Novel delivery systems for certain water-soluble vitamins.

Abstract

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

Description

Detailed Description of the Invention

[0001] The present invention relates to a novel delivery system for certain water-soluble vitamins to the large intestine. These nutritional components are beneficial for intestinal and metabolic health in monogastric animals (such as pigs and poultry, as well as fish), and particularly in humans.

[0002] During the last few years, there has been an increase in consumer interest in products that promote gut health. Many new products have been launched and have gained wide consumer acceptance.

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

[0004] Water-soluble vitamins (B vitamins and vitamin C) are known to be important health-promoting compounds (also for gut and metabolic health).

[0005] Water-soluble vitamins are generally formulated as powder particles or granules, in which the vitamin is embedded in an encapsulating matrix material. Typically, the matrix material dissolves easily in the stomach and releases the vitamin immediately. Thus, the vitamin is absorbed in the stomach or small intestine and does not reach the large intestine.

[0006] Release in the small or large intestine is usually achieved by using controlled release capsules or tablets. The active substance is incorporated into capsules or tablets that are coated with one or more coatings that provide controlled release. However, tablets and capsules as delivery systems have some disadvantages. The amount of active substance that can be incorporated into a single tablet or capsule is limited by the available volume. In particular, very young and elderly patients have difficulty swallowing tablets or capsules. The residence time of capsules and tablets in the stomach is very variable and release is very time-precise, which can lead to very high local concentrations of active substances, which can cause adverse effects.

[0007] Multiparticulate forms such as powders, granules, beadlets or pellets overcome these drawbacks. However, applying controlled release coatings to multiparticulate dosage forms is difficult due to their large specific surface area compared to tablets or capsules. The amount of coating material required to achieve a sufficiently thick and evenly distributed coating layer is significantly higher than for tablets or capsules, reducing the space available for the body load.

[0008] Coating materials suitable for release in the small intestine often contain pH-sensitive polymers. This approach takes advantage of the existence of a pH gradient in the digestive tract that 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®), hydroxypropyl methylcellulose phthalate (HPMCP) and methacrylate copolymers or methacrylic acid copolymers commonly known as Eudragit.

[0009] A significant limitation of pH-sensitive coating technology is the uncertainty of the site and environment in which the coating will begin to dissolve. Because gastrointestinal motility is variable, enteric coating alone may result in premature drug release in the small intestine.

[0010] The use of the gastrointestinal microflora as a mechanism of drug release in the colonic region has attracted great interest from researchers in the past. Bacteria are distributed throughout the gastrointestinal tract, but the majority reside in the distal gut. Colonic bacteria are predominantly anaerobic in nature and secrete enzymes capable of metabolizing both endogenous and exogenous substances, such as carbohydrates and proteins that escape digestion in the upper gastrointestinal tract. Naturally occurring polysaccharides of plant (e.g., pectin, guar gum, inulin), animal (e.g., chitosan, chondroitin sulfate), algal (e.g., alginate) or microbial (e.g., dextran) origin have been studied for colonic targeting. These are broken down by the colonic bacterial flora into simple sugars by glycolytic 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] Many of these polymers are specifically degraded in the large intestine, but are hydrophilic in nature and swell when exposed to the conditions of the upper gastrointestinal tract, resulting in premature drug release. Furthermore, these polymers usually exhibit extremely high viscosities when dissolved, 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 homogeneously distributed in a protective matrix (in this case the fermentable biopolymer). However, matrix encapsulation has some significant drawbacks. Due to the high viscosity of the biopolymer, for example in spray drying or gel encapsulation, the matrix solution is very dilute and difficult and expensive to dry. The load capacity in matrix encapsulation is relatively low (usually less than 50%).

[0013] It was therefore an object of the present invention to discover an improved multiparticulate delivery system (formulation) that improves the stability of certain water-soluble vitamins during transit through the stomach and small intestine (before being released in the large intestine), improving the availability and efficacy of certain water-soluble vitamins.

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

[0015] Vitamin B1, B3, B5, B6, B7, B9, B 12 It has been found that a delivery system has improved properties when a solid core containing at least one specific water soluble vitamin selected from the group consisting of and C is coated with a specific inner coating and a specific outer coating. Furthermore, the delivery system can be manufactured in batch and continuous processes.

[0016] In other words, the novel delivery system is suitable for all water-soluble vitamins except vitamin B2.

[0017] The novel delivery system (DS) according to the present invention comprises: (a) Vitamins B1, B3, B5, B6, B7, B9, and B 12 and C, and (b) an inner coating comprising at least one fermentable biopolymer, the inner coating being crosslinked; and (c) an outer coating that is resistant to gastric conditions and releases in the small intestine It consists of:

[0018] The novel delivery system (DS1) according to the present invention comprises: (a) a solid core comprising at least one water-soluble polymer; and (b) an inner coating comprising at least one fermentable biopolymer, the inner coating being crosslinked; and (c) an outer coating that is resistant to gastric conditions and releases in the small intestine However, vitamin B2 is excluded from this range.

[0019] Other nutritional ingredients can be incorporated into the core (or coating) as necessary and desired. Nutraceutical ingredients are compounds that provide a health benefit in animals.

[0020] A particular preferred water-soluble vitamin is vitamin C.

[0021] Thus, the present invention relates to a delivery system (DS) or (DS1), (DS1'), in which the specific water-soluble vitamin is vitamin C.

[0022] The delivery system according to the invention comprises an inner coating which must meet defined criteria. Suitable materials for the inner coating (fermentable biopolymers) are, for example, alginates, chitosan, pectin, cyclodextrins and other gums. Preferred coating materials for the inner coating are alginates or pectin.

[0023] The inner coating is crosslinked. This can be done by commonly known crosslinking compounds. When alginate is used, it can be done 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 applying the inner coating. Alternatively, the coated particles can be immersed in a solution containing the crosslinking agent.

[0024] Preferably, the crosslinking agent is sprayed onto the particles after the inner coating layer is applied.

[0025] Another advantage of the present invention is that the production of the novel delivery system according to the invention can be carried out batchwise and continuously, in contrast to the systems known from the prior art, which is also a major advantage when considering the industrial production of such products, the details of which are disclosed below.

[0026] Thus, the present invention relates to a delivery system (DS2) which is a delivery system (DS), (DS1) or (DS1') in which the material of the inner coating is selected from the group consisting of alginates, chitosan, pectin, cyclodextrins and other gums.

[0027] Thus, 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.

[0028] The inner coating layer (almost) completely covers the core. Ideally, the inner coating layer has (almost) the same thickness as if it were applied to a solid core.

[0029] Typically, the thickness of the inner coating layer is at least 5 μm and no more than 20 μm.

[0030] Preferably, the thickness of the inner coating layer is from 5 μm to 10 μm.

[0031] Thus, the present invention relates to a delivery system (DS3), which is a delivery system (DS), (DS1), (DS1'), (DS2) or (DS2'), wherein the thickness of the inner coating layer is between 5 μm and 10 μm.

[0032] The inner coating layer is crosslinked with at least one crosslinking agent. Any suitable crosslinking agent can be used. Zn, Mg and Ca ions (which are added in the form of their salts) are highly suitable (and therefore preferred).

[0033] Thus, the present invention relates to a delivery system (DS4) which is a delivery system (DS), (DS1), (DS1'), (DS2), (DS2') or (DS3), wherein the inner coating layer is crosslinked with at least one crosslinking agent (preferably Zn, Mg and / or Ca ions).

[0034] Thus, the present invention relates to a delivery system (DS5) which is a delivery system (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3) or (DS4) in which the crosslinked inner coating layer is Na alginate or pectin.

[0035] The delivery system according to the invention comprises an outer coating which must meet defined criteria. Suitable materials meeting the criteria for the outer coating are, for example, shellac, methacrylate copolymers and lipids.

[0036] Thus, the present invention relates to a delivery system (DS6) which is a delivery system (DS), (DS1), (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 lipids.

[0037] The outer coating layer (almost) completely covers the inner coating. Ideally, the outer coating layer has (almost) the same thickness when applied to the inner coating.

[0038] Typically the thickness of the outer layer is at least 10 μm and typically less than 30 μm.

[0039] Preferably, the thickness of the outer coating layer is from 10 to 20 μm.

[0040] Thus, the present invention relates to a delivery system (DS7) which is a delivery system (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5) or (DS6) having an outer coating layer thickness of 10 μm to 20 μm.

[0041] 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.

[0042] Thus, the present invention relates to a delivery system (DS8) which is a delivery system (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6) or (DS7), in which the solid core of the delivery system is 10 to 85% by weight, preferably 50 to 75% by weight, based on the total weight of the delivery system.

[0043] 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.

[0044] Thus, the present invention relates to a delivery system (DS9) which is a delivery system (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7) or (DS8) in which 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.

[0045] 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.

[0046] Thus, the present invention relates to a delivery system (DS10) which is a delivery system (DS), (DS1), (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.

[0047] The delivery system according to the present 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 a critical feature of the present invention. The size distribution of the particles is also not critical. The size and shape of the particle is defined primarily by the solid core of the delivery system. Depending on the use of the delivery system, the size can be adjusted.

[0048] The delivery system according to the invention is manufactured by commonly known techniques.

[0049] Usually, a solid core is manufactured in a first step and then the inner and outer coatings are applied.

[0050] The solid core particles can be prepared by known methods, such as spray drying, agglomeration, granulation, microtablet compression, extrusion or extrusion-spheronization.

[0051] As disclosed above, one of the main advantages of the novel delivery system (besides the properties of the delivery system) is the method of manufacturing the delivery system.

[0052] The novel delivery system can be manufactured batchwise or continuously.

[0053] When produced in batch mode, the novel particles can be produced as follows: in a first step, a solid core is coated with the coating material of the inner coating by spray coating, and then the particles are sprayed with a crosslinking agent; in a second step, the particles obtained by the previous step are sprayed with an outer coating, and finally the particles are dried.

[0054] The advantage of the method is that the steps including the production of the solid cores by granulation or agglomeration can be carried out in the same equipment (fluidized bed processing equipment), reducing the technical effort. Nevertheless, it is also possible to first produce the solid cores, store them and then coat them.

[0055] Another option for the production of the novel delivery systems is the continuous method, where the solid cores are first produced and then sprayed onto the particles in a coating step, which is ideal for application on an industrial scale.

[0056] The present invention therefore also relates to a process (P) for the production of any of the particles (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10), which is carried out batchwise.

[0057] The present invention therefore also relates to a process (P1) for the production of any of the particles (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (SD5), (DS6), (DS7), (DS8), (DS9) or (DS10), which is carried out continuously.

[0058] The novel delivery systems (DS), (DS1), (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.

[0059] The novel delivery systems ((DS), (DS1), (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.

[0060] The novel delivery systems (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10) may also be part of a premix formulation which can then be used to formulate any dietary supplement, food, feed product, personal care product or pharmaceutical product.

[0061] The present invention also relates to a method of producing a premix, dietary supplement, food, feed product, personal care product or pharmaceutical product using at least one delivery system (DS), (DS1), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10).

[0062] 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), (DS1'), (DS2), (DS2'), (DS3), (DS4), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10).

[0063] The following examples serve to illustrate certain embodiments of the invention claimed in this application. All percentages are listed by weight and all temperatures are listed in degrees Celsius.

[0064] [Example] [Example 1] 15 g of Na-alginate (grinsted sodium alginate) are dissolved in 485 g of water at 60 °C with stirring. 31.5 g of Ca chloride dihydrate are dissolved in 98.5 g of water. 100 g of Vitamin C powder (ascorbic acid, DSM) are charged into a fluidized bed processor (WFP Mini, DMR, Wurster configuration). All coating steps are carried out at a product temperature of 50-60 °C. First the alginate solution is sprayed onto the fluidized ascorbic acid powder. After spraying the alginate solution, the feed tube is briefly rinsed with water. A Ca chloride solution is sprayed on the inner coating at a product temperature of 53 °C and allowed to harden. After the solution has hardened, 154 g of an aqueous shellac preparation with a solids content of 25% (SSB Aquagold, Stroever) is sprayed as an outer coating. After spraying the shellac, the product is dried in the fluidized bed.

[0065] The composition of the final coated granules is 65% ascorbic acid, 9% alginate, 1% Ca chloride and 25% shellac.

Claims

1. (a) Vitamin B １ , B ３ , B ５ , B ６ , B ７ , B ９ , B １２ and C, and (b) an inner coating comprising at least one fermentable biopolymer, the inner coating being crosslinked; and (c) an outer coating that is resistant to gastric conditions and releases in the small intestine It consists of: the material of the inner coating is selected from the group consisting of alginate and pectin; The delivery formulation, wherein the outer coating is selected from the group consisting of shellac, methacrylate copolymers and lipids.

2. The delivery formulation of claim 1 , wherein the water-soluble vitamin is vitamin C.

3. 3. The delivery formulation of claim 1 or 2, wherein the inner coating is crosslinked with Zn, Mg and / or Ca ions.

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

5. A method for producing the delivery formulation according to any one of claims 1 to 3, which 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 delivery formulation according to any one of claims 1 to 3.

7. A premix comprising at least one delivery formulation according to any one of claims 1 to 3.

8. A dietary supplement comprising at least one delivery formulation described in any one of claims 1 to 3.

9. A food product comprising at least one delivery formulation described in any one of claims 1 to 3.

10. A feed product comprising at least one delivery formulation described in any one of claims 1 to 3.

11. A personal care product comprising at least one delivery formulation according to any one of claims 1 to 3.

12. A pharmaceutical comprising at least one delivery formulation described in any one of claims 1 to 3.