Multi-layered product for oral administration and controlled release of several different active ingredients in the digestive system of a farm animal.

Description

[0001] The present invention relates to the technical field of animal nutrition and, more particularly, to that of supplementation with active substances necessary for the animal, in particular for livestock, such as ruminants, especially in the context of precision feeding.

[0002] Livestock are animals raised for economic activities such as the production of meat, eggs or milk, or wool or fur. Examples include cattle, sheep, poultry, pigs and rabbits.

[0003] Precision feeding and supplementation of the diet of these animals with specific active substances allows these animals to receive a diet that is balanced, adapted to their needs, conditions, breed and age, which is favorable to their growth and well-being and which maintains their good health.

[0004] However, when providing supplementation, it is important to consider the specific characteristics of the animal's digestive system in order to best target the organ(s) in which a given active substance should be absorbed or utilized. For example, in ruminants, the digestive system consists of three foramina—the rumen, reticulum, and omasum—as well as a stomach, the abomasum (or stomach), and the intestines. The rumen is the first and largest of the three foramina. This organ is rich in microorganisms such as bacteria, protozoa, fungi, and archaea. These microorganisms break down the nutrients that enter the rumen through anaerobic fermentation. The rumen is particularly effective in breaking down indigestible nutrients such as cellulose, which would otherwise remain undigested.While it may be beneficial to provide the rumen with certain active substances for use there, other active substances would be unnecessarily degraded and would lose their physiological functionality.

[0005] As an example of active substances intended for delivery and use in the rumen, we can cite non-protein nitrogen sources. One of the distinctive features of ruminants is their ability to synthesize the proteins they need from such a source, particularly for growth, tissue function, and milk production. Indeed, the microorganisms present in the rumen are able to convert nitrogen from these concentrated sources into ammonia and use this ammonia to synthesize amino acids and then proteins essential for ruminants. This protein synthesis by microorganisms is closely linked to the amount of energy, in the form of ATP, produced by the fermentation of carbohydrates from the feed ration.However, a large supply of non-protein nitrogen sources is not desirable because the transformation of nitrogen into ammonia is very rapid, and this ammonia, if not metabolized by microorganisms, then passes into the bloodstream and becomes toxic to the animal. To address the problem of excessively rapid nitrogen utilization in the rumen, supplements with non-protein nitrogen sources, known as sustained-release nitrogen supplements, have been proposed. These supplements release nitrogen, for example, at a rate identical to the rate at which it is metabolized, notably by the microbial flora. In this regard, US patent 6,620,453 describes compounds containing such a nitrogen source protected by a semi-permeable membrane made of polyurethane, polyolefin, or polyester resin—polymers that are not degradable in the rumen. The semi-permeable nature of the membrane ensures the gradual release of nitrogen.Although effective, the use of such petroleum-derived compounds is not very advantageous. Furthermore, membrane formation can be technically complex. Regarding the prolonged release of nitrogen, we should also mention patent EP 1 043 295, which describes urea particles protected by coatings formed from relatively complex polymer networks, ensuring the prolonged release of nitrogen.

[0006] It is important to note that the amount of nitrogen supplied and its release rate are not the only factors to consider for the proper functioning of reactions occurring in the rumen. Indeed, the quality, quantity, and balance of rumen microorganism populations must also be taken into account, as these populations can be weakened by numerous factors. For example, a drop in rumen pH during acidosis can alter this balance and disrupt the gut flora. If these populations are not maintained at an optimal level, reactions such as the protein synthesis mentioned earlier cannot be sustained, even with the addition of nitrogen sources.However, the current state of the art, as previously mentioned, does not address the qualitative and quantitative maintenance of microorganisms, particularly the balance of microorganism populations such as rumen bacteria. It would therefore be clearly advantageous to have methods for delivering beneficial active substances into the rumen, in addition to non-protein nitrogen sources, to maintain a balance between microorganism populations or to direct the rumen flora towards a specific population that should be favored according to environmental conditions, for example, by providing agents that allow for the continuous regulation of rumen pH.

[0007] Examples of active substances that are beneficial to provide to ruminants and that must reach the post-rumen organs intact—that is, the organs downstream of the rumen in the digestive system, such as the abomasum or the intestine—include proteins, peptides, amino acids, vitamins, enzymes, medications, minerals, and so on. Since these active substances are ingested orally, they circulate through the ruminant's digestive system and, therefore, pass through the rumen. To prevent the digestion of these substances in the rumen, a protective coating is generally used, for example, made of hydrophobic materials or materials insoluble at a pH close to that of the rumen, i.e., around 6.European patent EP 2 197 293, for example, describes a so-called rumen bypass composition, which allows the delivery of an active substance to a post-rumen organ, preventing its degradation in the rumen. The composition is in the form of a granule whose core comprises an amino acid salt protected from degradation in the rumen by several coating layers. Patent applications EP 06 19 079, US 2010 / 272852, EP0588 346, and US 5 633 004 also describe such rumen bypass products in granule form. Similarly, patent EP 0 336 713 also describes a composition for rumen bypass, specifically a composition for coating the core of an active substance to be released post-rumen. These prior art statements also suggest the possibility of delivering several active substances through a single product.These active substances are then presented as mixtures constituting the granule cores, the cores being protected from degradation in the rumen by suitable coatings. However, it should be noted that the release of the active substances occurs simultaneously and in the same organ.

[0008] It thus appears from the state of the art that there are no solutions allowing the supplementation of a livestock animal by means of a single product and a single intake, with several active substances of a different nature, each intended to be released in the same organ of the digestive system, for example in the stomach or in one of the fore-stomachs in the ruminant, but according to different kinetics or at different times in the digestive cycle, or some intended to be released in a first organ of the digestive system, such as the stomach or in one of the fore-stomachs in the ruminant, and others intended to be released in another organ of the digestive system, such as the intestine.

[0009] It is in this context that the applicant company conducted its research and developed new products which offer all the aforementioned advantages, while being simple to produce and use.

[0010] To this end, the invention relates to a multilayer product intended for the oral administration and controlled release of several different active substances in the rumen of a livestock animal, the product comprising a urea core and progressing concentrically from the core: a coating matrix formed of hydrogenated fats based on rapeseed, sunflower or palm oil, exhibiting a degradation kinetics in the rumen of between 1 and 24h, a layer of second active substance chosen from micronized calcium carbonate, micronized sodium sulfate, micronized quilaia powder, micronized Ascophyllum Nodosum powder, a coating matrix formed of hydrogenated fats based on rapeseed, sunflower or palm oil, exhibiting a degradation kinetics in the rumen of between 1 and 24h, the quantity of coating matrix being between 2 and 13%, by weight of the product the product being in the form of a spherical bead having a diameter of between 0.01 and 5 mm.Livestock, as defined in the invention, includes animals whose digestive system comprises a stomach and, further down the digestive system, intestines—that is, monogastric animals—and those whose digestive system comprises forestomachs, a stomach, and, further down the digestive system, intestines—that is, polygastric animals. As an example of polygastric animals considered within the scope of the invention, ruminants may be cited, whose digestive system comprises, in the order of the digestive system, three forestomachs (including the rumen, reticulum, and omasum), a stomach, and intestines.

[0011] Thus, the product according to the invention has the advantage of being able to deliver more than one active substance at different times or at different release rates. This is made possible by the inclusion of the active substances in different layers that are superimposed one on top of the other around the core and by the use of coating matrices that protect the active substance and ensure gradual degradation in the stomach environment when this substance is to be delivered into the stomach of a monogastric animal or into one of the forestomachs or the stomach of a polygastric animal.

[0012] Advantageously, the coating matrices comprise hydrophobic compounds and / or compounds stable at a pH between 3 and 7, i.e., the pH of the stomach or forestomach. The coating matrices can be made of any materials or compounds that are not degradable in gastric juice or that are gradually degraded there, for example, by chemical or enzymatic reaction, so as to allow for prolonged release, but which are, on the other hand, degraded in the post-stomach organs. Those skilled in the art will find such materials or compounds in the prior art. Indeed, such coating matrices are already known and are not, as such, the subject of the present invention. Among the most commonly used coating matrices are those that are pH-sensitive or hydrophobic.Based on the known pH values ​​of the digestive system organs of the target animal, a professional skilled in the art can select the appropriate materials or compounds to form the desired coating matrix. For example, in ruminants, the pH of the rumen is around 6 and that of the intestines around 2. Thus, the matrix coating an active substance to be released in the intestines could be composed of polymers stable at pH 6 but unstable at pH 2. Alternatively, the coating matrix could be composed of fatty acids that are not reduced in the rumen but are reduced in the intestines. Furthermore, the desired release kinetics, in order to achieve a sustained or rapid release, will depend on the quantity of hydrophobic and / or pH-sensitive compounds, as well as the thickness of the coating matrix.

[0013] Advantageously, the coating matrix is ​​composed of a hydrogenated or partially hydrogenated animal or vegetable fat, such as palm, castor, cottonseed, rapeseed, soybean, corn, sunflower oil, fatty acids, preferably having more than 14 carbon atoms, fatty alcohols, fatty acid esters, such as glycerol, a wax, for example beeswax or castor wax, a microcrystalline wax, a cellulosic compound, one or more hydrophobic polymers and / or polymers stable at a pH between 3 and 7, or mixtures thereof.

[0014] Even more advantageously, the thickness of the coating matrices gradually decreases from the coating layer closest to the core to the coating layer furthest from the core, or vice versa.

[0015] The thicknesses of the different matrices will be chosen based in particular on the release kinetics of the desired active substances.

[0016] Advantageously, the coating matrices represent between 2 and 13% by weight of the product when the coating has a degradation kinetics in the stomach or one of the fore-stomachs of between 1 and 24 h, and more than 13% by weight of the product when the coating is not degradable in the stomach or one of the fore-stomachs, but degradable in one of the organs that follows it.

[0017] Even more advantageously, the layers of active substances are in the form of a powder or a liquid, or of the active substance fixed on a support, for example organic or mineral, or in a mixture with an adjunct such as a binder.

[0018] A product as described above is obtained by a process comprising the following steps: obtaining a core of an active substance and then superimposing around this core one or more of the motifs described above and containing another active substance, advantageously by spraying, atomizing, nebulizing, or pulverizing method.

[0019] The invention further relates to a set of products as defined above, in which the products are in the form of spherical balls homogeneous in size.

[0020] The features of the invention mentioned above, as well as others, will become clearer upon reading the following description of an example embodiment. Example 1 - Balls for oral administration of active substances for ruminants:

[0021] Spherical beads, with a diameter between 0.1 and 0.5 mm, were formulated to release into the rumen both urea (active substance 1) and an active substance 2 chosen from: micronized calcium carbonate, micronized sodium sulfate, micronized quilaia powder, micronized sodium bicarbonate, micronized lithothamnium, an essential oil, or micronized Ascophyllum nodosum powder. Each bead contains: a urea core and extending concentrically from this core: a coating matrix surrounding the core and formed of hydrogenated fats based on rapeseed, sunflower or palm oil, exhibiting a degradation kinetics in the rumen of between 1 and 24h a pattern, around the coating, comprising, in order: a layer of active substance 2, a coating matrix, surrounding the layer of active substance 2, and formed of hydrogenated fats based on rapeseed oil (melting point between 65 and 70°C), sunflower oil (melting point between 63 and 70°C) or palm oil (melting point between 56 and 60°C), exhibiting a degradation kinetics in the rumen of between 1 and 24h.

[0022] Such a ball is manufactured according to the following preparation process: (a1) obtaining urea beads or granules with an average diameter of between 1.5 and 2 mm, suitable for animal feed, (a2) preheating the urea beads or granules to a temperature of 35-60°C, (a3) ​​introducing the urea beads or granules into a turbine equipped with spray nozzles, and rotating the cylinder, (b1) spraying the coating matrix of the urea core (matrix preheated to a temperature above its melting point) and simultaneously mixing the mixture at a temperature in the turbine chamber below 65°C for 4 to 6 minutes, (b2) stopping the spraying but continuing mixing for 30 seconds to 1 minute, (b3) cooling the temperature in the chamber by adding air to 20°C for 2 to 3 minutes, (b4) spraying the coating matrix and simultaneously mixing the mixture for 2 to 4 minutes, (b5) stop spraying but continue kneading for 30 seconds to 1 minute,(b6) Cooling the temperature in the chamber by adding air at 20°C for 2 to 3 minutes, (c1) Spraying the active substance (in example 1: saponin in powder form) and simultaneously mixing the mixture for 2 to 4 minutes, (c2) Spraying the coating matrix intended to coat the layer of active substance (preheated to a temperature above the melting point of the matrix) and simultaneously mixing the mixture for 4 to 6 minutes, (c3) Stopping the spraying but continuing the mixing for 30 seconds to 1 minute, (c4) Cooling the temperature in the chamber by adding air to 20°C for 2 to 3 minutes. If other motifs containing other active substances are added by concentric overlap, steps (c1) to (c4) are repeated as many times as there are motifs.

[0023] In a product where the release of active substances is expected in the rumen, the amount of coating matrix is ​​2 to 13%, by mass, of the core mass Example 2 - Measurement of the release time of active substances in a medium representative of the rumen of a ruminant (Table 1):

[0024] Table 1 time Witness 1 Witness 2 Coated urea + quilaia Coated urea + calcium carbonate 30 min. 104 9 24 35 1h 104 21 47 59 2h 104 39 60 3h 103 57 79 82 4h 104 58 87 5h 103 73 89 6h 106 86 93 94 Granules tested:

[0025] Control 1: urea granules without coating Control 2: urea granules coated with a coating composed of hydrogenated palm oil, the coating representing 10% by weight of the granule.

[0026] Coated urea + quilaia: granules according to example 3 containing quilaia (2% by weight) as an active substance other than urea. The coating is composed of hydrogenated rapeseed oil and represents 11% by weight of the granule.

[0027] Coated urea + calcium carbonate: granules according to example 3 containing, as an active substance other than urea, calcium carbonate (3% by weight). The coating is composed of hydrogenated rapeseed oil and represents 10% by weight of the granule.

[0028] Reproduction in the middle of the rumen A demineralized water solution buffered to pH 6-6.5 using acetic acid is used and subjected to a water bath to maintain the temperature at 39°C. The granules are placed in this solution, with stirring.

[0029] ResultsThe percentage of urea release for each type of granule is measured over time. Without coating, control 1 shows almost immediate urea release in the rumen, with all the urea released after 30 minutes (104% + / - 5% of urea released). Control 2, serving as a positive control, demonstrates that coating the urea delays its release and makes it gradual over a 6-hour period. The granules according to the invention prove to be very effective in releasing urea gradually into the rumen over a 6-hour period. Furthermore, the addition of a second coated active ingredient layer, compared to control 2, tends to slightly accelerate urea release while maintaining the amount of substance released over time at an optimum level.

Claims

1. A multi-layered product for oral administration and controlled release of a plurality of different active substances into the rumen of a production-type animal, the product comprising a core of urea and progressing from the core in a concentric manner: - a coating matrix formed from hydrogenated fats based on rapeseed, sunflower, or palm oil, with degradation kinetics in the rumen of between 1 and 24 hours, - a layer of a second active substance selected from micronised calcium carbonate, micronised sodium sulphate, micronised quilaia powder, and micronised Ascophyllum Nodosum powder, - a coating matrix formed from hydrogenated fats based on rapeseed, sunflower, or palm oil, with degradation kinetics in the rumen of between 1 and 24 hours, the amount of coating matrix being between 2 and 13%, by weight of the product the product being in the form of a spherical ball with a diameter of between 0.01 and 5 mm.