WO2021099503A1 - Aliment pour animaux et procédés permettant d'améliorer les performances et la productivité d'animaux - Google Patents

Aliment pour animaux et procédés permettant d'améliorer les performances et la productivité d'animaux Download PDF

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Publication number
WO2021099503A1
WO2021099503A1 PCT/EP2020/082751 EP2020082751W WO2021099503A1 WO 2021099503 A1 WO2021099503 A1 WO 2021099503A1 EP 2020082751 W EP2020082751 W EP 2020082751W WO 2021099503 A1 WO2021099503 A1 WO 2021099503A1
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animal
ursolic acid
ester
salt
derivative
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PCT/EP2020/082751
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English (en)
Inventor
Theodorus Antonius Theresia Gerardus VAN KEMPEN
Gavin Maria BOERBOOM
Coenraad Henricus Maria Smits
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Nutreco Ip Assets B.V.
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Publication of WO2021099503A1 publication Critical patent/WO2021099503A1/fr

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    • 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
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • 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
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • the present invention is in the field of animal nutrition, in particular for use in animal husbandry and aquaculture.
  • the invention relates to an animal feed, ingredient, premix or supplement comprising ursolic acid, or a salt, ester or derivative thereof.
  • the invention further relates to a method for increasing body weight gain, average daily gain, feed intake, improving feed conversion ratio, increasing fat digestibility, protein digestibility, dry matter digestibility, increasing metabolizable energy, improving body weight uniformity in a herd of healthy animals, reducing stress and/or reducing weaning dip and/or weaning stress in an animal.
  • One way to produce animal protein more efficiently and sustainably is by improving nutrient utilization and animal performance through feed.
  • a farming animal more particularly a monogastric farming animal, preferably swine or poultry, more preferably a Galliforme, even more preferably a chicken, most preferably a broiler chicken.
  • the present invention relates to use of ursolic acid, or a salt, ester or derivative thereof for increasing body weight gain and/or average daily gain, for improving feed conversion ratio (FOR), for increasing fat digestibility, for increasing protein digestibility, for increasing dry matter digestibility, for increasing daily feed intake, for increasing the apparent metabolizable energy, for reducing stress and/or reducing weaning dip and/or weaning stress in an animal, preferably a farming animal.
  • FOR feed conversion ratio
  • the present invention also relates to use of ursolic acid, or a salt, ester or derivative thereof for improving body weight uniformity in a herd of animals.
  • the farming animal is a monogastric animal, preferably swine, such as growing/finishing pigs, sows, or piglets, or poultry, more preferably a Galliforme, even more preferably a chicken, most preferably a broiler.
  • the ursolic acid, or a salt, ester or derivative thereof is provided in an immediate release form.
  • the present invention relates to an animal feed comprising ursolic acid, or a salt, ester or derivative thereof, preferably 1 - 750 ppm, more preferably 1 - 200 ppm, even more preferably 1 - 50 ppm ursolic acid.
  • the ursolic acid, or a salt, ester or derivative thereof in the animal feed is provided in an immediate release form.
  • the invention provides for an ingredient, premix or supplement for an animal feed suitable for feeding animals comprising ursolic acid, or a salt, ester or derivative thereof, wherein the dosage of said ursolic acid, or a salt, ester or derivative thereof in said ingredient, premix or supplement is 0.5 kg or higher, e.g., 0.5 - 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • the animal feed, ingredient, premix or supplement further comprises one or more emulsifiers, the emulsifiers preferably being chosen from the group consisting of (partially) hydrolysed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid ester, and Polysorbate 80.
  • the ingredient, premix or supplement further comprises vitamins, trace elements, minerals and/or organic acids.
  • the invention provides for a method for increasing body weight gain and/or average daily gain, feed efficiency, fat digestibility, protein digestibility, dry matter digestibility, daily feed intake, apparent metabolizable energy, for reducing stress and/or reducing weaning dip and/or weaning stress in an animal, said method comprising feeding said animal with the animal feed taught herein or with the ingredient, premix or supplement taught herein.
  • the present invention relates to a method for increasing body weight uniformity in a herd of animals, preferably healthy animals, said method comprising feeding said animals with the animal feed taught herein or with the ingredient, premix or supplement taught herein.
  • the animal is a farming animal, preferably a monogastric farming animal, such as swine, e.g., growing/finishing pigs, sows, or piglets, or poultry, more preferably poultry, even more preferably a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • a monogastric farming animal such as swine, e.g., growing/finishing pigs, sows, or piglets, or poultry, more preferably poultry, even more preferably a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • a method of producing an animal feed comprising the step of mixing feed ingredients with ursolic acid, or a salt, ester or derivative thereof, and/or with an ingredient, premix or supplement as taught herein to obtain an animal feed as taught herein.
  • “Ursolic acid” is a pentacyclic triterpenoid identified in the epicuticular waxes of apples as early as 1920 and widely found in the peels of fruits, as well as in herbs and spices like rosemary and thyme. It has the following molecular structure:
  • Ursolic acid may be extracted from rosemary, from which it can be obtained in purity levels of about 90% or more. It can also occur in the form of a salt, ester, or derivative of ursolic acid.
  • ursolic acid is also referred to a salt, ester, or derivative of ursolic acid.
  • the term ‘ursolic acid or an ester or salt thereof refers to any ester form or salt form of ursolic acid.
  • Non-limiting examples of ursolic acid esters are cis- and trans-3-O-p-hydroxycinnamoyl esters of ursolic acid or ursolic acid alkyl esters like methyl ursolate.
  • ursolic acid salts are sodium ursolate or calcium ursolate.
  • feed conversion ratio is a ratio measuring the efficiency with which the bodies of livestock convert animal feed into the desired output, e.g., body weight.
  • the output may be the body mass gained by the animal.
  • FCR is the mass of the input divided by the output (thus kg feed / kg growth or body weight gain).
  • feed efficiency which is the output divided by the input (i.e. the inverse of FCR) may be used to express the efficiency with which the bodies of livestock convert animal feed into growth.
  • animal as used herein includes all non-human animals.
  • the animals may, for example, be selected from farming animals and companion animals.
  • farming animals also known as livestock animals, include poultry (e.g., chickens (such as a newborn chick, a starter chick, a grower chicken, a finisher chicken, a broiler chicken, a laying chicken, ducks, game hens, geese, guinea fowl/hens, quail, and turkeys), swine, beef cattle, milk cows, veal, pigs, goats, sheep, bison, fish, shellfish, and crustaceans (such as decapod crustaceans: crabs, lobsters, shrimp, crawfish, and prawns).
  • poultry e.g., chickens (such as a newborn chick, a starter chick, a grower chicken, a finisher chicken, a broiler chicken, a laying chicken, ducks, game hens, geese,
  • Suitable companion animals include, but are not limited to, cats, dogs, horses, rabbits, rodents (e.g., mice, rats, hamsters, gerbils, and guinea pigs), hedgehogs, and ferrets.
  • the farming animals are young mammals, e.g., piglets or calves, for example piglets or calves to be weaned off milk or milk replacer.
  • the animals may further be selected from monogastric animals and ruminant animals.
  • a monogastric animal has a simple single-chambered stomach, compared with a ruminant organism, like a cow, goat, or sheep, which has a four-chambered complex stomach.
  • Examples of monogastric farming animals include poultry, swine, fish, crustaceans, and the like.
  • poultry refers to domesticated birds kept by humans for their eggs, their meat, their organs, or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, quails, and turkeys). Poultry also includes other birds that are killed for their meat, such as the young of pigeons (known as squabs). Non-limiting examples of poultry include chickens, ducks, geese, turkeys, quails, guinea fowls, squabs, emus, ostriches, partridges, pigeons, pheasants, and the like.
  • broiler or “broiler chicken” as used herein refers to any chicken, such as of the species Gallus gallus domesticus, which is bred and raised specifically for meat production.
  • growing/finishing pigs refers to pigs that are raised for slaughtering purposes. Usually, the term is used for pigs at 25 kilogram bodyweight that are about two or three months old that are no longer reliant on their mother's milk (i.e., they have been weaned) which are then raised until slaughter weight (which typically takes about 3-6 months).
  • piglets is used for new born or young pigs up to 30 kilograms.
  • test animal refers to an animal that received ursolic acid and/or an emulsifier system as taught herein as part of its diet.
  • control animal refers to an animal of the same species that did not receive ursolic acid and/or an emulsifier system as taught herein as part of its diet.
  • both the test animals and control animals were fed the same diet, albeit with the exception of the presence of ursolic acid and/or the emulsifier system, and were kept under similar climatic conditions.
  • diet refers to the sum of feed and beverages or drinks or drinking water consumed by an animal.
  • An emulsifier is a substance that stabilizes an emulsion by increasing its kinetic stability.
  • Emulsifiers are compounds that typically have a polar or hydrophilic (i.e. water- soluble) part and a non-polar (i.e. hydrophobic or lipophilic) part.
  • An HLB value of 0 corresponds to a completely lipophilic/hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic/lipophobic molecule.
  • An emulsifier system is defined as an emulsifier or combination of emulsifiers.
  • an emulsifier system comprises one or more emulsifiers.
  • emulsifiers are (partially) hydrolysed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid esters, and polysorbate 80, and any combination thereof.
  • Lecithins are mixtures of lipids occurring in animal and plant tissues. They are mixtures of glycerophospholipids, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. Lecithins can easily be extracted chemically using solvents such as hexane, ethanol, acetone, petroleum ether, benzene, etc. Lecithins may be hydrolysed. E.g. enzymatically a portion of a phospholipid may have one or more, or all, fatty acids removed. This results in partially, or fully, hydrolysed lecithin.
  • Sorbitan fatty acid esters are also known as Spans. They are esters of sorbitan, which is a mixture of isomeric organic compounds derived from the dehydration of sorbitol, and one or more fatty acids.
  • sorbitan monolaurate diodecanoic acid [2- [(2R,3R,4S)-3,4-dihydroxy-2-tetrahydrofuranyl]-2-hydroxyethyl] ester
  • Sorbitan monolaurate is also known as Span 20.
  • Polysorbates are oily liquids derived from ethoxylated sorbitan esterified with fatty acids.
  • Polysorbate 80 for example is a fatty acid ester derived from polyethoxylated sorbitan and oleic acid. It is also known as polyoxyethylene (20) sorbitan monooleate.
  • the number 20 following the 'polyoxyethylene' part refers to the total number of oxyethylene - (CH2CH20)- groups found in the molecule.
  • the number following the 'polysorbate' part is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule.
  • Monolaurate is indicated by 20
  • monopalmitate is indicated by 40, monostearate by 60, and monooleate by 80.
  • Castor oil is a vegetable oil pressed from castor beans.
  • Ethoxylated castor oil also known as glyceryl polyethylene glycol ricinoleate or glycerol polyethylene glycol ricinoleate is a surfactant compound or an emulsifier admitted in the list of additives for animal nutrition (additive for animal nutrition E484 - EU Reg. 1831/2003).
  • immediate release also known as ‘fast release’, as used herein refers to a form wherein a particular compound or combination of compounds is directly, or in a fast way, physiologically available for the animal after ingestion of the said compound; in contrary to forms like controlled release, slow release or delayed release, where a compound or combination of compounds is released at a later point in time after ingestion of the compound.
  • immediate release composition no measures have been taken to control release of the composition.
  • controlled-, slow- or delayed release can be achieved for example by addition of controlled release agents or a coating or matrix around such a compound, delaying/controlling the availability of the said compound for the animal.
  • Immediate release means immediate or fast availability of the compound, for example by contact with the aqueous environment of the gastro-intestinal tract after ingestion of the compound.
  • in immediate release form is meant that no measures have been taken to control release of the ursolic acid, salt, ester or derivative thereof in the animal body.
  • said ursolic acid, salt or ester thereof may not be surrounded by a coating controlling its release, and is preferably essentially free or free of an enteric coating.
  • the animal feed, ingredient, supplement or premix is essentially free or free of a coating such as an enteric coating, or any other coating or measures controlling its release.
  • Controlled release means that an agent/drug/feed ingredient is liberated in the body in a predetermined rate, or at a predetermined location in the gastrointestinal tract. This may for example be achieved by providing the agent with a coating, which dissolves at a predetermined rate and/or at a predetermined location in the gastrointestinal tract.
  • immediate release indicates that no special measures have been taken to delay release of the agent/drug/feed ingredient once it has been consumed/entered the body. Therefore, it may be assumed that at least 50, 75, 90 or 95 wt% of the agent/drug/feed ingredient is liberated in the stomach.
  • no controlled release coating such as an enteric controlledrelease coating and/or a gastric-soluble controlled release coating has been provided.
  • polyacrylic resin coating agents such as polyacriylic resin No. II and polyacrylic resin No. IV.
  • An immediate release agent/drug/feed ingredient may be mixed as is with other feed ingredients by commonly known methods, e.g. grinding, mixing, etc. to provide the immediate release formulation or animal feed comprising ursolic acid in an immediate release form.
  • An animal feed as taught herein is any substance or combination of substances used for feeding animals. It may be a complete diet.
  • the term “complete feed” as used herein refers to a formulated feed which is balanced in all the essential nutrients needed for normal growth and production of animals. It may be in the form of mash, pellets, crumbles or any other form known to the skilled person.
  • An ingredient for an animal feed is meant to be any substance that is or may be used in producing an animal feed.
  • Premixes are composed of micro ingredients such as vitamins, minerals, chemical preservatives, antibiotics, fermentation products, and other essential ingredients. Premixes are used for blending into bulk feed products or complete feeds. Because of the availability of premixes, for example a farmer who uses his own grain can formulate his own rations and be assured his animals are getting the recommended levels of minerals and vitamins. Premixes also lead to the possibility of optimizing the properties of bulk feed which has sub- optimal properties, e.g. suboptimal nutritional value.
  • supplements can provide further nutrients such as vitamins, minerals, chemical preservatives, antibiotics, fermentation products, and other essential ingredients in order to increase the quantity of their consumption. Supplements are usually fed separately from other feed products.
  • An ingredient, premix or supplement according to the invention may be suitable for feeding animals such as mammals, birds and/or fish and crustaceans.
  • Parts per million, or ppm is a measure for the concentration.
  • a concentration of 1 ppm indicates presence of 1 part of a substance per million parts of a composition. In the context of this application, the parts are expressed in mass. Thus, a concentration of 1 ppm equalsl pg/g or 1 mg/kg, etc.
  • Digestibility refers to the extent to which a feedstuff is absorbed in the animal body as it passes through an animal’s digestive tract.
  • Dry matter digestibility is the portion of the dry matter in a feed that is digested by animals at a specified level of feed intake.
  • Dry matter represents everything contained in a feed sample except water; this includes protein, fiber, fat, minerals, etc. In practice, it is the total weight of feed minus the weight of water in the feed, expressed as a percentage. It is determined by drying the feed sample in an oven until the sample reaches a stable weight.
  • AME apparent metabolizable energy
  • AMEn refers to the available energy content of feedstuffs and diets, and it is calculated as the difference between the gross energy content intake of the feed consumed minus and the gross energy lost contained in the excreta (feces + urine) corrected by nitrogen retention. A correction for nitrogen retained in the body is usually applied to yield a nitrogen-corrected AME (AMEn) value.
  • AMEn as determined using the method described by Hill and Anderson (1958. The Journal of Nutrition, Volume 64, Issue 4, April 1958, Pages 587-603), is the most common measure of available energy used in formulation of poultry feeds.
  • Apparent digestibility of fat (after acid hydrolysis), protein, dry matter and apparent metabolizable energy may be measured according to ISO 9831, ISO 6492, ISO 17764 and IS05983-2, respectively.
  • weaning refers to the process of introducing a young mammal (e.g. a calf or a piglet) to what will be its adult diet and withdrawing the supply of its mother's milk and/or milk replacer.
  • weaning essentially consists of a transition from milk only (e.g. milk replacer or maternal milk) to solid feed only.
  • the transition from milk only to solid feed only may be performed gradually over time, e.g. milk supply may be gradually decreased while solid feed is gradually introduced) or may be performed suddenly (i.e. when milk supply is completely withdrawn and diet consists of solid feed only).
  • weaning stress refers to any stress experienced by a young mammal, particularly a young farming mammal, e.g., a calf or a piglet, during and/or after the weaning period.
  • weaning stress may include emotional stress and physiological stress caused by transitioning a young mammal from milk or liquid diet to solid feed diet.
  • weaning stress may be manifested in the form of e.g. reduced ability to digest and consume solid feed, digestive problems causing pain, intestinal tract problems such as increased gut permeability (e.g. leaky gut), diarrhea or other infections, body weight loss, somatic growth loss (e.g.
  • weaning dip Any of the consequences of weaning stress, e.g. on body weight, somatic growth, health, solid feed intake, etc may also be referred to as “weaning dip”.
  • weaning period refers to the period of time needed to complete the transition from milk only (e.g. milk replacer or maternal milk) to solid feed only. For instance, when the transition from milk to solid feed is performed gradually (e.g. milk supply is gradually decreased and solid feed is gradually introduced), the weaning period will encompass the time spanning from the onset of introducing solid feed, until the moment (time) when weaning is completed, i.e. when milk supply is completely withdrawn and diet consists of solid feed only.
  • an emulsifier system “consisting essentially of” a certain emulsifier or combination of emulsifiers is meant to be any emulsifier system comprising at least 50%, preferably at least 75%, most preferably at least 90% of the named emulsifier, emulsifier system, or combination of emulsifiers. This terminology is included to account for other ingredients which can act as an emulsifier, but are not specifically added for their emulsifying properties.
  • the present inventors have surprisingly found that administering ursolic acid, or a salt, ester or derivative thereof to farming animals increased fat digestibility, dry matter digestibility, and protein digestibility; increased average daily gain, increased body weight gain, increased daily feed intake; improved feed efficiency; and increased the apparent metabolizable energy in the farming animals. Further, it was found that administering ursolic acid influences the gut microbiota, e.g. by increasing levels of butyrate producing bacteria and decreasing levels of enterobacteriaceae, in particular Escherichia coli. Moreover, it was found that administration of ursolic acid to grow finishing pigs reduced cortisol levels, indicating that ursolic acid reduced stress levels in such pigs either on farm or post transportation to a slaughterhouse.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof for increasing body weight or body weight gain and/or average daily gain in an animal, in particular a farming animal.
  • the body weight or body weight gain of a test animal may be increased relative to the body weight or body weight gain of a control animal.
  • the body weight gain of a test animal for example a broiler, may be determined using any standard methodology known to the skilled person.
  • the animals both the control and the test animals
  • the body weight gain may be increased when the body weight gain of the test animals throughout the test period is higher than the body weight gain of the control animals.
  • the test period may be the period from birth or hatch up to the time of slaughter.
  • the test period may be from day 0 (day of birth/hatch) up to about the age of 25, 30, 35, 40, 45, 46, 50, 55, 60, 65, 70, or more days, depending upon the desired time of slaughter.
  • the body weight gain is divided by the number of days of the test period. It will be clear that average daily gain and body weight gain are closely related.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof for decreasing (i.e. improving) feed conversion ratio (FCR), i.e. , improving feed efficiency, in an animal, in particular a farming animal.
  • FCR feed conversion ratio
  • the FCR may be decreased in a test animal relative to the feed conversion ratio observed in a control animal.
  • the FCR may be determined using any standard methodology known to the skilled person. For example, feed intake (in, e.g., grams) may be recorded over a period, e.g., a week, as well as body weight gain (or mass gain) (in, e.g., grams) over the same period, and FCR can be calculated by dividing the total feed intake over that period by the body weight gain over that period.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof for increasing feed efficiency in an animal, in particular a farming animal.
  • the skilled person is capable of converting FCR into feed efficiency.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof to increase fat digestibility in an animal, preferably a farming animal.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof to increase protein digestibility in an animal, preferably a farming animal.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof to increase dry matter digestibility in an animal, preferably a farming animal.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof to increase daily feed intake in an animal, preferably a farming animal.
  • the daily feed intake may be determined by measuring the amount of feed that an animal eats each day.
  • the daily feed intake may be averaged over several days to calculate an average daily feed intake.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof to increase the apparent metabolizable energy (AME) in an animal, preferably a farming animal.
  • the apparent metabolizable energy is the gross energy of the feed consumed minus the gross energy contained in the feces, urine, and gaseous products of digestion.
  • the AME represents the gross energy of the feed minus the gross energy of the excreta. It may be determined by total (TC) or partial (PC) collection excreta methods known in the art.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof for reducing cortisol levels and/or for reducing stress in an animal, in particular a farming animal, e.g., a growing/finishing pig, either on farm or post-transport.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester or derivative thereof for increasing the level of butyrate producing bacteria in the gut of an animal, e.g., a farming animal.
  • the present disclosure provides the use of ursolic acid, or a salt, ester or derivative thereof for reducing the level of enterobacteriaceae and/or for reducing the level of Escherichia coli in the gut of an animal, especially a farming animal.
  • the present disclosure pertains to the use of ursolic acid, or a salt, ester or derivative thereof, for reducing the number of types of antibiotic resistance genes and/or for reducing the diversity of antibiotic resistance in an animal, particularly a farming animal.
  • the present disclosure teaches the use of ursolic acid, or a salt, ester, or derivative thereof, for reducing or preventing a weaning dip and/or weaning stress in a young mammal, preferably a young farming mammal, preferably in a young farming mammal that is being weaned off milk or milk replacer.
  • the present disclosure provides the use of ursolic acid, or a salt, ester, or derivative thereof, for increasing body weight and/or carcass weight uniformity and/or for reducing bodyweight and/or carcass weight variation in a herd of animals, particularly in a herd of healthy animals.
  • the uses taught herein may encompass administration of said ursolic acid, or a salt, ester, or derivative thereof to said animal, e.g. in the form of a feed supplement, or in the form of a topdress or a feed.
  • the farming animal is a monogastric animal, such as a pig, e.g., a growing-finishing pig, sow, or piglet, or poultry.
  • a monogastric animal such as a pig, e.g., a growing-finishing pig, sow, or piglet, or poultry.
  • the animal is poultry, more preferably a Galliforme, even more preferably a chicken, most preferably a broiler.
  • the ursolic acid, or a salt, ester or derivative thereof is provided in an immediate release form.
  • the ursolic acid, or salt, ester, or derivative thereof is not surrounded by an enteric coating.
  • the ursolic acid may be administered to said animals in any way known to the skilled person.
  • the ursolic acid is preferably administered orally.
  • the ursolic acid may be incorporated in starter, grower and/or finisher diets.
  • the composition of such diets is adjusted depending on the need of an animal, depending on its age.
  • Such diets may comprise about 23%, about 20% and about 18% protein, such as respectively between 21 and 25%, between 18 and 22%, and between 16 and 20% protein.
  • the diets may comprise between 1 and 750 ppm ursolic acid, such as between 1 and 200 ppm, preferably between 1 and 50 ppm ursolic acid.
  • the present disclosure also teaches an animal feed comprising ursolic acid, or a salt, ester or derivative thereof, e.g. from 1 - 750 ppm ursolic acid.
  • the animal feed may comprise the ursolic acid, or a salt, ester or derivative thereof, or the animal feed may be obtained by mixing a commercially obtainable animal feed with an ingredient, premix or supplement for an animal feed suitable for feeding animals, comprising ursolic acid, or a salt, ester or derivative thereof.
  • said ursolic acid, or a salt, ester or derivative thereof is provided in an immediate release form.
  • the ursolic acid, or salt, ester, or derivative thereof is not surrounded by an enteric coating.
  • the animal feed may be in the form of mash, pellets, crumbles or any other form known to the skilled person.
  • the animal feed, ingredient, premix or supplement taught herein is in an immediate release form, i.e. , no measures have been taken to achieve controlled release.
  • the present disclosure teaches an animal feed comprising 1 - 500, such as 5 -200 ppm, or 10 - 50 ppm ursolic acid, or a salt, ester or derivative thereof.
  • the animal feed taught herein may be in the form of mash, pellets, crumbles or any other form known to the skilled person.
  • the ursolic acid, or a salt, ester or derivative thereof may be incorporated into the drinking water.
  • inclusion rates of ursolic acid incorporated in drinking water may be 40-50% of the inclusion rates of ursolic acid, or a salt, ester or derivative thereof in feed.
  • the amount of ursolic acid, or a salt, ester or derivative thereof incorporated in drinking water may be, for example, in the range of between 0.4 and 375 ppm, such as between 0.4 and 100 ppm, or between 0.4 and 25 ppm.
  • the ursolic acid, or a salt, ester or derivative thereof is provided in an immediate release form.
  • the invention provides for an ingredient, premix or supplement, comprising ursolic acid, or a salt, ester or derivative thereof, wherein the dosage of said ursolic acid, or a salt, ester or derivative thereof in said ingredient, premix or supplement is 0.5g/kg or higher, preferably 0.5 - 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • the ingredient, premix or supplement comprises one or more emulsifiers
  • the emulsifiers preferably begin chosen from the group consisting of (partially) hydrolysed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid esters, and Polysorbate 80.
  • the ingredient, premix or supplement further comprises vitamins, trace elements, minerals and/or organic acids.
  • the invention provides for a method for increasing body weight gain, average daily gain, daily intake, feed efficiency, fat digestibility, protein digestibility, dry matter digestibility, apparent metabolizable energy, reducing cortisol levels and/or reducing stress, increasing the level of butyrate producing bacteria in the gut of an animal, reducing the level enterobacteriaceae, e.g., Escherichia coli, reducing the number of types of antibiotic resistance genes and/or for reducing the diversity of antibiotic resistance, and/or reducing or preventing a weaning dip and/or weaning stress in an animal, said method comprising feeding said animal with the ingredient, premix or supplement, or with the animal feed taught herein.
  • the invention also provides for a method for increasing body weight and/or carcass weight uniformity and/or for reducing bodyweight and/or carcass weight variation in a herd of animals, particularly in a herd of healthy animals, said method comprising feeding said herd of animals with the ingredient, premix or supplement taught herein, or with the animal feed taught herein.
  • the animal is a farming animal, such as a pig or poultry, preferably a monogastric animal, more preferably poultry or swine, even more preferably a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • a farming animal such as a pig or poultry, preferably a monogastric animal, more preferably poultry or swine, even more preferably a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • broilers further increased fat digestibility, dry matter digestibility, and protein digestibility; increased average daily gain, increased body weight gain, increased daily feed intake; improved feed efficiency; and increased the apparent metabolizable energy in the broilers.
  • an animal feed for example a complete feed, comprising ursolic acid, or a salt, ester or derivative thereof, and an emulsifier system having an HLB value in the range of about 6 to about 12.
  • An emulsifier system aids in the digestion of feed by dispersion of bulk fat, proteins, and other feed components into fine emulsion particles, thereby facilitating digestion the feed and increasing the absorption of nutrients.
  • the emulsifier system thereby enhances the positive effects of ursolic acid for increasing body weight gain and/or average daily gain, FCR, fat digestibility, protein digestibility, dry matter digestibility, and apparent metabolizable energy.
  • Emulsifier systems are known in the art.
  • An emulsifier system with an HLB value in the range of about 6 to about 12 is suitable for creating oil-in-water emulsions, which is therefore the required range for dispersion of fatty feed ingredients.
  • the ursolic acid, or a salt, ester or derivative thereof is comprised in the animal feed in an amount of 1 - 1000 ppm, more preferably preferably 2 - 750 ppm, even more preferably 5 - 500 ppm, such as 10 - 300 ppm ursolic acid, or a salt, ester or derivative thereof.
  • the emulsifier system is comprised in the animal feed in an amount in a range of 1 - 5000 ppm, preferably 1 - 2500 ppm, more preferably 23 - 1500 ppm, yet more preferably 40 - 1250 ppm, even more preferably 50 - 1000 ppm, most preferably in the range of 70 - 800, 100 - 500, or 150 - 350, ppm based on the total weight of the feed.
  • the emulsifier system has an HLB value in the range of about 7 to about 11.
  • Such emulsifier systems are particularly suitable for creating oil-in-water emulsions upon digestion of animal feed.
  • the emulsifier system has an HLB value in the range of about 8 to about 10, as such emulsifier systems are most suitable for creating oil-in-water emulsions upon digestion of animal feed, and thereby are most suitable for facilitating the uptake of nutrients.
  • the emulsifier system comprises one or more emulsifiers selected from the group consisting of (partially) hydrolyzed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid esters and Polysorbate 80. All beforementioned emulsifiers are, or shortly will be, allowed for use in animal feed.
  • the emulsifier system consists of (partially) hydrolyzed lecithins and ethoxylated castor oil (E484).
  • E484 ethoxylated castor oil
  • the combination of (partially) hydrolysed lecithins, E484 and ursolic acid leads to improved results as compared to the control group, and groups which have only been administered either ursolic acid or the emulsifier system consisting of lecithine and E484.
  • there is a synergistic effect there is a synergistic effect.
  • the (partially) hydrolyzed lecithins and ethoxylated castor oil are present in a ratio of about 1 :4 to about 4: 1 , preferably about 1 :3 to about 3: 1 , even more preferably about 1:2 to 2:1.
  • the emulsifier system consists of ethoxylated castor oil and sorbitan monolaurate (span 20).
  • the ethoxylated castor and sorbitan monolaurate are present in a ratio of about 1:4 to about 4:1, preferably about 1:3 to about 3:1, even more preferably about 1:2 to 2:1.
  • the emulsifier system consists of sorbitan monolaurate (span 20).
  • the emulsifier system consists of (partially) hydrolyzed lecithins and sorbitan monolaurate (span 20).
  • the (partially) hydrolyzed lecithins and sorbitan monolaurate are present in a ratio of about 1:4 to about 4: 1 , preferably about 1 :3 to about 3: 1 , even more preferably about 1 :2 to 2: 1.
  • the invention further provides for an ingredient, premix or supplement for an animal feed suitable for feeding mammals, birds and/or fish, comprising ursolic acid, or a salt, ester or derivative thereof and an emulsifier system, said emulsifier system having a HLB value in the range of about 6 to about 12, wherein the dosage of said ursolic acid, or a salt, ester or derivative thereof in said ingredient, premix or supplement is 0.5 g/kg or higher, preferably between 0.5 g/kg and 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • the dosage of the emulsifier system in the ingredient, premix or supplement is in the range of about 0.5 to about 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • the ingredient, premix or supplement further comprises vitamins, trace elements, minerals and/or organic acids.
  • no measures have been taken to control release of the ursolic acid, salt or ester thereof in the animal body.
  • said animal feed, ingredient, supplement or premix is essentially free or free from a coating such as an enteric coating, or any other coating or measures controlling its release.
  • the invention also provides for a method for increasing the average daily gain, feed efficiency, daily feed intake, fat digestibility, protein digestibility, dry matter digestibility and/or apparent metabolizable energy in an animal, said method comprising feeding said animal, e.g., a mammal, bird or fish, with the animal feed taught herein or with the ingredient, premix or supplement taught herein.
  • ursolic acid or a salt, ester or derivative thereof for increasing body weight gain and/or average daily gain in an animal, preferably a farming animal.
  • ursolic acid, or a salt, ester or derivative thereof for improving feed conversion ratio (FCR) in an animal, preferably a farming animal.
  • FCR feed conversion ratio
  • ursolic acid or a salt, ester or derivative thereof for increasing protein digestibility in an animal, preferably a farming animal.
  • ursolic acid or a salt, ester or derivative thereof for increasing dry matter digestibility in an animal, preferably a farming animal.
  • ursolic acid or a salt, ester or derivative thereof for increasing daily feed intake in an animal, preferably a farming animal.
  • ursolic acid or a salt, ester or derivative thereof for increasing the apparent metabolizable energy in an animal, preferably a farming animal.
  • the farming animal is a monogastric animal, preferably poultry or swine, more preferably poultry such as a Galliforme, even more preferably a chicken, most preferably a broiler.
  • Animal feed comprising 1 - 750 ppm ursolic acid, or a salt, ester or derivative thereof, preferably 1 - 200 ppm, more preferably 1 - 50 ppm ursolic acid, or a salt, ester or derivative thereof.
  • Ingredient, premix or supplement for an animal feed comprising ursolic acid, or a salt, ester or derivative thereof, wherein the dosage of said ursolic acid, or a salt, ester or derivative thereof in said ingredient, premix or supplement is 0.5 g/kg or higher, preferably 0.5 - 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • emulsifiers preferably being chosen from the group consisting of (partially) hydrolysed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid esters, and Polysorbate 80.
  • Method of producing an animal feed comprising the step of mixing feed ingredients with ursolic acid, or a salt, ester or derivative thereof, and/or with an ingredient, premix or supplement according to any of embodiments 12-14 to obtain an animal feed according to any one of embodiments 10 or 11.
  • Method for increasing body weight gain and/or average daily gain, feed efficiency, daily intake, fat digestibility, protein digestibility, dry matter digestibility and/or apparent metabolizable energy in an animal comprising feeding said animal with the animal feed as defined in any of embodiments 10 - 11 or with the ingredient, premix or supplement according to any one of embodiments 12 to 14.
  • Method according to embodiments 16 wherein the animal is a farming animal, preferably a monogastric animal, more preferably swine or poultry, even more preferably poultry, such as a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • Animal feed comprising:
  • an emulsifier system said emulsifier system having a HLB value in the range of about 6 to about 12.
  • emulsifier system comprises one or more emulsifiers selected from the group consisting of (partially) hydrolyzed lecithins, ethoxylated castor oil (E484), sorbitan fatty acid esters, and Polysorbate 80.
  • Ingredient, premix or supplement for an animal feed comprising ursolic acid, or a salt, ester or derivative thereof and an emulsifier system, said emulsifier system having a HLB value in the range of about 6 to about 12, wherein the dosage of said ursolic acid, or a salt, ester or derivative thereof in said ingredient, premix or supplement is 0.5 g/kg or higher, preferably between 0.5 g/kg and 2.5 g/kg, based on the total weight of said ingredient, premix or supplement.
  • Ingredient, premix or supplement according to embodiment 31 which further comprises vitamins, trace elements, minerals and/or organic acids.
  • Method for increasing the average daily gain, feed efficiency, daily feed intake, fat digestibility, protein digestibility, dry matter digestibility and/or apparent metabolizable energy in an animal comprising feeding a mammal, bird or fish with the animal feed as defined in any of embodiments 18-30 or with the ingredient, premix or supplement according to any one of embodiments 31 or 32.
  • Method according to embodiment 33 wherein the animal is a farming animal, preferably a monogastric animal, more preferably poultry or swine, even more preferably a Galliforme, yet more preferably a chicken, most preferably a broiler.
  • Method of feeding a broiler comprising administering to said broiler ursolic acid or a salt, ester or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of feeding a piglet comprising administering to said piglet ursolic acid or a salt, ester or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of reducing or preventing a weaning dip and/or weaning stress in a young mammal comprising the step of feeding said young mammal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of reducing cortisol and/or stress levels in a farming animal comprising the step of feeding said young mammal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of increasing the level of butyrate producing bacteria in the gut of a farming animal comprising the step of feeding said young mammal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of reducing the level of enterobacteriaceae, in particular Escherichia coli (E. coli), in the gut of a farming animal comprising the step of feeding said farming animal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Escherichia coli Escherichia coli
  • Method of reducing the number of types of antibiotic resistance genes and/or for reducing the diversity of antibiotic resistance in an animal comprising the step of feeding said farming animal with ursolic acid or a salt, ester, or derivative thereof, or an animal feed as taught herein.
  • Method of increasing uniformity in weight in a herd of healthy animals comprising the step of feeding said farming animal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Method of decreasing weight variation in a herd of healthy animals comprising the step of feeding said farming animal with ursolic acid or a salt, ester, or derivative thereof, or a feed containing the same, e.g., a composition as taught herein.
  • Example 1 Effect of ursolic acid (40 ppm) +/- emulsifier on performance parameters
  • Broilers used in this study were 552 one-day-old ROSS 308 males (Ross 308, Aviagen, Huntsville, AL, USA) sourced from a commercial hatchery (SADA, Cazalegas, Toledo,
  • the basal diet between the treatments was similar, but the following additions were included: 1) control, no additions; 2) ursolic acid at 40 ppm; 3) 250 ppm (lyso)lecithine + 250 ppm E484 + 40 ppm ursolic acid; and 4) 250 ppm (lyso)lecithine + 250 ppm E484.
  • the pen was considered the experimental unit and the treatments were randomly assigned to each pen. Performance parameters such as body weight (BW), daily feed intake (DFI), average daily gain (ADG) and feed conversion rate (FCR), were determined at day 7 and 25. Table 1 summarizes the results of the study.
  • Example 1 The experiment of Example 1 was repeated except that treatments 2 and 3 contained 20 ppm ursolic acid rather than 40 ppm ursolic acid. Additionally, diets contained titanium dioxide as a marker for measuring apparent metabolizable energy (AMEn), protein digestibility, dry matter digestibility and fat digestibility.
  • AMEn apparent metabolizable energy
  • Faeces samples were collected during days 15-17. This was done by placing trays below the cages. Feaces and feed samples were analyzed for nutrient content and titanium dioxide level in order to calculate apparent digestibility of fat (after acid hydrolysis), protein, dry matter and apparent metabolizable energy according to ISO 9831, ISO 6492, ISO 17764 and IS05983-2, respectively. The apparent total tract digestibility of dry matter, protein, and fat was calculated according to eq. [1]:
  • fat digestibility increased by 3.1%
  • protein digestibility by 0.6%
  • dry matter digestibility by 2.4%
  • AMEn increased with 68 kcal/kg of dry matter.
  • Broilers used in this study were 2420 one-day-old ROSS 708 males. Upon arrival at the farm, birds were randomly distributed, assigning 55 birds in each pen with 44 pens in total. Birds were fed a commercial corn-soy based diet. From day 1 to 35 the birds received experimental diets. The basal diet between the treatments was similar, but the following additions were included: 1) control, no additions; 2) 500 ppm Span20 + 40 ppm ursolic acid; 3) 250 ppm (lyso)lecithine + 250 ppm E484 + 40 ppm ursolic acid; and 4) 250 ppm (lyso)lecithine + 250 ppm E484.
  • the pen was considered the experimental unit and the treatments were randomly assigned to each pen. Performance parameters such as body weight, feed intake, daily weight gain and feed conversion rate (FCR), were determined at day 0 and 35. Table 3 summarizes the results of the study. Table 3. Performance indicators of the various treatments.
  • control diet basic diet, no ursolic acid
  • diet containing ursolic acid basal diet + 20 or 40 ppm ursolic acid
  • microbiota of animals receiving a diet containing ursolic acid had increased levels of butyrate producing microbes and decreased levels of E. coli compared to animals receiving control diet, indicating an improved content of beneficial microbes.
  • fewer types of antibiotic resistance genes were present in animals receiving diet containing ursolic acid compared to animals receiving control diet, indicating that fewer antibiotic species/genus were present in the gut microbiota.
  • feeding ursolic acid may aid in reducing diversity of antibiotic resistance in animals.
  • Example 5 Effect of ursolic acid on FCR and carcass composition in growing/finishing pigs
  • 384 pigs were selected.
  • the 384 pigs were divided over 48 pens based on their bodyweight, with pigs of similar bodyweight in the same pen.
  • the weights of the pigs were divided into three groups: heavy, medium or light. Pigs of different sex were equally divided over treatments. Pens were grouped by initial bodyweight. Pigs were offered a common commercial-type grower finisher diet with high amino acid levels to avoid limitations on growth due to amino acid requirements (‘basal diet’).
  • the treatments were arranged in a dose response fashion, with a control diet (no ursolic acid) and addition of 20, 40, and 80 ppm of ursolic acid to the basal diet.
  • Cortisol levels in saliva were measured at the start of the trial, pre-transport, and post-transport to the slaughterhouse. It was found that cortisol levels for pre- and post-transport were much lower for the animals having received diets containing ursolic acid compared to those for animals having received the control diet. Thus, it seems that ursolic acid is capable of lowering stress in animals.
  • Example 6 Effect of ursolic acid on weaning in piglets
  • Piglets were weighed a day before weaning and ranked according to body weight and separated by gender. The animals were grouped per 15 animals with each group being comparable in body weight and gender distribution. The 15 animals per group were randomly allocated over three treatments:
  • the increase in body weight in the first 7 days of weaning was 500g (i.e. , +8%) for piglets receiving ursolic acid at 40 ppm in comparison to the control. Even at final bodyweight (day 41) the difference between these two treatments was high, being 1.1 kg (i.e., +5%).
  • Average daily gain during the first 21 days of weaning in piglets receiving ursolic acid at 40 ppm increased by almost 40g a day compared to the control treatment. Over the entire period the increase in average daily gain for piglets receiving ursolic acid at 40 ppm was around 30 grams a day.

Abstract

La présente invention porte sur le domaine de la nutrition animale, en particulier pour une utilisation dans l'élevage et l'aquaculture. L'invention concerne un aliment, un ingrédient, un prémélange ou un complément pour animaux comprenant de l'acide ursolique, ou un sel, un ester ou un dérivé correspondant, et éventuellement un système émulsifiant. Des animaux nourris avec l'aliment, l'ingrédient, le prémélange ou le complément présentent un accroissement du poids corporel, de la prise de poids quotidienne moyenne et de la prise d'aliment, une amélioration de la vitesse de conversion des aliments, une augmentation de la digestibilité des graisses, une augmentation de la digestibilité des protéines, une augmentation de la digestibilité de la matière sèche, une augmentation de l'énergie métabolisable, une réduction des taux de cortisol, une réduction du stress, une réduction des entérobactériacées, par exemple Escherichia coli, dans l'intestin, une augmentation de microbes produisant du butyrate dans l'intestin, une réduction du trempage post-sevrage et/ou une augmentation de l'uniformité du poids corporel.
PCT/EP2020/082751 2019-11-19 2020-11-19 Aliment pour animaux et procédés permettant d'améliorer les performances et la productivité d'animaux WO2021099503A1 (fr)

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