EP1722885A1

EP1722885A1 - Method and device for the production of storage stable multi-micro-capsules comprising adjustable synergistically active functional content components

Info

Publication number: EP1722885A1
Application number: EP04714281A
Authority: EP
Inventors: Erich Windhab
Original assignee: Eidgenoessische Technische Hochschule Zurich ETHZ
Current assignee: Eidgenoessische Technische Hochschule Zurich ETHZ
Priority date: 2004-02-25
Filing date: 2004-02-25
Publication date: 2006-11-22
Also published as: WO2005079969A1

Abstract

The invention relates to a method and to a device for the production of multi-componented capsule systems (= multi-microcapsule), wherein two or several functional substances/substance components are encapsulated in a spatially separated manner, such that during storage, interaction of the encapsulated components is prevented, but when said multi-capsules are administered, the encapsulated substances and/or substance components are released in a targeted simultaneous or successive manner, according to the field in which they are used, and optionally, the rate of release and synergistic interaction thereof is adjusted. The inventive method and/or associated device enable the multi-microcapsules, wherein several functional substances/substance components are surrounded by means of one and/or several material layers having defined mechanical, thermal and physico-chemical and/or biochemical stability properties, which are adapted to the conditions of use of the place of release of the encapsulated functional substances/substance components in addition to the kinetic release thereof and to synergistic interaction, to be received.

Description

Method and device for producing storage-stable multi-microcapsules with adjustable, synergistically effective functional content components

Description genus

The invention relates to methods and devices for producing multi-microcapsules.

task

The invention has for its object to provide a method by means of which it should be possible to encapsulate functional substances / substance components with respect to a pharmacological / medical and / or nutritional effect in such a way that on the one hand they show no interactions under storage conditions and on the other hand, when applied in accordance with the ambient conditions, a defined adjustable release of the encapsulated substances / substance components with regard to the time of release and release rate, as well as a synergistic interaction.

For example, in the case of oral absorption into the digestive tract of the human being, the release of one or more of the encapsulated functional substances / substance components should be adjustable at a specific location in the digestive tract and with a certain release rate of the substances / substance components and a synergistic interaction between the different released substance components should take place in such a way that that this leads to an improvement in bioavailability or active ingredient intake in the human organism.

Furthermore, the invention has for its object to provide a suitable device for performing the method according to the invention.

Solution to the problem regarding the procedure

The object is achieved by the features set out in claims 1, 2, 17 or 18. Other embodiments

Further inventive embodiments of the procedure according to the invention are described in claims 3 to 17.

Some advantages

By means of the method according to the invention, several substances / substance components with functional properties can be integrated into a "multi-microcapsule" such that there is no interaction of the encapsulated substances / substance components during the storage of such ICapsules, i.e. Storage stability is guaranteed.

A further significant advantage results from the spatial proximity of the substances / substance components fixed in a microcapsule, since this leads to their release from the microcapsule for contact and, as a result of the appropriate substance / substance component combination, for targeted synergistic interactions.

Another advantage is the setting according to the invention of the time of release and the rate of release of encapsulated functional substances / substance components by a suitable choice coordinated with the environmental conditions during use, which is based on these functional Capsule materials forming shell layers, as well as their layer thickness and microstructure.

In the fields of pharmaceuticals / medicine, cosmetics and nutrition, functional substances / substance components (pharmaceuticals / medicine: pharmaceutical substances, medicines, cosmetics: dermatological substances, food: nutritive substances / substance components) play an increasing role with regard to their defined release, e.g. B. in the gastrointestinal tract of humans in a form or with a release kinetics, which ensure the best possible absorption by the organism or the best possible bioavailability and effectiveness. In many applications, the effectiveness of functional substances / substance components is significantly impaired by their interaction with other substances that are in the digestive tract. Such undesirable interacting substances in the digestive tract can originate from food and can also be part of the digestive system. For example, iron remedies taken to remedy iron deficiency symptoms under the general conditions in the stomach of humans (low pH values), as well as by oxidation effects when interacting with e.g. B. oxidized phytic acids from plant foods or dairy products, so impaired in terms of their absorbability in the small intestine and thus limited in bioavailability. This raises the question of the possibilities of transporting functional substances / substance components on the one hand without damage to the place of the desired release and absorption and on the other hand to optimize the absorption conditions at the place of release.

The concept according to the invention (method and device) provides such optimization options due to the encapsulation methodology according to the invention of several functional substance / substance components in a multi-capsule.

Solution of the problem regarding the device

This object is solved by the features of claim 19.

Further features and advantages emerge from the following description of the drawing, in which the invention is illustrated, for example, in part schematically. Show it:

1 shows a multi-microcapsule morphology in a roughly schematic representation;

2 shows a process diagram; 3 crystalline functional material phases with surrounding amorphous layer and additional outer amorphous boundary layer;

Fig. 4 shows the representation of multi-microcapsules in foods with fat matrix in the digestive tract and

Fig. 5 shows a device according to the invention.

The complex structure of the multi-microcapsules according to the invention is shown in FIG. 1. The abbreviations used in the text below can be found in Figure 1 and Table 1 (nomenclature overview; Appendix).

According to the invention, multi-microcapsules are made up of subcapsules (SKi) with i = 1 to n different encapsulated functional substances / substance components (FSi; i = index 1 ... n) by embedding these SKi in a main capsule matrix phase (HKMP). This HKMP is chosen in such a way that a diffusion-based exchange of the encapsulated functional substances / substance components (FSi) is largely prevented. According to the invention, the FSi are preferably used in solid, crystalline or partially crystalline form. In pre-encapsulation steps, the FSi is first embedded in a subcapsule matrix phase (SKMPi). According to the invention, these SKMPi are chosen opposite to the FSi in terms of their hydrophilicity / hydrophobicity. The molecular structure of the SKMPi is preferably largely amorphous (glass-like), crystalline / semi-crystalline or gel-like using the SKMP-specific manufacturing process. If necessary, additional boundary surface layers (GFi) are created by means of surface-active substances as diffusion barriers between FSi and SKMPi and between SKMPi and HKMP. Such an interface layer can also surround the main capsule as a surface layer (GFH).

The following sizes of the multi-microcapsule are adapted according to the invention to set the time of release of the SKi and its release kinetics:

Geometric parameters

• Diameter of the FSi particles / drops: a few nanometers-50 micrometers

• Diameter of the subcapsules (SKi): 1 - 200 micrometers • Diameter of the main capsule (HK): a few micrometers - a few millimeters • Thickness of the interface layers (GFi)

• Form of the FSi, SKi and HK (interface enlargement)

Structural parameters • Glass-like, crystalline or gel-like structure of the FSi, SKMPi, HKMP

• Polymorphic form with polymorphic crystalline structures

• Single / multi-phase structure

Physical material parameters • Phase transition temperatures of the FSi, SKMPi and HKMP

• interfacial tension / contact angle between adjacent phases

• Hydrophobicity / hydrophilicity of the phases

• diffusion coefficients • water absorption (aw value, sorption isotherms)

According to the invention, the multi-microcapsules are produced in 4 main steps according to the process scheme described in detail below and shown in FIG. 2. Step 1: PRE-MIXING - First, premix the FSi with the corresponding fluid subcapsule matrix phases (SKMPi). Mixing / stirring systems consisting of tempered mixing tanks and agitators are preferably used for this purpose.

Step 2: DISPERSION - Wet grinding in the case of solid-based FSi / drop dispersion in the case of fluid FSi in an immiscible fluid phase, which corresponds to the sub-capsule matrix phase SKMPi or at least one of its main components, and according to the invention preferably surface-active components GFi for the formation of interface layers (GFSi) between functional ones Substance component FSi and subcapsule matrix phase SKMPi, and optionally network-forming macromolecules (NMSi), which allows the SKMPi to crosslink in a gel-like manner.

Wet grinding is preferably carried out in a ball mill with grinding bodies which are matched in size to the grinding fineness to be achieved and preferably consist of ceramic material. Alternatively, roller or hammer mills can also be used.

The droplet dispersion is preferably carried out in rotor / stator droplet dispersing devices (for example colloid mill or gear rim disperser) or high-pressure homogenizers, more preferably according to the invention Setting a very narrow drop size distribution in the capillary jet expansion flow dispersion channel (K-JetDSDK).

To set the narrowest possible solid particle

/ According to the invention, droplet size distributions of the FSi are preferably additionally followed by a classification step (= separation according to particle Z droplet size) (sub-step to 2) by means of wet sieving (i) or sedimentation separation in the centrifugal field (ii), and the coarse particles / droplets in returned the grinding / dispersing room.

Step 3: SUBCAPSEL PRODUCTION - The subcapsules (SKi) are preferably produced according to the invention by spraying in a suspension / emulsion consisting of the finely ground / finely dispersed, optionally classified and GIF-coated FSi particles / drops suspended / emulsified in the SKMPi , in a cold room (cold spray tower). The temperature of this room is fiction

selected according to preferably <20-50 ° C. below the phase change and / or gel formation temperature of the SKMPi with network-forming macromolecular substances (NMSi) contained therein. According to the invention, the temperature of the spray chamber is selected in such a way that a glass-like / amorphous (1), crystalline (2) or gel-like (3) solidification of the SKMPi takes place.

(1) is achieved according to the invention with water and fat / wax based SKMPi and high temperature gradients, (2) also applies to water and fat / vachs based SKMPi with less high temperature gradients, (3) only refers to water based SKMPi comparatively moderate cooling temperature gradients. If multi-microcapsules are to be stably stored under room temperature conditions, water-based SKMPi are only solidified according to mechanism (3).

The solidified, subcapsules SKi with various encapsulated functional substances / substance components FSi are preferably suspended in a fluid main capsule matrix phase HKMP in a last sub-step of main process step 3. This can be water or fat / wax based. The fluid / solid phase change

HKMP is selected according to the invention preferably> 2-5 ° C below the phase transition temperature of the SKMPi. According to the invention, the HKMP can in turn contain surface-active layer-forming components GSi. These can form layers both at the interfaces between SKMPi and HKMP and at the interface of the main capsule (HK) with the surroundings. In the case of water based According to the invention, macromolecular network formers NMH are also added to HKMP.

Method step 3 is carried out for several different FSi and sub-capsule matrix phases SKMPi matched to them. The resulting suspensions of i subcapsule types in the fluid main capsule matrix phase are mixed in defined ratios. These mixing ratios are matched to the notified application of the main capsules with regard to interactions of the FSi and their concentrations optimized for the specific application (e.g. with regard to the physiological activity intensity).

Step 4: MAIN CAPSULE PRODUCTION - The mixed suspension of i subcapsule types in fluid HKMP, which is defined in terms of the quantitative ratio and concentration of the various SKi and is produced from steps 3, is again sprayed into a cold room in a further process step preferred according to the invention and is then hardened or solidified according to mechanisms. Description solidified in step 3 and thus formed the main capsules. These are removed in powder form at the end of step 4.

The main capsules obtained are stored at temperatures which are below the melting and / or glass transition temperatures the layer-forming substance components or substance component mixtures.

Optional additional / intermediate steps: According to the invention, both the subcapsules and the main capsules can be spray-coated with one or more additional layers.

The fluid phase (s) forming the coatings are sprayed into the cold spray tower as far as below the spray device installed in the head space of the tower for the subcapsule suspensions / emulsions (see step 3) or the main capsule suspensions (see step 4), that the fluid spray droplets of the coating fluids are deposited on the surfaces of the already solidified or partially solidified subcapsules / main capsules, solidify there as a result of heat removal, also as a result of crystallization, glass or gel formation, and form additional enveloping layers.

Alternative process step 2 in the case of fluid FSi: if FSi are to be encapsulated in solution or fluid dispersion, the latter is incorporated according to the invention in the form of disperse drops in an emulsion with a coordinated fluid subcapsule matrix phase SKMPi as a continuous fluid phase containing the FSi immiscible fluid phase. In a first process step, the emulsion is then finely dispersed instead of wet-ground (see solid-based FSi). Depending on the required width of the disperse FSi fluid phases, droplet size distribution, according to the invention, rotor / stator dispersion systems or high-pressure homogenizers (wide droplet size distribution), or laminar nozzle dispersion processes such as e.g. B. Capillary jet expansion flow dispersion channel (K-JetDSDK) (very narrow drops)

size distribution with standard deviation: s «<1%). The

Cold spray to solidify the subcapsule is connected as described in step 3 above. According to the invention, the fluid phase (s) containing FSi are also solidified in the cold spraying process. In principle, they can be retained in fluid form, but are generally not preferred for reasons of stability.

Alternative process steps 3 and 4 for capsule phases / layers to be solidified under the application of heat: In principle, according to the invention, it is also possible to replace the cold spray solidification steps for certain material systems by spray drying steps. The corresponding subcapsule / main capsule phases and / or additional coatings are solidified by thermally induced crosslinking reactions (eg coagulation of protein molecules) and / or drying (eg water removal from biopolymer solutions or concentrated sugar / salt solutions). Here too, the formation of amorphous (glass-like) and / or crystalline layers depending on the drying speed can be set according to the invention. According to the invention, this setting of the drying speed is preferably carried out via the temperature and the moisture content of the drying air.

Possibilities for reducing the complexity of the capsule structure and manufacturing process:

In principle, it is possible to embed several FSi in a solid and / or fluid form in a subcapsule matrix phase. In this case, the main capsule matrix phase may correspond to an additional coating layer. If necessary, this can also be omitted.

Individual encapsulation and an increase in the number of “enveloping layers” (GFi, SKMPi, HKMP) allow on the one hand an improvement in the stability properties of the capsules under storage conditions. On the other hand, these cladding layers allow flexible adaptation to the application boundary conditions.

The aim of the use of microcapsules in general is to transport the functional substances / substance components FSi to the preferred location for their release and to set their release kinetics as defined as possible. An additional aim of the multi-microcapsules according to the invention is to release several FSi in the immediate vicinity at the same time or in a defined sequence, and thus to enable a reaction of these released FSi without significant interferences from material components from the wider environment. The combination of the encapsulated FSi takes place according to the invention in such a way that synergistic interactions are realized. For example, the interaction of an antioxidant (FS1) with a nutritionally or pharmacologically / medically relevant compound (FS2) that is readily soluble in the aqueous digestion medium leads to protection against oxidation of the FS2 and thus to an improved absorption and bioavailability of the FS2.

A plurality of "enveloping layers" around the FSi allows the implementation of specifically adapted protective functions against varying environmental conditions by way of the multi-microcapsule to their "target location" (= location of the FSi release). For example, during transport in the human digestive tract, the following main zones pass through with specific stresses: A. mouth / throat (pH neutral; heavy mechanical stress); B. stomach (pH low; mechanical stress); C. Gastric exit / small intestine (pH neutral; introduction of enzymes (e.g. fat-soluble lipases (bile)). In many cases, there are additional increased requirements for mechanical and temperature stability (eg when preparing dishes that contain the multi microcapsules) before being absorbed into the human gastrointestinal tract.

FIG. 3 shows an example of the microstructure of a subcapsule solidified according to the invention by cold spraying with a glass-like solidified boundary layer and glassy inner lamellar structures with embedded crystal structures corresponding to the FSi phases.

For example, such multi-microcapsules can be used to transport nutritive substance components, such as water-soluble iron salts (1st substance component; FS1), to the small intestine of subjects suffering from iron deficiency, and there these salts are synchronized with an antioxidant (2nd substance component, FS2) from the Release the capsule. The intense interaction of these components in the microenvironment of the capsule will protect the iron salt from oxidation and the iron bioavailability i.e. significantly improve its absorption in the small intestine.

For the selected example, the cladding layers enable the thermal, mechanical, pH and enzymatic stability properties to be set. The corresponding can also be dismantled Wrapping layer may be desired in order to finally ensure the release of the FSi at the destination.

In the human digestive tract, for example, fat-based layers are broken down by the action of lipases and gel layers based on macromolecular networks in water by water-soluble enzymes (e.g. cellulases, proteases) at the stomach exit or in the small intestine. Adjusting the thickness of such layers allows the location of the FSi release e.g. B. move along the small intestine, or affect the FSi release kinetics.

The step-by-step disruption of a multi-microcapsule in the human gastrointestinal tract is shown schematically as an example in FIG.

Device for the production of multi-microcapsule systems

A device according to the invention for the production of multi-microcapsules was configured in accordance with the 4 relevant and the further optional / alternative method steps described above.

This is described below and is shown schematically in detail in FIG. The basic device consists of a pre-mixing system for FSi and subcapsule matrix phase ^) SKMPi (1) from its container (2) by means of a displacement pump (3) either in the case of FSi in solid particle form, a pre-suspension (4a) by a ball mill (5), or in the case FSi in fluid form, a pre-emulsion (4b) is pumped through a drop disperser (6). At 4a / 4b, coarse FSi particles / drops are separated by means of a separating device (7) (e.g. filter or sedimentation stage) and returned to the grinding chamber of the ball mill / dispersion chamber of the droplet dispersion system.

The FSi suspensions / emulsions set in particle or droplet size distribution are fed to a high-pressure cold spray system (9) via a temperature-controlled pipeline (8). In this, the FSi suspension / emulsion is sprayed into fine drops by means of a spray nozzle (10), which are solidified by cooling in a cold gas atmosphere (generated by spraying and evaporating a fluid gas). According to the invention, a suspension container (12) with agitator (13) is installed in the floor space (11) of the conical cold spray tower (9). After they have solidified, the cold-sprayed subcapsules are collected in the temperature-controlled suspension container (12) and suspended in the fluid main capsule matrix phase (HKMP). Surface-active substances (GFi) dissolved in this form surface layers which prevent agglomeration / aggregation of the subcapsules (SK). According to the invention, this subcapsule suspension is fed to a second cold spray tower (15) by means of a pump (14) via a pipeline (31) and also sprayed via a spray nozzle (16) and solidified in a cold atmosphere.

In both cold spray towers, the cold is preferably achieved according to the invention by injecting nitrogen mist from a storage tank (19) which contains liquid nitrogen via nozzles (20, 22). In order to achieve an improved heat transfer from the cold nitrogen mist to the sprayed subcapsules / main capsules and to extend their fall time in the cold spray towers (9, 15), a cold gas flow in the cold spray towers which is opposite to the spray direction is introduced in the cold spray towers via fans (23, 24) generated. The suction of the cold gas in the lower part of the cold spray towers and the supply in the upper tower areas are preferably carried out tangentially from / to the cylindrical cold spray tower cross sections. This results in helical swirl flows that run from bottom to top. The centrifugal forces acting in such currents favor the separation of the sprayed subcapsules / main capsules on the spray tower walls in the lower conical tower areas (11, 32). The completed multi-microcapsules (main capsules) are usually the second cold spray tower removed by means of a rotary valve (33) or an alternative discharge device.

In principle, subcapsules after the first cold spray tower can also represent a preferred end product and can be removed as such. On the other hand, it is also possible to connect more than two cold spray units in series, so that additional sub-capsule categories can be realized.

Several subcapsules created as described, which at the end of process step 3, i.e. at the outlet of the subcapsule cold spray or spray drying system as suspensions of subcapsules in the fluid main capsule matrix phase (HKMP) (35/1 ... 35 / n) are preferred according to the invention in an intermediate mixing container 34 in defined ratios matched to the application of the FSi mixed and this mixed suspension for carrying out process step 4 (main capsule production) is fed to a further cold spray or spray drying unit 15 by means of a pump 14 via a temperature-controlled pipeline 31.

In order to apply further layers of material to cold-sprayed capsules, so-called coating spray nozzles (27, 30) are provided in the cold spray towers according to the invention. Through this coating fluids from containers (17, 28) by means of pumps (18, 29) to the in the Cold spray towers are sprayed onto the capsules and solidified on their surfaces due to the removal of heat. In principle, each cold spray tower can have one or more such coating spray devices.

The respectively associated coating spray nozzles are then preferably arranged according to the invention in zones lying one above the other in order to produce defined coatings lying one above the other.

In the case of the inventive solidification of subcapsules, main capsules and / or spray layers additionally applied to them by thermal energy supply and resulting thermally induced crosslinking reactions or by drying, a supply takes place here in the cold spray towers according to the invention instead of the cold gas injection (nozzles 20, 22) of hot gas / drying gas. In this case, the nitrogen tank (19) is also replaced by an air heater.

The features described in the abstract, in the patent claims and in the description and evident from the drawing can be essential for realizing the invention both individually and in any combination. appendix

abbreviations

HKMP = main capsule - matrix phase

SKMPi = subcapsule - matrix phases

FSi = functional fabrics / fabric components

GFH = interface outer layer of the main capsule

GFSi = interface outer layers of the subcapsules

GFi = interface layers of the FSi

NMH = network-forming macromolecules in the main capsule matrix phase NMSi = network-forming macromolecules in the subcapsule matrix phase

Claims

claims

1.Procedure for the production of microcapsules which contain several functional substance / substance components which are effective in the nutritive and / or pharmacological / medical sense, characterized in that at least two of these substances / substance components in four main process steps: premixing of functional substance components and subcapsule matrix phases ( 1), grinding / dispersing the functional substance components in subcapsule matrix phases (2), subcapsule production (3) and main capsule production (4) in a common capsule matrix so separately integrated / arranged that interactions of the integrated / arranged substances / material components are prevented under defined storage conditions and, when these capsules are applied, a partially synchronous / synchronous release of said substance / substance components into the microenvironment of the disrupted capsule is made possible.

2. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that individual of these substances / substance components by means of the four main process steps: premixing of functional substance components and subcapsule matrix phases (1), grinding / dispersing the functional substance components in subcapsule matrix phases (2), subcapsule production (3) and main capsule production (4) are first fixed / arranged in subcapsules and a defined mixture of such subcapsules is then separately integrated into a common main capsule, that interactions of the integrated substances / substance components are prevented under defined storage conditions, and when these capsules are applied, a partially synchronous / synchronous release of said substance / substance components into the microenvironment of the unlocked capsule is made possible.

3. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritive and / or pharmacological / medical sense according to claims 1 or 2, characterized in that between the incorporated substances / substance components and the subcapsule Matrix phase and / or between the subcapsule matrix phase and the Main capsule matrix phase additional interface layers consisting of surface-active substances are generated by adsorption from the fluid sub- / main capsule phases.

4. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claims 1 or 2, characterized in that between the incorporated substances / substance components and the subcapsule Matrix phase and / or between the subcapsule matrix phase and the main capsule matrix phase additional layers can be produced by spray coating.

5. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, as claimed in claims 1 or 2, characterized in that the main capsule which has several subcapsules encapsulated therein , nutritionally and / or pharmacologically / medically functional substances / substance components, is applied with additional closed spray coatings.

6. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritive and / or pharmacological / medical sense, as claimed in claims 1 or 2, characterized in that the sequence of the formation of the substance / substance encapsulated Layers surrounding the material components in subcapsules and main capsule, to which the application of these capsule systems is coordinated in such a way that, in the event of parallel or successive mechanical, thermal and / or physical / chemical stresses occurring, either targeted protection is provided or a targeted layer degradation takes place , which realizes the exposure of a next lower layer in order to deliver optimized boundary conditions for the next application-specific step.

7. Process for the production of microcapsules, which contain several functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, according to claims 1 or 2, characterized in that the capsule is application-specific via the chemical and physical structure - Seldom layers surrounding substances / substance components and their layer thickness are influenced in a targeted manner on the duration of the layer degradation and the possibly overlaid release. tongue kinetics of encapsulated functionally effective substance / substance components.

8. A process for the preparation of microcapsules which contain several functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, according to claims 1 or 2, characterized in that encapsulated functional substances are specific to the application and are based on the particle size in the case of solids - / Substance components or via the drop size in the case of fluid-based encapsulated functional substances / substance components as well as via the released quantitative ratios of these substance / substance components, their interaction reactions with one another and with the application environment are specifically set or controlled.

9. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to Claim 1 or one of the subsequent claims, characterized in that the particle size in the case of solids-based encapsulated Functional substances / substance components by means of wet grinding in the particle size range between 10 nanometers and 100 micrometers, or encapsulated in fluid-based droplet sizes Functional substances / substance components can be set in a comparable size range using the drop dispersion method.

10. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that the production of subcapsules, each one (n) Encapsulated (n) functional substance (s) include cold spray, whereby the sub-capsule suspension consisting of fluid sub-capsule matrix phase and functional solid particles or the sub-capsule emulsion consisting of fluid sub-capsule matrix phase and functional fluid drop phase in a cold gas atmosphere is sprayed finely dispersed and solidified crystalline or glassy by heat extraction.

11. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that the production of main capsules which have a plurality of subcapsules contained by means of cold spraying, the main capsule suspension consisting of fluid main capsule matrix phase and suspended solidified subcapsules is sprayed finely dispersed in a cold gas atmosphere and the main capsule matrix phase is solidified crystalline or glassy by heat removal.

12. A method for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that the sub- and / / or main capsules are coated with additional spray layers, the spraying of the coating materials in fluid form into the cold spray tower below the spray zone of the sub- or main capsule suspensions / emulsions and thus the fluid coating materials covering the already solidified / partially solidified sub- / main capsules with a fluid spray layer , which in turn is crystallized or crystallized on the capsule surfaces

13. A method for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that the sub- and / / or Main capsules and additionally applied spray layers either consist of fats and / or waxes and / or water-based gel systems and / or of mixtures / dispersions thereof.

14. A method for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that the water-based gel systems from which Layers of sub-capsules and / or main capsules and additionally applied spray layers can be produced, contain polysaccharides and / or proteins in a cross-linked or cross-linking form upon cooling.

15. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 1 or one of the subsequent claims, characterized in that between different layers in sub- and / or main capsules and between the capsule surface and optionally applied spray layers additional boundary layers of surface-active substances which one or both of the other touching phases can be added in their fluid state.

16. A process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that at least two of these substances / substance components in four main process steps: premixing (1), milling / Dispersion (2), capsule formation (3) and capsule solidification (4) are integrated / arranged separately in a common capsule matrix in such a way that interactions between the integrated / arranged substances / substance components are prevented under defined storage conditions, and when these capsules are applied, a partially synchronous / synchronous release of the said substance / substance components into the microenvironment of the unlocked capsule is made possible, whereby the solidification of subcapsules, each containing an encapsulated functional substance / substance component, takes place by means of a spray drying step, the Subcapsule suspension consisting of fluid he subcapsule matrix phase and functional solid particles or the subcapsule emulsion consisting of fluid subcapsule matrix phase and functional fluid drop phase are sprayed finely dispersed into a drying gas atmosphere and solidified amorphously, crystalline or gel-like.

7. Process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that at least two of these substances / substance components in four main process steps: premixing (1), Grinding / dispersing (2), capsule formation (3) and capsule consolidation (4) are integrated / arranged separately in a common capsule matrix in such a way that interactions between the incorporated / arranged substances / substance components are prevented under defined storage conditions, and when these capsules are applied, a partially synchronous / synchronous release of said substance / substance components into the microenvironment of the disrupted capsule is made possible, the solidification of main capsules, which include more than two different subcapsules, is carried out by means of a spray drying step, the main capsule suspension consisting of a fluid main capsule matrix phase and the like nd in a defined ratio in these suspended subcapsules with at least two different functional substances / substance systems, sprayed finely dispersed into a drying gas atmosphere and solidified amorphously, crystalline or gel-like.

18. Process for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that at least two of these substances / substance components in four main process steps: premixing (1), milling / Dispersing (2), capsule formation (3) and capsule solidification (4) are separately integrated / arranged in a common capsule matrix in such a way that interactions of the integrated / arranged substances / substance components are prevented under defined storage conditions, and when these capsules are applied, a partially synchronous / synchronous release of said substance / substance components into the microenvironment of the disrupted capsule is made possible, whereby the solidification of spray layers additionally applied to the capsule (= main capsule) or to subcapsules integrated / arranged therein takes place by means of a spray drying step, the spraying on such layers on the solidified / partially solidified main or subcapsules in a drying gas atmosphere.

19. Device for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmaceutical / medical sense according to claim 1 or one of the subsequent claims, thereby characterized in that device components (A) for premixing the functional substance / substance components (FSi) in fluid subcapsule matrix phases (SKMPi) with device components (B) for defined fine dispersion / comminution of the functional substance / substance component phases and device components (C) for generating Subcapsules and device components (D) for producing main capsules, which contain several subcapsules in the order A, B, C, D arranged one behind the other and can be operated batchwise or continuously in this order.

20. Device for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that device components (A) for premixing the functional substance / substance components (FSi ) in fluid subcapsule matrix phases (SKMPi) consist of mixing vessels and stirring systems, which are connected to the downstream device components via pipes and displacement pumps are integrated into these pipes.

21. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, according to claim 19 or one of the subsequent claims, characterized in that device components (B) for defined fine dispersion / Comminution of the functional substance / substance component phases (FSi) for solid FSi from a wet mill, e.g. B. from a ball mill, roller mill or hammer mill, preferably from a ball mill and for FSi dissolved or dispersed in the fluid phase consist of a rotor / stator dispersing device or a pressure dispersing device.

22. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (B) for defined fine dispersion / Shredding of the functional substance / substance component phases (FSi) a classification unit, e.g. B. a sieve for the separation of not sufficiently comminuted coarse material, and this coarse material is returned via a pipeline to the comminution device.

3. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmaco-logical / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (C) for production of subcapsules correspond to cold spray devices, which essentially consist of a spray nozzle for finely atomizing the subcapsule suspension / emulsion (i), a cylindrical spray chamber into which the subcapsule suspension / emulsion is sprayed (ii), a supply device for cold gas (e.g. cold Nitrogen vapor) (iii) a circulation unit for the cold gas in the spray chamber, preferably with gas flow in the counterflow direction to the spray direction of the subcapsule suspension / emulsion (iv), a combined collecting-resuspending unit, consisting of a stirrer integrated in the bottom space of the cold spray device / Mixing container with integrated Agitator in which the solidified subcapsules are resuspended in the fluid main capsule matrix phase (vi) and a discharge unit for this main capsule suspension, consisting of a pipeline and an integrated displacement pump, are configured.

4. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (C) for production of subcapsules correspond to spray dryers, which essentially consist of a spray nozzle for finely atomizing the subcapsule suspension / emulsion (i), a cylindrical spray chamber into which the subcapsule suspension / emulsion is sprayed (ii), a feed device for hot, dry gas ( e.g. hot dry air) (iii), a circulating unit for the hot, dry gas in the spray chamber, preferably with gas flow in the counterflow direction to the spray direction of the subcapsule suspension / emulsion (iv), a combined collecting-resuspending unit, consisting of one in the floor space the spray drying chamber integrated mixing / mixing tank with i integrated agitator in which the solidified subcapsules are resuspended in the fluid main capsule matrix phase (vi) and a discharge unit for this main capsule suspension, consisting of a pipeline and an integrated displacement pump, are configured.

25. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (D) for production of main capsules correspond to cold spray devices, which essentially consist of a spray nozzle for finely atomizing the subcapsule suspension / emulsion (i), a cylindrical spray chamber into which the main capsule suspension is sprayed (ii), a supply device for cold gas (e.g. cold nitrogen vapor) (iii) a circulation unit for the cold gas in the spray chamber, preferably with gas flow in the counterflow direction to the spray direction of the subcapsule suspension / emulsion (iv) and a collection and discharge unit for the solidified subcapsules (v).

26. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (D) for production of main capsules correspond to spray-drying devices which essentially consist of a spray nozzle for finely atomizing the sub-capsule suspension / emulsion (i), a cylindrical spray chamber which the main capsule suspension is sprayed in (ii), a supply device for hot, dry gas (for example hot pre-dried air) (iii) a circulating unit for the hot, dry gas in the spray chamber, preferably with gas flow in the counterflow direction to the spraying direction of the Subcapsule suspension / emulsion (iv) and a collection and discharge unit for the solidified subcapsules (v).

27. Device for the production of microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (C and D) for production of sub or main capsules correspond to cold spray devices, which are provided with additional coating spray devices for the spraying of fluid material systems into the cold spray chamber below the spray units for the sub capsule suspension / emulsion or main capsule suspension installed in the head space thereof, with which on the sub / Main capsule surfaces layers are applied.

8. Device for producing microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense according to claim 19 or one of the subsequent claims, characterized in that device components (C and D) correspond to spray drying devices for the production of sub or main capsules, which are provided with additional coating spray devices for spraying fluid material systems into the spray drying chamber below the spray units for the sub capsule suspension / emulsion or main capsule suspension installed in the head space thereof, with which on the sub / Main capsules layers are applied.