New delivery system

Abstract

The present invention relates to a new delivery system, in particular to a new delivery system for nutritional ingredients (nutraceuticals). These nutritional ingredients are useful for the gut and metabolic health of monogastric animals, in particular humans.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880071097.1 (PCT / EP2018 / 079662) entitled "New Delivery System", filed by the applicant DSM Intellectual Property Asset Management Co., Ltd. on October 30, 2018. Technical Field

[0002] This invention relates to a novel delivery system for water-soluble vitamins (i.e., vitamin B (especially B2)) in the large intestine. These nutrients are beneficial for the intestinal and metabolic health of monogastric animals (such as pigs and poultry, as well as fish), and especially humans. Background Technology

[0003] Over the past few years, increased consumer interest in products that promote gut health has been observed. Many new products have been launched and widely accepted by consumers.

[0004] Research on the potential effects of gut microbiota on metabolism and immunity, as well as obesity, inflammation, cardiovascular disease, and diabetes has also increased.

[0005] Riboflavin (vitamin B2) is known to have a beneficial effect on the growth of *Faecalibacterium prausnitzii*, a marker species for a healthy gut, upon delivery to the large intestine. EP2914135 describes the use of riboflavin to selectively stimulate *F. prausnitzii*. However, very high doses of riboflavin are required because most of it is destroyed or absorbed before reaching the large intestine.

[0006] Controlled-release capsules or tablets are typically used to achieve release in the small or large intestine. The active substance is incorporated into a capsule or tablet coated with one or more coatings that result in controlled release. However, tablets and capsules as delivery systems have several drawbacks. The amount of active substance that can be incorporated into a single tablet or capsule is limited by the available volume. Swallowing tablets or capsules is particularly difficult for very young and elderly patients. The residence time of capsules and tablets in the stomach varies greatly and the release is very precise, which can lead to extremely high local concentrations of the active substance, potentially causing adverse effects.

[0007] Multi-particle forms, such as powders, granules, beads, or pellets, overcome these drawbacks. However, applying controlled-release coatings to multi-particle dosage forms is challenging due to their larger surface area compared to tablets or capsules. To achieve a uniformly distributed coating layer of sufficient thickness, a significantly larger amount of coating material is required than for tablets or capsules, thus reducing the available space for the effective payload.

[0008] Suitable coating materials for release in the small intestine often contain pH-sensitive polymers. This method utilizes the pH gradient present in the GIT, which gradually increases from the stomach (pH 1.5–3.5) and small intestine (pH 5.5–6.8) to the large intestine (pH 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) ® Hydroxypropyl methylcellulose phthalate (HPMCP) and methacrylic acid copolymer (commonly known as methacrylate copolymer or Eudragit).

[0009] A significant limitation of pH-sensitive coating technology is the uncertainty of the location and environment at which the coating can begin to dissolve. It is possible that enteric coating alone can lead to premature drug release in the small intestine due to changes in GI dynamics.

[0010] The use of GI bacteria as a mechanism for drug release in the colon has previously attracted considerable interest from researchers. Most bacteria reside in the distal gut, although they are distributed throughout the gastrointestinal tract. Colonic bacteria are primarily anaerobic and secrete enzymes capable of metabolizing both endogenous and exogenous substrates, such as undigested carbohydrates and proteins in the upper gastrointestinal tract. Polysaccharides naturally occurring in plant (e.g., pectin, guar gum, inulin), animal (e.g., chitosan, chondroitin sulfate), algae (e.g., alginate), or microbial (e.g., dextran) sources have been investigated for colonic targeting. These are broken down into simple sugars by glycolytic species in the colonic flora, 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 they specifically degrade in the large intestine, many of these polymers are hydrophilic and swell upon exposure to the upper gastrointestinal tract, leading to premature drug release. Furthermore, these fermentables typically exhibit very high viscosity in solution, making them difficult or impossible to process at high concentrations.

[0012] Fermentable biopolymers have been used as encapsulation matrices. In matrix encapsulation, the active substance is uniformly distributed within a protective matrix (in this case, a fermentable biopolymer). However, matrix encapsulation has several significant drawbacks. Due to the high viscosity of biopolymers, the matrix solution (e.g., in spray drying or gel encapsulation) is very dilute, making its drying difficult and expensive. The effective loading in matrix encapsulation is relatively low (typically less than 50%). Summary of the Invention

[0013] On one hand, this application relates to a delivery system comprising the following components: (a) A solid core containing at least one water-soluble vitamin, and (b) An inner coating comprising at least one fermentable biopolymer, which is cross-linked and selected from the group consisting of alginate, pectin, cyclodextrin, and other gums. (c) An outer coating that resists the gastric environment and is released in the small intestine, wherein the outer coating is selected from the group consisting of shellac, methacrylate copolymers, and fats, and wherein Based on the total weight of the delivery system, the solid core of the delivery system is typically 10-85% by weight, and Based on the total weight of the delivery system, the inner coating of the delivery system is typically 10-85% by weight, and Based on the total weight of the delivery system, the outer coating of the delivery system is typically 1-30% of the weight.

[0014] Secondly, this application relates to a method for producing a delivery system according to the first aspect described above, wherein the method is performed in batches.

[0015] Thirdly, this application relates to a method for producing a delivery system according to the first aspect described above, wherein the method is performed continuously.

[0016] Fourthly, this application relates to a method for producing premixes, dietary supplements, food products, feed products, personal care products, or pharmaceutical products using at least one delivery system according to the first aspect.

[0017] Fifthly, this application relates to a premix, dietary supplement, food, feed product, personal care product, or pharmaceutical product comprising at least one delivery system according to the first aspect. Detailed Implementation

[0018] The present invention aims to find an improved multi-particle delivery system (formulation) to improve the stability of water-soluble vitamins (i.e., vitamin B (especially B2)) during transport via the stomach and small intestine (before release into the large intestine), thereby improving the availability and efficacy of water-soluble vitamins (i.e., vitamin B (especially B2)).

[0019] Furthermore, the new delivery system should be able to be manufactured in a simple and industrially applicable manner.

[0020] It was found that when a solid core containing at least one nutrient is coated with a specific inner coating and a specific outer coating, the delivery system exhibits improved properties. Furthermore, the delivery system can be produced in batches as well as through continuous methods.

[0021] The novel delivery system (DS) according to the present invention comprises the following: (a) A solid core containing at least one water-soluble vitamin (particularly vitamin B2), and (b) An inner coating comprising at least one cross-linked fermentable biopolymer, and (c) The outer coating resists the gastric environment and is released in the small intestine.

[0022] The active substances in the core are water-soluble vitamins, especially vitamin B, and more preferably vitamin B2.

[0023] If needed and desired, other nutrients can be incorporated into the core (or coating). Nutrients are compounds that provide health benefits in animals.

[0024] Preferred nutrients in this invention include organic acids, ω3 fatty acids, ω6 fatty acids, ω8 fatty acids, long-chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

[0025] Therefore, the present invention relates to a delivery system (DS1), which is a delivery system (DS) wherein the solid core contains at least one nutrient selected from the group consisting of: organic acids, ω3 fatty acids, ω6 fatty acids, ω8 fatty acids, long-chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils and antimicrobial peptides.

[0026] The preferred organic acids are short-chain fatty acids (SCFAs) and their salts.

[0027] Short-chain fatty acids are fatty acids having two to six carbon atoms. In the context of this invention, SCFAs are the following substances: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid, as well as salts of these acids. Propionic acid and its salts are particularly preferred.

[0028] In the context of this invention, the most preferred water-soluble vitamin is vitamin B2 (riboflavin).

[0029] Therefore, the present invention relates to a delivery system (DS2), which is a delivery system (DS) or (DS1), wherein the water-soluble substance is vitamin B2.

[0030] Furthermore, another embodiment of the invention relates to a delivery system that contains only vitamin B2 as the active ingredient (nutrient). This means that the delivery system (solid core and coating) does not contain any other nutrients 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 (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

[0031] Therefore, the present invention relates to a delivery system (DS3), which is a delivery system (DS), (DS1) or (DS2) wherein the delivery system (solid core and coating) does not contain any other nutrients selected from the group consisting of: organic acids, ω3 fatty acids, ω6 fatty acids, ω8 fatty acids, long-chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils and antimicrobial peptides.

[0032] The delivery system according to the invention includes an inner coating that needs to meet defined criteria. Suitable materials for the inner coating (fermentable biopolymers) are, for example, alginate, chitosan, pectin, cyclodextrin, and other gums. Preferred coating materials for the inner coating are alginate or pectin.

[0033] The inner coating is cross-linked. This can be accomplished with commonly known cross-linking compounds. In the case of alginate, this can be accomplished by Mg ions and / or Ca ions (using salt). The cross-linking agent can be sprayed onto the solid core after or simultaneously with the application of the inner coating. Alternatively, the coated particles can be immersed in a solution containing the cross-linking agent.

[0034] Preferably, the crosslinking agent is sprayed onto the particles after the inner coating layer is applied.

[0035] Another advantage of this invention is that it enables the production of the new delivery system according to the invention to be completed in batches and continuously. Compared with systems known from the prior art, this is a significant advantage considering the industrial production of such products. Details of the method are disclosed below.

[0036] Therefore, the present invention relates to a delivery system (DS4), which is a delivery system (DS), (DS1), (DS2) or (DS3), wherein the inner coating material is selected from the group consisting of alginate, chitosan, pectin, cyclodextrin and other gums.

[0037] Therefore, the present invention relates to a delivery system (DS4'), wherein the inner coating material is alginate or pectin.

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

[0039] Typically, the thickness of the inner coating layer is at least 5 μm and no more than 20 μm. Preferably, the thickness of the inner coating layer is between 5 μm and 10 μm.

[0040] Therefore, the present invention relates to a delivery system (DS5), which is a delivery system (DS), (DS1), (DS2), (DS3), (DS4) or (DS4'), wherein the thickness of the inner coating layer is 5 μm–10 μm.

[0041] The inner coating layer is cross-linked with at least one cross-linking agent. Any suitable cross-linking agent can be used. Mg ions and Ca ions (added in the form of salts) are very suitable and therefore preferred.

[0042] Therefore, the present invention relates to a delivery system (DS6), which is a delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4') or (DS5), wherein the inner coating layer is cross-linked with at least one cross-linking agent (preferably Mg ions and / or Ca ions).

[0043] Therefore, the present invention relates to a delivery system (DS7), which is a delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4'), (DS5) or (DS6), wherein the cross-linked inner coating layer is sodium alginate or sodium pectin.

[0044] The delivery system according to the invention includes an outer coating that needs to meet defined standards. Suitable materials that meet the outer coating standards are, for example, shellac, methacrylate copolymers, and fats.

[0045] Therefore, the present invention relates to a delivery system (DS8), which is a delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4'), (DS5), (DS6) or (DS7), wherein the material of the outer coating is selected from the group consisting of shellac, methacrylate copolymer and fat.

[0046] The outer coating layer (approximately) completely covers the inner coating. Ideally, the outer coating layer should have (approximately) the same thickness as the inner coating layer when applied.

[0047] The outer layer typically has a thickness of at least 10 μm and usually less than 30 μm. Preferably, the thickness of the outer coating layer is between 10 μm and 20 μm.

[0048] Therefore, 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 μm–20 μm.

[0049] Based on the total weight of the delivery system, the solid core of the delivery system according to the present invention is typically 10-85% by weight, preferably 50-75% by weight.

[0050] Therefore, 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 core of the delivery system is 10-85% by weight, preferably 50-75% by weight, based on the total weight of the delivery system.

[0051] Based on the total weight of the delivery system, the inner coating of the delivery system according to the present invention is typically 1-20% by weight, preferably 1-10% by weight.

[0052] Therefore, the present invention relates to a delivery system (DS11), which is 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 10-85% by weight, preferably 1-10% by weight, based on the total weight of the delivery system.

[0053] Based on the total weight of the delivery system, the outer coating of the delivery system according to the present invention is typically 1-30% by weight, preferably 15-30% by weight.

[0054] Therefore, the present invention relates to a delivery system (DS12), which is a delivery system (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10) or (DS11), wherein the outer coating of the delivery system is 1-30% by weight, preferably 15-30% by weight, based on the total weight of the delivery system.

[0055] The delivery system according to the invention can be up to 2 mm in size. This size is defined by the longest diameter of the particle. The shape of the particle is not a significant feature of the invention. Furthermore, the size distribution of the particle is not important. The size and shape of the particle are primarily defined by the solid core of the delivery system. The size can be adjusted according to the intended use of the delivery system.

[0056] The delivery system according to the invention is produced using generally known techniques.

[0057] Typically, a solid core is produced in the first step, followed by the application of inner and outer coatings.

[0058] As disclosed above, one of the main advantages of the new delivery system (besides the nature of the delivery system) lies in its production method. The new delivery system can be produced in batches or continuously.

[0059] When producing in batches, new pellets can be produced as follows: In the first step, a solid core is produced by spray drying. Then, in the second step, the solid core (obtained in the first step) is coated with an inner coating material by spray coating, followed by spraying a crosslinking agent onto the particles. In the third step, an outer coating is sprayed onto the particles obtained through the previous steps, and finally, the particles are dried.

[0060] The advantage of this method is that the steps can be performed in the same equipment (coating machine), which reduces the amount of technical work. However, it is also possible to: first produce a solid core, store the solid core, and then coat the solid core.

[0061] Another option for producing new delivery systems is a continuous approach, in which a solid core is first produced, and then coated onto the particles one after another in a coating step. These methods are ideal for industrial-scale applications.

[0062] Therefore, the present invention also relates to a method (P) for producing any one of granules (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11), or (DS12), wherein the method is performed in batches.

[0063] Therefore, the present invention also relates to a method (P1) for producing any one of particles (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11), or (DS12), wherein the method is performed continuously.

[0064] The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and / or (DS12) according to the invention can be used as is or incorporated into the application.

[0065] The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and / or (DS12) can be used as is in any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0066] The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and / or (DS12) may also be part of a premixed formulation which can then be used to formulate any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0067] The present invention also relates to methods for producing premixes, dietary supplements, food, feed products, personal care products or pharmaceutical products using at least one delivery system (DS), (DS1), (DS2), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12).

[0068] 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), (DS3), (DS3'), (DS3”), (DS4), (DS5), (DS5'), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12).

[0069] The following examples illustrate specific embodiments of the invention claimed herein. All percentages are given by weight and all temperatures are given in degrees Celsius.

[0070] This application provides the following technical solution: Technical Solution 1. A delivery system, said delivery system comprising the following: (a) A solid core containing at least one water-soluble vitamin, and (b) An inner coating comprising at least one cross-linked fermentable biopolymer, and (c) The outer coating resists the gastric environment and is released in the small intestine.

[0071] Technical Solution 2. The delivery system according to Technical Solution 1, wherein the solid core contains vitamin B2.

[0072] Technical Solution 3. The delivery system according to any one of the foregoing technical solutions, wherein the material of the inner coating is selected from the group consisting of alginate, chitosan, pectin, cyclodextrin and other gums.

[0073] Technical Solution 4. The delivery system according to any one of the foregoing technical solutions, wherein the inner coating layer is cross-linked with Mg ions and / or Ca ions.

[0074] Technical Solution 5. The delivery system according to any one of the foregoing technical solutions, wherein the outer coating is selected from the group consisting of shellac, methacrylate copolymer and fat.

[0075] Technical Solution 6. A method for producing a delivery system according to any one of the preceding technical solutions 1-5, wherein the method is performed in batches.

[0076] Technical Solution 7. A method for producing a delivery system according to any one of the preceding technical solutions 1-5, wherein the method is performed continuously.

[0077] Technical Solution 8. A method for producing premixes, dietary supplements, food, feed products, personal care products or pharmaceutical products using at least one delivery system according to any one of Technical Solutions 1-5.

[0078] Technical Solution 9. A premix, dietary supplement, food, feed product, personal care product or pharmaceutical product comprising at least one delivery system according to technical solutions 1-5.

[0079] Example Example 1: 12 g of sodium alginate (ground) was dissolved in 568 g of water with 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 fluidized bed processor (WFP mini, DMR, Wurster configuration). All coating steps were performed at a product temperature of approximately 40 °C. First, the alginate solution was sprayed onto the fluidized riboflavin granules. After spraying the alginate solution, the feed pipe was briefly rinsed with water. Calcium chloride solution was sprayed onto the inner coating at 40 °C for hardening. After hardening the solution, 117 g of an aqueous shellac preparation (Aquagold SSB, Stroever) with a solids content of 25% was sprayed as the outer coating. After shellac spraying, the product was dried in a fluidized bed. 103 g of coated granules were obtained.

[0080] The final coated granules consist of 60% riboflavin, 9% alginate, 1% calcium chloride, and 30% shellac.

[0081] The protection of riboflavin in a gastric environment was tested using a USP-4 (SOTAX) instrument at 37.5°C with 0.1N HCl. After 1 hour, less than 20% of the riboflavin was released.

Claims

1. A delivery system comprising: (a) A solid core containing at least one water-soluble vitamin, and (b) An inner coating comprising at least one fermentable biopolymer, which is cross-linked and selected from the group consisting of alginate, pectin, cyclodextrin, and other gums. (c) An outer coating that resists the gastric environment and is released in the small intestine, wherein the outer coating is selected from the group consisting of shellac, methacrylate copolymers, and fats, and wherein Based on the total weight of the delivery system, the solid core of the delivery system is typically 10-85% by weight, and Based on the total weight of the delivery system, the inner coating of the delivery system is typically 10-85% by weight, and Based on the total weight of the delivery system, the outer coating of the delivery system is typically 1-30% of the weight.

2. The delivery system of claim 1, wherein the solid core comprises vitamin B2.

3. The delivery system according to any one of the preceding claims, wherein the inner coating layer is cross-linked with Mg ions and / or Ca ions.

4. A method for producing a delivery system according to any one of claims 1-3, wherein the method is performed in batches.

5. A method for producing a delivery system according to any one of claims 1-3, wherein the method is performed continuously.

6. A method for producing premixes, dietary supplements, food products, feed products, personal care products or pharmaceutical products using at least one delivery system according to any one of claims 1-3.

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