WO2025002999A1 - Produits protégés dans le rumen - Google Patents

Produits protégés dans le rumen Download PDF

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Publication number
WO2025002999A1
WO2025002999A1 PCT/EP2024/067423 EP2024067423W WO2025002999A1 WO 2025002999 A1 WO2025002999 A1 WO 2025002999A1 EP 2024067423 W EP2024067423 W EP 2024067423W WO 2025002999 A1 WO2025002999 A1 WO 2025002999A1
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Prior art keywords
solid dispersion
biologically active
active ingredient
cellulose
mixture
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Ceased
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PCT/EP2024/067423
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English (en)
Inventor
Thomas HÄUSSNER
Waldemar Hessberger
Ursula RIESEN
Andrea KOPP
Jessie GUYADER
Philipp Roth
Ulrike Kottke
Claudia Parys
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Evonik Operations GmbH
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Evonik Operations GmbH
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Publication of WO2025002999A1 publication Critical patent/WO2025002999A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/174—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A23K40/35—Making capsules specially adapted for ruminants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0068—Rumen, e.g. rumen bolus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention is on the field of animal nutrition and relates to ruminant nutrition. Specifically, the present invention relates to rumen protected products for feeding ruminants in the form of a solid dispersion, a process for their production and mixtures containing the solid dispersion and/or the products obtained by said process.
  • Ruminant animals are mammals of the suborder Ruminantia including the well-known cattle, sheep, and goats. They have a stomach divided into four morphologically distinct compartments: the rumen, the reticulum, the omasum, and the abomasum.
  • the rumen and the reticulum are derived from the terminal portion of the esophagus, and the omasum and abomasum are considered to be a genuine stomach.
  • Bacteria present in the rumen enable ruminants to digest cellulosic materials such as grass. Conventional digestion occurs in the abomasum, sometimes called the true stomach.
  • the rumen which is essentially a continuous fermenter, supports a variety of microorganisms, which attack and digest much of the ingested feedstuffs consumed by a ruminant as part of their normal life cycle. Ingested protein material is broken down in the rumen to soluble peptides and amino acids that are used as nutrients by the microorganisms. A stream of ingesta, rich in microbial cells, passes out of the rumen into the omasum. The function of the omasum is to separate liquids and solids. Much of the liquid reenters the rumen while the remainder of the material enters the abomasum.
  • the microbial action of the rumen has the great advantage of being able to convert many feed components, which have no direct nutritive value for the host into products, which can be assimilated and utilized by the host.
  • cellulose may be converted to a mixture of volatile fatty acids, which can serve as a source of energy to the host.
  • soluble proteins of high nutritive value may be broken down and digested in the rumen and in part resynthesized into microbial protein of lower nutritive value.
  • Amino acids are also chemically changed by the rumen microorganisms, which convert amino acids to carbon dioxide, volatile fatty acids, and ammonia.
  • All proteins present in animals are constituted by combinations of more than 20 different amino acids.
  • ten essential amino acids are not adequately synthesized in the animal body, and the animal must take them in.
  • These ten amino acids are also referred to as essential or growth limiting amino acids.
  • essential amino acids When essential amino acids are lacking in the ruminant diet the ruminant's health, milk production, etc., are all negatively affected. It is therefore common practice in ruminant production to supply biologically active ingredients in the daily diet of the animals in order to improve their conditions of health and their productive performance.
  • Active ingredients of interest include amino acids, vitamins, enzymes, nutrients such as protein and carbohydrates, probiotic microorganisms, prebiotic foods, mineral salts, choline, guanidino acetic acid, etc.
  • WO 2006/32958 A2 discloses a composition in pellets with controlled release of physiologically active substances comprising a comprising a one or more physiologically active substances; a matrix comprising a carnauba wax and/or a microcrystalline wax, a first layer of a coating comprising a first hydrophobic substance, and a second layer of a coating comprising a second hydrophobic substance.
  • WO 2014/011857 A1 discloses the preparation of coated particles, wherein particles of the calcium salt of HMTBa (2-hydroxy-4-methylthiobutanoic acid) are coated with a first layer of a polymer such as ethyl cellulose (EC), followed by a second layer comprising stearic acids and hydrogenated soybean oil, or the HMTBa oligomer, ethyl cellulose and/or CaCCh.
  • a polymer such as ethyl cellulose (EC)
  • EC ethyl cellulose
  • CaCCh ethyl cellulose
  • EP 678246 A2 discloses a granular additive composition for ruminant feed, which comprises a core comprising a biologically active substance and a coating composition coated thereon, said coating composition comprising 65 to 90 % by weight of (A) at least one hydrophobic protecting substance selected from the group consisting of hardened animal and plant oil and fat, an animal and plant fat, and a fatty acid ester, 2 to 10 % by weight of (B) a surface active agent compatible with said hydrophobic protecting substance (A) and 8 to 30 % by weight of (C) talc powder.
  • the disclosed protective materials in particular fats or waxes, mostly have brittle material properties. This has negative effects on the particles coated with said protective materials upon typical handling or storage of the particles.
  • the brittleness reduces the mechanical stability. Due to the action of pressure and shear forces on the particles, they can either break or material can be removed at corners and edges. In any case this leads to a significantly increased release rate of the biologically active substance in the rumen, which significantly reduces the protection of the biologically active substance against degradation.
  • the storage conditions in particular temperature and air humidity, also negatively affect the protection of the biologically active substance against degradation since they lead to a softening of the protection material or to a separation of the individual components in the coating or protection composition.
  • the protective materials must also provide for a sufficient mechanical stability so that the product can be further processed easily without deforming, crushing, or destructing the product.
  • WO 2010/143066 A1 discloses an edible oleogel comprising an oil, an ethylcellulose and a surfactant, prepared by combining ethylcellulose with an edible oil and a surfactant, and heating the mixture to a temperature above the glass transition temperature of the ethylcellulose. Once the ethylcellulose has fully dissolved and the solution is clear, it is allowed to cool and set as a gel. In this way, liquid edible oils are transformed into anhydrous semisolid gels. The resulting oleogel is homogeneous, elastic, substantially anhydrous, and has a gelation temperature below 100 °C. In the contest of the present invention, Example 2 of WO 2010/143066 A1 was reproduced (see comparative Example below).
  • One object of the present invention is therefore a solid dispersion for feeding a ruminant comprising or consisting of i) from 40 wt.-% to 60 wt.-% of a biologically active ingredient, based on the total weight of the solid dispersion, ii) from 60 wt.-% to 40 wt.-% of a carrier, wherein the carrier comprises a mixture comprising from 35 wt.-% to less than 60 wt.-% of a hydrogenated fat and from more than 0 to 5 wt.-% of cellulose, each based on the total weight of the solid dispersion.
  • Solid dispersions have achieved significant interest in the field of pharmaceutics or drug formulation as an effective means of enhancing the dissolution rate and thus the bioavailability of a range of weakly water-soluble drugs. Hence, solid dispersions of weakly water-soluble drugs with water- soluble carriers have lowered these problems and improved dissolution.
  • solid dispersions are known as a solubilization technology emphasizing mainly on drug-polymer two- component systems in which drug dispersion and its stabilization is the key to formulation development.
  • the term solid dispersion is defined as a group of solid products consisting of a hydrophobic drug dispersed in at least one hydrophilic carrier, resulting in increased surface area and, enhanced drug solubility and dissolution rate.
  • the term solid dispersion is used to denote a group of solid products.
  • the biologically active ingredient which is typically readily water-soluble, is formulated with a carrier to form a solid dispersion, which provides rumen protection to said biologically active ingredient.
  • the thus formed solid dispersion aims at achieving a high protection of the biologically active ingredient in the rumen, in particular under the conditions in the rumen, and at a high bioavailability of the biologically active ingredient after the rumen, in particular under the conditions in the small intestine.
  • typical rumen protection compositions are coated products comprising a core with the active ingredient and upon the core a layer with the coating material.
  • the solid dispersion according to the present invention does not have a core and it does not have a layer or shell. Consequently, the solid dispersion according to the present invention also has no concentration gradient for the active ingredient over the cross section of the product as in a traditional core-shell product, where you do not have any active ingredient in the shell but only in the core. Rather, the active ingredient is homogeneously and evenly distributed over the whole solid dispersion.
  • the biologically active ingredient is sufficiently dispersed in the carrier to provide the said active ingredient with the desired rumen protection.
  • the term carrier is used for the mixture of components which allow for the formulation of a solid dispersion of the biologically active ingredient.
  • the carrier comprises a mixture comprising from 35 wt.-% to less than 60 wt.-% of a hydrogenated fat and from more than 0 to 5 wt.-% of cellulose, each based on the total weight of the solid dispersion.
  • the biologically active ingredient is homogeneously distributed over the whole solid dispersion.
  • biologically active ingredient is used to denote any compound which has a functional or nutritive activity to a biological system, such as the organism of an animal, in particular of a ruminant, e.g., cattle, sheep or goat.
  • a biologically active ingredient exhibits low stability and thus a reduced or even no bio-effectiveness when being exposed to unfavorable conditions, for example moisture, elevated temperature, oxygen and acidic and/or basic pH.
  • unfavorable conditions for example moisture, elevated temperature, oxygen and acidic and/or basic pH.
  • the biologically active ingredient can for example decompose, dissociate, deactivate, and/or lose availability.
  • biologically active ingredient therefore refers to, for example, i) amino acids, such as lysine, methionine, tryptophan, arginine, histidine, isoleucine, leucine, phenylalanine, valine, and threonine, derivatives of amino acids, such as A/-acylamino acids, e.g., A/-acylmethionine, and A/-guanylamino acids, e.g., A/-guanylglycine also known as guinidinoacetic acid, and/or salts of amino acids, such as lysine sulfate, lysine hydrochloride, and the salts of lysine with polyunsaturated fatty acids, and/or of their derivatives, such as 2-hydroxy-4-(methylthio)butyric acid calcium salt, also known as the calcium salt of methionine hydroxy analogue (calcium MHA), ii) proteins, such as casein, corn proteins,
  • the biologically active ingredient is readily water-soluble.
  • the biologically active ingredient is selected from the list consisting of i) amino acids, derivatives of amino acids, and/or salts of amino acids and/or of their derivatives, ii) proteins, iii) peptides, iv) carbohydrates, v) vitamins, and derivatives of vitamins, vi) probiotic microorganisms, vii) prebiotic feeds, viii) choline, choline salts and/or derivatives thereof, ix) polyunsaturated fats (PUFAs), derivatives thereof, and/or salts thereof, and x) pharmaceuticals.
  • PUFAs polyunsaturated fats
  • the solid dispersion according to the present invention is not subject to any limitation regarding the number of biologically active ingredients comprised in it. Therefore, the solid dispersion according to the present invention can comprise one or more biologically active ingredients.
  • the term fat is used to denote the esters formed of fatty acids with the alcohol glycerol, which are also known as glycerides.
  • fats are triglycerides, i.e. , esters formed of three fatty acids with glycerol, wherein all three alcohol groups of glycerol are esterified.
  • fat and in particular the terms saturated fat, hydrogenated fat, saturated vegetable oil, and hydrogenated vegetable oil also comprises monoglycerides and/or diglycerides, where only one or two of the alcohol groups of glycerol are esterified.
  • saturated fat e.g., hydrogenated fat
  • saturated fat also includes hydrogenated fats, in which all or most of the double bonds which were or may have previously been present in the fat were reacted with hydrogen to form single bonds. They are called hydrogenated, because the second bond is broken up and each half of the bond is attached to (saturated with) a hydrogen atom.
  • Hydrogenated vegetable oil typically contains triglycerides of a mixture of saturated fatty acids with different chain lengths.
  • the hydrogenated vegetable oil can also contain monoglycerides or diglycerides.
  • saturated fat also includes those saturated fats which are obtained by fractionated distillation of a mixture of different fats, e.g., mixture of unsaturated and saturated fats.
  • any indications of weight or weight percent also indicate that (slight) deviations from the mentioned or encompassed values, which however, still lead to essentially the same effect as the present invention, are also encompassed by the present invention.
  • This is particularly relevant with respect to saturated fats, and in particular hydrogenated vegetable oils, because the fat from which the saturated fat, and in particular the hydrogenated vegetable oil, is obtained is a natural product of varying quality and composition, irrespective of whether it is a natural, synthetic, or fractionated (hydrogenated) vegetable oil.
  • the present invention is not subject to any limitations regarding the number of saturated fats comprised by the carrier according to the present invention. Therefore, said carrier can comprise one or more saturated fats.
  • saturated fat e.g., hydrogenated fat
  • BAI metabolizable biologically active ingredient
  • a further advantage of the carrier as taught herein is that it adds nutritional value to the solid dispersion according to the present invention.
  • Vegetable oils contain a mixture of various fats.
  • vegetable oils contain a variety of glycerides of different fatty acids, i.e. , fatty acids with different chain lengths.
  • palm oil contains about 41 to about 46% of glycerides of palmitic acid, about 37 to about 42% of glycerides of oleic acid, about 8 to about 10% of glycerides of linoleic acid, about 4 to about 7% of glycerides of stearic acid, and about 2% or less of glycerides of other fatty acids
  • soybean oil contains about 17 to about 31 % of glycerides of oleic acid, about 48 to about 59% of glycerides of linoleic acid, about 2 to about 1 1 % of glycerides of linolenic acid, and glycerides of other fatty acids, such as about 2 to about 11 % of glycerides of palmitic acid and/or 2 to 7% of glycerides of stearic acid.
  • Possible saturated fats or oils in the context of the present invention are for example hydrogenated plant oils, such as palm oil, soya oil, rapeseed oil, sunflower oil or castor oil. Accordingly, the present invention is not subject to any limitations regarding the use of a specific hydrogenated fat and in particularly, with respect to the use of a specific hydrogenated fat. However, it was found that the use of a hydrogenated vegetable oil provides the solid dispersions according to the present invention with a high rumen protected fraction of the biologically active ingredient. Preferably, said hydrogenated vegetable oil is completely hydrogenated.
  • the saturated fat comprises or consists of a hydrogenated fat, e.g., a hydrogenated vegetable oil.
  • the solid dispersion according to the present invention is also not subject to any limitations regarding the number of hydrogenated vegetable oils. Therefore, the hydrogenated fat can also be a mixture of two or more hydrogenated vegetable oils, for example two, three or even more hydrogenated vegetable oils. Suitable hydrogenated vegetable oils comprise hydrogenated palm oil, hydrogenated rapeseed oil and hydrogenated soybean oil or mixtures of any of these.
  • solid dispersions according to the present invention wherein the saturated fat is a hydrogenated vegetable oil, preferably a hydrogenated palm oil, hydrogenated soybean oil, and/or hydrogenated rapeseed oil, allow the release of a high fraction of biologically active ingredient in the small intestine and thus allow to provide the ruminant with a high amount of metabolizable biologically active ingredient.
  • the saturated fat is a hydrogenated vegetable oil, preferably a hydrogenated palm oil, hydrogenated soybean oil, and/or hydrogenated rapeseed oil
  • the hydrogenated fat comprises or consists of a hydrogenated vegetable oil.
  • the hydrogenated fat comprises or consists of hydrogenated palm oil, hydrogenated soybean oil and/or hydrogenated rapeseed oil.
  • the solid dispersion according to the present invention is not subject to any limitation regarding a specific type of cellulose. Therefore, any type of cellulose can be used in the solid dispersion according to the present invention.
  • the cellulose can be cellulose as such or a cellulose derivative, such as, a carboxymethyl cellulose (CMC), an ethyl cellulose (EC), a methyl cellulose (MC), or a hydroxypropyl methylcellulose (HPMC).
  • the cellulose can be any cellulose powder, i.e., powdery cellulose, any cellulose fiber, i.e., fibrous cellulose, any type of powdered cellulose or a mixture of any of these.
  • the cellulose is powdery cellulose, it is preferred that it is microcrystalline cellulose.
  • the cellulose is fibrous cellulose, it is preferred that it has an average fiber length of ca. 200 to ca. 300 pm.
  • the cellulose is cellulose powder and/or cellulose fiber.
  • the solid dispersion according to the present invention comprises from more than 0 to 2 wt.-% of cellulose, in particular, cellulose powder and/or cellulose fiber.
  • the solid dispersion according to the present invention comprises from 0.25 wt.-% to 2 wt.-% of cellulose, in particular, of cellulose powder and/or cellulose fiber.
  • the carrier of the solid dispersion according to the present invention is not subject to any limitations regarding the number of fatty acids. Therefore, said carrier can comprise one or more fatty acids.
  • fatty acid is used as known to the person skilled in the art and denotes a carboxylic acid with a long C4 to C28 aliphatic chain, which is either saturated or unsaturated. Said fatty acid may be branched or unbranched, but preferably it is unbranched.
  • the carrier further comprises from more than 0 to 10 wt.-% of a fatty acid, based on the total weight of the solid dispersion.
  • the carrier is also not subject to any limitations regarding the chain lengths of the one or more fatty acids.
  • the most prevalent fatty acids in hydrogenated fats preferably hydrogenated vegetable oils, such as palm oil, hydrogenated soybean oil, and/or rapeseed oil, are C14 to C22 carboxylic acids. It was found that a fatty acid with a similar or even identical chain length as the one or those ones comprised in the hydrogenated vegetable oil improves the quality of the carrier, both in terms of a protective material against degradation in the rumen and in terms of the release rate in the intestinal tract of the rumen.
  • the fatty acid comprises or consists of a CM to C22 carboxylic acid.
  • Preferred hydrogenated vegetable oils are palm oil and/or soybean oil.
  • the most prevalent fatty acids in these hydrogenated vegetable oils are C16 to C22 carboxylic acid. It is therefore preferred that the fatty acid comprises or consists of a C16 to C22 carboxylic acid.
  • suitable C16 to C22 carboxylic acids are palmitic aid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, and behenic acid.
  • the carrier comprises a hydrogenated fat, preferably a hydrogenated vegetable oil.
  • a hydrogenated fat preferably a hydrogenated vegetable oil.
  • the fatty acid is also hydrogenated.
  • the fatty acid comprises of consists of a saturated fatty acid.
  • the fatty acid comprises or consists of an optionally substituted palmitic acid, oleic acid, and/or stearic acid.
  • an emulsifier in the carrier of the solid dispersion according to the present invention leads to an increase in digestibility of the biologically active ingredient. Specifically, it was found that the presence of from more than 0 to 5 wt.-%, preferably from 0.5 to 2 wt.-%, of an emulsifier, optimizes the digestibility of the biologically active ingredient up to 100%.
  • the term emulsifier or emulsifying agent is used synonym to emulgent and denotes a substance that stabilizes an emulsion by increasing its kinetic stability.
  • Emulsifiers are part of a broader group of compounds known as surfactants, or “surface active agents”.
  • Surfactants are compounds that are typically amphiphilic, meaning they have a polar or hydrophilic, i.e., water-soluble, part and a non-polar, i.e., hydrophobic or lipophilic, part.
  • Suitable emulsifiers may be egg yolk, mustard, lecithin, e.g., soy lecithin, sodium phosphates, mono- and diglycerides, a lactate, sodium stearoyl lactylate, diacetyl tartaric esters of mono- and diglycerides, and proteins.
  • the emulsifier is a lecithin, a lactate and/or a citrate.
  • the carrier further comprises from more than 0 to 5 wt.-% of an emulsifier, based on the total weight of the solid dispersion.
  • the carrier further comprises from 0.5 wt.-% to 2 wt.-% of an emulsifier, based on the total weight of the solid dispersion.
  • biologically active ingredient is not subject to any limitations. Rather, this term is used to denote any compound which provides a functional or nutritive benefit to an animal, in particular to a ruminant, e.g., a cattle, sheep, or goat.
  • a biologically active ingredient exhibits low stability and thus has a reduced or even no bio-effectiveness when being exposed to unfavorable conditions, for example, moisture, elevated temperatures, oxygen, and an acidic and/or basic milieu. When being exposed to such conditions, the biologically active ingredient can decompose, dissociate, deactivate and/or lose availability.
  • Preferred biologically active ingredients are i) amino acids, such as lysine, methionine, tryptophan, arginine, histidine, isoleucine, leucine, phenylalanine, valine, and threonine, derivatives of amino acids, such as /V- acylamino acids, e.g., A/-acylmethionine, and A/-guanylamino acids, e.g., A/-guanylglycine, also known as guanidinoacetic acid, and/or salts of amino acids, such as lysine sulfate, lysine hydrochloride, and the salts of lysine with polyunsaturated fatty acids, and/or of their derivatives, such as 2-hydrox-4-(methylthio)butyric acid calcium salt, also known as the calcium salt of methionine hydroxy analogue (calcium MHA), ii) proteins, such as casein, corn proteins, and
  • the biologically active ingredient is selected from the list consisting of i) amino acids, derivatives of amino acids, and/or salts of amino acids and/or of their derivatives, ii) proteins, iii) peptides, iv) carbohydrates, v) vitamins, and derivatives of vitamins, vi) probiotic microorganisms, vii) prebiotic feeds, viii) choline, choline salts, and/or derivatives thereof, ix) polyunsaturated fatty acids (PUFAs), and salts and/or derivatives thereof, and x) pharmaceuticals.
  • PUFAs polyunsaturated fatty acids
  • a further feed ingredient e.g., nutritional ingredients, veterinary, or medicinal agents etc., or other ingredients to the solid dispersion as taught herein.
  • the one or more ingredients to be added can be selected from grain products, plant products, animal products, proteins (e.g., protein ingredients obtained from sources such as dried blood or meat meal, bone meal, cottonseed meal, soybean meal, rapeseed meal, sunflower meal, canola meal, safflower meal, dehydrated alfalfa, corn gluten meal, soybean protein concentrate, potato protein, dried and sterilized animal and poultry manure, fish meal, fish and poultry protein isolates, crab protein concentrate, hydrolyzed protein feather meal, poultry by-product meal, liquid or powdered egg, milk whey egg albumen, casein, fish solubles, cell cream, brewer’s residues, and the like), mineral salts, sugars and complex carbohydrates (e.g., water-soluble and water-insoluble monosaccharides, disaccharides, oligosaccharides, and polysaccharides), veterinary compounds (e.g., promazine hydrochloride, chloromedoniate acetate, chlorotetracycline
  • the solid dispersion according to the present invention should have a particle diameter of not more than 5 mm, in order to avoid getting chewed.
  • the solid dispersion according to the present invention has a particle diameter of from 1 to 5 mm, or from 2 to 4 mm, each with the endpoints being included.
  • the solid dispersion according to the present invention is not limited to any specific process for its preparation, provided that it gives or provides the product in question with the beneficial properties according to the present invention.
  • the solid dispersion according to the present invention is produced by providing a liquefied mixture comprising the components of the product to be prepared, i.e., comprising the biologically active ingredient to be dispersed in the carrier and the components of the matrix, followed by portioning the liquefied mixture, and cooling the thus obtained portions or allowing them to cool down to give the solid dispersion.
  • a further object of the present invention is therefore a process for the production of a solid dispersion according to the present invention, comprising the steps of a) providing a liquefied mixture comprising from 40 wt.-% to 60 wt.-% of a biologically active ingredient, from less than 60 wt.-% to 35 wt.-% of a hydrogenated fat and from more than 0 to 5 wt.-% of cellulose, each based on the total weight of the solid dispersion to be prepared, b) portioning the liquefied mixture provided in step a), and c) cooling the portions obtained in step b) or allowing them to cool down to give the solid dispersion.
  • step a) of said process further comprises the steps of a1) providing a melt of a hydrogenated fat, e.g., a hydrogenated vegetable oil, a2) adding an emulsifier, e.g., from more than 0 to 5 wt.-% of an emulsifier, based on the total weight of the solid dispersion to be prepared, to the melt of step a) to give a first mixture, a3) adding a biologically active ingredient to the first mixture of step a2) to give a second mixture, and a4) adding cellulose powder and/or cellulose fiber to the second mixture of step a3) to give a liquefied mixture.
  • a hydrogenated fat e.g., a hydrogenated vegetable oil
  • an emulsifier e.g., from more than 0 to 5 wt.-% of an emulsifier, based on the total weight of the solid dispersion to be prepared
  • the resulting liquefied mixture can vary in its appearance.
  • the biologically active ingredient is an amino acid, it will not give a solution with the cellulose, and then the resulting mixture will be a melt dispersion.
  • step a) is not subject to any limitations regarding the sequence of the steps a1) to a4). Therefore, the sequence of steps a1) to a4) may vary in any conceivable way from the sequence mentioned above, provided that the thus obtained solid dispersion has the same beneficial properties as the solid dispersion according to the present invention.
  • step a2) may be followed directly by step a4), which then would be followed by step a3).
  • each of the steps a1) to a4) is performed under stirring. It is further preferred that mixing is continued after the completed addition of all components until the thus obtained mixture is clear or at least makes a homogeneous impression.
  • the biologically active ingredient is preferably used in fine-grained form, e.g., having a particle size of not more than 100 pm, in order to provide for the best possible dispersion.
  • the step a) of said process further comprises adding a fatty acid, e.g., from more than 0 to 10 wt.-% of a fatty acid, based on the total weight of the solid dispersion to be prepared, to any of the mixtures, e.g., to the mixture of a1), a2), a3), and/or a4).
  • a fatty acid e.g., from more than 0 to 10 wt.-% of a fatty acid, based on the total weight of the solid dispersion to be prepared, to any of the mixtures, e.g., to the mixture of a1), a2), a3), and/or a4).
  • This step may be performed either as a single step or simultaneously with any of the steps a1) to a4).
  • the said fatty acid is a saturated fatty acid.
  • the step b) of said process is not subject to any limitations regarding the way the portioning is performed, e.g., regarding the type of equipment or device used for portioning, provided that the thus obtained solid dispersion has the same beneficial properties as the solid dispersion according to the present invention.
  • the portioning can be done by pastillation, flaking, granulation, drip casting, prilling, or spraying.
  • the step b) of said process is performed using one or more nozzles, a perforated sheet, a roller with a series or multitude of nozzles, or a rotating disc with a series or multitude of nozzles.
  • premix is used synonymous with nutrient premix and denotes a mixture comprising one or more ingredients such as vitamins, trace minerals, pharmaceuticals, feed supplements and diluents.
  • the use of premixes has the advantage that a farmer who uses his own grain can formulate the diets for the livestock on his own and be assured that the livestock always gets the recommended level of minerals and vitamins.
  • the feed, feed material, feed additive or premix further comprises a vitamin, trace minerals), feed supplement diluent(s), and/or pharmaceuticals, probiotics and/or prebiotics.
  • administering the solid dispersion according to the present invention, and/or the solid dispersion obtained by the process according to the present invention is suitable to compensate amongst others for a lack of nutrients, e.g., essential amino acids, in a ruminant diet.
  • Yet a further object of the present invention is therefore a method of supplementing the diet of a ruminant with a biologically active ingredient, comprising the step of providing the ruminant with the solid dispersion according to the present invention, and/or the solid dispersion obtained by the process according to the present invention.
  • Ethylcellulose 22cp 9% w/w (from Sigma-Aldrich) and 3% w/w sorbitan monostearate (chip 60, from TCI) in a 30:70 w/w mixture of fully hydrogenated soybean oil (from Fauth) with liquid soybean oil were placed in a 100mL three-neck flask and heated up to 140 °C using an oil bath. It was ensured that a full solubilization of the polymer in oil was achieved. After about 30 minutes, all three components have melted. Upon cooling of the melt, at 90 °C, algae oil (from Veramaris) heated to 90 °C was slowly added under a nitrogen blanket at a ratio of 1 :2 (1/3 dilution).
  • the final concentration of the components was 6% ethylcellulose, 2% sorbitan monostearate, 20% fully hydrogenated soybean oil, and 72% algae oil.
  • the result was a brown, clear solution.
  • a sample was taken from the solution with a Pasteur pipette. With the help of the pipette, attempts were made to produce some pastilles. For this purpose, individual drops were carefully placed on the worktop. However, these drops did not harden enough for any type of further processing, such as cutting or chopping into smaller pieces. Rather, the drops hardly solidified, they remained very soft, so that they could be crushed without any effort and without using any power.
  • Example 2 of WO 2010/143066 A1 is not a solid product and in particular not a solid dispersion.
  • the saturated fat (hydrogenated palm oil) was provided in a beaker and pre-heated to 80 °C with a heated magnetic stirrer to cause a melting of the fat. If necessary, the saturated fat was liquefied by heating to 120 °C and it was well mixed with a magnetic stirrer. For products 8 to 10 lecithin was added to the molten or liquefied fat. Subsequently, the fine-grained ( ⁇ 100 pm) biologically active ingredient, i.e. , Lys*HCI, was added in portions and under stirring to the homogeneous melt to give a suspension. Next, cellulose fibers (fiber length of 200 to 300 pm) were added under stirring to the suspension and the thus obtained mixture was further stirred for ca.
  • composition of the thus prepared products 1 to 7 is given in the Table 1 .
  • composition of the thus prepared products 8 to 10 is given in the Table 2.
  • solid dispersions according to the invention comprising a biologically active ingredient were prepared according to the procedure of Example I above, with the exception that a mixture of the saturated fat (hydrogenated palm oil) and the fatty acid (stearic acid) was provided in a beaker.
  • composition of the thus prepared solid dispersions 11 to 13 is given in the Table 3.
  • the products 1 to 7 and 11 to 13 according to the invention and the product C1 not according to the invention were subjected to mechanical strength tests for determining the breaking strength of the products.
  • the breaking strength of the products was determined using a rheometer (Anton Paar, powder rheometer). For this purpose, particles of the products in question were mechanically loaded (only pressure, no shearing force) by means of a disc/disc arrangement, and the resulting breaking force was measured in newton [Nj.
  • the products 1 to 7 according to the invention and the product C1 not according to the invention were subjected to an in vitro test to simulate the ruminal digestion, in particular to simulate the release rates of the biologically active ingredient, i.e., Lys*HCI, in the three different compartments rumen, abomasum and small intestine of the ruminal digestive tract according to the in vitro protocol below.
  • the biologically active ingredient i.e., Lys*HCI
  • the tests were performed in a three-step incubation procedure: in the first step the conditions in the rumen were simulated by use of the McDougall’s buffer, in the second step the conditions in the abomasum were simulated by use of hydrochloric acid and pepsin, and in the third step the conditions of the small intestine were simulated by use of pancreatin and a suitable buffer to adjust a pH of 8.
  • the in vitro tests were performed according to the following procedure:
  • the ruminal release fraction of the biologically active ingredient (BAI) was calculated with the following formula:
  • test substance comprising Lys*HCI were used. This corresponds to an initial amount of 2.5 g of BAI.
  • Ruminal BAI release fraction [%] ((initial amount of BAI [g] - residual amount of BAI after the 1 st step of the McDougall method [g]) I initial amount of BAI [g])) x 100%.
  • RP(BAI) The rumen protected (RP) fraction of the biologically active ingredient
  • total digestible BAI fraction [%] is used to denote the percentage of the initial amount of BAI [g] that is subject to digestion in all steps of the McDougall method. It was calculated with the following formula:
  • Total digestible BAI fraction [%] ((initial amount of BAI [g] - residual amount of BAI after the 3 rd step of the McDougall method [g]) / (initial amount of BAI [g])) x 100%.
  • initial amount of BAI 2.5 g
  • Residual amount of BAI after the 3 rd step 0.25 g
  • the total digestible BAI fraction [g/kg] was calculated with the following formula:
  • Total digestible BAI fraction [g/kg] total digestible BAI fraction [%] x weight fraction of BAI in product [g/kg].
  • the total digestible BAI fraction [g/kg] is the difference of the initial amount of BAI [g/kg] and the residual amount of BAI after the 3 rd step of the McDougall method [g/kg].
  • the RP(BAI) [g/kg] is the residual amount of BAI [g/kg] after the 1 st step of the McDougall method.
  • the ruminally released BAI fraction [g/kg] is the amount of BAI released in the 1 st step of the McDougall method.
  • the products 8 to 10 according to the invention and product C2 not according to the invention were first subject to an abrasion test, followed by the in vitro test.
  • the thus tested products are identified in Table 2 as products after abrasion test.
  • the products 8 to 10 according to the invention and product C2 not according to the invention were first subjected to a 1 -week storage at 40°C and 75% relative humidity, followed by the in vitro test.
  • the thus tested products are identified in Table 2 as products after 1 -week storage.
  • Table 1 Tested products 1 to 7 according to the invention and comparative product C1 , their compositions, and the results of their testing
  • Table 2 Tested products 8 to 10 according to the invention and comparative product C2, their compositions, and the results of their testing
  • Table 3 Tested products 1 1 to 13 according to the invention and comparative product C1 , their compositions, and the results of their testing
  • Table 4 Tested products 1 1 to 13 according to the invention and comparative product C2, their compositions, and the results of their testing

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Abstract

La présente invention concerne une dispersion solide pour l'alimentation d'un ruminant contenant ou constitué de i) 40 % en poids à 60 % en poids d'un ingrédient biologiquement actif, sur la base du poids total de la dispersion solide, ii) 60 % en poids à 40 % en poids d'un excipient, l'excipient contenant un mélange contenant 35 % en poids à moins de 60 % en poids d'une matière grasse hydrogénée et plus de 0 à 5 % en poids de cellulose, chacun sur la base du poids total de la dispersion solide.
PCT/EP2024/067423 2023-06-30 2024-06-21 Produits protégés dans le rumen Ceased WO2025002999A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5068108A (en) * 1989-03-03 1991-11-26 Industria Italiana Integratori Trei S.P.A. Controlled release protective matrices for zootechnical and veterinary use
EP0678246A1 (fr) 1994-04-20 1995-10-25 Ajinomoto Co., Inc. Additif alimentaire pour ruminants
JP2000060440A (ja) * 1998-08-19 2000-02-29 Ajinomoto Co Inc 反芻動物用飼料添加剤組成物の製造法
WO2006032958A2 (fr) 2004-09-24 2006-03-30 Ascor Chimici S.R.L. Composition sous forme de micro-pastilles a liberation controlee de la substance physiologiquement active, procede de preparation et utilisation dans le domaine zootechnique
WO2010143066A1 (fr) 2009-06-12 2010-12-16 Mars, Incorporated Gélification polymère d'huiles
CN102187943A (zh) * 2010-03-11 2011-09-21 河北农业大学 一种蛋氨酸过瘤胃添加剂及其制备方法
WO2014011857A1 (fr) 2012-07-12 2014-01-16 Novus International Inc. Compositions de matrice et de couche pour la protection de composés bioactifs
CN105166414A (zh) * 2015-10-10 2015-12-23 山西农业大学 肉牛过瘤胃泛酸添加剂及其制备方法
US20170143006A1 (en) * 2014-06-24 2017-05-25 Dupont Nutrition Biosciences Aps Composition and Use Thereof
EP3498104A1 (fr) * 2016-08-10 2019-06-19 Ajinomoto Co., Inc. Composition d'additif alimentaire pour ruminants et son procédé de fabrication
CN110692821A (zh) * 2019-10-21 2020-01-17 安徽农业大学 一种改善牛瘤胃发酵效率的饲料添加剂

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5068108A (en) * 1989-03-03 1991-11-26 Industria Italiana Integratori Trei S.P.A. Controlled release protective matrices for zootechnical and veterinary use
EP0678246A1 (fr) 1994-04-20 1995-10-25 Ajinomoto Co., Inc. Additif alimentaire pour ruminants
JP2000060440A (ja) * 1998-08-19 2000-02-29 Ajinomoto Co Inc 反芻動物用飼料添加剤組成物の製造法
WO2006032958A2 (fr) 2004-09-24 2006-03-30 Ascor Chimici S.R.L. Composition sous forme de micro-pastilles a liberation controlee de la substance physiologiquement active, procede de preparation et utilisation dans le domaine zootechnique
WO2010143066A1 (fr) 2009-06-12 2010-12-16 Mars, Incorporated Gélification polymère d'huiles
CN102187943A (zh) * 2010-03-11 2011-09-21 河北农业大学 一种蛋氨酸过瘤胃添加剂及其制备方法
WO2014011857A1 (fr) 2012-07-12 2014-01-16 Novus International Inc. Compositions de matrice et de couche pour la protection de composés bioactifs
US20170143006A1 (en) * 2014-06-24 2017-05-25 Dupont Nutrition Biosciences Aps Composition and Use Thereof
CN105166414A (zh) * 2015-10-10 2015-12-23 山西农业大学 肉牛过瘤胃泛酸添加剂及其制备方法
EP3498104A1 (fr) * 2016-08-10 2019-06-19 Ajinomoto Co., Inc. Composition d'additif alimentaire pour ruminants et son procédé de fabrication
CN110692821A (zh) * 2019-10-21 2020-01-17 安徽农业大学 一种改善牛瘤胃发酵效率的饲料添加剂

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