which were produced using the method according to the invention with a uniform size distribution and an average core diameter of 270 μm have an average core diameter of 550 µm.

[0140] FIG. 11 shows the size distribution of an arrangement of alginate capsules with an MCT oil core according to an embodiment of the invention. The size distribution on the left shows the distribution of shell thickness across the capsules. The average shell thickness of the capsules of the assembly is 94 µm. The middle diagram shows the average diameter of the oil core of each of the capsules of 265 µm and a coefficient of variation of 2.4%. The right diagram shows the total size distribution of the capsules of the assembly, i.e. twice the shell thickness and the oil core diameter. The average particle size of the capsules is 453 µm with a coefficient of variation of 3.9%.

The table below shows suitable formulations that can be used in the method according to the invention:

Table 1: Generation of the nucleating emulsion from an aqueous dispersed phase in an oil phase

Water 20-30 CaCl2 2-5 PGPR 0.03-0.15 Sunflower Oil 64.85-77.97

Table 2: Production of the aqueous shell-forming solution that leads to capsules with a core size of >270 µm

Sodium alginate 0.1-2 ethanol 10-20 water 78-89.9

Table 3: Preparation of the aqueous shell-forming solution that leads to capsules with a core size of <270 µm

Sodium alginate 0.1-2 ethanol 21-30 water 68-78.9

The second aqueous phase is a 1% by weight solution of PVA in water.

Claims (11)

1. Process for the production of capsules with a matrix shell enclosing an oil core, the process comprising the following steps: a. providing in a first chamber a nucleating emulsion of an aqueous dispersed phase in an oil phase, the aqueous dispersed phase comprising water and a gelation inducing agent, the emulsion also containing a first surfactant; b. providing a second aqueous solution in a second chamber, the aqueous solution containing water and a second surfactant; wherein the first chamber and the second chamber are fluidly connected by one or more channels, preferably by microchannels; the method further comprising c. passing the nucleating emulsion of step a. from the first chamber through the one or more channels into the second chamber to form a dispersion of the nucleating emulsion of step a. in the second aqueous solution from step b. to build; i.e. mixing the in step c. 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 undergoing a chemical reaction with one another to form a water-insoluble matrix shell; the method further comprising: e. reacting the gelation-inducing agent and the matrix-forming agent in the step c. formed dispersion to form capsules of a water-insoluble matrix shell enclosing an oil core. 2. The method according to claim 1, wherein the oil phase in step a. additionally contains at least one compound of interest. 3. The method according to claim 1 or 2, wherein step a. the sub-steps a1. dissolving the gelation inducing agent in water to form a solution, and a2. mixing the formed solution with the oil phase and with the first surfactant. 4. The method according to any one of the preceding claims, wherein after step c. those in step c. dispersion formed is placed in a gelling vessel containing the aqueous shell-forming solution from step d. and optionally further comprising stirring the formed dispersion of nucleating emulsion from step a. in the aqueous solution from step b. and the aqueous shell-forming solution within the gelling vessel. 5. The method according to any one of the preceding claims, wherein the first surfactant is a nonionic surfactant such as polyglycerol polyricinoleate (PGPR) or Span derivatives such as Span 80 or Span 85 and / or wherein the second surfactant is selected from polyvinyl alcohol (PVA), a Polysorbate such as Tween 20 or Tween 80, saponins, sapogenins such as Quillaja extract, gum arabic, beta-lactoglobulin, sodium dodecyl sulfate, soy lecithin, sodium caesinate, potato protein isolate, whey protein isolate, starch octenyl succinate, preferably polyvinyl alcohol, a polysorbate such as Tween 20 or Tween 80, beta-lactoglobulin and starch octenyl succinate. 6. The method according to any one of the preceding claims, wherein the matrix-forming agent is a polysaccharide or a salt thereof and / or wherein the gelation-inducing agent is an inorganic salt, in particular an alkaline earth metal salt, in particular an alkaline earth metal halide, an alkaline earth metal pseudohalide, an alkaline earth metal carboxylate or an alkaline earth metal nitrate, or a is an alkali metal halide, an alkali metal pseudohalide, an alkali metal carboxylate or an alkali metal nitrate. 7. The method according to any one of the preceding claims, wherein after step e. the capsules are coated with an additional layer by dip coating and optionally the capsules are coated with two or more additional layers. 8. Arrangement of capsules, in particular microcapsules, comprising a large number of capsules which have been produced by the method according to any one of claims 1 to 7. 9. An array of capsules according to claim 8, wherein the capsules have a uniform size distribution with a coefficient of variation of 10% or less. 10. 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, the aqueous dispersed phase comprising water and a dissolved gelation inducing agent, each microdroplet further comprising a first surfactant; and wherein the dispersion of micro-droplets further comprises a second surfactant. 11. Device for the production of capsules with a matrix shell which encloses an oil core, the device comprising: a. A first inlet (2) for feeding a nucleating emulsion of an aqueous dispersed phase in an oil phase, said aqueous dispersed phase comprising water and a dissolved gelation inducing agent, said emulsion further comprising a first surfactant, said first inlet (2) in a first chamber (4) opens; b. a second inlet (3) for supplying a second aqueous solution, the aqueous solution comprising water and a second surfactant, the second inlet (3) opening into a second chamber (5); c. A dispersion outlet (6) for collecting the dispersion or micro-droplets from the second chamber (5); i.e. One or more channels (10), preferably microchannels, the one or more channels (10) fluidly connecting the first chamber (4) to the second chamber (5); e. A gelling vessel (105), preferably fluidly connected to the dispersion outlet (6), the gelling vessel comprising an aqueous shell-forming solution, the aqueous shell-forming solution comprising water and a water-soluble matrix-forming agent.