EP1722884A1

EP1722884A1 - Storage stable multi-microcapsules having adjustable synergitically active functional content components

Info

Publication number: EP1722884A1
Application number: EP04714290A
Authority: EP
Inventors: Erich Windhab; Michael Zimmermann
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: WO2005079968A1

Abstract

The invention relates to novel multi-component micro capsule systems, wherein two and several functional substances and/or substance components are encapsulated in a spatially separated manner, such that during storage of said type of multi-capsule systems, interaction of the encapsulated components is prevented, but when said multi-capsules are administered, the different encapsulated functional substances/substance components are released in a targeted simultaneous or successive manner in relation to a point of release, a time of release and a rate of release, according to the field in which they are used. The inventive multi-micro-capsules act as a covering for several functional substances/substance components, provided with one and/or several material layers having defined mechanical, thermal and physicochemical and/or biochemical stability properties, which are optimised such that they are adapted to the conditions of use in relation to the desired interaction and release of the encapsulated substances/substance components.

Description

Storage-stable multi-microcapsules with adjustable, synergistically effective functional content components

Description genus

The invention relates to multi-microcapsules in which several, in the sense, for. B. pharmaceutical / medical and / or nutritional properties of functional substances or substance components are encapsulated.

Background of the Invention

In the areas of pharmaceuticals / medicine, cosmetics and nutrition, functional substances / substance components (pharmaceuticals / medicine: active pharmaceutical ingredients, medicines, cosmetics: dermatological active ingredients, food: nutritional 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. Already during the storage of functional reactive substance / substance components, there are often interactions with the surrounding substance matrix and associated significant losses with regard to the effectiveness of the functional substances / substance components.

In many applications, the effectiveness of functional substances / components is also significantly affected by their interaction with other substances that are in the human 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 preparations added to remedy iron deficiency symptoms under the general conditions in the stomach of humans (low pH values), as well as through 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.

In the following, reference is made to the interaction effects of iron, iodine and vitamin A deficiency in order to exemplify a possible synergistic approach to remedying nutritional deficiency symptoms. On the basis of this example, the advantages of the multi-microcapsules according to the invention will also go further explained in detail. Iron deficiency-related anemia, thyroid enlargement (goiter) resulting from iodine deficiency and vitamin A deficiency affect more than a third of the world's population. Often these shortcomings occur simultaneously, such. B. in regions of West and North Africa where approx. 1/3 of schoolchildren suffer from iron, iodine and vitamin A deficiency at the same time. These three nutritional components are extremely important for human metabolism. Iron and vitamin A deficiency affect the thyroid metabolism of iodine and reduce the effectiveness of iodized salt. Vitamin A deficiency also affects iron transport in the body and worsens iron deficiency-related anemia.

This makes a combined approach against iron, iodine and vitamin A deficiency particularly suitable as an example of an effective and synergistic strategy for food fortification.

The following main questions arise for the application of functional substance components / active substances:

1. How can these substances be transported to the place of the desired release and absorption (e.g. small intestine) without prior loss of quantity and effectiveness during storage and application preparation (e.g. integration in meals)? 2. How can the absorption conditions at the site of release be optimized to achieve maximum bioavailability.

task

The object of the invention is to configure a multi-microcapsule for incorporating several pharmacologically / medically and / or nutritionally active functional substances / substance components in such a way that the encapsulated substances / substance components on the one hand show no interactions under storage conditions and on the other hand in coordination when applied The encapsulated substances / substance components can be released in a defined manner to the ambient conditions with regard to the time of the release and the release rate. The aim is also to combine the encapsulated substances in such a way that positive synergistic effects (e.g. mutual protective action against oxidation, improved bioavailability) can be achieved during storage, release and interaction.

Solution of the task

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

Further inventive embodiments of the procedure according to the invention are described in claims 3 to 11

Some advantages

By means of the multi-microcapsules according to the invention, several substances / substance components with functional properties can be integrated into a "multi-microcapsule" such that no interaction of the encapsulated substances / substance components takes place during the storage of such capsules. H. Storage stability is guaranteed.

Another important advantage results from the spatial proximity of the substances / substance components fixed in a microcapsule, since when they are released from the microcapsule, this leads to contact and, as a result of a corresponding combination, to targeted synergistic interactions

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

For example, multi-microcapsules can be used to transport nutrient components, such as water-soluble iron salts (1st component), to the small intestine, who are deficient in oxidation, and to release these salts from the capsule synchronously with an antioxidant (2nd component). The intensive interaction of these components in the microenvironment of the capsule will protect the iron salt from oxidation and the iron bioavailability d. H. significantly improve its absorption in the small intestine.

Thus, the multi-microcapsules according to the invention allow the integration / encapsulation of several functional substances / substance components in a multi-capsule with the possibility of setting separating layers between these substances / substance components with regard to diffusion permeability, time of release and release kinetics. This is the prerequisite for the production of a multi-microcapsule suitable for storage stability and optimized release of several functional synergistically interacting substances / substance components.

The invention is illustrated for example in the drawing. Show it: 1 shows a multi-microcapsule morphology;

Fig. 2 crystalline functional material phases with surrounding amorphous layer and additional outer amorphous boundary layer;

Fig. 3 shows the digestive route of a multi-microcapsule in the human gastrointestinal tract.

The complex structure of a multi-microcapsule is shown in FIG. 1 for illustration. 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 encapsulated functional individual substance components (FSi) by embedding these SKi in a main capsule matrix phase (HKMP). This main capsule matrix phase is chosen such that a diffusion-based exchange of the encapsulated functional substances / substance components (FSi) is largely prevented under storage conditions. According to the invention, the FSi are preferably used in solid, mostly crystalline form. The different FSi are preferably included in a subcapsule matrix phase (SKMPi). According to the invention, these SKMPi are chosen opposite to the FSi with regard to their hydrophilicity / hydrophobicity. The molecular structure of the SKMPi is preferably largely amorphous (glass-like), possibly also crystalline or gel-like, via the composition and manufacturing process. If necessary, additional interface layers (GFi) are created by means of surface-active substances as diffusion barriers between FSi and SKMPi and between SKMPi and HKMP. Finally, such an interface layer can also surround the main capsule (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: 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 (GSi)

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

structural parameters

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

• Polymorphism in crystalline structures

• Single / multi-phase structure

Physical material parameters

• Phase transition temperatures of the FSi, SKMPi and HKMP

• interfacial tension / contact angle between neighboring phases • hydrophobicity / hydrophilicity of the phases

• diffusion coefficients

• water absorption capacity (aw value, sorption isotherms)

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 corresponds to an additional coating layer. If necessary, this can also be omitted. Individual encapsulation of the FSi in subcapsules and an increase in the number of "cladding 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 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 interference from material components from the 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 large number 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 “destination” (= 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, water-soluble enzyme activity); B. stomach (pH low; mechanical stress); C. Gastric exit / small intestine (pH neutral; introduction of enzymes (e.g. fat-soluble lipases (bile), water-soluble enzymes in the digestive juice).

In many cases, there are additional increased requirements for mechanical and temperature stability (e.g. when preparing dishes that contain the multi microcapsules) before being absorbed into the human gastrointestinal tract.

For the selected example, the cladding layers enable the thermal, mechanical, pH and enzymatic stability properties to be set. It may also be desirable to break down the corresponding coating layer in order to ensure the release of the FSi at the destination. In the selected example of the human digestive tract, fat-based layers, for example, are affected by the action of lipa- and macromolecular networks in water-based layers are degraded 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 influence 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.

Design / application example for a multi-microcapsule

An exemplary embodiment and specific application for a multi-microcapsule are shown below, which as functional FSi contain the substances iron pyrophosphate (functional, nutritive component: iron), sodium iodate (functional, nutritive component: iodine and retinyl palmitats (functional Component: Vitamin A) in encapsulated form. The encapsulation was carried out in hydrogenated (hardened) palm kernel fat as the common main capsule matrix phase. In addition, soy lecithin was used as a surface-active substance to form interface layers (GSi, HGS) around the FSi (here = subcapsule). Matrix phase) and used on the capsule surface. The iron (Fe) -iodine (J) -Vitamin A multi-microcapsules (short: FeJA-CAPS)

with an average diameter of approx. 100 micrometers (μm) contained approx.

40% FSi (substrate) and were not crushed table salt (particle size approx. 1-2 mm) as a nutritional reinforcing component in the ratio: 60

μγ vitamin A: 25 μg iodine: 2 mg iron: 1 g table salt (corresponds to 6: 2.5:

200: 100000) was added. The iron content was found to be stable during the production of the FeJA-CAPS. With regard to vitamin A, about 30-35% production losses occurred, iodine about 15-20% production losses. These losses were compensated for by appropriate overdosing in order to obtain the optimal concentrations in the fortified batches of salt from a nutritional point of view.

Saline is considered the ideal vehicle for the nutritional reinforcement of food and is therefore also suitable for experiments on "three-component enrichment" with iron, iodine and vitamin A. So far, such enrichments have not been successful because water-soluble iron compounds with moisture from salt or Ambient air and impurities in the table salt caused unacceptable color changes, and iodine and vitamin A in enriched table salt were oxidized and thus lost in the presence of moisture and oxygen.

The enrichment of table salt with FeJA-CAPS was tested in Africa (Morocco). Storage stability tests were carried out 0, 2, 4 and 6 months after mixing the multi-microcapsules with the table salt. The enriched table salt was packed in transparent 2 kg polyethylene bags and exposed to indirect daylight in rooms.

Table 1 shows the mean concentrations of vitamin A, iodine and iron from each of the 12 50 g salt samples examined for each storage period.

Table 1

Stability of vitamin A, iodine and iron content of "triple enriched" table salt (average values).

The values shown in Table 1 underline the very good storage stability of the nutritive components encapsulated in the FeJA-CAPS. A corresponding enrichment of With salt, the results obtained using the described multi-microcapsules are significantly improved.

Without the appropriate encapsulation, vitamin A showed losses of 80-90% in one month and iodine about 40-50% in six months.

For these saline samples enriched with FeJA-Caps, tests for absorption, bioavailability and efficacy were also carried out in a random double-blind series of tests with 184 Moroccan schoolchildren aged 6-15 years, who showed a high frequency of anemia, enlarged thyroid and vitamin A deficiency symptoms. The families participating in the research were in

divided into two random groups. One group received only 30 μg iodine / g

Salt-enriched table salt. The other group is the triple fortified salt TFS (FeJA-CAPS).

Each family received 2 kg of salt for 5 months at the beginning of each month to cover all household needs. After 5 months, the same blood and urine tests of the 184 children included were repeated. Table 2 shows the resulting comparison results. Table 2 Results of the efficacy study for the comparison of triple enriched salt (TFS; FeJA-CAPS) with iodized salt. (Mean values ¹ ; percentage values ² )

As the results shown in Table 2 show, vitamin A, iodine and iron were bioavailable in the triple-enriched TFS salt samples (FeJA-CAPS) and showed a markedly good effectiveness in the school children included in the study. Both the iron, as well Vitamin A status improved significantly in the TFS group, but not in the comparison group. As expected, the iodine status of both comparison groups developed in a comparable manner.

This example underlines the effectiveness of multi-microcapsules in terms of achieving good storage stability that has not yet been achieved, as well as improved functionality in terms of bioavailability of the investigated nutritional substance components.

The features described in the abstract, in the patent claims and in the description, as well as 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 = FSi interface outer layers

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

Claims

claims

1. Multi-microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that some of these substances / substance components are integrated into a common capsule matrix in such a way that defined under Storage conditions interactions of the incorporated substances / substance components are prevented, and when these capsules are applied, a synchronous release of said substance / substance components and their resulting interactions in the microenvironment of the disrupted capsule bring an additional benefit.

2. Multi-microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological / medical sense, characterized in that some of these substances / substance components are each fixed in sub-microcapsules and these sub-microcapsules are integrated in a common main capsule in such a way that under defined storage interactions of the incorporated substances / substance components are prevented, and when these capsules are applied, a synchronous release of said substance / substance components and their resulting interactions in the microenvironment of the disrupted capsule bring an additional benefit.

3. Multi-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 interface-active substances are arranged.

4. Multi-microcapsules which contain a plurality of functional substance / substance components which are effective in the nutritional and / or pharmacological-anedical sense according to claims 1 or 2, characterized in that subcapsules which contain the individual, nutritional and / or contain encapsulated pharmacologically / medically functional substances / substance components, with additional Chen closed spray layers are applied and integrated into a common main capsule.

5. Multi-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 , contains nutritive and / or pharmacologically / medically functional substances / substance components, is applied with additional closed spray layers.

6. Multi-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 sequence of the substance / substance components encapsulated surrounds them Layers in subcapsules and main capsule are coordinated with the application of these capsule systems in such a way that specific parallel protection or mechanical, thermal and / or physical / chemical stresses that occur during application either provide targeted protection or deliberate layer degradation , which realizes the exposure of a next lower layer in order to deliver optimized boundary conditions for the next application-specific step.

7. Multi-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 application-specific via the chemical and physical structure of the encapsulated Layers surrounding substance / substance components and their layer thickness are influenced in a targeted manner on the duration of the layer degradation and the possibly superimposed release kinetics of encapsulated functionally active substance / substance components.

8. Multi-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 encapsulated functional substances are specific to the application and are based on the particle size in the case of solids - / Substance components or the drop size of fluid-based encapsulated functional substances / substance components as well as the released quantitative ratios of these substance / substance components, their interaction reactions with each other and with the application environment can be set or controlled in a targeted manner.

9. Multi-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 solid-based encapsulated functional substances - / Substance components or the drop size for fluid-based encapsulated functional substances / substance components is between 10 nanometers and 100 micrometers.

10. Multi-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- and / or main capsules as well as additionally applied spray layers can be generated, contain polysaccharides and / or proteins in a cross-linked or cross-linking form upon cooling.

11. Multi-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 have additional boundary layers of surface-active substances.