New delivery system

Abstract

The present invention relates to a novel delivery system for a nutritional component (nutritional supplement). The nutritional component is useful for the digestive tract and metabolic health of monogastric animals, particularly humans.

Description

Technology Field

[0001] The present invention relates to a novel delivery system for water-soluble vitamins for the large intestine (i.e., vitamin B (especially vitamin B2)). The nutrient is useful for the digestive tract and metabolic health of monogastric animals (e.g., swine, poultry, and fish), particularly humans. Background Technology

[0002] Over the past few years, it has been observed that consumer interest in products promoting digestive tract health has increased. Numerous new products have been launched and widely purchased by consumers.

[0003] In addition, there has been an increase in research on the potential effects of the gut microbiome on metabolism, immunity, obesity, inflammation, cardiovascular disease, and diabetes.

[0004] When riboflavin (vitamin B2) is delivered to the small intestine, it is a marker species for a healthy digestive tract, Faecalibacterium prosnitch ( Faecalibacterium prausnitzii It is known to have beneficial effects on the growth of ). EP 2914135 describes the use of riboflavin for the selective stimulation of Faecalibacterium prosnitch. However, very high doses of riboflavin are required because the majority of riboflavin is already destroyed or absorbed before reaching the small intestine.

[0005] Release in the small or large intestine is typically achieved through controlled release of capsules or tablets. The active substance is incorporated into capsules or tablets coated with one or more coatings that induce controlled release. However, tablets and capsules have several disadvantages as delivery systems. In particular, very young or elderly patients experience difficulty swallowing tablets or capsules. Due to the highly variable retention time of capsules and tablets in the stomach and the very immediate release, very high local concentrations of the active ingredient can occur, which may lead to adverse effects.

[0006] Multiply forms, such as powders, granules, beadlets, or pellets, overcome these disadvantages. However, applying controlled release to multiply dosage forms is difficult due to the larger specific surface area compared to tablets or capsules. The amount of coating material required to achieve an evenly dispersed coating layer of sufficient thickness is much greater than that in tablets or capsules, which reduces the available space for the payload.

[0007] Coating materials suitable for release in the small intestine often contain pH-sensitive polymers. This approach utilizes the presence of a gradually increasing pH gradient from the gastrointestinal tract (GIT) to the stomach (pH 1.5 to 3.5) and from the small intestine (pH 5.5 to 6.8) to the large intestine (pH 6.4 to 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), hydroxymethyl cellulose phthalate (HPMCP), and methacrylic acid copolymers (commonly known as methacrylate copolymers or Eudragit).

[0008] A significant limitation of pH-sensitive coating techniques is the uncertainty regarding the location and environment in which the coating may begin to dissolve. Due to changes in gastrointestinal (GI) motility, enteric coatings alone may lead to premature drug release.

[0009] In the past, the use of the gastrointestinal microflora as a mechanism for drug release in the colon has been of great interest to researchers. Although bacteria are distributed throughout the gastrointestinal tract, the majority of bacteria are found in the terminal digestive tract. Colonic bacteria are naturally primarily anaerobic and can metabolize both endogenous and exogenous substances, such as carbohydrates and proteins, released from digestion in the upper gastrointestinal tract. Naturally occurring polysaccharides derived from plants (e.g., pectin, guar gum, and inulin), animals (e.g., chitosan and chondroitin sulfate), algae (e.g., alginate), or microorganisms (e.g., dextran) have been studied for colonic targeting. This is broken down into simple sugars by glycolytic species of the colonic microbiome, such as Bacteroides and Bifidobacteria (Reference [Jose, S., K. Dhanya, TA Cinu, J. Litty and AJ Chacko (2009). "Colon targeted drug delivery: different approaches." J. Young Pharm. 1(1): 13-19]).

[0010] Although these polymers are specifically degraded in the large intestine, the majority are naturally hydrophobic and swell under exposure to upper gastrointestinal conditions, which leads to premature drug release. Additionally, these fermentable substances exhibit very high viscosity in solution, making it difficult or impossible to process them into higher concentrations. Fermentable biopolymers have been used as encapsulation substrates. In substrate encapsulation, the active substance is homogeneously dispersed within a protective substrate, in this case, a fermentable biopolymer. However, substrate encapsulation has several serious disadvantages. Due to the high viscosity of biopolymers, the substrate solution is highly diluted, for example in spray drying or gel encapsulation, making drying difficult and costly. The yield loading in substrate encapsulation is relatively low (typically less than 50%).

[0011] The object of the present invention is to discover an improved multiply-particle delivery system (formulation) to improve the availability and efficacy of said water-soluble vitamin (i.e., vitamin B (especially vitamin B2)) by improving the stability of said water-soluble vitamin (i.e., vitamin B (especially vitamin B2)) during transport through the stomach and small intestine (before release from the large intestine).

[0012] In addition, the novel cutting system must be capable of being manufactured by simple and industrially applicable means. It has been found that when a solid core containing one or more nutrient supplements is coated with a specific inner coating and a specific outer coating, the delivery system exhibits improved characteristics. Furthermore, the delivery system can be produced by batch and continuous processes. Specific details for implementing the invention

[0013] The novel delivery system (DS) according to the present invention is

[0014] (a) a solid core containing one or more water-soluble vitamins (especially vitamin B2);

[0015] (b) an inner coating comprising one or more cross-linked fermentable biopolymers; and

[0016] (c) Exocoating that is resistant to gastrointestinal conditions and releases in the small intestine

[0017] It consists of.

[0018] The active substance present within the solid core is a water-soluble vitamin, in particular vitamin B, more preferably vitamin B2. Depending on the needs and desires, other nutritional supplements may be incorporated into the core (or coating). Nutritional supplements are compounds that provide health benefits to animals.

[0019] Preferred nutritional supplements of the present invention are organic acids, omega-3 fatty acids, omega-6 fatty acids, omega-8 fatty acids, long-chain fatty acids, polyphenols (e.g., resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

[0020] Accordingly, the present invention relates to a delivery system DS1 in which a solid core comprises one or more nutritional supplements selected from the group consisting of organic acids, omega-3 fatty acids, omega-6 fatty acids, omega-8 fatty acids, long-chain fatty acids, polyphenols (e.g., resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

[0021] Preferred organic acids are short-chain fatty acids (SCFAs) and salts thereof. Short-chain fatty acids are fatty acids having 2 to 6 carbon atoms. In the context of the present invention, SCFAs are formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid, and salts of said acids. Propionic acid and salts thereof are particularly preferred.

[0022] In the context of the present invention, the most desirable water-soluble vitamin is vitamin B2 (riboflavin).

[0023] Accordingly, the present invention relates to a delivery system DS or a delivery system DS2 in which the water-soluble vitamin is vitamin B2 or DS1.

[0024] In addition, another aspect of the present invention relates to a delivery system comprising only vitamin B2 as an active ingredient (nutritional supplement). This means that the delivery system (solid core and coating) does not contain any other nutritional supplement selected from the group consisting of organic acids, omega-3 fatty acids, omega-6 fatty acids, omega-8 fatty acids, long-chain fatty acids, polyphenols (e.g., resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

[0025] Accordingly, the present invention relates to a delivery system DS, DS1, or DS2, wherein the delivery system (solid core and coating) does not contain any other nutritional supplement selected from the group consisting of organic acids, omega-3 fatty acids, omega-6 fatty acids, omega-8 fatty acids, long-chain fatty acids, polyphenols (e.g., resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides, and a delivery system DS3.

[0026] The delivery system according to the present invention includes an anti-coating necessary to meet defined criteria. Materials suitable for the anti-coating (fermentable biopolymers) are, for example, alginate, chitosan, pectin, cyclodextrin, and other gums. Preferred coating materials for the anti-coating are alginate or pectin.

[0027] The inner coating is crosslinked. This can be accomplished using commonly known crosslinking compounds. In this case, alginate is used, and this can be accomplished by Mg and / or Ca ions (by using salts). The crosslinking agent may be sprayed onto the solid nucleus after or simultaneously with the application of the inner coating. Alternatively, the coated particles may be immersed in a solution containing the crosslinking agent. Preferably, the crosslinking agent is sprayed onto the particles after the inner coating layer is applied.

[0028] Furthermore, another advantage of the present invention is that the novel delivery system according to the present invention can be manufactured in both batch and continuous manner. In contrast to systems known from the prior art, this is highly advantageous for the industrial production of such products. Detailed manufacturing methods are disclosed below.

[0029] Accordingly, the present invention relates to a delivery system DS4, in which the inner coating material is selected from the group consisting of alginate, chitosan, pectin, cyclodextrin, and other gums, and the delivery system DS1, DS2, or DS3.

[0030] Accordingly, the present invention relates to a delivery system DS4' in which the inner coating material is alginate or pectin.

[0031] The anti-coating layer completely covers the nucleus (more or less). Ideally, the anti-coating layer has the same thickness (more or less) when applied to a solid nucleus. Typically, the thickness of the anti-coating layer is 5 μm or more and less than 20 μm. Preferably, the thickness of the anti-coating layer is 5 to 10 μm.

[0032] Accordingly, the present invention relates to a delivery system DS, DS1, DS2, DS3, DS4, or DS4', wherein the thickness of the anti-coating layer is 5 to 10 μm.

[0033] The inner coating layer is crosslinked with one or more crosslinking agents. Any suitable crosslinking agent may be used. Highly suitable (and thus desirable) are Mg and Ca ions (which are added in the form of salts).

[0034] Accordingly, the present invention relates to a delivery system DS6, which is a delivery system DS, DS1, DS2, DS3, DS4, DS4', or DS5, in which the inner coating layer is crosslinked with one or more crosslinking agents (preferably Mg and / or Ca ions).

[0035] Accordingly, the present invention relates to a delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, or DS7 in which the cross-linked inner coating layer is sodium alginate or sodium pectin.

[0036] Another delivery system of the present invention includes an external coating necessary to meet defined criteria. Suitable materials that meet the criteria for the external coating are, for example, shellac, methacrylate copolymers, and fats.

[0037] Accordingly, the present invention relates to a delivery system DS8 in which the coating material is selected from the group consisting of shellac, methacrylate copolymer and fat, such as delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, or DS7.

[0038] The outer coating layer completely covers the inner coating (more or less). Ideally, the inner coating layer has the same thickness (more or less) when applied to the inner coating.

[0039] Typically, the thickness of the anti-coating layer is 10 μm or more to typically less than 30 μm. Preferably, the thickness of the anti-coating layer is 10 to 20 μm.

[0040] Accordingly, the present invention relates to a delivery system DS9, which is a delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, or DS8, wherein the thickness of the outer coating layer is 10 to 20 μm.

[0041] The solid nucleus of the delivery system according to the present invention is typically 10 to 85 weight%, preferably 50 to 75 weight%, based on the total weight of the delivery system.

[0042] Accordingly, the present invention relates to a delivery system DS10, which is a delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, or DS9, wherein the solid nucleus of the delivery system is typically 10 to 85 weight%, preferably 50 to 75 weight%, based on the total weight of the delivery system.

[0043] The inner coating of the delivery system according to the present invention is typically 1 to 20 weight percent, preferably 1 to 10 weight percent, based on the total weight of the delivery system.

[0044] Accordingly, the present invention relates to a delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, or DS10, wherein the inner coating of the delivery system is typically 1 to 20 weight%, preferably 1 to 10 weight%, based on the total weight of the delivery system.

[0045] The outer coating of the delivery system according to the present invention is typically 1 to 30 weight%, preferably 15 to 30 weight%, based on the total weight of the delivery system.

[0046] Accordingly, the present invention relates to a delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, or DS12, wherein the outer coating of the delivery system is typically 1 to 30 weight%, preferably 15 to 30 weight%, based on the total weight of the delivery system.

[0047] The size of the delivery system according to the present invention may be 2 mm. The size is defined by the longest diameter of the particle. The shape of the particle is not an essential feature of the present invention. The size distribution of the particle is also not essential. The size and shape of the particle are primarily determined by the solid nucleus of the delivery system. Depending on the application of the delivery system, the size may be adjusted.

[0048] The delivery system according to the present invention is manufactured by a commonly known technique. Typically, after a solid core is manufactured in the first step, an inner coating and an outer coating are applied. As disclosed above, a major advantage of the novel delivery system (in addition to the characteristics of the delivery system) lies in the method of manufacturing the delivery system. The novel delivery system can be manufactured in a batch or continuous manner.

[0049] When manufactured in a batch process, the novel particles may be produced as follows: in the first step, a solid nucleus is prepared by a spray drying method; in the second step, the solid nucleus (obtained in the first step) is coated by spray coating with an inner coating material; and then a crosslinking agent is sprayed onto the particles. In the third step, an outer coating is sprayed onto the particles obtained in the preceding step, and finally, the particles are dried.

[0050] The advantage of the above method is that the steps are performed in the same device (spray coating machine), thereby reducing technical effort. However, it is also possible to manufacture the solid nucleus first, store it, and then coat it.

[0051] Another option for manufacturing the novel delivery system is a continuous process, in which a coating step is performed by first manufacturing a solid nucleus and then sequentially spraying it onto the particles. This method is ideal for industrial-scale application.

[0052] Accordingly, the present invention relates to a method P for manufacturing any particle among DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11, or DS12, wherein the manufacturing method is performed in a batch manner.

[0053] Accordingly, the present invention relates to a method P1 for manufacturing any particle among DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11, or DS12, wherein the manufacturing method is performed continuously.

[0054] The novel delivery systems DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11 and / or DS12 according to the present invention may be used as they are or incorporated into an application form.

[0055] The novel delivery system DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11 and / or DS12 according to the present invention may be used in any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0056] The novel delivery systems DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11 and / or DS12 according to the present invention may be part of a premix formulation that can be used to formulate any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0057] In addition, the present invention relates to a method for manufacturing a premix, dietary supplement, food, feed product, personal care product or pharmaceutical product using one or more delivery systems DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11 or DS12.

[0058] In addition, the present invention relates to a premix, dietary supplement, food, feed product, personal care product or pharmaceutical product comprising one or more delivery systems DS, DS1, DS2, DS3, DS4, DS4', DS5, DS6, DS7, DS8, DS9, DS10, DS11 or DS12.

[0059] The following examples are used as illustrative examples of specific embodiments of the invention claimed herein. All % refers to weight, and all temperatures are given in °C.

[0060] Examples

[0061] Example 1

[0062] 12 g of sodium alginate (Grindsted sodium alginate) was dissolved in 568 g of water by stirring at 50°C. 1.5 g of calcium chloride dihydrate was dissolved in 148.5 g of water. 80 g of granulated riboflavin (B2 Universal, DSM) was loaded into a fluid bed processor (WFP mini, DMR, Worcester configuration). All coating steps were performed at a manufacturing temperature of approximately 40°C. First, the alginate solution was sprayed onto the fluidized riboflavin granules. After spraying the alginate solution, the supply pipe was briefly rinsed with water. The calcium chloride solution was sprayed at 40°C to cure the solution. After curing the solution, 117 g of an aqueous shellac formulation (Aquagold SSB, Stroever) with a solid content of 25% was sprayed as an external coating. After spraying the shellac, the product was dried in a fluidized bed. 103 g of coated granules were obtained. The composition of the final coated granules was 60% riboflavin, 9% alginate, 1% calcium chloride, and 30% shellac. Protection of riboflavin under gastrointestinal conditions was tested with 0.1 N HCl using a USP-4 (SOTAX) device at 37.5°C. After 1 hour, less than 20% of riboflavin was released.

Claims

Claim 1 A delivery system of solid particles for delivering one or more water-soluble vitamins, wherein each solid particle comprises (a) a solid core containing one or more water-soluble vitamins; (b) an inner coating surrounding the solid core and comprising one or more cross-linked fermentable biopolymers; and (c) an outer coating surrounding the inner coating, wherein the inner coating is formed of a material that is resistant to gastrointestinal conditions and resistant to the release of one or more water-soluble vitamins in the small intestine, wherein the inner coating is formed of a material selected from the group consisting of alginate, pectin, and mixtures thereof, and the outer coating is formed of a material selected from the group consisting of shellac, fat, and mixtures thereof. Claim 2 A delivery system according to claim 1, wherein the solid core comprises vitamin B2. Claim 3 A delivery system according to claim 1 or 2, wherein the inner coating layer is cross-linked with Mg and / or Ca ions. Claim 4 A method for manufacturing a delivery system according to claim 1 or 2, performed in batches. Claim 5 A method for manufacturing a delivery system according to claim 1 or 2, performed in a continuous manner. Claim 6 A method for manufacturing a premix using one or more delivery systems according to paragraph 1 or 2. Claim 7 A premix comprising one or more delivery systems according to paragraph 1 or 2.

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