Particles containing active agent and method for production thereof

Abstract

The invention relates to particles (15) comprising agglomerates of base particles bonded to each other, the agglomerates having a substantially spherical shape, each base particle consisting of a mixture comprising an active agent and a binder for bonding the base particles together. The method of producing these particles uses spray granulation.

Description

[0001] This invention relates to particles containing at least one active agent. These particles are particularly suitable for addition during granulation or tablet manufacturing processes in the animal feed, food additive, pharmaceutical, or cosmetic industries.

[0002] In the context of this invention, “pelletization” (or in other words “granulation”) refers to the process of assembling or agglomerating solid particles together to form larger-sized elements of various geometries, such as spheres or cylinders.

[0003] The invention has been specifically described with reference to the animal feed industry, but this does not limit the scope of the invention. In fact, the problems inherent to the active agents and related to the animal feed industry described below may also arise in the pharmaceutical industry, the human food additive manufacturing industry, or the cosmetic industry.

[0004] Forming animal feed into pellets during the pelleting process is particularly preferred compared to drying. In fact, its advantages include higher quality, fewer pathogens, less dust generated during manufacturing, better suitability for handling procedures, and ultimately allows for a more uniform dosage of active agents in the animal feed to improve their productivity. These active agents can be enzymes, vitamins, proteins, antimicrobial agents, or prebiotics or probiotics specifically designed to improve feed digestibility.

[0005] However, other compounds that are also present in animal feed compositions and are alleged to be “aggressive” to the activators (e.g., organic or inorganic acidic or basic compounds, reducing sugars, and hygroscopic substances, especially choline chloride or sodium chloride) have an adverse effect on these activators, thereby reducing their beneficial activity.

[0006] These adverse effects may occur during the storage of premixes or animal feeds containing these surfactants and compounds. In the context of this invention, a "premix" refers to a premix of surfactants (such as those described above) with a variety of other organic or inorganic compounds (e.g., carrier compounds such as limestone or clay), particularly compounds allegedly "toxic" to the surfactants, said premixes being intended to be incorporated into animal feed. Indeed, during storage, in the presence of water in the premixes or animal feed, redox reactions may occur, leading to a significant reduction in the activity of surfactants (e.g., enzymes).

[0007] In addition, some active agents (especially enzymes) may cause allergic reactions when handled by operators.

[0008] Furthermore, steps in animal feed manufacturing that involve harsh conditions (such as high humidity, high temperature, and high pressure) can also negatively impact the activity of surfactants. In fact, these agents (especially enzymes) are not always stable under such conditions, particularly during the pelleting process in animal feed manufacturing.

[0009] Finally, some surfactants are sensitive to moisture, especially during the storage of animal feed, which can last for several years.

[0010] The solution of storing these so-called "sensitive" surfactants outside the premix is ​​not entirely satisfactory due to logistical reasons and therefore in terms of animal feed manufacturing costs. Furthermore, it does not address the harsh conditions inherent in the animal feed manufacturing process, nor the risk of operator allergies.

[0011] This is why, in industry, particularly in the animal feed industry, but also in the pharmaceutical industry, these active agents are often formulated in a protected form so that they can retain their activity (even when subjected to harsh industrial processing conditions and mixed with other compounds that are allegedly “harmful” to them) and minimize the risk of operator allergies.

[0012] There are different ways to protect surfactants. For example, surfactants can be incorporated into the particles, or more precisely: - Incorporated into the core of said particles composed of porous materials (e.g., inorganic salts such as sodium sulfate), thereby relatively retained on the surface of the core by blocking its pores, and / or - Incorporated within a layer consisting of a binder (e.g., sugar) surrounding the core of the particles. The core (in the case of a suitable adhesive layer) is coated with one or more protective layers (in other words, a "coating") to obtain particles containing protected active agents.

[0013] In this respect, patent EP 3 270 893 B1 describes an example of such particles.

[0014] It is important to emphasize that in these embodiments of prior art particles, the protective layer is crucial for properly protecting the active agent present on the core surface (i.e., in the layer surrounding the core and / or in the pores on the core surface). Indeed, in these embodiments of prior art particles, the active agent is not uniformly distributed throughout the entire volume of the particle, and therefore is not optimally protected; this necessitates the presence of a protective layer.

[0015] Furthermore, patent application EP 1 072 612 A1 describes granules obtained from starch seeds, which have been sprayed with a mixture of pregelatinized starch and starch granules, such that the seed is coated with multiple layers of the mixture until the desired granule diameter is obtained. The surfactant can be present in different layers of the mixture. The surfactant may not be present within the volume occupied by the core. Therefore, the surfactant is not uniformly distributed throughout the entire volume of the granule. Consequently, the surfactant is not optimally protected.

[0016] To simplify the manufacture of heat-stable particles containing surfactants and limit their costs by reducing, for example, the number of raw materials, it would be advantageous to develop particles that do not require such a protective layer without compromising their ability to protect the surfactants.

[0017] Furthermore, particles in which the protective properties of the surfactant are enhanced compared to prior art particles would be advantageous. This improved protection of the surfactant also provides the advantage of being able to reduce their amount in the particles, thereby lowering their production costs. In other words, due to the improved protection of the surfactant, using particles containing less surfactant than prior art particles can achieve activity of the surfactant comparable to that of prior art particles.

[0018] Therefore, there is still a need to improve the development of heat-stable particles containing active agents that remain fully protected when these particles come into contact with other compounds that are allegedly “harmful” or when they are used in granulation or tablet manufacturing processes.

[0019] The inventors of this invention have surprisingly discovered particles containing at least one active agent that perfectly achieve these objectives.

[0020] Therefore, the present invention relates to a particle characterized in that it comprises aggregates of grains bonded together and being substantially spherical in shape, each grain consisting of a mixture comprising at least: - Surfactants and - A reagent used to bond the granules together.

[0021] The binder allows the matrix particles to adhere together in such a way that they form aggregates of matrix particles that are bonded together. The aggregates have a generally spherical shape.

[0022] The ingenuity of the particles according to the invention lies in the fact that the binder contained in the mixture forming the particles ensures the adhesion between the particles to each other, resulting in a substantially spherical aggregate of particles. Due to this aggregate of particles, the activator is uniformly distributed (or in other words, "confined") within the particles, thus achieving perfect protection.

[0023] Unlike the prior art particles described above (where the active agent to be protected can be distributed in a layer surrounding the core of the particle, or retained relatively on the surface of the core by blocking the pores of the porous material constituting the core of the particle), in the particles according to the invention, the active agent is advantageously uniformly distributed throughout the entire (preferably spherical) volume of the particle.

[0024] In the particles according to the invention, since the surfactant is distributed not only on the surface of the particles but throughout their entire volume, a protective layer for the surfactant is not required. Due to this agglomeration of the matrix composed of the mixture described above, the particles according to the invention have achieved sufficient protection of the surfactant without a protective layer.

[0025] In fact, as shown in the experimental section below, the inventors have surprisingly discovered that the particles without a protective layer according to the present invention provide surfactant protection equivalent to that of the prior art particles described above, which include at least one protective layer around the core of these particles.

[0026] The particles according to the present invention can be thermally stable.

[0027] The granules according to the invention can ensure good moisture protection for activators, especially during the storage of products in which they are incorporated (e.g., animal feed).

[0028] The particles according to the invention may have a median diameter of 300 μm to 800 μm, preferably between 400 μm and 700 μm, and more preferably between 500 μm and 600 μm.

[0029] Preferably, the particles according to the invention have excellent sphericity. For example, sphericity can be evaluated by parameters of circularity and / or roundness.

[0030] The roundness of the particles is determined according to the following mathematical equation (1): Roundness = (4 × π × particle area) / (particle perimeter) 2 (1) When its roundness is at least 0.85, the particles according to the present invention have good sphericity.

[0031] The roundness of the particles is determined according to the following mathematical equation (2): Roundness = (4 × particle area) / (π × length of particle principal axis) 2 (2) When its roundness is at least 0.85, the particles according to the invention have good sphericity.

[0032] As described below, the excellent sphericity of the particles according to the invention facilitates coating them with at least one protective layer in a high-quality manner. In fact, if the particles do not have good sphericity, pores may form on the surface of the protective layer during this coating step. These pores can facilitate water penetration into the particles, thus reducing the activity of the surfactant if it is sensitive to moisture.

[0033] Advantageously, the particles according to the invention have a compact particle size distribution, i.e., a span of less than or equal to 0.5.

[0034] The span is defined according to the following mathematical equation (3): Span = [D(v,0.9)-D(v,0.1)] / D(v,0.5) (3) in: - D(v,0.9) represents the particle size, where 90% of the sample volume has particles smaller than this size; - D(v,0.1) represents the particle size, where 10% of the sample volume has particles smaller than this size. - D(v,0.5) represents the particle size, where 50% of the sample by volume has particles smaller than this size.

[0035] The lower the span value, the more uniform the particle size distribution. A span value less than or equal to approximately 1 indicates a very uniform particle size distribution, and when the span value is less than or equal to approximately 0.5, these particles have a completely uniform size distribution.

[0036] The active agent may be selected from the group consisting of proteins (especially enzymes, peptides and polypeptides), antimicrobial agents, amino acids and vitamins, used alone or in mixtures thereof.

[0037] In a preferred embodiment of the present invention, the activator is at least one protein selected from enzymes, peptides, and polypeptides.

[0038] Preferably, the active agent is an enzyme. For example, it can be phytase, xylanase (especially endo-1,4-β-xylanase), β-glucanase, phosphatase, protease, amylase (especially α-amylase, β-amylase or glucosylamylase), cellulase, lipase, cutinase, oxidase, transferase, reductase, hemicellulase, mannanase, esterase, isomerase, pectinase, lactase, peroxidase, laccase, or oxidoreductase (e.g., glucose oxidase, glutamate oxidase, lactate oxidase), used alone or in mixtures thereof.

[0039] In a preferred embodiment of the invention, the enzyme is selected from phytase, xylanase (e.g., endo-1,4-β-xylanase), phosphatase, protease, amylase, esterase, oxidoreductase, lipase, transferase, cellulase, and β-glucanase, used alone or in mixtures thereof. These enzymes are commonly used in the formulation of animal feed.

[0040] In another preferred embodiment of the invention, the enzyme is selected from the group consisting of proteases, amylases, lipases, hemicellulases, oxidoreductases, peroxidases, transferases, and cellulases, used alone or in mixtures thereof. These enzymes are commonly used in the formulation of food additives or cosmetics.

[0041] The particles according to the invention may contain one or more different activators (e.g., up to three different activators).

[0042] In embodiments of the invention, the particles contain a single enzyme or two or three different enzymes. For example, the particles may contain xylanase (e.g., endo-1,4-β-xylanase) and β-glucanase, or xylanase (e.g., endo-1,4-β-xylanase), β-glucanase, and phytase.

[0043] The enzymes described above are given by way of example and do not limit the scope of the invention. They can be any type of enzyme.

[0044] The active agent can be in solid or liquid form. When it is an enzyme, it can be in solid or liquid form. Preferably, it is in liquid form.

[0045] The amount of surfactant present in the particles according to the invention depends on their application. The amount of surfactant selected according to the intended application of the particles according to the invention is within the capabilities of a person skilled in the art.

[0046] The particles according to the invention may contain 10% to 90%, preferably 15% to 70%, more preferably 15% to 30%, and even more preferably 15% to 20% of an active agent, expressed as a mass percentage relative to the total mass of the particles.

[0047] The particles according to the invention exhibit higher surfactant protection performance than prior art particles. Due to this improved surfactant protection, the amount of surfactant contained in the particles according to the invention can be reduced, thereby lowering their production costs. In fact, due to this enhanced surfactant protection, particles according to the invention, containing less surfactant than prior art particles, can achieve activity of the surfactant comparable to that of prior art particles.

[0048] The adhesive is configured to ensure bonding strength between the matrix particles.

[0049] It can be composed of hydrophilic polymers or hydrophobic polymers.

[0050] In an advantageous embodiment of the invention, the adhesive is water-soluble.

[0051] In an advantageous embodiment of the invention, the binder containing 15% by mass of the dry extract in water has a viscosity of 5 mPa·s to 20 mPa·s at 25°C.

[0052] When the active agent is an enzyme, a binder can be selected to limit the diffusion of the enzyme at the high temperatures of the industrial process described above. In other words, a binder can be selected that allows the enzyme to maintain its tertiary structure, even when subjected to high processing temperatures.

[0053] The binder may be selected from the group consisting of maltodextrin, lactose, maltose, and starch, used alone or in mixtures thereof.

[0054] Preferably, the binder is selected from the group consisting of maltodextrin and starch.

[0055] The particles may contain 10% to 90%, preferably 15% to 85%, more preferably 50% to 80% of the binder, expressed as a percentage of the total mass of the particles.

[0056] The mixture constituting each matrix may also contain at least one additional compound. Advantageously, the additional compound is selected from the group consisting of sodium sulfate, calcium carbonate, and polyols.

[0057] The total mass content of the additional compound, expressed relative to the total mass of the particles, can be 5% to 35%, preferably 5% to 10%.

[0058] In one embodiment of the invention, the particles further include at least one protective layer surrounding the aggregated medullary aggregates that are bonded together. The presence of the protective layer improves the protection of the surfactant, which is confined within the aggregated medullary aggregates.

[0059] Advantageously, the protective layer allows the active agent to be protected from moisture, especially during the storage of products containing particles according to the invention, and this can last for several years.

[0060] In one embodiment of the invention, the particles include a plurality of protective layers, which may be the same as or different from each other.

[0061] For example, the particles may include one, two, three, or four protective layers, which may be the same as or different from each other.

[0062] The thickness of each protective layer can be from 2 μm to 80 μm, preferably from 5 μm to 20 μm.

[0063] Furthermore, in this embodiment of the invention, the particles according to the invention may include, expressed as a mass percentage relative to the total mass of the particles: - At least one protective layer comprising 5% to 50%, preferably 15% to 40%. - 50% to 95%, preferably 60% to 85% of the said mutually bonded granular aggregates.

[0064] The selection of the protective layer components is entirely within the capabilities of a skilled technician. In fact, as mentioned above, at least one protective layer is typically applied to the core of the particles to protect the active agents contained within the particles.

[0065] Therefore, in the context of this invention, the at least one protective layer may include one or more components typically used to implement such a protective layer.

[0066] As a non-limiting example of the invention, these components may be polymers, sugars, proteins, lipids, oils, fatty acids, inorganic salts, or gums, used alone or in mixtures thereof.

[0067] Preferably, one or more components of the at least one protective layer have a melting point below 80°C. This is particularly suitable for obtaining a high-quality protective layer that best protects the aggregates of particles that are bonded together.

[0068] The polymer may be selected from the group consisting of: polysaccharides (e.g., alginate), polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polyacrylate, polyethylene oxide, polylactic acid, polyvinyl chloride, polyvinyl acetate, polyvinylpyrrolidone, cellulose ethers, natural or modified starch and their substituted derivatives, as well as their hydrolysates and copolymers, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, and ethylcellulose, used alone or in mixtures thereof. Preferably, these may be polyvinyl alcohol, methylcellulose, or hydroxypropyl methylcellulose.

[0069] Regarding starch, these starches can be natural or modified starches derived from corn, sorghum, rice, wheat, rye, barley, oats, potatoes, cassava, or tapioca.

[0070] Regarding sugars, these sugars can be sucrose, corn syrup extract, molasses, glucose, fructose, and lactose.

[0071] Regarding proteins, these proteins can be whey powder or concentrate, caseinate, soy protein concentrate, albumin, and gelatin.

[0072] Regarding lipids, oils, and fatty acids, these lipids, oils, and fatty acids can be waxes (e.g., plant waxes, mineral waxes, and synthetic waxes: e.g., carnauba wax, candelilla wax, beeswax, paraffin wax, and microcrystalline wax), lecithin, fatty acids (e.g., stearic acid, palmitic acid, linoleic acid, oleic acid, butyric acid, and arachidonic acid), and their sodium, potassium, calcium, and zinc salts, fats and oils, particularly hydrogenated or partially hydrogenated fats and oils (e.g., soybean oil, corn oil, cottonseed oil, sunflower oil, or linseed oil). Preferably, these lipids, oils, and fatty acids are lecithin. In one embodiment of the invention, these lipids, oils, and fatty acids are hydrogenated sunflower oil.

[0073] Regarding the inorganic salts, these inorganic salts can be sulfates, citrates, chlorides, carbonates, sulfites, phosphates, or phosphonates, as well as bicarbonates of sodium, ammonium, potassium, calcium, magnesium, and zinc. Preferably, these inorganic salts are sulfates of magnesium, sodium, ammonium, or sodium. In one embodiment of the invention, these inorganic salts are sodium sulfate.

[0074] Regarding gums, these gums can be gum arabic, guar gum, agar, tragacanth gum, locust bean gum, carrageenan, and xanthan gum.

[0075] Preferably, the protective layer comprises at least one component selected from the group consisting of: alginate, stearic acid, ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, and soybean oil, corn oil, cottonseed oil, or linseed oil, used alone or in mixtures thereof.

[0076] The at least one protective layer may also contain at least one component selected from the group consisting of: plasticizers, lubricants, pigments and powders (e.g., talc, bentonite, kaolin, magnesium silicate, calcium carbonate and chitosan), used alone or in mixtures thereof.

[0077] In one embodiment of the invention, the particles include a first protective layer and a second protective layer, the first protective layer comprising at least one inorganic salt (preferably sodium sulfate), and the second protective layer surrounding the first protective layer and comprising stearic acid or hydrogenated sunflower oil. This embodiment of the protective layer provides optimal protection for the active agent.

[0078] Preferably, in this embodiment of the invention, the active agent is an enzyme.

[0079] Preferably, in this embodiment of the invention, the binder is maltodextrin.

[0080] Therefore, in one embodiment of the invention, the activator is an enzyme, the binder is maltodextrin, and the particles further include a first protective layer and a second protective layer, the first protective layer comprising at least one inorganic salt (preferably sodium sulfate), and the second protective layer surrounding the first protective layer and comprising stearic acid or hydrogenated sunflower oil.

[0081] Preferably, the particles according to the invention are incorporated into the premix as defined above.

[0082] Therefore, the present invention also relates to premixes comprising at least some of the particles according to the invention as described above. Expressed as a mass percentage relative to the mass of the premix, the premix may contain 0.2% to 10%, preferably 0.1% to 3%, of the particles. For example, if the active agent is an enzyme, the enzyme activity in the premix may be approximately 500 U / g.

[0083] The premix can be incorporated into animal feed.

[0084] Therefore, the present invention also relates to animal feed comprising at least a premix according to the present invention.

[0085] The animal feed may contain 0.5% to 6%, preferably 2% to 5%, of the premix according to the invention, expressed as a percentage by weight relative to the weight of the animal feed.

[0086] In another embodiment of the invention, the granules according to the invention are directly incorporated into animal feed.

[0087] When the pellets according to the invention are incorporated into animal feed, the amount of the pellets per ton of the feed is up to about 5000 g, preferably about 25 g to about 400 g. In fact, the amount of each component of the animal feed per ton of the animal feed is typically from 0.001 g to 400 g.

[0088] Therefore, the amount of active agent in each ton of said animal feed can be from about 0.0001 g to about 80 g.

[0089] The present invention also relates to a method for manufacturing particles according to the invention, characterized in that the method comprises at least the following steps: a) Prepare a mixture comprising at least an activator and a binder, and optionally at least one solvent, such that the mixture can be spray-granulated. b) Spray granulation of the mixture thus obtained in step a) to obtain the particles according to the invention.

[0090] Advantageously, the manufacturing method further includes at least one step c), namely coating the particles obtained at the end of step b), to cover them with at least one protective layer.

[0091] In step a), the mixture may optionally contain at least one additional compound as described above in the description of the particles according to the invention.

[0092] The components of the surfactant, binder, any additional compounds, and at least one protective layer have been described above in the description of the particles according to the invention.

[0093] In step a), the mixture may optionally contain at least one solvent.

[0094] In fact, in step a), if it is not feasible to spray granulate using only these other components of the mixture, at least one solvent can be added to the other components of the mixture to enable spray granulation of the mixture.

[0095] Deciding whether to add at least one solvent to the mixture containing at least an surfactant and a binder in step a) to enable subsequent spray granulation step b) is entirely within the capabilities of a person skilled in the art. Determining the amount of solvent to be added to the mixture in step a) is also within the capabilities of a person skilled in the art. In fact, spray granulation technology is well-known to a person skilled in the art.

[0096] The solvent may be water, preferably demineralized water.

[0097] Preferably, the mixture obtained at the end of step a) has a viscosity of 10 mPa•s (cP) to 50 mPa•s (cP), more preferably 12 mPa•s (cP) to 48 mPa•s (cP), at 25°C. This viscosity of the mixture is particularly suitable for spray granulation, in which the mixture is sprayed through at least one nozzle. In other words, advantageously, the viscosity of the mixture from step a) is compatible with the use of the nozzle through which it is sprayed.

[0098] Advantageously, the mixture is stable over time. This means that it does not undergo phase separation or increase in mass over time, and it is understood that spray granulation can continue for several hours.

[0099] The selection of all components of the mixture in step a) and their respective amounts is entirely within the capabilities of a person skilled in the art, who will be able to determine them without difficulty based on the final composition of the particles according to the invention that he desires to obtain.

[0100] In step a), advantageously, the binder and any additional compounds are gently incorporated into the activator.

[0101] Step a) is preferably performed at room temperature.

[0102] At the end of step a), the mixture is preferably homogeneous.

[0103] Preferably, in step a), the mixture is prepared using a paddle mixer, for example at a speed of 300 rpm to 700 rpm, to make the mixture homogeneous.

[0104] In one embodiment of the invention, when step a), the surfactant may be in the form of a surfactant concentrate suspended in an aqueous solution.

[0105] The active agent concentrate may advantageously have 10% to 50%, preferably 25% to 35%, of dry extract.

[0106] These active agent concentrates can be enzyme concentrates. For example, an enzyme concentrate sold by the company Danisco under the trade name "Rovabio Advance SD" can be mentioned.

[0107] The adhesive may also have, for example, 98% dry extract, and therefore contain a small amount of water.

[0108] In other words, in these embodiments of the invention, a portion of the solvent (e.g., water) supplied by an surfactant concentrate and / or binder concentrate may need to be added to the mixture obtained at the end of step a) to make the mixture suitable for spray granulation.

[0109] The implementation of spray granulation in step b) is entirely within the capabilities of a skilled technician. Step b) of spray granulation can advantageously be performed using, for example, […]. Figure 1 The apparatus is schematically shown and described below.

[0110] During step b) of spray granulation, the solvent (e.g., water, especially demineralized water) contained in the mixture obtained at the end of step a) is evaporated, preferably until the mass content of the solvent in the mixture is less than 6%, preferably less than 4%.

[0111] Advantageously, the manufacturing method further includes at least one step c), namely coating the particles obtained at the end of step b), to cover them with at least one protective layer.

[0112] The coating step c) is entirely within the capabilities of a skilled technician. For example, it can be carried out in a fluidized bed.

[0113] The invention will be better understood with the following aids: - Experimental section using particles according to the present invention and comparative particles - Referring to the detailed embodiments disclosed below in the accompanying drawings, which illustrate by way of non-limiting examples one embodiment of an apparatus for performing step b) of the spray granulation method according to the invention.

[0114] [ Figure 1 ] Figure 1 This is a schematic diagram of an apparatus for implementing step b) of the particle manufacturing method according to the present invention.

[0115] Experimental section: Experiments were conducted on particles according to the present invention and comparative particles of the prior art.

[0116] I-Preparation of particles according to the present invention without a protective layer: Five types of particles according to the invention were prepared according to steps a) to b) of the manufacturing method according to the invention.

[0117] These five types of particles contain enzymes as activators. More specifically, they are endo-1,4-β-xylanase and β-glucanase.

[0118] During step a) of the granulation method, these enzymes are added to the mixture in the form of an enzyme concentrate. This is an enzyme concentrate sold by the company Danisco under the trade name "Rovabio Advance SD". It has a dry extract content of 28% by mass.

[0119] The binder that ensures the granules adhere to each other is maltodextrin, which has a 98% dry extract content.

[0120] During step a), the solvent is demineralized water.

[0121] Step a) of the manufacturing method is carried out at room temperature using a paddle mixer set at approximately 600 rpm to prepare a homogeneous mixture comprising the following: - The above enzyme concentrate; - The aforementioned maltodextrin powder; - Water, in an amount such that the mixture has 30% dry extract.

[0122] These five types of particles according to the invention differ only in the amount of enzyme concentrate, maltodextrin, and demineralized water used to prepare the mixture in step a) of the method for manufacturing the particles.

[0123] Table 1 below details the amounts of enzyme concentrate, maltodextrin, and demineralized water for each type of particle: - Type I particles, hereinafter referred to as INV1 particles. - Type II particles, hereinafter referred to as INV2 particles. - Type III particles, hereinafter referred to as INV3 particles. - Type 4 particles, hereinafter referred to as INV4 particles, - Type 5 particles, hereinafter referred to as INV5 particles, Table 1 Based on the mass values ​​of enzyme concentrate and maltodextrin described in detail in Table 1 above, and knowing that the enzyme concentrate has 28% dry extract and the maltodextrin has 98% dry extract, the mass content of the dry extract of enzyme concentrate and maltodextrin can be calculated as the sum of the mass of the dry extract of enzyme concentrate and maltodextrin used relative to each of the four types of particles.

[0124] Table 2 below details these mass contents of enzyme concentrates and dry extracts of maltodextrin for each type of particle from INV1 to INV5. Table 2 Table 2 shows the dry extracts of enzyme concentrate and maltodextrin with different mass contents of particles INV1 to INV5.

[0125] Next, in Figure 1 The mixture obtained at the end of step a) is spray-granulated in the device 1 shown schematically.

[0126] The device 1 includes: - Container 2, which is configured to contain the mixture 3 obtained at the end of step a) of the manufacturing method as described above. - Peristaltic pump 5, with a flow rate of 945 to 1000 grams per hour. - A first device 4, which is used to convey the mixture 3 from the container 2 to the pump 5. - Nozzle 8, which has a needle with an internal opening diameter of 1.2 mm and an atomization pressure of 2.5 bar, is substantially vertically positioned on the bottom wall 18 of the tank 7 for spray granulation. - A second device 6, which is used to deliver the mixture 3 from the pump 5 to the nozzle 8. - The first air injector (called "processing air" because it is used to implement spray granulation) 12, which is in tank 7, - A first air flap 9a and a second air flap 9b, wherein the first air flap 9a has an opening to the left at +15° and the second air flap 9b has an opening to the right at +30°. - A third device 19, which is used to convey the particles formed in tank 7 to separator 11. - Separator 11, comprising an elongated zigzag portion 20 configured to perform continuous pneumatic separation, and a first end 20a and a second end 20b, the second end 20b being fluidly connected on one hand to the third device 19 for conveying particles formed in tank 7 to separator 11, and on the other hand to a fourth device 10 for conveying excessively fine particles from separator 11 to tank 7. - A second air injector 13 (referred to as "air pressure" to allow separation of particles within separator 11 by continuous pneumatic separation) is located at the first end 20a of separator 11. - Container 14, which is used to receive particles 15 obtained at the end of step b) of spray granulation, the particles 15 being sufficiently dense to pass through separator 11. - Air outlet 21 is used to prevent overpressure in tank 7, ensuring the renewal of the aforementioned processing air and thus removing humid air. - Filtration system 22, which is configured to retain particles formed by spray granulation within tank 7 so that they do not leave tank 7 through the aforementioned air outlet 21.

[0127] exist Figure 1 In the figure, reference numeral 16 indicates the circulating motion of air and particles produced by spray granulation in tank 7. Reference numeral 23 indicates the mixture 3 sprayed by nozzle 8. Reference numeral 17 indicates the airflow injected into tank 7 via the Venturi effect.

[0128] Device 1 operates in continuous mode.

[0129] The air temperature at the first air injector 12 is 56°C to 60°C. The air flow rate injected into the tank 7 through the first air injector 12 is 100 to 150 m³ / h. 3 / hour. This is dry, unsaturated air.

[0130] The first air baffle 9a and the second air baffle 9b enable a uniform airflow to be obtained in the tank 7.

[0131] The air temperature at air outlet 21 is between 32°C and 39°C.

[0132] Furthermore, compressed air at a pressure of 0.8 bar is injected into the separator 11 via a second air injector 13, causing particles with a median diameter of at least 500 μm to pass through the entire separator 11 and then fall by gravity, thus being collected in the container 14. The remaining particles that are too small are pushed upwards and rise within the zigzag section 20 to the second end 20b of the separator 11, where they are reintroduced into the tank 7 via a fourth conveying device 10 consisting of flexible plastic tubing. The particles that are too small are then spray-granulated again in the tank 7 until they reach a median diameter of at least 500 μm.

[0133] Container 14 allows collection of particles 15 according to the invention that have passed through the entire separator 11.

[0134] Comparison of existing technology particles The prior art's comparative particles were produced by the company Adisseo France SAS under the trade name "Rovabio". ® "Advance T-Flex" sold as pellets.

[0135] Expressed as a mass percentage relative to the mass of the comparative particles, they contain: - 15% of the same enzyme concentrate as the particles according to the invention (i.e., enzyme concentrate Rovabio) ® AdvanceSD). - 20% calcium carbonate, - 15% maltodextrin, and - 50% stearic acid.

[0136] The control particle contains a calcium carbonate core with a diameter of approximately 285 μm, covered by a first layer with a thickness of approximately 65 μm, and contains a mixture of maltodextrin and enzyme concentrate. This first layer itself is coated with a protective layer of approximately 55 μm thickness composed of stearic acid. Therefore, in the control particle, the enzyme of the enzyme concentrate is protected by the protective layer composed of stearic acid.

[0137] Measurements of particles according to the present invention and comparative particles The size and size distribution of the particles and control particles according to the present invention were measured using a laser particle size analyzer (MasterSizer S model, sold by Malvern Instruments, LLC) in dry mode. The results were obtained after calculating 5000 particles.

[0138] Table 3 below describes in detail the comparative particles and five types of particles according to the invention (i.e., INV1, INV2, INV3, INV4 and INV5): D(v,0.1), D(v,0.5), and D(v,0.9) are expressed in µm and the span is as defined above. Table 3 Given the results described in detail in Table 3 above, and especially the span values, note that: - The five types of particles according to the invention have lower span values ​​than the comparative particles, especially for particles INV1, INV3, INV4 and INV5: therefore, the particles according to the invention have a more uniform size distribution than the comparative particles; - The five types of particles according to the invention have a uniform size distribution. Particle INV5 has a very uniform size (span of 0.40), and particle INV1 has excellent uniformity in size distribution with a span of only 0.34.

[0139] II-Preparation of particles according to the invention with a protective layer: Then, the five types of particles according to the invention are subjected to an additional coating step, i.e., optional step c of the manufacturing method according to the invention.

[0140] Three coating compositions were used.

[0141] The first coating composition was obtained by dissolving 73 g of an ethyl cellulose solution containing 8% dry extract in 847 g of ethanol at room temperature using a paddle stirrer. The dry matter content of the first coating composition thus obtained was 8%.

[0142] The second coating composition was obtained by melting 133 g of 92% reagent grade stearic acid on a hot plate.

[0143] The third coating composition was obtained by dissolving 491 g of sodium sulfate in 1062 g of demineralized water at 80°C.

[0144] The particles according to the invention are coated in a fluidized bed using a first, second, or third coating composition.

[0145] More specifically, the following three different coatings are applied to particles INV1 to obtain three novel coated particles according to the invention: INV1A, INV1B, and INV1C: - The coated particles INV1A are obtained from particles INV1, which are coated with a single protective layer consisting of a second coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV1A is 75% particles INV1 and 25% the protective layer. - The coated particles INV1B are obtained from particles INV1, which are coated with a single protective layer consisting of a first coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV1B is 90% particles INV1 and 10% the protective layer. - The coated particles INV1C are obtained from particles INV1, which are coated with a first protective layer consisting of a first coating composition, and then the first protective layer itself is covered with a second protective layer of a second coating composition, the amount of the second coating composition being such that the mass percentage relative to the total mass of these coated particles INV1C is: 77% particles INV1, 8% first protective layer and 15% second protective layer.

[0146] Two different coatings were applied to particles INV2 to obtain two novel coated particles INV2A and INV2B according to the present invention: - The coated particles INV2A are obtained from particles INV2, which are coated with a single protective layer consisting of a second coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV2A is 75% particles INV2 and 25% the protective layer. - The coated particles INV2B are obtained from particles INV2, which are coated with a single protective layer consisting of a second coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV2B is 50% particles INV2 and 50% the protective layer. Two different coatings were applied to particles INV3 to obtain two novel coated particles INV3A and INV3B according to the present invention: - The coated particles INV3A are obtained from particles INV3, which are coated with a single protective layer consisting of a first coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV3A is 90% particles INV3 and 10% the protective layer. - The coated particles INV3B are obtained from particles INV3, which are coated with a single protective layer consisting of a second coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV3B is 75% particles INV3 and 25% the protective layer. Apply one of the following coatings to the particles INV4 to obtain a novel coated particle INV4A according to the present invention: - The coated particles INV4A are obtained from particles INV4, which are coated with a single protective layer consisting of a first coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV4A is 95% particles INV4 and 5% the protective layer. Two different coatings were applied to particles INV5 to obtain two novel coated particles INV5A and INV5B according to the present invention: - The coated particles INV5A are obtained from particles INV5, which are coated with a single protective layer consisting of a third coating composition in an amount such that the mass percentage of these coated particles INV5A is 45% particles INV5 and 55% of the protective layer relative to the total mass of these coated particles INV5A. - The coated particles INV5B are obtained from particles INV5, which are coated with a first protective layer consisting of a third coating composition, and then the first protective layer itself is covered with a second protective layer of a second coating composition, the amount of which is such that the mass percentage relative to the total mass of these coated particles INV5B is: 31% particles INV1, 41% first protective layer and 25% second protective layer. Therefore, particles INV1 to INV5 constitute the "core" of these other particles according to the invention, which includes one or two protective layers, and their particle size characteristics are described in detail in Table 4.

[0147] More specifically, Table 4 below describes in detail the coated particles INV1A to INV1C, INV2A, INV2B, INV3A, INV3B, INV4A, INV5A and INV5B according to the invention: D(v,0.1), D(v,0.5), D(v,0.9) and span. Table 4 Given the results described in detail in Table 4 above, and especially the span values, note that: - All of these coated particles according to the invention have a span value of less than 1: therefore they have a uniform size distribution; - The particles INV1A, INV2B, INV3B, INV4A, INV5A, and INV5B according to the invention comprise protective layers that are distinct from each other and have very low span values: their size distribution is completely uniform. This indicates that the particles according to the invention can have a completely uniform size distribution even if the composition of the protective layers varies greatly.

[0148] Tables 5 and 6 below describe in detail particles INV1 to INV5, coated particles INV1A to INV1C, INV2A, INV2B, INV3A, INV3B, INV4A, INV5A, INV5B, and control particles: - Enzyme content, expressed in mg / g; - Activity of endo-1,4-β-xylanase, expressed in U / g; - Relative humidity level measured for 2 g particles at 105°C; - Water activity; - Tap density d10 (g / L); - Roundness.

[0149] The activity of endo-1,4-β-xylanase was measured according to a protocol for the enzymatic hydrolysis of xylosidic bonds in a soluble solution of wheat arabinoxylan and β-1,4-xylan polysaccharide substituted with arabinose. In fact, endo-1,4-β-xylanase hydrolyzes the xylosidic bonds of xylan. Therefore, in the presence of the enzyme to be tested, the enzyme activity decreases proportionally to the decrease in viscosity of the soluble solution.

[0150] The relative humidity level was determined using an infrared balance sold by Mettler Toledo under the trade name HS153. Approximately 2 g of test particle sample was placed in a pre-tare aluminum pan. After the balance was turned off, the sample was heated to 105°C to remove as much moisture as possible, thereby determining the relative humidity level.

[0151] Water activity was determined at room temperature using an Aw-meter device sold by Novasina under the trade name Labswift-aw.

[0152] The tapped density d10 is determined as follows: The test particle sample is placed in a graduated plastic tube, and the density d0 is calculated by dividing the mass by the volume and multiplying by 100. The tube is then placed in an automated packing tapped density analyzer sold by Anto Paar under the trade name Autotap, which taps the tube 10 times. The density d10 is obtained by dividing the mass by the volume of the tapped sample and then multiplying by 100.

[0153] Microscopic observation was performed using a microscope from Techsystems equipped with an optical camera from Navitar. The particle sample was placed on a glass slide. Images were captured at different magnifications using Archimed software. The images obtained through the microscope were analyzed using ImageJ software to determine the roundness of the test particles. This parameter was determined by tracing the outline of the particles.

[0154] The roundness is determined by the mathematical equation (2) described in detail above. Table 5 Based on the results described in detail in Table 5 above, note that: - These particles according to the invention have excellent sphericity because their roundness is always greater than 0.8; - The activity of endo-1,4-β-xylanase increases with increasing enzyme content; - The relative humidity is very low (3.5% to 4%), and this value is perfectly acceptable for avoiding enzymatic degradation; - The water activity is also very low, and its value is perfectly acceptable for avoiding enzymatic degradation. Table 6 Based on the results described in detail in Table 6 above, note that: These coated particles according to the invention exhibit excellent sphericity because their roundness is always greater than a value of 0.8. They have better sphericity than the control particles; - The relative humidity of these particles according to the invention is lower than that of the comparative particles.

[0155] Then, the granulation thermal stability of particles INV1 to INV5, INV1A to INV1C, INV2A, INV2B, INV3A, INV3B, INV4A, INV5A, INV5B and control particles was tested.

[0156] All these pellets are introduced into the poultry premix at a rate of 200 g / ton and then extruded in a press at 90°C to obtain pellets.

[0157] The granulation conditions are as follows: - Press output: 44 to 46 kg / hour; - Conditioner outlet temperature: 90℃; - Mold temperature: 85℃; - Material flow rate: 2.6 kg / hour; - Material flow pressure: 1.6 bars; - Mold size: 4 mm x 24 mm.

[0158] Enzyme activity retention rate is the ratio of the enzyme activity contained in the pellet to the enzyme activity stated before the pellet was incorporated into the animal feed. It is determined according to the following mathematical equation (4): (4) in: - A represents the activity of the enzymes contained in the animal feed pellets (in other words, after pelleting), expressed in U / kg. - B represents the enzyme activity, expressed in U / g, prior to the incorporation of the pellets into animal feed. - C is the amount of pellets mixed into the feed, expressed in g / T.

[0159] Table 7 below details the enzyme activity retention rates obtained by particles INV1 to INV5 and control particles according to the present invention. Table 7 Based on the results described in detail in Table 7 above, it is noted that all these particles according to the invention have an enzyme activity retention rate comparable to that of the comparative particles, which can be 47% to 67%. Therefore, although the particles according to the invention do not have any protective layer, their enzyme protection efficacy is almost equivalent to that of the prior art comparative particles containing a protective layer.

[0160] Table 8 below details the enzyme activity retention rates obtained by the coated particles INV1A to INV1C, INV2A, INV2B, INV3A, INV3B, INV4A, INV5A and INV5B according to the present invention, as well as the comparative particles. Table 8 Based on the results described in detail in Table 8 above, note that: - These coated particles according to the present invention all have excellent enzyme activity retention rates, which are much higher than those of the control particles. - Particles INV1C, INV3B, and INV5B exhibit the best enzyme activity retention.

[0161] Comparing the results in Table 7 with those in Table 8, it is noted that adding one or more protective layers improves the enzyme activity retention rate of the particles according to the invention.

Claims

1. A particle (15), characterized in that It comprises aggregates of granules bonded together, and is substantially spherical in shape, each granule consisting of a mixture comprising at least: - Surfactants and - A reagent used to bond the granules together.

2. The particles (15) according to claim 1, characterized in that... It has a median diameter of 300 μm to 800 μm, preferably between 400 μm and 700 μm, and more preferably between 500 μm and 600 μm.

3. The particles (15) according to claim 1 or 2, characterized in that... The active agent is selected from the group consisting of proteins, antimicrobial agents, amino acids, and vitamins, used alone or in mixtures thereof.

4. The particles (15) according to claim 3, characterized in that... The active agent is at least one protein selected from the following: enzymes, peptides, and polypeptides.

5. The particles (15) according to any one of claims 1 to 4, characterized in that... It contains 10% to 90%, preferably 15% to 70%, more preferably 15% to 30% of an active agent, expressed as a mass percentage relative to the total mass of the particles.

6. The particles (15) according to any one of claims 1 to 5, characterized in that The binder is selected from the group consisting of maltodextrin, lactose, maltose, and starch, used alone or in mixtures thereof.

7. The particles (15) according to any one of claims 1 to 6, characterized in that... It contains 10% to 90%, preferably 15% to 85%, more preferably 50% to 80% of the binder, expressed as a mass percentage relative to the total mass of the particles.

8. The particles according to any one of claims 1 to 7, characterized in that... It also includes at least one protective layer that surrounds the aggregates of granules that are bonded together.

9. The particles according to claim 8, characterized in that... The protective layer comprises at least one component selected from the group consisting of: alginate, stearic acid, ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, and soybean oil, corn oil, cottonseed oil, or linseed oil, used alone or in mixtures thereof.

10. The particles according to claim 8, characterized in that... The activator is an enzyme, the binder is maltodextrin, and the particles include a first protective layer and a second protective layer, the first protective layer containing at least one inorganic salt, preferably sodium sulfate, and the second protective layer surrounding the first protective layer and containing stearic acid or hydrogenated sunflower oil.

11. A premix, characterized in that... It contains at least the particles according to any one of claims 1 to 10.

12. An animal feed, characterized in that... It contains at least the premix as described in claim 11.

13. A method for manufacturing particles (15) according to any one of claims 1 to 7, characterized in that... It includes at least the following steps: a) Prepare a mixture comprising at least the surfactant and the binder, and optionally at least one solvent, such that the mixture can be spray-granulated. b) Spray granulation of the mixture thus obtained in step a) to obtain the particles.

14. The method for manufacturing particles according to any one of claims 8 to 10 according to claim 13, characterized in that... It also includes step c) of coating at least one of the particles (15) obtained at the end of step b) to cover them with at least one protective layer.

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