Novel delivery systems for fat-soluble vitamins.

Abstract

The present invention relates to a novel delivery system for fat-soluble vitamins.

Description

Detailed Description of the Invention

[0001] The present invention relates to a novel delivery system of fat-soluble vitamins for the large intestine. These nutritional ingredients are beneficial for intestinal and metabolic health in monogastric animals (e.g. pigs and poultry, as well as fish), especially in humans.

[0002] Over the last few years, we can observe an increase in consumer interest in products that promote gut health. Many new products have been launched and have been widely accepted by consumers.

[0003] There is also increasing research into the potential influence of the gut microbiota on obesity, inflammation, cardiovascular disease, and diabetes, as well as metabolism and immunity.

[0004] The fat-soluble vitamins (A, D, E and K) are known to be important and healthy compounds (also for gut health and metabolic health).

[0005] Fat-soluble vitamins are generally formulated as powder particles or granules, in which the vitamin is embedded as small oily or waxy droplets in an encapsulating matrix material. The encapsulating material can be, for example, modified food starch or gelatin. These matrix materials dissolve easily in the stomach and release the vitamin immediately. Thus, the vitamin is absorbed in the stomach or small intestine and does not reach the large intestine.

[0006] The release in the small or large intestine is usually achieved by sustained release capsules or tablets. The active substance is incorporated in a capsule or tablet coated with one or more coatings that provide sustained release. However, tablets and capsules as a delivery system have several disadvantages. The amount of active substance that can be incorporated in a single tablet or capsule is limited by the available volume. It is difficult to swallow tablets or capsules, especially for very young and elderly patients. The residence time of capsules and tablets in the stomach is highly variable and the release is very regular, resulting in very high local concentrations of active substances, which can cause harmful effects.

[0007] These disadvantages are overcome by multiparticulate forms such as powders, granules, beadlets, or pellets. However, applying sustained release coatings to multiparticulate dosage forms is difficult due to their large specific surface area compared to tablets or capsules. To obtain a coating layer that is sufficiently thick and uniformly distributed, the amount of coating material required is much larger than that of tablets or capsules, reducing the space available for the payload.

[0008] Suitable coating materials for release in the small intestine often include pH-sensitive polymers. This approach takes advantage of the pH gradient present in the digestive tract, which gradually increases from the stomach (pH 1.5-3.5) and small intestine (pH 5.5-6.8) to the large intestine (6.4-7.0). The most commonly used pH-dependent polymers are derivatives of acrylic acid and cellulose. Various pH-dependent coating polymers include cellulose acetate phthalate (CAP) (Aquateric®), polyvinyl acetate phthalate (PVAP) (Coateric®), hydroxypropylmethylcellulose phthalate (HPMCP), and methacrylic acid copolymers, commonly known as methacrylate copolymers or Eudragit.

[0009] A significant limitation of pH-sensitive coating technology is the uncertainty of the location and environment in which the coating may begin to dissolve. Enteric coatings alone may result in premature drug release in the small intestine due to variations in gastrointestinal motility.

[0010] Utilizing the gastrointestinal microflora as a drug release mechanism in the colonic region has been of great interest to researchers. Bacteria are distributed throughout the gastrointestinal tract, but the majority reside in the distal gut. Colonic bacteria are primarily anaerobic in nature and secrete enzymes that can metabolize both endogenous and exogenous substrates, such as carbohydrates and proteins, that escape digestion in the upper gastrointestinal tract. Natural polysaccharides of plant (e.g., pectin, guar gum, inulin), animal (e.g., chitosan, chondroitin sulfate), algae (e.g., alginate), or microbial (e.g., dextran) origin have been investigated to target the colon. These are broken down by the colonic flora into simple sugars by saccharolytic species such as Bacteroides and Bifidobacteria [Jose, S., K. Dhanya, TACinu, J. Litty and AJ Chacko (2009). “Colon targeted drug delivery: different approaches.” J. Young Pharm. 1(1):13-19].

[0011] Although specifically degraded in the large intestine, many of these polymers are hydrophilic in nature and swell upon exposure to upper gastrointestinal conditions, thereby resulting in premature drug release. Furthermore, these fermentable materials usually exhibit very high viscosities in solution, which makes them difficult or impossible to process at high concentrations.

[0012] The encapsulation matrix is ​​fermentable Living organismPolymers are used. In matrix encapsulation, the active substance is homogeneously distributed within a protective matrix (in this case, a fermentable biopolymer). However, matrix encapsulation has some serious drawbacks. Due to the high viscosity of biopolymers, for example, the matrix solution during spray drying or gel encapsulation is very dilute and difficult and expensive to dry. The payload in matrix encapsulation is relatively low (typically less than 50%).

[0013] Here, the goal of the present invention was to find an improved multiparticulate delivery system (formulation) that improves the stability of fat-soluble vitamins during transport through the stomach and small intestine (before they are released in the large intestine), thereby improving their availability and effectiveness.

[0014] Furthermore, the new delivery system should be capable of being manufactured in a simple and industrially applicable manner.

[0015] It has been found that coating a solid core of at least one fat-soluble vitamin with a specific inner coating and a specific outer coating improves the properties of the delivery system, which can be manufactured in a continuous process as well as in a batch mode.

[0016] The novel delivery system (DS) according to the present invention comprises: (a) a solid core comprising at least one fat-soluble vitamin; (b) at least one cross-linked fermentable Living organism an inner coating comprising a polymer; (c) an outer coating that is resistant to gastric conditions and releases in the small intestine.

[0017] The active substance (or mixture) in the core is a fat-soluble vitamin.

[0018] Other nutritional ingredients may be incorporated into the core (or coating) if necessary and desired. Nutraceutical ingredients are compounds that provide a health benefit to the animal.

[0019] Thus, the present invention relates to a delivery system (DS1), the solid core of which is a delivery system (DS) comprising at least one fat-soluble vitamin selected from the group consisting of vitamins A, D, E and K (and any commonly used derivatives of these vitamins).

[0020] The delivery system according to the invention comprises an inner coating, which must meet defined criteria. Living organism Suitable materials for the inner coating are, for example, alginates, chitosan, pectin, cyclodextrin, as well as other gums. Preferred coating materials for the inner coating are alginates or pectin.

[0021] The inner coating is crosslinked. Crosslinking can be achieved by commonly known crosslinking compounds. When alginates are used, crosslinking can be achieved by Zn, Mg, and / or Ca ions (by using salts). The crosslinking agent can be sprayed onto the solid core after or at the same time as the inner coating is applied. Alternatively, the coated particles can be immersed in a solution containing the crosslinking agent.

[0022] After the inner coating layer is applied, the particles are preferably sprayed with a crosslinking agent.

[0023] Another advantage of the present invention is that the production of the novel delivery system according to the invention can be carried out continuously as well as batchwise, which is a great advantage in terms of the industrial production of such products, in contrast to the systems known in the prior art. The process details are disclosed below.

[0024] Thus, the present invention relates to a delivery system (DS2) in which the material of the inner coating is a delivery system (DS) or (DS1) selected from the group consisting of alginates, chitosan, pectin, cyclodextrin, and other gums.

[0025] Therefore, the present invention relates to a delivery system (DS2') which is a delivery system (DS2) in which the material of the inner coating is alginate or pectin.

[0026] The inner coating layer covers the core (almost) completely. Ideally, the inner coating layer has (almost) the same thickness when applied to the solid core. Typically, the inner coating layer has a thickness of at least 5 μm and no more than 20 μm. Preferably, the inner coating layer has a thickness of 5 μm to 10 μm.

[0027] Thus, the present invention relates to a delivery system (DS3), which is a delivery system (DS), (DS1), (DS2) or (DS2') having an inner coating layer thickness of 5 μm to 10 μm.

[0028] The inner coating layer is crosslinked by at least one crosslinking agent. Any suitable crosslinking agent can be used. Very suitable and therefore preferred are Zn, Mg and Ca ions (which are added in the form of their salts).

[0029] Thus, the present invention relates to a delivery system (DS4), which is a delivery system (DS), (DS1), (DS2), (DS2') or (DS3), in which the inner coating layer is crosslinked by at least one crosslinking agent, preferably by Zn, Mg and / or Ca ions.

[0030] Thus, the present invention relates to a delivery system (DS5) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3) or (DS4) in which the crosslinked inner coating layer is sodium alginate or pectin.

[0031] The delivery system according to the invention comprises an outer coating, which must meet defined criteria. Suitable materials that meet the criteria for the outer coating are, for example, shellac, methacrylate copolymers, and fats.

[0032] Thus, the present invention relates to a delivery system (DS6) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4) or (DS5) in which the material of the outer coating is selected from the group consisting of shellac, methacrylate copolymers and fats.

[0033] The outer coating layer covers the inner coating (almost) completely. Ideally, when applied to the inner coating, the outer coating layer is of (almost) the same thickness.

[0034] Usually the thickness of the outer layer is at least 10 μm and usually less than 30 μm. The thickness of the outer coating layer is preferably 10 to 20 μm.

[0035] Thus, the present invention relates to a delivery system (DS7) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5) or (DS6) having an outer coating layer thickness of 10 μm to 20 μm.

[0036] The solid core of the delivery system according to the invention usually comprises 10-85% by weight, preferably 50-75% by weight, based on the total weight of the delivery system.

[0037] Thus, the present invention relates to a delivery system (DS8) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6) or (DS7) in which the solid core of the delivery system represents 10 to 85% by weight, preferably 50 to 75% by weight, based on the total weight of the delivery system.

[0038] The inner coating of the delivery system according to the invention typically comprises 1-20% by weight, preferably 1-10% by weight, based on the total weight of the delivery system.

[0039] Thus, the present invention relates to a delivery system (DS9) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7) or (DS8) in which the inner coating of the delivery system represents 10-85% by weight, preferably 1-10% by weight, based on the total weight of the delivery system.

[0040] The outer coating of the delivery system according to the invention typically comprises 1-30% by weight, preferably 15-30% by weight, based on the total weight of the delivery system.

[0041] Thus, the present invention relates to a delivery system (DS10) which is a delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8) or (DS9) in which the outer coating of the delivery system is 1 to 30% by weight, preferably 15 to 30% by weight, based on the total weight of the delivery system.

[0042] The delivery system according to the invention can be up to 2 mm in size. The size is defined by the longest diameter of the particle. The shape of the particle is not an essential feature of the invention. Also, the size distribution of the particles is not essential. The size and shape of the particles are mainly determined by the solid core of the delivery system. The size can be adjusted depending on the use of the delivery system.

[0043] The delivery systems according to the invention are generally manufactured by known techniques.

[0044] Usually, a solid core is produced in a first step, followed by an inner and outer coating. The solid core particles can be prepared by known methods such as spray drying, agglomeration, granulation, microtabletting, extrusion, or extrusion / spheronization.

[0045] As disclosed above, one of the main advantages of the novel delivery system (in addition to its properties) is the manufacturing process of the delivery system. The novel delivery system can be manufactured batchwise or continuously.

[0046] When produced batchwise, the novel particles can be prepared as follows. In the first step, the solid core is coated by spray coating with the coating material of the inner coating, then the particles are sprayed with a crosslinking agent, in the second step, the particles obtained in the previous step are sprayed with an outer coating, and finally the particles are dried.

[0047] The advantage of this process is that the step involving the production of solid cores by granulation or agglomeration can be carried out in the same equipment (fluidized bed processing equipment), which reduces the technical effort. However, it is also possible, i.e. to first produce the solid cores, store them and then coat them.

[0048] Another option for producing this novel delivery system is a continuous process, where the solid cores are produced first and then sprayed onto the particles in alternating coating steps. These processes are ideal for application on an industrial scale.

[0049] The present invention therefore also relates to a process (P) for the production of any of the particles (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10), wherein the process is carried out batchwise.

[0050] The present invention therefore also relates to a process (P1) for the production of any of the particles (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (SD5), (DS6), (DS7), (DS8), (DS9) or (DS10), in which the steps are carried out successively.

[0051] The novel delivery systems (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) and / or (DS10) according to the present invention can be used on their own or can be incorporated into application forms.

[0052] The novel delivery systems ((DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) and / or (DS10) may be used as such in any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0053] The novel delivery systems (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10) may also be part of a premix formulation which may then be used to formulate any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0054] The present invention also relates to a process for the manufacture of a premix, a dietary supplement, a food, a feed product, a personal care product or a pharmaceutical product using at least one delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10).

[0055] The present invention also relates to a premix, dietary supplement, food, feed product, personal care product or pharmaceutical product comprising at least one delivery system (DS), (DS1), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10).

[0056] The following examples serve to illustrate certain embodiments of the invention claimed herein. All percentages are given by weight and all temperatures are given in degrees Celsius.

[0057] [Example] [Example 1:] 15 g of Na-alginate (grinsted sodium alginate) was dissolved in 485 g of water at 60°C under stirring. 31.5 g of Ca-chloride dihydrate was dissolved in 98.5 g of water. 100 g of vitamin E beadlets (containing 44% vitamin E in a matrix of modified food starch) were loaded into a fluidized bed processor (WFP mini, DMR, Worcester Configuration). All coating steps were carried out at a product temperature of 50-60°C. First, the alginate solution was sprayed onto the fluidized vitamin E powder. After spraying the alginate solution, the supply tube was briefly rinsed with water. For hardening, at a product temperature of 53°C, Ca-chloride solution was sprayed on the inner coating. After the hardening solution, 154 g of an aqueous shellac preparation (SSB Aquagold, Stroever) at 25% solids was sprayed as an outer coating. After spraying the shellac, the product was dried in the fluidized bed. 102 g of coated granules were obtained.

[0058] The composition of the final coated granules was 65% core material, (=29% Vitamin E), 9% alginate, 1% Ca chloride, and 25% shellac.

Claims

1. (a) a solid core comprising at least one fat-soluble vitamin; (b) an inner coating comprising at least one crosslinked fermentable biopolymer; (c) an outer coating that is resistant to gastric conditions and releases in the small intestine; It consists of:

1. A multiparticulate delivery formulation for release in the large intestine, wherein the material of the inner coating is selected from the group consisting of alginate, chitosan, pectin, cyclodextrin, guar gum, inulin, chondroitin sulfate, and dextran, and the material of the outer coating is selected from the group consisting of shellac, methacrylate copolymers, and fats.

2. 2. The multiparticulate delivery formulation of claim 1, wherein the solid core comprises at least one fat-soluble vitamin selected from the group consisting of vitamins A, D, E and / or K (and derivatives thereof).

3. 3. A multiparticulate delivery formulation according to claim 1 or 2, wherein the inner coating is crosslinked by Zn, Mg and / or Ca ions.

4. A method for producing a multiparticulate delivery formulation according to any one of claims 1 to 3, wherein the method is carried out batchwise.

5. A method for producing a multiparticulate delivery formulation according to any one of claims 1 to 3, wherein the method is carried out continuously.

6. A method for producing a premix, a dietary supplement, a food, a feed product, a personal care product or a pharmaceutical product using at least one multiparticulate delivery formulation according to any one of claims 1 to 3.

7. A premix, dietary supplement, food, feed product, personal care product or pharmaceutical product comprising at least one multiparticulate delivery formulation according to any one of claims 1 to 3.