Granules containing an active substance, a method for preparing the same, and its use in food for human consumption or animal feed.

Abstract

The present invention relates to a granule comprising sodium butyrate particles and a fatty substance matrix containing fatty acids encapsulating said sodium butyrate particles, said granules retaining their morphology after simulating gastric and intestinal digestion in an in vitro test, said granules being characterised by a gastroresistance which gives protection to said sodium butyrate particles in the stomach and by a sustained release of said sodium butyrate particles in the intestinal tract.

Description

【Technical Field】 【0001】 The present invention relates to granules containing an active substance, a method for preparing the same, and use for human or animal consumption. In particular, the present invention relates to granules containing sodium butyrate. 【Background Art】 【0002】 Technical Problem Compounds derived from butyric acid have many advantageous biological effects, particularly on the digestive system, by stimulating the growth of the intestinal wall and the development of microorganisms in the intestinal flora. In particular, they selectively characterize an antibacterial effect against some strains of microorganisms in the digestive system. For example, they limit the development of bacteria such as Clostridium acetobutylicum, Escherichia coli, Streptococcus cremoris, Lactococcus lactis and cremoris and Salmonella strains, while Lactobacillus and Streptococcus bovis strains are less affected by them. 【0003】 However, like butyric acid, these derived compounds have a rancid butter odor that makes their production and storage difficult. 【0004】 Among these compounds derived from butyric acid, sodium butyrate has the advantage of being in a solid state and stable up to temperatures exceeding 250°C. However, sodium butyrate is susceptible to the influence of an acidic environment such as that found in the stomach, where it hydrolyzes to form butyric acid, which is volatile or easily absorbed in the stomach in a liquid state. Therefore, the direct oral absorption of sodium butyrate particles mainly results in dissolution and absorption in the stomach, which limits the uptake of sodium butyrate into the intestinal tract. 【0005】 The intestinal tract consists of the small intestine and the large intestine, which ends in the colon. In each of these parts, the environment has evolved and differs, particularly in terms of pH and the presence of enzymes. Protection of sodium butyrate particles should enable not only bioavailability at the small intestine level but also dissolution along the intestinal tract. In particular, protection is needed to enable enteric release of sodium butyrate particles in the large intestine, especially the colon. 【0006】 Patent document EP2352386 describes a method for preparing granules containing sodium butyrate particles in a fatty substance matrix, in which calcium sulfate is incorporated into the matrix to enhance the gastric resistance of the granules. 【0007】 Patent document EP2727472 teaches a method for preparing granules of butyrate particles in a fatty substance by extrusion, the method comprising coating with a gastric protective layer. 【0008】 PCT application WO2018 / 033935 describes a continuous spraying process for obtaining multilayer granules of sodium butyrate, fatty acids, and minerals that pass through the gastric barrier of ruminants. [Overview of the Initiative] [Problems that the invention aims to solve] 【0009】 While maintaining the bioavailability efficiency of sodium butyrate particles along the intestinal tract, it is necessary to protect the sodium butyrate particles from the acidic environment of the stomach so that they can pass through the gastric barrier. 【0010】 Another objective of the present invention is to provide granules containing sodium butyrate particles protected in a fatty substance matrix, characterized by providing gastric resistance that offers protection in the stomach and sustained release in the intestinal tract. 【0011】 Another object of the present invention is to provide an aggregate of granules containing sodium butyrate particles in a stable powder form that is easily handled and suitable for the intended use of the granules. 【0012】 Another object of the present invention is to provide a method for preparing granules containing sodium butyrate particles having gastric resistance and appropriate enteric-coated release properties. 【0013】 Another object of the present invention is to provide an animal or human food composition containing such granules. [Means for solving the problem] 【0014】 invention The present invention - Sodium butyrate particles and, - A fatty acid matrix containing the sodium butyrate particles and Regarding granules containing, The granules retain their shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance, which provides protection to the sodium butyrate particles in the stomach, and by the sustained release of the sodium butyrate particles in the intestinal tract. 【0015】 The inventors of this application have surprisingly and unexpectedly demonstrated that granules containing sodium butyrate particles, encapsulated in a fatty acid-containing lipid matrix and obtained under specific preparation conditions, retain their shape in gastric and intestinal digestive media. This results in structural resistance of the matrix after digestion in in vitro studies modeling the gastric, small intestine, and large intestine environments, and this structural resistance allows for gastric resistance of sodium butyrate particles in the stomach and sustained release of sodium butyrate particles along the intestinal tract. 【0016】 Gastric resistance and sustained release are improved compared to conventional granules. Accordingly, the product marketed by Adisseo under the number ERP80, corresponding to the commercially available product Adimix® precision, is characterized by releasing 85% sodium butyrate in only the gastric simulation step, while another encapsulated butyrate granule marketed by Novation under the trade name Butirex C4 is characterized by complete release of butyrate in the stomach. 【0017】 "Digestion in the stomach" should be understood as the breakdown of ingested products in the stomach by stomach acid and its effects. 【0018】 Gastric digestion can be modeled in vitro using a solution with a composition similar to gastric juice. 【0019】 Gastric juice (or stomach acid) secreted by the stomach contains drugs such as hydrochloric acid, and several enzymes such as pepsin that dissolve proteins. 【0020】 Generally, the state of the stomach can be modeled by a solution containing water with an acidic pH maintained at 1-4 and, for example, a pepsin-type proteolytic enzyme, wherein the enzyme is present in an amount of 0.025-2.5% by weight relative to the total weight of the solution. 【0021】 Pepsin breaks down food proteins by hydrolyzing amino acid peptide bonds. 【0022】 The simulated in vitro gastric digestion test used conforms to Boisen's method (Boisen et al., Animal Feed Science Technology 68 (1997), 277-286). This test is performed by incubating a certain amount of granules, for example 1 g, in a pH=2 solution in the presence of, for example, 25 mg of pepsin, at 39°C for 2 hours, which simulates the gastric environment. 【0023】 "Intestinal digestion" should be understood as intestinal digestion in the small and large intestines. 【0024】 "Intestinal digestion in the small intestine" should be understood as the decomposition of the ingested product in the small intestine environment. 【0025】 Generally, intestinal digestion in the small intestine is modeled in vitro by a solution having a near-liquid composition that is present in the small intestine, particularly including pancreatin. 【0026】 Pancreatin is an enzyme derived from pancreatic juice. 【0027】 The in vitro test used to model intestinal digestion in the small intestine is adapted to the method of Boisen. This test is performed by incubating a certain amount of granules, for example 1 g, in a solution at pH = 6.8 in the presence of, for example, 100 mg of pancreatin for 4 hours at 39 °C, which models the intestinal environment of the small intestine. 【0028】 "Intestinal digestion in the large intestine" should be understood as the decomposition of the ingested product in the intestinal environment of the large intestine. 【0029】 Intestinal digestion in the large intestine is modeled in vitro by a solution having a near-liquid composition that is present in the large intestine, particularly including lipase. Lipase is a digestive enzyme secreted by the pancreas. 【0030】 The in vitro test used to model intestinal digestion in the large intestine is adapted according to the method of Boisen. This test is performed by incubating a certain amount of granules, for example 1 g, in a solution at pH = 7 in the presence of, for example, 100 mg of lipase for 18 hours at 39 °C, which models the intestinal environment of the large intestine. 【0031】 "The form of the granules" should be understood as the outer shape of the granules. 【0032】 The inventors of the present application surprisingly observed that after the digestion test adapted according to the method of Boisen, the granules according to the present invention maintain their form. 【0033】 The maintenance of granular morphology indicates that the structure of the granular fatty substance matrix is ​​preserved in three tests that model gastric and intestinal digestion. 【0034】 "Gastric resistance" should be understood as the resistance of granules to decomposition in the gastric environment. This "gastric resistance" is generally determined, for example, by the amount of sodium butyrate remaining in the granules after a simulated gastric transit experiment of 2 hours in a gastric fluid medium. 【0035】 "Sustained release" should generally be understood as the gradual release of sodium butyrate from the inclusion lipid matrix along the digestive tract by digestive enzymes, bile salts, or microorganisms, through the digestion or solubilization of the inclusion lipid matrix. 【0036】 This "sustained release" is generally determined by the amount of sodium butyrate released by the granules after a simulated intestinal transit experiment, for example, 4 hours in a liquid modeling the small intestine and 18 hours in a liquid modeling the large intestine. 【0037】 Morphological analysis of granules can be performed by observation using an optical microscope or an electron microscope, preferably a scanning electron microscope. 【0038】 According to a favorable embodiment, the present invention is - Sodium butyrate particles and, - A fatty acid matrix containing the sodium butyrate particles, Granules containing, The granules retained their shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that protects sodium butyrate particles in the stomach, and by sustained release of sodium butyrate particles in the intestinal tract. The butyric acid level is less than 5% of the total amount of sodium butyrate, particularly less than 2%, particularly less than 1%, particularly less than 0.5%, and preferably less than 0.1%, for granules. 【0039】 The butyric acid that may be present in the granules originates from the hydrolysis of sodium butyrate. 【0040】 According to an advantageous embodiment, the present invention relates to granules wherein the gastric protective rate (TRC1) of sodium butyrate is 50% or more. 【0041】 According to an advantageous embodiment, the present invention relates to granules wherein the gastric protective rate (TRC1) of sodium butyrate is 65% or more. 【0042】 According to an advantageous embodiment, the present invention relates to granules wherein the gastric protective rate (TRC1) of sodium butyrate is 70% or more. 【0043】 It should be understood that "50% or more" also includes the ranges of 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, and 95-100%. 【0044】 It should be understood that "65% or more" also includes the ranges of 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, and 95-100%. 【0045】 It should be understood that "70% or more" also includes the ranges of 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, and 95-100%. 【0046】 "Gastric protection rate TRC1" should be understood as the relative amount of sodium butyrate protected from gastric digestion after the aforementioned in vitro test incubated in a suitable gastric environment according to Boisen's method. It corresponds to the proportion of sodium butyrate that is protected during gastric digestion and available for release in the intestinal tract. 【0047】 The gastric protective rate (TRC1) of sodium butyrate is calculated after the in vitro test of incubation in the gastric environment according to the following formula. 【0048】 【number】 【0049】 Here, Qt represents the initial total amount of sodium butyrate, and Qd represents the amount of sodium butyrate dissolved during digestion in the stomach. The gastric protection ratio TRC1 is defined by the ratio of the amount of sodium butyrate retained in the granules to the initial total amount of sodium butyrate in the granules. 【0050】 The amount of butyrate retained is determined by subtracting the amount of sodium butyrate dissolved in the solution Qd after the in vitro test of incubation in the gastric environment from the initial total amount of sodium butyrate Qt. 【0051】 The amount of sodium butyrate dissolved in a solution can be determined by quantitative analytical techniques known to those skilled in the art, such as GC-MS or colorimetric analysis, for example, using crystal violet. 【0052】 For comparison, conventional products such as commercially available Adimix® precision yield a measured gastric protection rate of 15%. The product disclosed in EP2352386 reports a gastric protection rate of 61%. 【0053】 According to an advantageous embodiment, the present invention is characterized in that sodium butyrate particles are released gradually along the entire length of the intestinal tract. The enteric release rate (TRC2) of sodium butyrate in the small intestine is 25% or more. The granules described above have an enteric release rate (TRC3) of sodium butyrate in the large intestine of 50% or more. 【0054】 It should be understood that "25% or more" also includes the ranges of 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, and 95-100%. 【0055】 The enteric release rates TRC2 and TRC3 are analyzed after an in vitro test of intestinal digestion adapted according to Boisen's method, which models the intestinal environment. 【0056】 "Release rate TRC2" should be understood as the relative amount of sodium butyrate released and dissolved in solution after the aforementioned in vitro test of incubation in the small intestinal environment, adapted according to Boisen's method. This release rate TRC2 characterizes the amount of available sodium butyrate released during intestinal digestion in the small intestine. 【0057】 The sodium butyrate release rate (TRC2) is calculated after the aforementioned in vitro test of incubation in the small intestine environment according to the following formula. 【0058】 【number】 【0059】 Here, Qt represents the initial total amount of sodium butyrate, and Qd represents the amount of sodium butyrate dissolved during intestinal digestion in the small intestine. 【0060】 This is defined by the ratio between the amount of sodium butyrate released and dissolved in the solution from the granules and the initial total amount of sodium butyrate in the granules. 【0061】 In comparison, the conventional product Adimix(registered trademark) precision can achieve an enteric release rate (TRC2) of 87%. 【0062】 "Release Rate TRC3" should be understood as the relative amount of sodium butyrate released and dissolved in solution after the aforementioned in vitro test of incubation in the colonic environment, adapted according to Boisen's method. This TRC3 level characterizes the amount of available sodium butyrate released during intestinal digestion in the colon. 【0063】 The sodium butyrate release rate (TRC3) is calculated after the aforementioned in vitro test of incubation in the colonic environment. This is defined as the ratio between the amount of sodium butyrate released and dissolved in the solution from the granules and the initial total amount of sodium butyrate in the granules. 【0064】 The amount of sodium butyrate dissolved in the solution can be determined by quantitative analytical techniques known to those skilled in the art, such as GC-MS or colorimetric analysis. 【0065】 Sustained release can be characterized by determining the enteric-coated release rates TRC2 and TRC3. 【0066】 The release rates TRC2 and TRC3 allow for a comparison of the release efficiency of sodium butyrate particles with that of products from the prior art. 【0067】 A release rate of TRC2 higher than 25% indicates that 25% of the initial total amount of sodium butyrate was released from the granules into the small intestine. 【0068】 A release rate of TRC3 higher than 50% indicates that 50% of the initial total amount of sodium butyrate was released from the granules into the intestinal environment of the large intestine. 【0069】 According to an advantageous embodiment, the present invention relates to the granules wherein the sodium butyrate release rate TRC3 in the large intestine is 60% or more. 【0070】 According to an advantageous embodiment, the present invention relates to granules having a sodium butyrate release rate TRC3 in the large intestine of 70% or more. 【0071】 In comparison, the enteric release rate (TRC3) of the conventional product, Adimix® precision, can be as high as 79%. 【0072】 According to an advantageous embodiment, the present invention relates to the granules defined above, wherein the gastric protective rate (TRC1) of sodium butyrate is 50% or more, particularly 65% ​​or more, and preferably 70% or more. and / or characterized by the sustained release of sodium butyrate particles over the entire length of the intestinal tract, The enteric release rate (TRC2) of sodium butyrate in the small intestine is 25% or higher. The enteric release rate (TRC3) of sodium butyrate in the large intestine is 50% or more, particularly 65% ​​or more, and preferably 70% or more. 【0073】 According to a favorable embodiment, the present invention is - Sodium butyrate particles and, - A fatty acid matrix containing the sodium butyrate particles and Regarding granules containing, The granules retained their shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that provides protection against sodium butyrate particles in the stomach, and by the sustained release of sodium butyrate particles in the intestinal tract. The gastric protective rate (TRC1) of sodium butyrate is 50% or more, particularly 65% ​​or more, preferably 70% or more, and the gastric protective rate TRC1 is the relative amount of sodium butyrate protected from gastric digestion after an in vitro test of incubation in a gastric environment adapted according to Boisen's method. and / or, It is characterized by the sustained release of sodium butyrate particles along the entire length of the intestinal tract. - The enteric release rate (TRC2) of sodium butyrate in the small intestine is 25% or higher. This release rate (TRC2) is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the small intestinal environment, adapted according to Boisen's method. - The enteric release rate TRC3 of sodium butyrate in the colon is 50% or more, particularly 65% ​​or more, and preferably 70% or more, where "release rate TRC3" is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the intestinal environment of the colon adapted according to Boisen's method. 【0074】 According to a favorable embodiment, the present invention is - Sodium butyrate particles and, - A fatty acid matrix containing the sodium butyrate particles and Regarding granules containing, The granules retain their shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that provides protection against sodium butyrate particles in the stomach, and by the sustained release of sodium butyrate particles in the intestinal tract. The gastric protective rate (TRC1) of sodium butyrate is 50% or more, particularly 65% ​​or more, preferably 70% or more, and the gastric protective rate TRC1 is the relative amount of sodium butyrate protected from gastric digestion after an in vitro test of incubation in a gastric environment adapted according to Boisen's method, and / or It is characterized by the sustained release of sodium butyrate particles along the entire length of the intestinal tract. - The enteric release rate (TRC2) of sodium butyrate in the small intestine is 25% or higher. This release rate (TRC2) is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the small intestinal environment, adapted according to Boisen's method. - The enteric release rate (TRC3) of sodium butyrate in the large intestine is 50% or more, particularly 65% ​​or more, and preferably 70% or more. This "release rate (TRC3)" is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the intestinal environment of the large intestine, adapted according to Boisen's method. The butyric acid level is less than 5% of the total amount of sodium butyrate, particularly less than 2%, particularly less than 1%, particularly less than 0.5%, and preferably less than 0.1%. 【0075】 According to a favorable embodiment, the present invention relates to the granules defined above, comprising long-chain fatty acids, wherein the fatty substance comprises more than 12 carbon atoms, particularly 12 to 22 carbon atoms, preferably 12, 14, 16, 18, 20, and 22 carbon atoms, and more preferably 16 and 18 carbon atoms. 【0076】 "C16" should be understood as a fatty acid containing a chain of 16 carbon atoms. 【0077】 Similarly, "C18" should be understood as a fatty acid containing a chain of 18 carbon atoms. 【0078】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the fatty substance contains long-chain fatty acids, particularly those containing 16 and 18 carbon atoms, in an amount of 70% or more of the total weight of the fatty substance. 【0079】 "70% or more" should be understood to also include the ranges of 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, and 95-100%. 【0080】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the C16 / C18 weight ratio of the fatty acids is 0.7 to 1.7. 【0081】 The range "0.7~1.7" should also be understood as encompassing the following ranges: 0.7~0.8, 0.8~0.9, 0.9~1.0, 1.0~1.1, 1.1~1.2, 1.2~1.3, 1.3~1.4, 1.4~1.5, 1.5~1.6, and 1.6~1.7. 【0082】 According to an advantageous embodiment, the present invention relates to granules, wherein the fatty substance is - 40-65% C16 fatty acids, - 30-60% C18 fatty acids and It contains [the specified amount of C16 fatty acids], and the sum of the proportions of C16 and C18 fatty acids is less than 1. 【0083】 "40-65%" should be understood to also mean the ranges of 40-45%, 45-50%, 50-55%, 55-60%, and 60-65%. 【0084】 "30% to 60%" should be understood to also mean the ranges of 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, and 55-60%. 【0085】 According to an advantageous embodiment, the present invention relates to granules in which the C16:C18 weight ratio of fatty acids is 1.0 to 1.7, particularly 1.1, 1.6, or 1.7. 【0086】 According to an advantageous embodiment, the present invention relates to granules, wherein the fatty substance is - 50-60% C16 fatty acids, - 30-45% C18 fatty acids and It contains [the specified amount of C16 fatty acids], and the sum of the proportions of C16 and C18 fatty acids is less than 1. 【0087】 Preferably, the fatty substance in the granules contains 57% C16 fatty acids and 36% C18 fatty acids. 【0088】 Preferably, the fatty substance in the granules contains 59% C16 fatty acids and 35% C18 fatty acids. 【0089】 Preferably, the fatty substance in the granules contains 55% C16 fatty acids and 41% C18 fatty acids. 【0090】 According to an advantageous embodiment, the present invention relates to granules having a C16:C18 weight ratio of fatty acids of 0.7 to 1.0, particularly 0.8 or 0.9. 【0091】 According to an advantageous embodiment, the present invention relates to granules, wherein the fatty substance is - 40-50% C16 fatty acids, - 50-60% C18 fatty acids and This includes, where the sum of the proportions of C16 fatty acids and C18 fatty acids is less than 1. 【0092】 Preferably, the fatty substance in the granules contains 44% C16 fatty acids and 54% C18 fatty acids. 【0093】 Preferably, the fatty substance in the granules contains 46% C16 fatty acids and 52% C18 fatty acids. 【0094】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the fatty substance comprises long-chain fatty acids containing more than 12 carbon atoms, particularly 12 to 22 carbon atoms, particularly long-chain fatty acids containing 16 carbon atoms and long-chain fatty acids containing 18 carbon atoms, wherein the content of the C16 fatty acids and C18 fatty acids is particularly 70% or more of the total weight of the fatty substance, and the C16:C18 weight ratio of the fatty acids is particularly 0.7 to 1.7. 【0095】 According to an advantageous embodiment, the present invention relates to the granules defined above, which are in a spherical form. 【0096】 In the context of this invention, "spherical shape" should be understood as a regular shape with an aspect ratio close to 1. 【0097】 In the context of this invention, "aspect ratio" should be understood as the ratio of the dimension of the axis of the largest dimension, the so-called principal axis, to the dimension of the axis of the smallest dimension, the so-called secondary axis, of a granule. A particle is considered spherical if the ratio of the principal axis to the secondary axis is less than 1.1. 【0098】 The analysis can be performed using shape recognition tools, image analysis, for example, with ELLIX software from Microvision Instruments, version 6.0.2. It allows for the measurement of particle size, roundness, and orientation, and can be used to characterize sphericity. This operating software is coupled with a camera for image acquisition. 【0099】 The sphericity of the granules gives them powder compressibility properties that allow for easier storage and transport. 【0100】 The sphericity of the granules can also limit decomposition by minimizing the surface area that is exchanged with the outside of the granules. 【0101】 Particularly advantageous, the spherical morphology of the granules of the present invention results in a smaller surface area for exchange compared to granules having an elongated or oval shape of the same volume. Therefore, by limiting the surface area for exchange, the spherical granules of the present invention minimize degradation by gastric or intestinal juices in the stomach and intestines, while maintaining their structural integrity to enable sustained release along the intestinal tract. 【0102】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the matrix is ​​free of all minerals. The absence of minerals in the matrix is ​​advantageous from a cost standpoint. 【0103】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the matrix comprises one or more minerals. 【0104】 Minerals should be understood as inorganic substances. 【0105】 Minerals can have several functions. They can be used in processes as buffers. They may also be incorporated to create or improve the properties of granules. 【0106】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the matrix contains minerals in a proportion of 2 to 10% of the total weight of the granules. 【0107】 "2-10%" should be understood as encompassing the ranges of 2-3%, 3-4%, 4-5%, 5-6%, 6-7%, 7-8%, 8-9%, and 9-10%. 【0108】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the mineral is selected from calcium carbonate, tricalcium phosphate (TCP), calcium sulfate, calcium silicate, magnesium sulfate, magnesium carbonate, aluminum phosphate, cobalt carbonate, zinc carbonate, and mixtures thereof. 【0109】 In contrast to Patent Document EP2352386, the particles obtained in the present invention, containing calcium sulfate, surprisingly exhibit gastric protection rates (TRC1) of 71% and 73%, compared to a protection rate of 15% for the product Adimix® precision. 【0110】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the mineral is tricalcium phosphate (TCP) in a content of 2 to 10% of the total weight of the granules. 【0111】 According to an advantageous embodiment, the present invention relates to granules as defined above, which may or may not contain calcium sulfate, and more particularly to granules containing calcium sulfate. 【0112】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the mineral is calcium sulfate, in particular, in an amount of 2 to 10% of the total weight of the granules. 【0113】 In an advantageous embodiment, the present invention relates to pregranules as defined above, wherein the matrix comprises one or more minerals, particularly minerals in proportion to 2 to 10% of the total weight of the granules, preferably the minerals being selected from calcium carbonate, tricalcium phosphate, calcium sulfate, calcium silicate, magnesium sulfate, magnesium carbonate, aluminum phosphate, cobalt carbonate, zinc carbonate and mixtures thereof, particularly tricalcium phosphate and calcium sulfate. 【0114】 According to an advantageous embodiment, the present invention relates to the granules defined above, - 40-80% by weight of fatty substances, - 20-60% by weight of sodium butyrate and The granules include the above. 【0115】 "40-80%" should also be understood as encompassing the ranges of 40-50%, 50-60%, 60-70%, and 70-80%. 【0116】 "20-60%" should be understood as also encompassing the ranges of 20-30%, 30-40%, 40-50%, and 50-60%. 【0117】 According to an advantageous embodiment, the present invention relates to the granules defined above, - 50-70% by weight of fatty substances, - 30-50% by weight of sodium butyrate and The granules include the above. 【0118】 "30-70%" should be understood as also encompassing the ranges of 30-40%, 40-50%, 50-60%, and 60-70%. 【0119】 "30-50%" should be understood as encompassing the ranges of 30-35%, 35-40%, 40-45%, and 45-50%. 【0120】 According to a favorable embodiment, the present invention relates to the granules defined above, comprising 80% by weight of a fatty substance and 20% by weight of sodium butyrate. 【0121】 According to an advantageous embodiment, the present invention relates to the granules defined above, comprising 70% by weight of a fatty substance, 10% by weight of minerals, and 20% by weight of sodium butyrate. 【0122】 According to a favorable embodiment, the present invention relates to the granules defined above, comprising 70% by weight of a fatty substance and 30% by weight of sodium butyrate. 【0123】 According to an advantageous embodiment, the present invention relates to the granules defined above, comprising 60% by weight of a fatty substance, 10% by weight of minerals, and 30% by weight of sodium butyrate. 【0124】 According to a favorable embodiment, the present invention relates to the granules defined above, comprising 50% by weight of a fatty substance and 50% by weight of sodium butyrate. 【0125】 In a favorable embodiment, the present invention relates to the granules defined above, wherein the fatty substance is selected from the group consisting of hydrogenated palm oil, hydrogenated sunflower oil, hydrogenated rapeseed oil, beeswax, candelilla wax, carnauba wax, palm stearin, stearic acid, or mixtures thereof. 【0126】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the fatty substance is hydrogenated palm oil. 【0127】 Hydrogenated palm oil may be commercially available, for example, supplied by Mosselman sa (Belgium) or ADM-SIO (France). 【0128】 According to an advantageous embodiment, the present invention relates to the granules defined above, - 40-80% by weight, preferably 50-70% by weight, fatty substances, - 20-60% by weight, preferably 30-50% by weight, of sodium butyrate and Includes, The fatty substance relates in particular to the granules defined above, selected from the group consisting of hydrogenated palm oil, hydrogenated sunflower oil, hydrogenated rapeseed oil, beeswax, candelilla wax, carnauba wax, palm stearin, stearic acid, or mixtures thereof. 【0129】 According to an advantageous embodiment, the present invention relates to the granules defined above, wherein the matrix contains air bubbles within the granules. 【0130】 According to a favorable embodiment, the present invention relates to the granules defined above, which are free of emulsifiers. 【0131】 An "emulsifier" should be understood as an additive that enables the formation of a stable and uniform emulsion. Emulsifiers to avoid include, for example, polyethylene glycol (PEG), polysorbate (Tween 20 or 80), sunflower, soy, or rapeseed lecithin, and mono and diglycerides of fatty acids. 【0132】 According to an advantageous embodiment, the present invention relates to the above-described granules, which are free from unpleasant odors. 【0133】 "Unpleasant odors" should be understood as the release of malodorous molecules into the air. 【0134】 "Odorless" should be understood as meaning that, during the manufacture, handling, or storage of the granules, the release of butyric acid, in particular, is at a low level and does not cause inconvenience to the user. 【0135】 According to a favorable embodiment, the present invention relates to granules as defined above, which do not include an additional outer protective coating layer. The granules according to the present invention have the advantage of not requiring the incorporation of a gastric protective layer or a protective layer against its decomposition by air. In fact, butyric acid, which causes the strong odor of spoiled butter that complicates its handling and storage, is not released by the granules according to the present invention, given their structure. The stability of the granules also has advantages in terms of safety. In fact, the REACH regulation (EC No. 1907 / 2006) sets the worker exposure limit at 36.8 mg / m². 3 It is recommended that, regarding the storage of the product, it should be noted that butyric acid has a lower explosive limit of 2% by volume, i.e., 2,000 ppm. According to an advantageous embodiment, the present invention relates to the granules defined above, wherein the level of free butyric acid is less than 5%, particularly less than 2%, particularly less than 1%, particularly less than 0.5%, preferably less than 0.1%. 【0136】 According to a favorable embodiment, the present invention relates to the granules defined above, wherein the level of free butyric acid is zero. 【0137】 The "level of free butyric acid" should be understood as the level of free butyric acid present in the granules. This rate can be determined by extracting the granules after grinding in an organic solvent such as hexane, in which butyric acid is soluble and sodium butyrate is insoluble. The amount of butyric acid extracted into the organic solvent can be determined by analytical techniques such as gas chromatography. The level of free butyric acid is defined by the ratio of this molar amount extracted from butyric acid to the initial total molar amount of sodium butyrate and butyric acid from the granules. 【0138】 "Less than 5%" should be understood to mean the range of less than 5%, less than 4%, less than 3%, less than 2%, and less than 1%. 【0139】 "Less than 0.5%" should be understood as being within the range of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, and less than 0.1%. 【0140】 "Less than 0.1%" should be understood as being within the range of less than 0.1%, less than 0.09%, less than 0.08%, less than 0.07%, less than 0.06%, less than 0.05%, less than 0.04%, less than 0.03%, less than 0.02%, less than 0.01%, and less than 0.001%. 【0141】 A "level of zero" should be understood as a level that cannot be detected by gas chromatography analysis. 【0142】 According to an advantageous embodiment, the present invention relates to the granules defined above, wherein the esterification rate is less than 15%, preferably less than 10%, and particularly less than 1.0%. 【0143】 The "esterification rate" should be understood as the level of butyric acid bound to a fatty acid or fatty acid triglyceride. This rate is defined as the ratio of the molar amount of bound butyric acid to the total initial molar amount of butyrate. 【0144】 This ratio can be determined by back titration using ion chromatography after grinding the granules and extracting water. In fact, ion chromatography allows for the determination of the total amounts of sodium butyrate and butyric acid without distinguishing between acidic and basic forms obtained by extraction in the aqueous phase. In the presence of fatty acids or fatty acid triglycerides, sodium butyrate can form butyric acid esters by esterification. These esters do not have the same spectrum as sodium butyrate and butyric acid in ion chromatography. 【0145】 "Less than 15%" should be understood to mean the range of less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, and less than 1%. 【0146】 "Less than 1.0%" should be understood as being within the range of less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, and less than 0.1%. 【0147】 Analysis of the products of Admix® precision indicates the presence of an esterification rate higher than 16%. The presence of butyrate ester in Admix® precision is confirmed by phase change analysis in a basic medium, which allows the butyrate ester bound to the fatty acid to be saponified and released. 【0148】 The form of butyric acid—that is, the form of free butyric acid, the form of sodium butyrate, or the form of an ester bound to a fatty acid or fatty acid triglyceride—is one factor that determines its bioavailability in the intestinal tract. 【0149】 The present invention also relates to an aggregate of granules, wherein the granules are as defined above. 【0150】 According to a favorable embodiment, the present invention relates to an aggregate of granules as defined above, wherein the particle size of the granules is 200 μm to 1.5 mm, preferably 400 to 1,000 μm, and preferably 600 to 800 μm. According to a favorable embodiment, the present invention relates to an aggregate of granules as defined above, wherein the average particle size Dv(0.5) is 600 to 800 μm, particularly 630 μm. 【0151】 The average particle size Dv(0.5) of the product of Adimix® precision is approximately 990 μm. 【0152】 The average particle size Dv(0.5) should be understood as the average particle size such that 50% of the granules in the group have a diameter larger than the average particle size, and 50% of the particles in the composition have a diameter smaller than the average particle size. 【0153】 For oval particles, the average diameter takes into account the particle's width and length. 【0154】 The average particle size can be measured by laser diffraction or sieving. 【0155】 According to an advantageous embodiment, the present invention relates to an aggregate of the granules defined above, wherein the average size of the sodium butyrate particles is 50 to 1,200 μm, particularly 100 to 800 μm, and preferably 200 to 300 μm. 【0156】 According to an advantageous embodiment, the present invention relates to an aggregate of granules as defined above, wherein the sodium butyrate particles are in the form of compressed particles. 【0157】 "Compressed particles" should be understood as particles formed by compressing fine sodium butyrate powder using a compression granulation device, such as the Alexanderwerk WP120. 【0158】 According to an advantageous embodiment, the present invention relates to an aggregate of granules as defined above, wherein the SPAN value of the granules is 1.0 or less, particularly 0.8 or less, and preferably 0.5 or less, and the SPAN value is calculated according to the following formula: 【0159】 【number】 【0160】 Here, D(90%), D(50%), and D(10%) represent the diameters of the granular aggregates where 90%, 50%, and 10%, respectively, have a diameter smaller than this value. 【0161】 The SPAN value of a granular aggregate is an index of the variance of the granular sizes within the aggregate. 【0162】 If the SPAN value is less than 0.5, the population is considered to have a simple variance. 【0163】 According to an advantageous embodiment, the present invention relates to the above-defined aggregate of granules having a flow index of 4 to 7 [Flodex™ index], particularly 4 or 5, which is the aggregate of granules forming the powder. 【0164】 The Flodex™ method (Dow-Lepetit) measures the fluidity (or flowability) of a powder. The sample is placed in a smooth cylinder with circular openings of varying sizes (ranging from 4 to 34) at the bottom. The openings are sealed during filling. Once the entire volume of powder has been introduced, the openings are opened. Powders with good fluidity flow through small openings, while powders with poor fluidity require larger openings to exit the cylinder. The Flodex™ fluidity index is equal to the diameter (in millimeters) of the smallest opening through which the powder falls three times consecutively. 【0165】 A liquidity index of 4-7 is considered to indicate excellent liquidity. 【0166】 A liquidity index of 8-12 is considered to indicate good liquidity. 【0167】 A liquidity index of 14-18 is considered to represent average liquidity. 【0168】 A liquidity index of 20-28 is considered to indicate moderate liquidity. 【0169】 A liquidity index of 28-34 is considered to indicate poor liquidity. 【0170】 According to a preferred embodiment, the present invention provides a material with an apparent density of 0.45 to 0.65 g / cm³. 3 This relates to the aggregate of granules as defined above. 【0171】 According to a preferred embodiment, the present invention provides a filling density of 0.50 to 0.71 g / cm³. 3 This relates to the aggregate of granules as defined above. 【0172】 The apparent density and packing density are measured according to the AFNOR NF V 04-344 standard. 【0173】 According to an advantageous embodiment, the present invention relates to an aggregate of granules as defined above, wherein the moisture absorption value is 3 to 10%, particularly 5 to 10%, after 24 hours. 【0174】 The moisture absorption value is measured in a sealed desiccator maintained at 25°C with a relative humidity of 75% using a saturated NaCl solution. 2 g of powder is weighed in a pre-calibrated cup. 【0175】 The cup is kept in this humidity-controlled atmosphere for 24 hours. The moisture absorption value is measured every 5 hours, and then again after 24 hours. 【0176】 The moisture absorption value is measured as a percentage relative to the initial humidity. 【0177】 The hygroscopic value reflects the hygroscopicity of the powder, or its property of capturing water and then dissolving it. Extending this, this method indirectly indicates the solubilization rate of the compound in the powder. 【0178】 According to an advantageous embodiment, the present invention is an aggregate of granules as defined above, The particle size of the granules is 200 μm to 1.5 mm, preferably 400 to 1,000 μm, preferably 600 to 800 μm, and in particular the particle size of the sodium butyrate particles is 50 to 1,200 μm, particularly 200 to 300 μm, or • The SPAN value of the granules is 1 or less, particularly 0.8 or less, preferably 0.5 or less, and the SPAN value is given by the following formula: 【0179】 【number】 【0180】 It is calculated according to the formula, where D(90%), D(50%), and D(10%) represent the diameters at which 90%, 50%, and 10% of the granular aggregates have a diameter smaller than this value, respectively. Alternatively, the aggregate of granules forming the powder has a flow index of 4-7 [Flodex™ index], particularly 4 or 5. Alternatively, the moisture absorption value is 3-10%, especially 5-10%. Regarding aggregates of granules. 【0181】 According to an advantageous embodiment, the present invention relates to an aggregate of granules in which at least 90% by weight of the granules have a spherical shape. 【0182】 According to a favorable embodiment, the present invention relates to an odorless aggregate of the granules defined above. 【0183】 According to an advantageous embodiment, the present invention relates to an aggregate of granules as defined above, wherein the granules do not include an additional outer protective coating layer. The aggregate of granules according to the present invention has the advantage of being stable with respect to decomposition in air without the use of a protective layer, thereby enabling handling and storage without the inconvenience of odor. 【0184】 The present invention also relates to a method for preparing aggregates of granules, - Sodium butyrate particles and, - A fatty acid matrix containing the sodium butyrate particles and Includes, The granules retained their shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that protects the sodium butyrate particles in the stomach, and by the sustained release of the sodium butyrate particles in the intestinal tract. The aforementioned method, - A step of preparing a mixture of solid sodium butyrate particles in a liquid of the molten fatty substance to obtain a suspension, - From the suspension, granules may be formed and then solidified in the form of dispersed particles in a crystallized fatty substance. Includes, Prior to the step of forming the granules, the viscosity of the suspension composed of the mixture of sodium butyrate particles in the molten fatty substance is less than 8,000 mPa·s, preferably less than 5,000 mPa·s, more preferably less than 2,500 mPa·s, and particularly between 10 and 8,000 mPa·s. Regarding the method. 【0185】 Viscosity is measured using a Brookfield digital DV-E viscometer as follows: Viscosity is analyzed by placing 10 ml of the product to be analyzed into the thermostat-controlled measuring chamber of the Brookfield digital DV-E viscometer. The viscometer consists of a coaxial cylinder with a rotating spindle of reference number S31 inside the thermostat-controlled measuring chamber. The viscosity measurement temperature is 85°C and is maintained by a thermostat-controlled water bath. Viscosity is determined by a spindle rotation speed of 10 rpm. 【0186】 In the step of preparing the suspension of this method, the inventors observed an increase in the viscosity of the liquid fatty substance while adding sodium butyrate particles to the liquid fatty substance. It is possible to obtain granules according to the present invention having the gastric protective and sustained-release properties in the intestines described above at a viscosity of less than 8,000 mPa·s. 【0187】 The range "10-8,000 mPa·s" should be understood as also encompassing the ranges of 10-100 mPa·s, 10-200 mPa·s, 10-300 mPa·s, 10-500 mPa·s, 10-1,000 mPa·s, 10-1,500 mPa·s, 10-2,000 mPa·s, 10-2,500 mPa·s, 10-3,000 mPa·s, 10-4,000 mPa·s, 10-5,000 mPa·s, 10-6,000 mPa·s, 10-7,000 mPa·s, and 10-8,000 mPa·s. 【0188】 Prior to the step of forming granules, the viscosity of the suspension consisting of a mixture of sodium butyrate particles in a molten fatty substance may be less than 8,000 mPa·s, less than 7,000 mPa·s, less than 6,000 mPa·s, less than 5,000 mPa·s, less than 4,000 mPa·s, less than 3,000 mPa·s, less than 2,500 mPa·s, less than 2,000 mPa·s, less than 1,500 mPa·s, less than 1,000 mPa·s, less than 900 mPa·s, less than 800 mPa·s, less than 700 mPa·s, less than 600 mPa·s, less than 500 mPa·s, less than 400 mPa·s, less than 300 mPa·s, less than 250 mPa·s, or less than 200 mPa·s. 【0189】 In a preferred embodiment of the method according to the present invention, the mixture is maintained in the form of the suspension for a period of 15 minutes or less, particularly 2 seconds to 10 minutes. 【0190】 According to an advantageous embodiment, the present invention relates to a method for which the temperature of a molten fatty substance in liquid form is 5 to 30°C higher than the melting point of the fatty substance. 【0191】 "5-30°C" should be understood to also refer to the ranges of 5-10°C, 10-15°C, 15-20°C, 20-25°C, and 25-30°C. 【0192】 According to an advantageous embodiment, the present invention relates to a method for a molten fatty substance in liquid form having a temperature of 50 to 120°C, particularly 65 to 110°C, and preferably 65 to 95°C. 【0193】 "50-120°C" should be understood to also mean the ranges of 50-60°C, 60-70°C, 70-80°C, 80-90°C, 90-100°C, 100-110°C, and 110-120°C. 【0194】 According to a favorable embodiment, the present invention relates to the method defined above, - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance to obtain a suspension, - The step of forming droplets from the suspension, - A step that enables the solidification of the fatty substance, which involves cooling the droplets to form granules and creating a matrix that encapsulates the sodium butyrate particles. Includes. 【0195】 According to a favorable embodiment, the present invention relates to the method defined above, - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance, comprising the step of introducing the powder into the liquid molten fatty substance by appropriate means, particularly using a mixer, to obtain a suspension. - The step of forming droplets by spraying the suspension, - A step of cooling the aforementioned droplets in a cooling chamber at a temperature of -20 to 30°C, particularly under airflow. Includes. 【0196】 "-20 to 30°C" should be understood to also refer to the ranges of -20 to -10°C, -10 to 0°C, 0 to 10°C, 10 to 20°C, and 20 to 30°C. 【0197】 According to an advantageous embodiment, the step of preparing the mixture is carried out in a device such as a static or dynamic mixer, particularly a mixer, extruder, or ultrasonic mixer without internal components. 【0198】 According to an advantageous embodiment, the step of preparing the mixture is carried out in a static mixer. 【0199】 According to an advantageous embodiment, the step of preparing the mixture is carried out in a dynamic mixer. 【0200】 According to an advantageous embodiment, the step of preparing the mixture is carried out in an extruder. 【0201】 According to a favorable embodiment, the present invention relates to the method defined above, - A step of preparing a mixture of powdered sodium butyrate particles and the powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - The step of forming the droplets of the suspension, - A step of cooling the aforementioned droplets in a cooling chamber at a temperature of -20 to 30°C, particularly under airflow. Includes. 【0202】 According to an advantageous embodiment, the step of preparing the mixture is carried out in an extruder. 【0203】 According to an advantageous embodiment, the step of preparing the mixture is carried out in a small, thermostat-controlled tank having a capacity of 0.5 to 5 liters. 【0204】 According to an advantageous embodiment, the step of preparing the mixture is carried out in a dynamic mixer that includes an inlet leading to a reactor for a liquid, pre-melted fatty substance and an inlet for adding butyric acid powder. 【0205】 According to a favorable embodiment, the present invention relates to the method defined above, - A step of preparing a mixture of powdered sodium butyrate particles and a powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - A step of obtaining a dispersion of particles in the crystallized fatty substance by cooling the suspension, - The step of forming granules from the dispersion, - A step of cooling the granules and Includes. 【0206】 According to an advantageous embodiment, the step of preparing a mixture from powder is carried out in an extruder. 【0207】 According to a favorable embodiment, the present invention relates to the method defined above, This method is - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance to obtain a suspension, - The step of forming droplets from the suspension, - A step that enables the solidification of the fatty substance, which involves cooling the droplets to form granules and creating a matrix that encapsulates the sodium butyrate particles. Includes, • Or, - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance, comprising the step of introducing the powder into the liquid molten fatty substance by appropriate means, particularly using a mixer, to obtain a suspension. - The step of forming droplets by spraying the suspension, - A step of cooling the aforementioned droplets in a cooling chamber at a temperature of -20 to 30°C, particularly under airflow. Includes, • Or, - A step of preparing a mixture of powdered sodium butyrate particles and a powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - The step of forming the droplets of the suspension, - A step of cooling the aforementioned droplets in a cooling chamber at a temperature of -20 to 30°C, particularly under airflow. Includes, • Or, - A step of preparing a mixture of powdered sodium butyrate particles and a powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - A step of obtaining a dispersion of particles in the crystallized fatty substance by cooling the suspension, - The step of forming granules from the dispersion. Includes. 【0208】 According to an advantageous embodiment, the present invention relates to the method wherein the fatty substance comprises long-chain fatty acids having more than 12 carbon atoms, particularly 12 to 22 carbon atoms. 【0209】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance comprises long-chain fatty acids containing 16 carbon atoms and long-chain fatty acids containing 18 carbon atoms, in particular in an amount of 70% or more of the total weight of the fatty substance. 【0210】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the C16:C18 weight ratio of the fatty acid is 0.7 to 1.7. 【0211】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance contains long-chain fatty acids containing 16 carbon atoms and long-chain fatty acids containing 18 carbon atoms, particularly in an amount of 70% or more of the total weight of the fatty substance, and preferably the C16:C18 weight ratio of the fatty acids is 0.7 to 1.7. 【0212】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance is - 40-65% C16 fatty acids, - 30-60% C18 fatty acids and It contains [the specified amount of C16 fatty acids], and the sum of the proportions of C16 and C18 fatty acids is less than 1. 【0213】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the C16:C18 weight ratio of the fatty acid is 1.0 to 1.7, particularly 1.1, 1.6, or 1.7. 【0214】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance is - 50-60% C16 fatty acids, - 30-45% C18 fatty acids and It contains [the specified amount of C16 fatty acids], and the sum of the proportions of C16 and C18 fatty acids is less than 1. 【0215】 Preferably, the fatty substance of the method defined above comprises 57% C16 fatty acids and 36% C18 fatty acids. 【0216】 Preferably, the fatty substance of the method defined above comprises 59% C16 fatty acids and 35% C18 fatty acids. 【0217】 Preferably, the fatty substance of the method defined above comprises 55% C16 fatty acids and 41% C18 fatty acids. 【0218】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the C16:C18 weight ratio of the fatty acid is 0.7 to 1.0, particularly 0.8 or 0.9. 【0219】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance is - 40-50% C16 fatty acids, - 50-60% C18 fatty acids and It contains [the specified amount of C16 fatty acids], and the sum of the proportions of C16 and C18 fatty acids is less than 1. 【0220】 Preferably, the fatty substance of the method defined above comprises 44% C16 fatty acids and 54% C18 fatty acids. 【0221】 Preferably, the fatty substance of the method defined above comprises 46% C16 fatty acids and 52% C18 fatty acids. 【0222】 According to an advantageous embodiment, the present invention relates to the method defined above, wherein the fatty substance contains long-chain fatty acids containing 16 carbon atoms and long-chain fatty acids containing 18 carbon atoms, in particular in an amount of 70% or more of the total weight of the fatty substance, and preferably the C16:C18 weight ratio of the fatty acids is 0.7 to 1.7. 【0223】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance matrix is ​​free of any minerals. 【0224】 In a favorable embodiment, the present invention relates to the method defined above, wherein the fatty matrix is ​​free of any minerals and the viscosity of the suspension is less than 5,000 mPa·s, particularly between 10 and 5,000 mPa·s. 【0225】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance matrix comprises at least one mineral. 【0226】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance matrix contains minerals, and the viscosity of the resulting suspension is less than 8,000 mPa·s, particularly between 10 and 8,000 mPa·s. 【0227】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance matrix comprises at least one mineral in an amount of 2 to 10% of the total weight of the granules. 【0228】 According to an advantageous embodiment, the present invention relates to the method defined above, wherein the mineral is calcium carbonate in a content of 2 to 10%, preferably 5 or 10%, of the total weight of the granules. 【0229】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the mineral is tricalcium phosphate, particularly in an amount of 2 to 10% of the total weight of the granules. 【0230】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the mineral is tricalcium phosphate and has a content of 5%. 【0231】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the mineral is calcium sulfate, particularly in an amount of 2 to 10% of the total weight of the granules. 【0232】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the calcium sulfate content is 2 to 10% of the total weight of the granules, and the C16:C18 weight ratio of the fatty acids is 1.0 to 1.7, particularly 1.1, 1.6, or 1.7. 【0233】 In a favorable embodiment, the present invention relates to the method defined above, wherein the granules have a calcium sulfate content of 2% and a calcium carbonate content of 5% based on their total weight, and the fatty substance matrix comprises 57% C16 fatty acids and 36% C18 fatty acids. 【0234】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the fatty substance matrix comprises at least one mineral in an amount of 2 to 10% of the total weight of the granules, wherein the mineral is particularly tricalcium phosphate or calcium sulfate. 【0235】 According to an advantageous embodiment, the present invention relates to the method defined above, wherein the viscosity is adjusted by a known method, particularly by adding inorganic or organic additives. 【0236】 According to a favorable embodiment, the present invention relates to the method defined above, wherein the method is carried out in the absence of an emulsifier. 【0237】 An emulsifier should be understood as an additive that enables the formation of a stable and uniform emulsion. Emulsifiers to avoid include, for example, polyethylene glycol (PEG), polysorbate (Tween 20 or 80), sunflower, soy, or rapeseed lecithin, and mono or diglycerides. 【0238】 According to a favorable embodiment, the present invention relates to the method defined above, which does not include the additional step of coating granules. 【0239】 The present invention also relates to a suspension of a liquid fatty substance containing sodium butyrate particles having a viscosity of less than 8,000 mPa·s. 【0240】 According to an advantageous embodiment, the present invention relates to the suspension wherein the fatty substance is hydrogenated palm oil. 【0241】 The present invention also relates to aggregates of granules that can be obtained by the method defined above. 【0242】 Another object of the present invention relates to a food composition for animals or humans comprising granules or aggregates of granules as defined above. [Brief explanation of the drawing] 【0243】 [Figure 1] Figure 1 is an optical microscope image of PR1G1F granules obtained by the present invention. [Figure 2] Figure 2 shows a set of scanning electron microscope (SEM) images of the product of the prior art Adimix® precision (first row) and two products PR1G1F and PCaG1R1 prepared according to the present invention, shown in the second and third rows. [Figure 3] Figure 3 shows optical microscope images used for morphological analysis by the image analysis software Ellix. [Figure 4] Figure 4 is a table showing the morphology of the granules using an optical microscope image, compared with the measured viscosity of the suspension, before the step of forming the granules. 【Embodiments for Carrying Out the Invention】 【0244】 Figure 1 is an optical microscope image of the PR1G1F granules obtained according to the present invention. 【0245】 Figure 2 is a set of scanning electron microscope SEM images of the product of the prior art Adimix (registered trademark) precision (first row) and two products PR1G1F and PCaG1R1 prepared according to the present invention shown in the second and third rows. 【0246】 Figures a), b), and c) in the first row of Figure 2 are images of the prior art granules Adimix (registered trademark) precision containing 30% sodium butyrate, 63% fatty substances, 5% calcium carbonate, and 2% calcium sulfate as the composition. 【0247】 Figures d), e), and f) in the second row of Figure 2 are figures of the granules of the product PR1G1f containing 30% sodium butyrate and 70% fatty substances (hydrogenated palm oil) without adding minerals, prepared according to the present invention. 【0248】 Figures g), h), and i) in the third row of Figure 2 are images of the granules of the product PCaG1R1 prepared according to the present invention, containing 30% sodium butyrate and 60% fatty substances (hydrogenated palm oil) and 10% calcium carbonate. 【0249】 Figures a), d), and g) in the first column of Figure 2 show the initial morphology of the granules before the in vitro gastric or intestinal digestion test. 【0250】 Figures b), e), and h) in the second column of Figure 2 show the morphology of the granules after the in vitro gastric digestion test at pH 2 in the presence of pepsin at 39°C for 2 hours. 【0251】 Figures c), f), and i) in the third column of Figure 2 show the morphology of granules after an in vitro intestinal digestion test at pH 7, in the presence of lipase, and at 39°C for 18 hours. 【0252】 The scale bar in the lower right of the scanning electron microscope image represents 400 μm in images a), b), c), d), e), f), g), and h), and 600 μm in image i). 【0253】 For the three products analyzed, their morphology was preserved after in vitro gastric digestion tests. 【0254】 Regarding the granules prepared according to the present invention, cracks are observed in the granules of products PR1G1F and PCaG1R1, but the initial spherical morphology is preserved after intestinal digestion testing with lipase. In the case of Adimix® precision products, the coating matrix degrades after intestinal incubation, resulting in the loss of the initial granule morphology. 【0255】 Therefore, the PR1G1F and PCaG1R1 granules prepared according to the present invention maintain the structure of the coating matrix in both the gastric and intestinal environments. 【0256】 Figure 3 shows optical microscope images used for morphological analysis using the image analysis software Ellix. Figure 3a) shows an overview of the granules used for the analysis of product PR1G1F prepared according to the present invention, containing 30% sodium butyrate and 70% fatty substances (hydrogenated palm oil) without the addition of minerals; Figure 3b) shows an overview of the granules used for the analysis of product PCaR1G1F prepared according to the present invention, containing 30% sodium butyrate and 65% fatty substances, and containing 5% tricalcium phosphate; and Figure 3c) shows an overview of the granules used for the analysis of the Adimix® precision product. 【0257】 Figure 4 is a table showing the morphology of granules using optical microscope images, compared to the measured viscosity of the suspension before the granule formation step. 【0258】 example Example 1: First, at room temperature (20-25°C), weigh 1.2 kg of finely powdered sodium butyrate (more than 90% less than 200 μm as measured by sieving) and 2.8 kg of hydrogenated palm oil in solid particle form (supplier: MOSSELMAN) into a container. Pour the contents of this container into a tumbler mixer and stir the mixture for 5 minutes. At room temperature (20-25°C), a homogeneous mixture of the two powders is obtained. 【0259】 This mixture is placed in a filling hopper and supplied at a rate of 7 kg / h to a temperature-controlled extruder equipped with a thermostat-controlled wall via a powder feeder. The extruder's heating setting is set to 90°C. 【0260】 Under the influence of pressure and heat, hydrogenated palm oil becomes liquid, thereby distributing sodium butyrate into the suspension of the liquid fatty substance. 【0261】 The extruder consists of a screw with a length of 15 cm, rotating at 35 revolutions per minute (rpm), and ultimately producing a product with a flow rate of 7 kg / h. 【0262】 The resulting suspension passes through the entire outlet opening and exits the extruder in liquid form. 【0263】 The suspension is delivered by gravity to a temperature-controlled turbine at the top of the atomization tower, at 70°C, and then into an atomization chamber with a counterflow of temperature-controlled cold air at 15-20°C, which allows for the formation of 700 μm (+ / - 200 μm) droplets, enabling the suspension to solidify in the form of spherical particles. 【0264】 The particles correspond to a dispersion of sodium butyrate in a fatty substance matrix. The resulting particles are spherical, ranging in size from 600 μm to 1 mm. 【0265】 Example 2: By using a temperature-controlled extruder, it becomes possible to perform the steps of mixing, blending, and shaping granules in a single apparatus within a temperature range of 20 to 100 °C. 【0266】 5 kg of hydrogenated palm oil (supplier MOSSELMAN) is prepared in a tank at a temperature of 70 °C until the fatty substance is obtained in a molten state. 【0267】 Into the filling hopper of the first section of the extruder, fine powder sodium butyrate (more than 90% is less than 200 μm measured by the sieving method) is put. The powder feeder supplies sodium butyrate to the extruder at a flow rate of 1.2 kg / h. 【0268】 The liquid hydrogenated palm oil is injected into the second section of the extruder at a flow rate of 2.8 kg / h through an injector located 10 cm from the filling hopper into which sodium butyrate is introduced. 【0269】 The configuration of the extruder consists of a screw length of 15 cm, the rotation is 35 revolutions per minute, and finally the flow rate of the product is 4 kg / h. 【0270】 By passing the extrusion screw at a temperature of 70 to 85 °C, a uniform suspension of butyrate in the liquid fatty substance can be obtained before passing through the extrusion die. 【0271】 The product is cooled to 25 °C at the outlet of the extruder and comes out of the die in the form of a solid product cylinder. 【0272】 A rotating disk having a blade located 3 mm from the die cuts the elongated part of the product, and regular particles come out. The particles have a length of 750 μm ± 200 μm and a diameter of 700 μm. 【0273】 Thereafter, these particles are rotated at 500 rpm in a part of the apparatus adjusted to 50 °C to be made spherical. 【0274】 These particles correspond to a dispersion of sodium butyrate in a fatty substance matrix. 【0275】 Example 3: Ten kilograms of hydrogenated palm oil (supplier MOSSELMAN) were placed in a double-jacketed melting apparatus with a heating setting of 90°C until the fatty substance was completely melted, i.e., in a liquid state. 【0276】 The melted fatty material is discharged from the bottom of the tank using a Watson Marlow-type peristaltic pump with a thermostat-controlled heating cord set to a flow rate of 7 kg / h. 【0277】 The pump supplies a 2.5-3 kg capacity suspension to a 5-liter capacity, thermostat-controlled mixing tank with a double jacket maintained at 90°C and equipped with an IKA RW20 type bladed propeller agitator. 【0278】 To this same thermostat-controlled mixing tank, finely powdered sodium butyrate (more than 90% less than 200 μm, as measured by sieving) is supplied by a powder dispenser at a flow rate of 3 kg / h. The mixing tank allows for the uniform dispersion of sodium butyrate in the liquid fatty substance in less than 20 seconds, and a liquid suspension is obtained. 【0279】 The liquid suspension is pumped at a flow rate of 10 kg / h to a thermostat-controlled tank outlet and then transferred to a spray nozzle. 【0280】 The spraying of the fatty substance / butyrate suspension is carried out in a housing at room temperature (20-25°C) using a two-fluid type nozzle with internal mixing (spraying system). 【0281】 A matrix product is obtained in which butyrate particles are contained within a fatty substance matrix. 【0282】 The resulting product is a powder composed of spherical granules that make up a dispersion of sodium butyrate in a fatty substance matrix. 【0283】 The final mixture consists of 70% hydrogenated palm oil and 30% sodium butyrate. 【0284】 Example 4: 4,200 g of hydrogenated palm oil (supplier MOSSELMAN) was placed in a double-jacketed melting apparatus with a heating setting of 90°C until the fatty substance was completely melted, i.e., in a liquid state. 【0285】 The melted fatty material is discharged from the bottom of the tank using a Watson Marlow-type peristaltic pump with a thermostat-controlled heating cord set to a flow rate of 700 g / h, and is supplied by the pump to a thermostat-controlled reactor. To this same thermostat-controlled reactor, finely powdered sodium butyrate (more than 90% less than 200 μm, as measured by sieving) is supplied at a flow rate of 300 g / h by a powder feeder. A homogeneous suspension of sodium butyrate in the liquid fatty material is obtained in less than 30 seconds. 【0286】 This suspension is transferred at the outlet of a thermostat-controlled reactor, via a thermostat-controlled pipe, to a spraying device known to those skilled in the art (turbine, rotating disk, two-fluid spray nozzle). 【0287】 The spraying of the fatty substance / butyrate suspension is carried out in a chamber at room temperature (20-25°C) to allow the suspension droplets to freeze. 【0288】 The resulting product is a powder consisting of spherical granules with an average particle size of 400 μm, which constitute a dispersion of sodium butyrate in a fatty substance matrix. 【0289】 Example 5: This example proceeds in the same way as Example 4. 【0290】 4,200 g of hydrogenated palm oil (supplier MOSSELMAN) was placed in a double-jacketed melting apparatus with a heating setting of 90°C until the fatty substance was completely melted, i.e., in a liquid state. 【0291】 Mix 600g of finely powdered sodium butyrate (more than 90% of which is less than 200μm as measured by sieving) with 100g of tricalcium phosphate to obtain a homogeneous powder mixture containing 85.7% sodium butyrate and 14.3% tricalcium phosphate. Place this mixture into a powder dispenser. 【0292】 The melted fatty material is discharged from the bottom of the tank using a Watson Marlow-type peristaltic pump with a thermostat-controlled heating cord set to a flow rate of 650 g / h, and is then supplied by the pump to a thermostat-controlled reactor. 【0293】 A mixture of butyrate powder and tricalcium phosphate is supplied to this same thermostat-controlled reactor at a flow rate of 350 g / h by a powder dispenser. 【0294】 A homogeneous liquid suspension of sodium butyrate and mineral powder in a liquid fatty substance can be obtained in less than 30 seconds. 【0295】 This suspension is transferred to a rotating disk via a thermostat-controlled pipe at the outlet of a thermostat-controlled reactor. 【0296】 The spraying of fatty substances / butyrate and mineral suspensions is carried out in a chamber at room temperature (20-25°C) to allow the suspension droplets to freeze. 【0297】 The resulting product is a powder consisting of spherical granules that make up a dispersion of sodium butyrate in a fatty substance matrix. 【0298】 The final mixture consists of 65% hydrogenated palm oil, 5% tricalcium phosphate, and 30% sodium butyrate. 【0299】 Example 6: The same procedure as in Example 5 is carried out with 10% calcium carbonate, 60% hydrogenated palm oil, and 30% sodium butyrate added to the total composition. 【0300】 Calcium carbonate is mixed with sodium butyrate powder in the appropriate proportions. 【0301】 The melted fatty material is discharged from the bottom of the tank using a Watson Marlow-type peristaltic pump with a thermostat-controlled heating cord set to a flow rate of 650 g / h, and is then supplied by the pump to a thermostat-controlled reactor. 【0302】 A mixture of butyrate powder and tricalcium phosphate is supplied to this same thermostat-controlled reactor by a powder dispenser at a flow rate of 350 g / h. 【0303】 A homogeneous liquid suspension of sodium butyrate and mineral powder in a liquid fatty substance can be obtained in less than 30 seconds. 【0304】 This suspension is transferred to a rotating disk via a thermostat-controlled pipe at the outlet of a thermostat-controlled reactor. 【0305】 The spraying of the fatty substance / butyrate suspension is carried out in a chamber at room temperature (20-25°C) to allow the suspension droplets to freeze. 【0306】 The resulting product is a powder consisting of spherical granules that make up a dispersion of sodium butyrate and calcium carbonate in a fatty substance matrix. 【0307】 The final mixture consists of 60% hydrogenated palm oil, 10% calcium carbonate, and 30% sodium butyrate. 【0308】 Example 7: Finally, the same procedure as in Example 5 is carried out with 5% calcium carbonate, 2% calcium sulfate, 30% sodium butyrate, and 63% hydrogenated palm oil. 【0309】 The calcium salt is mixed with sodium butyrate powder in the appropriate proportions. 【0310】 The melted fatty material is discharged from the bottom of the tank using a Watson Marlow-type peristaltic pump with a thermostat-controlled heating cord set to a flow rate of 650 g / h, and is then supplied by the pump to a thermostat-controlled reactor. 【0311】 A mixture of butyrate powder and tricalcium phosphate is supplied to this same thermostat-controlled reactor by a powder dispenser at a flow rate of 350 g / h. 【0312】 A homogeneous suspension of sodium butyrate and mineral powder in a liquid fatty substance can be obtained in less than 30 seconds. 【0313】 This suspension is transferred to a rotating disk via a thermostat-controlled pipe at the outlet of a thermostat-controlled reactor. 【0314】 The spraying of the fatty substance / butyrate suspension is carried out in a chamber at room temperature (20-25°C) to allow the suspension droplets to freeze. 【0315】 The resulting product is a powder consisting of spherical granules that make up a dispersion of sodium butyrate and calcium carbonate in a fatty substance matrix. 【0316】 The final mixture consists of 63% hydrogenated palm oil, 5% calcium carbonate, 2% calcium sulfate, and 30% sodium butyrate. 【0317】 Example 8: 15,000 kg of hydrogenated palm oil (supplier SIO) is placed in a double-jacketed melting apparatus heated to a temperature of 70°C until the fatty substance is completely melted, i.e., in a liquid state. 【0318】 Transfer 500g of finely powdered sodium butyrate (more than 90% of which is less than 200μm as measured by sieving) to the powder feeder. 【0319】 The melted fatty material is discharged from the bottom of the tank and transferred at a flow rate of 390 kg / h through a double-jacketed line temperature-controlled to 80°C using a positive displacement pump. The positive displacement pump then supplies it to a thermostat-controlled reactor. 【0320】 Sodium butyrate powder is supplied to this same thermostat-controlled reactor at a rate of 167 kg / h by a powder feeder. 【0321】 A homogeneous liquid suspension of sodium butyrate powder in a liquid fatty substance can be obtained in less than 30 seconds. 【0322】 This suspension is transferred to a two-fluid spray nozzle with internal mixing at the outlet of a temperature-controlled reactor via a pipe temperature-controlled to 75°C. Granules with Dv(0.50) of 1 mm are obtained. 【0323】 The fatty substance / butyrate suspension is sprayed through a nozzle into a spray chamber with a counterflow of low-temperature air regulated to 15-20°C at a flow rate of 557 kg / h, allowing the suspension to solidify in the form of spherical particles. The resulting solidified particles correspond to a dispersion of sodium butyrate in a solid fatty substance matrix. 【0324】 The spraying continued uninterrupted for 45 minutes. 【0325】 The resulting powder is composed of spherical particles, and its particle size, as measured by laser particle size distribution analysis, is characterized by a median Dv (0.50) of 658 μm. 【0326】 Example 9: Analysis of protection rate and release rate The protection rate TRC1 and the release rates TRC2 and TRC3 were evaluated according to the method described above. Digestion of the stomach and intestines was carried out as follows. 【0327】 In vitro gastric digestion for TRC1 evaluation Gastric digestion is modeled by adding 1 g + / - 0.1 mg of granules to an Erlenmeyer flask containing 25 ml of phosphate buffer (pH 6, 0.1 M) and 10 ml of HCl (0.2 M). The solution is then adjusted to pH = 2 using 1 M HCl or NaOH solution. Next, 1 ml of pepsin solution (25 mg / ml) prepared from pepsin derived from porcine gastric mucosa (SIGMA number P-7000, 250 U / mg solid) is added. The solution is incubated at 39°C for 2 hours. After that, the solution is filtered through a pleated filter, and granules observable under an environmental scanning electron microscope are collected according to the method described by E. Conforto et al., “An optimized methodology to analyze biopolymer capsules by environmental scanning electron microscopy”, Materials Science and Engineering: C, Volume 47, February 1st, 2015, Pages 357-366. 【0328】 The filtrate is collected in a 100 ml graduated flask containing 10 ml of 2-methylhexanoic acid, and butyric acid is analyzed according to the standard analytical method for volatile fatty acids by gas chromatography. 【0329】 In vitro intestinal digestion in the small intestine for evaluation of TRC2 Intestinal digestion was modeled by adding 1 g + / - 0.1 mg of granules to an Erlenmeyer flask containing 25 ml of phosphate buffer (pH 6, 0.1 M) and 10 ml of HCl (0.2 M). The solution was then adjusted to pH 6.8 using 1 M HCl or NaOH solution. Next, 1 mL of pancreatin solution (100 mg / mL) prepared from pancreatin derived from porcine pancreas (SIGMA number P-7545) was added to the mixture. The solution was incubated at 39°C for 4 hours. After that, the solution was filtered, and granules observable under an environmental scanning electron microscope were collected according to the method described by E. Conforto et al., “An optimized methodology to analyze biopolymer capsules by environmental scanning electron microscopy”, Materials Science and Engineering: C, Volume 47, February 1st, 2015, Pages 357-366. 【0330】 The filtrate is collected in a 100 ml graduated flask containing 10 ml of 2-methylhexanoic acid, and butyric acid is evaluated according to the standard method for evaluating volatile fatty acids by gas chromatography. 【0331】 In vitro intestinal digestion in the colon for evaluation of TRC3 Intestinal digestion was modeled by adding 1 g + / - 0.1 mg of granules to a solution containing 25 ml of phosphate buffer (pH 6, 0.1 M) and 10 ml of HCl (0.2 M). This solution was then adjusted to pH = 7 using a 1 M solution of HCl or NaOH. Next, 100 mg of lipase derived from porcine pancreatic lipase (SIGMA number L3126) was added to the mixture. The solution was incubated at 39°C for 18 hours. The solution was then filtered, and granules observable under an environmental scanning electron microscope were collected according to the method described by E. Conforto et al., “An optimized methodology to analyze biopolymer capsules by environmental scanning electron microscopy”, Materials Science and Engineering: C, Volume 47, February 1st, 2015, Pages 357-366. 【0332】 The filtrate is collected in a 100 ml graduated flask containing 10 ml of 2-methylhexanoic acid, and butyric acid is evaluated according to the standard method for evaluating volatile fatty acids by gas chromatography. 【0333】 Table 1 below shows the gastric protection rate TRC1 and enteric release rates TRC2 and TRC3 for granules prepared according to the present invention and a reference product derived from the prior art Adimix® precision, where the sodium butyrate (30%) content (Buty) is the same but the mineral content (0-10%) differs. In all of the analyzed products, the fatty matrix (MG) is hydrogenated palm oil. 【0334】 The mineral-free product PR1G1F was prepared according to Example 4. The product PCaR1G1F, containing 5% tricalcium phosphate, was prepared according to Example 5. The product PCaR1G2F, containing 5% calcium carbonate and 2% calcium sulfate, was prepared according to Example 7. The product PCaR1G1, containing 10% calcium carbonate, was prepared according to Example 6. 【0335】 [Table 1] 【0336】 All of the products according to the present invention (PR1G1F, PCaR1G1F, PCaR1G2F, and PCaR1G1) have a gastric protection rate TRC1 higher than 65%, which is 3 to 4 times higher than that of the conventional product Adimix® precision. 【0337】 The release rate TRC2 of the product according to the present invention is 25-40%, which is lower than that of the conventional Adimix® precision. 【0338】 The release rate TRC3 of the product according to the present invention is higher than 80%, which is higher than that of the conventional Adimix® precision. 【0339】 The TRC2 and TRC3 values ​​show kinetic differences in release compared to the conventional Adimix® precision technology. In particular, the product according to the present invention is subsequently released in the intestinal tract, especially in the intestinal environment of the large intestine. 【0340】 It should be noted that the mineral-free product according to the present invention (PR1G1F) has the highest gastric protection rate of TRC1 at 79%. 【0341】 It can be seen that PCaR1G2F has the same composition as Adimix(registered trademark) precision, but the protection and release rates are different. 【0342】 Example 10: Particle size analysis and morphological analysis a. Granule morphology The morphology of PR1G1F granules prepared according to the present invention, containing 30% sodium butyrate and 70% fatty substances (hydrogenated palm oil) without the addition of minerals, is observed using an optical microscope. Figure 1 shows the individual spherical particles. The monodispersity of the powder size is confirmed by laser particle size analysis, which reveals an average particle size value Dv(0.5) of 630 μm and a SPAN value of 0.638. 【0343】 In comparison, Adimix® precision granules have an average granule size Dv(0.5) of 990 μm and a SPAN value of 1.450. 【0344】 b. Morphology before and after digestion The initial morphology of PR1G1F and PCaR1G1 granules, as well as their morphology after gastric and intestinal digestion in vitro, is observed by scanning electron microscopy in environmental mode according to the method described by E. Conforto et al., “An optimized methodology to analyze biopolymer capsules by environmental scanning electron microscopy”, Materials Science and Engineering: C, Volume 47, February 1st, 2015, Pages 357-366. 【0345】 In vitro gastric digestion Gastric digestion is modeled by adding 1 g + / - 0.1 mg of granules to an Erlenmeyer flask containing 25 ml of phosphate buffer (pH 6, 0.1 M) and 10 ml of HCl (0.2 M). The pH of this solution is adjusted to 2 using 1 M HCl or NaOH solution. Next, 1 ml of pepsin solution (25 mg / ml) prepared from porcine gastric mucosa (SIGMA number P-7000, 250 U / mg solid) is added. This solution is incubated at 39°C for 2 hours. Afterward, the solution is filtered through a pleated filter, and granules observable under a scanning electron microscope in ambient mode are collected. 【0346】 In vitro lipase-mediated digestion of the intestines Intestinal digestion is modeled by adding 1 g + / - 0.1 mg of granules to a solution containing 25 ml of phosphate buffer (pH 6, 0.1 M) and 10 ml of HCl (0.2 M). This solution is then adjusted to pH 7 using 1 M HCl or NaOH solution. Next, 100 mg of lipase derived from porcine pancreatic lipase (SIGMA number L3126) is introduced into this mixture. The solution is incubated at 39°C for 18 hours. The solution is then filtered to collect granules that can be observed under a scanning electron microscope in ambient mode. 【0347】 Figure 2 shows the granular morphology of the product of the prior art Adimix® precision (first row) and the two products PR1G1F and PCaR1G1 prepared according to the present invention, shown in the second and third rows. 【0348】 The products PR1G1F and PCaR1G1 according to the present invention retain their form after gastric digestion and thereafter. 【0349】 c. Sphericity analysis The sphericity analysis of PR1G1F, PCaR1G1F, and Adimix(registered trademark) precision granules is performed using an image-based shape recognition tool with Microvision Instruments' ELLIX software version 6.0.2. 【0350】 This software surrounds the granules, analyzes their size, roundness, and orientation, and provides an index of sphericity based on the ratio of the particle axes. Figure 3 shows the image used for morphological analysis by the ELLIX software. 【0351】 Table 2 shows the data provided by the software, with reference to Figure 3a), an image of the granules of the product PR1G1F, and the aspect ratio index, which is the ratio between length and width. 【0352】 [Table 2] 【0353】 Table 3 shows the data provided by the software, with reference to Figure 3b), an image of the granules of the product PCaR1G1F, and the aspect ratio index, which is the ratio between length and width. 【0354】 [Table 3] 【0355】 Table 4 shows the data provided by the software, with reference to Figure 3c), images of Adimix® precision granules and the aspect ratio index, which is the ratio of length to width. 【0356】 [Table 4] 【0357】 In the case of the granules PR1G1F and PCaR1G1F according to the present invention, the ratio of the length and width values ​​calculated by the software is 1.1 or less. This confirms that the granules according to the present invention are spherical. 【0358】 For granules derived from Adimix® precision, the ratio of length to width calculated by the software is greater than 1.1, except for one granule corresponding to the spherical granule in the center of the image in Figure 3c). The aspect ratio of the analyzed granules from Adimix® precision confirms the observed visual assessment that most granules do not feature a spherical morphology. 【0359】 Example 11: Absorption and Moisture Analysis This method is used to determine the amount of moisture absorbed by a powder over time. This moisture content is important for providing information about the stability of the powder. 【0360】 The humidity is measured in a sealed desiccator maintained at 25°C and with a relative humidity of 75% using a saturated NaCl solution. 【0361】 Weigh 2-4g of granular powder into a pre-calibrated cup. 【0362】 The cup is kept in this humidity-controlled atmosphere for 24 hours. Humidity is measured hourly for 5 hours, and then again after 24 hours. 【0363】 Moisture absorption is measured as a percentage of moisture absorption relative to the initial moisture content. 【0364】 Table 5 below shows the hygroscopic values ​​over time for PR1G1F, a product that does not contain minerals in the composition of the fatty matrix. 【0365】 [Table 5] 【0366】 Table 6 below shows the hygroscopic values ​​over time for PCaR1G1F, a product of the present invention containing 5% tricalcium phosphate (TCP). 【0367】 [Table 6] 【0368】 Table 7 below shows the moisture absorption values ​​over time for the conventional product, Adimix® precision. 【0369】 [Table 7] 【0370】 Tests performed on samples show that the product according to the present invention absorbs twice as little moisture as the Adimix® precision powder. In fact, the Adimix® precision product dissolves twice as fast. This can be partially explained as the Adimix® precision product being released more quickly in the stomach than the product obtained from the present invention. 【0371】 Example 12: Relationship between process viscosity and morphology The viscosity of the suspension is evaluated under the preparation conditions for the suspension of sodium butyrate in a liquid fatty substance in the process according to the present invention, which enables the acquisition of granules according to the present invention. This is compared with the morphology of the obtained granules and the composition of the granules in Figure 4. 【0372】 Viscosity is analyzed by placing a 10 ml volume into the temperature chamber of a Brookfield digital DV-E viscometer. The viscometer is configured with a coaxial cylinder in the chamber using a spindle numbered S31. The viscosity measurement temperature is 85°C. Viscosity is determined for a spindle rotation speed of 10 rpm. 【0373】 It was found that spherical granules can be obtained from the suspension of this process at viscosity values ​​of 2,500 mPa·s or less than 3,000 mPa·s. 【0374】 Example 13: Level of free butyric acid obtained by extraction in an organic phase Granules of product PR1G1F according to the present invention, prepared to be mineral-free in the matrix, were compared with granules of the commercially available product Adimix® precision. The granules were crushed and extracted in the organic phase of hexane. Sodium butyrate remains solid as it is insoluble in hexane, while butyric acid is miscible with hexane. The extracted solution was then analyzed by CPG phase chromatography to determine the amount of butyric acid in the organic phase. It should be noted that fatty acid dissolution in the organic phase was not observed visually. 【0375】 Table 8 below shows the release rates for PR1G1F and Adimix® precision. 【0376】 [Table 8] 【0377】 These results indicate the presence of free butyric acid in the product of Adimix® precision at a range of 0.6%, while no butyric acid content was detected in the product PR1G1F according to the present invention. 【0378】 Example 14: Esterification rate by extraction in aqueous phase The granules of the products PR1G1F and PCaR1G1F according to the present invention were compared with the commercially available product Adimix® precision. The granules were crushed and extracted in water. The solution was then analyzed by ion chromatography. This method does not determine whether the butyrate is in the form of an acid (butyric acid) or a base (butyrate) in the granules. 【0379】 Table 9 shows the content of butyric acid or butyrate present in the extracted aqueous solution. 【0380】 [Table 9] 【0381】 Unlike the product of Adimix® precision, the products of PR1G1F and PCaR1G1F have a titration volume of sodium butyrate that is close to the initial nominal value of 30%. 【0382】 The titration volume of 22.4% of the product of Adimix® precision indicates that some of the initially introduced butyrate is unavailable in the form of butyric acid or butyrate. The presence of butyrate esters bound to other molecules, which may result from esterification reactions with fatty acids or triglycerides, is a possible explanation. This assumption appears to be supported by the analysis shown in Example 15 below. 【0383】 Example 15: Identification of the presence of esters by phase change analysis in a basic medium. A portion of the organic phase in hexane derived from Example 13 of the products of Adimix® precision, along with 0.2 M equivalent of sodium hydroxide, is collected while stirring. After stirring and centrifugation, the two organic and aqueous phases are analyzed. This phase change step in a basic medium should allow sodium butyrate to dissolve in the basic aqueous phase, enabling the butyrate to pass from the organic phase to the aqueous phase in the form of butyrate salt. In particular, sodium hydroxide also, if present, allows for the saponification of butyrate if it is bound to a triglyceride or fatty acid. 【0384】 Table 10 below shows the extraction results of Adimix® precision during phase transition in a basic medium, compared with the results obtained by extraction in water. 【0385】 [Table 10] 【0386】 These results demonstrate that the phase change with sodium hydroxide allows for the saponification and release of butyrate esters in their bound form. In the case of Adimix® precision, the butyrate content is higher in the phase change (27.6%) than in the water extract (22.4%). This appears to support the presence of at least 5.2% of the ester by total weight, i.e., about 17% of the butyrate is in a form bound to triglycerides or fatty acids. 【0387】 Conversely, in the case of PR1G1F, phase change extraction by adding water to the hexane phase in Example 13 showed a butyrate content of 29% after analysis of the solution, which is equivalent to the content obtained with water extraction (29.8%). The results in Table 11 show that the product PR1GF1 according to the present invention contains only a small amount of butyrate ester in its bound form. 【0388】 [Table 11]

Claims

[Claim 1] It is a granule, - Sodium butyrate particles, - A fatty acid-containing fatty substance matrix that encapsulates the sodium butyrate particles and Includes, The granules have a spherical shape and retain their spherical shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that protects the sodium butyrate particles in the stomach, and by the sustained release of the sodium butyrate particles in the intestinal tract. The gastric protective rate TRC1 of sodium butyrate is 65% or more, and the gastric protective rate TRC1 is the relative amount of sodium butyrate protected from gastric digestion after an in vitro test of incubation in a gastric environment adapted according to Boisen's method. and / or, - The enteric release rate TRC2 of sodium butyrate in the small intestine is 25% or more, and the enteric release rate TRC2 is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the small intestinal environment, adapted according to Boisen's method. - The enteric release rate TRC3 of sodium butyrate in the large intestine is 50% or more, and the enteric release rate TRC3 is the relative amount of sodium butyrate released and dissolved in solution after an in vitro test of incubation in the intestinal environment of the large intestine, adapted according to Boisen's method, for granules. [Claim 2] The granules according to claim 1, wherein the butyric acid level is less than 5% of the total amount of sodium butyrate. [Claim 3] The granules according to claim 1 or 2, wherein the fatty substance comprises a long-chain fatty acid containing 16 carbon atoms and a long-chain fatty acid containing 18 carbon atoms, the content of the long-chain fatty acid containing 16 carbon atoms and the long-chain fatty acid containing 18 carbon atoms is 70% or more of the total weight of the fatty substance, and the weight ratio of the long-chain fatty acid containing 16 carbon atoms to the long-chain fatty acid containing 18 carbon atoms is 0.7 to 1.

7. [Claim 4] In the granules according to any one of claims 1 to 3, The matrix contains one or more minerals in a proportion of 2 to 10% of the total weight of the granules. The mineral is selected from calcium carbonate, tricalcium phosphate, calcium sulfate, calcium silicate, magnesium sulfate, magnesium carbonate, aluminum phosphate, cobalt carbonate, zinc carbonate, and mixtures thereof, in granular form. [Claim 5] The granules according to any one of claims 1 to 4, wherein the granules are - 40-80% by weight of fatty substances, - 20-60% by weight of sodium butyrate and Includes, The fatty substance is granules selected from the group consisting of hydrogenated palm oil, hydrogenated sunflower oil, hydrogenated rapeseed oil, beeswax, candelilla wax, carnauba wax, palm stearin, stearic acid, or mixtures thereof. [Claim 6] A granular aggregate comprising the granules described in any one of claims 1 to 5, The particle size of the granules is 200 μm to 1.5 mm, and the particle size of the sodium butyrate particles is 50 to 1,200 μm. Alternatively, the SPAN value of the granules is 1 or less, and the SPAN value is calculated according to the following formula: [Math 5] In the formula, D(90%), D(50%), and D(10%) represent the diameters at which 90%, 50%, and 10% of the aggregate of granules have a diameter smaller than this value, respectively. Alternatively, the aggregate of granules forming the powder has a flow index of 4 to 7 [Flodex™ index]. Alternatively, granules with a moisture absorption value of 3-10%. [Claim 7] A method for preparing aggregates of granules, The granules mentioned above are - Sodium butyrate particles, - A fatty acid-containing fatty substance matrix that encapsulates the sodium butyrate particles and Includes, The granules have a spherical shape and retain their spherical shape after simulated gastric and intestinal digestion experiments in in vitro tests. The granules are characterized by gastric resistance that protects the sodium butyrate particles in the stomach, and by the sustained release of the sodium butyrate particles in the intestinal tract. The gastric protective rate TRC1 of sodium butyrate is 65% or more, and the gastric protective rate TRC1 is the relative amount of sodium butyrate protected from gastric digestion after an in vitro test of incubation in a gastric environment adapted according to Boisen's method. and / or, - The enteric release rate TRC2 of sodium butyrate in the small intestine is 25% or more, and the enteric release rate TRC2 is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the small intestinal environment, adapted according to Boisen's method. - The enteric release rate TRC3 of sodium butyrate in the large intestine is 50% or more, and the enteric release rate TRC3 is the relative amount of sodium butyrate released and dissolved in the solution after an in vitro test of incubation in the intestinal environment of the large intestine, adapted according to Boisen's method. The aforementioned method, - A step of preparing a mixture of solid sodium butyrate particles in a liquid of the molten fatty substance to obtain a suspension, - From the suspension, granules can be formed and then solidified in a dispersed form of particles in a crystallized fatty substance. Includes, A method wherein, prior to the step of forming the granules, the viscosity of the suspension composed of the mixture of sodium butyrate particles in the molten fatty substance is less than 8,000 mPa·s. [Claim 8] In the method of claim 7, - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance to obtain a suspension, - A step of forming droplets from the suspension, - A step that enables the solidification of the fatty substance, which involves cooling the droplets to form granules and creating a matrix that encapsulates the sodium butyrate particles. including, or - A step of preparing a mixture of sodium butyrate particle powder in a liquid molten fatty substance, comprising the step of introducing the powder into the liquid molten fatty substance using a mixer to obtain a suspension, - The step of forming droplets by spraying the suspension, - A step of cooling the aforementioned droplets in a cooling chamber under an airflow at a temperature of -20 to 30°C. including, or - A step of preparing a mixture of powdered sodium butyrate particles and the powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - The step of forming the droplets of the suspension, - A step of cooling the aforementioned droplets in a cooling chamber under an airflow at a temperature of -20 to 30°C. including, or - A step of preparing a mixture of powdered sodium butyrate particles and the powdered fatty substance, and then increasing the temperature of the mixture to melt the fatty substance containing the sodium butyrate particles and obtain a suspension, - A step of obtaining a dispersion of particles in the crystallized fatty substance by cooling the suspension, - The step of forming granules from the dispersion and Methods that include... [Claim 9] The method according to claim 7 or 8, wherein the fatty substance contains long-chain fatty acids containing 16 carbon atoms and long-chain fatty acids containing 18 carbon atoms in an amount of 70% or more of the total weight of the fatty substance, and the weight ratio of the long-chain fatty acids containing 16 carbon atoms to the long-chain fatty acids containing 18 carbon atoms is 0.7 to 1.

7. [Claim 10] The method according to any one of claims 7 to 9, wherein the fatty substance matrix comprises at least one mineral in an amount of 2 to 10% of the total weight of the granules, and the mineral is tricalcium phosphate or calcium sulfate. [Claim 11] Granules according to any one of claims 1 to 5, which do not contain an emulsifier. [Claim 12] The method according to any one of claims 7 to 10, wherein the granules do not contain an emulsifier.

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