WO2020245303A1 - Bolus intraruminal et son procédé de préparation - Google Patents

Bolus intraruminal et son procédé de préparation Download PDF

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Publication number
WO2020245303A1
WO2020245303A1 PCT/EP2020/065538 EP2020065538W WO2020245303A1 WO 2020245303 A1 WO2020245303 A1 WO 2020245303A1 EP 2020065538 W EP2020065538 W EP 2020065538W WO 2020245303 A1 WO2020245303 A1 WO 2020245303A1
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WIPO (PCT)
Prior art keywords
intraruminal
intraruminal bolus
bolus
wax
amino acid
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PCT/EP2020/065538
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English (en)
Inventor
Philip Thomas JOBSON
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Nutripharm Limited
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Publication date
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Publication of WO2020245303A1 publication Critical patent/WO2020245303A1/fr

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Classifications

    • 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
    • A23K20/142—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
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • 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
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/30—Oligoelements
    • 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

Definitions

  • the present invention relates to an intraruminal bolus and a method of making the intraruminal bolus.
  • the invention relates to an intraruminal bolus for delivering a mineral nutrient to a ruminant animal.
  • An intraruminal bolus is a capsule or tablet that is administered by placement thereof in the rumen of a ruminant animal, where it is retained and gradually releases its contents over an extended period of time.
  • the contents can include, for example, mineral nutrients, therapeutic agents and/or bioactive substances.
  • the use of an intraruminal bolus avoids the need to provide a ruminant animal with frequent doses of a nutrient, agent or substance, and can reduce the likelihood of excessive or insufficient consumption of the nutrient, agent or substance by the animal. Examples of ruminant animals are cattle, sheep and goats.
  • US 2013/0344167 A1 discloses an intraruminal bolus comprising mineral chelates that releases its contents over a period of 1 hour to 30 days only, and also a bolus comprising mineral chelates that releases its contents over a period of 31 days to 90 days only.
  • intraruminal boluses comprise synthetic chelating agents, such as EDTA
  • the present inventors have found that delivery of a mineral nutrient to a ruminant animal can be achieved by providing an intraruminal bolus which has a mineral nutrient in the form of an amino acid chelate, thereby avoiding the use of a synthetic industrial chelating agent such as EDTA.
  • the present invention seeks to address the drawbacks discussed above.
  • the present invention proposes that the incorporation of an amino acid chelate in an intraruminal bolus leads to improved biocompatibility and reduced harmful ecological effects, compared with the use of a synthetic industrial chelating agent.
  • intraruminal boluses The production of previously known intraruminal boluses has generally involved heating to high temperatures, at which an amino acid would be expected to denature, in order to melt the matrix in which the mineral is dispersed. Surprisingly, the inventors have discovered through experimentation that the present intraruminal bolus comprising an amino acid chelate can be manufactured without denaturation of the amino acid component.
  • the present disclosure provides an intraruminal bolus comprising a mineral nutrient dispersed in an erodible matrix, the erodible matrix being erodible in the rumen of a ruminant animal to release the mineral nutrient; wherein the mineral nutrient is in the form of an amino acid chelate.
  • the amino acid chelate may be a glycinate, a lysinate, a methionine, a selenomethionine, a cysteine or a selenocysteine, or a derivative thereof.
  • the amino acid chelate is preferably a glycinate or a methionine, or a derivative thereof.
  • the amino acid chelate preferably comprises a metal, wherein the metal is optionally selected from selenium, copper, cobalt, zinc, iron, magnesium and manganese.
  • the intraruminal bolus accordingly comprises an amino acid chelate that is thermally stable at the melting point of the erodible matrix.
  • the intraruminal bolus disclosed herein may comprise a densifier dispersed in the erodible matrix.
  • the densifier may be barium sulfate.
  • the density of the intraruminal bolus may be in a range of 2.5 g/cm 3 to 3.0 g/cm 3 or 2.4 g/cm 3 to 3.0 g/cm 3 or be approximately 2.8 g/cm 3 .
  • the erodible matrix of the boluses described herein may comprise a wax or a mixture of waxes.
  • the bolus may comprise carnauba wax or glycerol monostearate, or a combination of both.
  • the erodible matrix is comprised in a shell.
  • the shell may be made of plastic, such as a heat shrink plastic.
  • the intraruminal bolus according to the present disclosure may comprise one or more inorganic components selected from copper sulfate, copper oxide, cobalt acetate, cobalt sulfate, cobalt carbonate, selenomethionine, selenocysteine, sodium selenite, sodium selenate, calcium iodate, calcium propionate, potassium iodide, sodium iodide, iron carbonate, iron sulfate, magnesium oxide, magnesium sulfate, manganese carbonate, manganese oxide, manganese sulfate, and zinc oxide.
  • the inorganic components may independently comprise cobalt, zinc, selenium, iodine and, optionally, copper.
  • the inorganic component may be in addition to one or more metal chelates.
  • the intraruminal bolus disclosed herein may comprise selenomethionine.
  • the intraruminal bolus disclosed herein is formulated such that in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 100 days, at least 1 10 days or at least 120 days.
  • the mineral nutrient may be released over a period of at least 6 months, at least 7 months or at least 8 months. In some cases, the mineral nutrient is released at an increasing release rate, when the intraruminal bolus is in the rumen of a ruminant animal.
  • Also disclosed herein are methods of delivering a mineral nutrient to a ruminant animal comprising administering the intraruminal bolus disclosed herein, as well as intraruminal boluses for use in such methods.
  • the disclosure provides a method of making an intraruminal bolus, the method comprising the steps of:
  • the method may further comprise the step of:
  • step (A) pressure is applied.
  • step (B) the composition is simultaneously agitated, such that segregation of the mineral nutrient and the wax or mixture of waxes is inhibited.
  • the invention relates to an intraruminal bolus.
  • An intraruminal bolus is a pharmaceutical preparation that may be administered into the rumen of an animal.
  • the bolus provides for a controlled release of one or more active agents, following a single dosage.
  • a ruminant animal is any even-toed ungulate mammal that chews the cud regurgitated from its rumen.
  • the ruminant animal is a cow, a sheep or a goat. More preferably the ruminant animal is a cow or a sheep.
  • the ruminant animal may be of any breed.
  • the ruminant animal may be of any age and any sex. For example, where the ruminant animal is a sheep, the sheep may be a lamb, a ewe, a ram or a wether.
  • the specifications of the intraruminal bolus may be varied according to the ruminant animal, and may be further varied according to the breed, sex, age and/or condition of the ruminant animal.
  • the present invention provides an intraruminal bolus comprising a mineral nutrient dispersed in an erodible matrix, the erodible matrix being erodible in the rumen of a ruminant animal to release the mineral nutrient; wherein the mineral nutrient is in the form of an amino acid chelate.
  • amino acids as organic chelating agents, can deliver nutrients in a highly bioavailable form originating from an intraruminal bolus.
  • Amino acid chelates are better assimilated into tissue, blood and milk, for example, and also do not persist to pollute the environment, compared with synthetic chelates.
  • amino acid chelates additionally retain the beneficial properties associated with synthetic chelates, including protecting the mineral from degradation in the rumen before absorption takes place, decreasing the concentration of minerals required in animal feed, and reducing the amount of minerals excreted.
  • the mineral nutrient when the intraruminal bolus of the present invention is in the rumen of a ruminant animal, the mineral nutrient is released over an extended period of time. Accordingly, the mineral nutrient is released over a period of at least 91 days or at least 100 days.
  • the amino acid chelate is a glycinate, a lysinate, a methionine, a
  • amino acid species of the amino acid chelate may be in a neutral or ionic form.
  • the chelating agent may be in a zwitterionic, anionic or cationic form.
  • a particular ionic form may correspond to the loss or addition of a hydrogen ion (H + ).
  • “glycinate” includes“glycine” in any neutral or ionic form.
  • the amino acid chelate is a glycinate, a lysinate, a methionine, a
  • the amino acid chelate is a glycinate, a lysinate, a methionine or a cysteine. In even more preferred embodiments, the amino acid chelate is a glycinate or a methionine. In most preferred embodiments, the amino acid chelate is a glycinate.
  • the amino acid chelate is a lysinate, a methionine or a cysteine.
  • the amino acid chelate is a lysinate or a methionine. More preferably the amino acid chelate is a lysinate.
  • the amino acid chelate is a glycinate, a lysinate, a methionine, a cysteine, or a derivative thereof. In more preferred embodiments, the amino acid chelate is a glycinate or a methionine, or a derivative thereof. In most preferred embodiments, the amino acid chelate is a glycinate or a derivative thereof.
  • the amino acid chelate is a lysinate, a methionine, a cysteine, or a derivative thereof.
  • the amino acid chelate is a lysinate or a methionine, or a derivative thereof. More preferably the amino acid chelate is a lysinate or a derivative thereof.
  • Amino acid moieties such as glycinate and methionine can be incorporated in proteins in the body of the ruminant animal, and have beneficial effects on the health and growth of the ruminant animal.
  • methionine is an essential amino acid which can also act as a precursor to useful compounds such as cysteine and taurine in the body.
  • the amino acid chelate comprises a metal.
  • the amino acid chelate thus involves the formation or presence of two or more separate co-ordinate bonds between the polydentate amino acid ligand and the single central metal.
  • the metal is selected from copper, cobalt, zinc, iron, magnesium and manganese.
  • the metal is selected from copper, cobalt and zinc. These metals are essential trace elements for many ruminant animals. More preferably the metal is selected from copper and zinc.
  • the bolus will contain more than one metal, such as two, three, four, five, six, seven or eight different metals.
  • the bolus will contain more than one metal chelate, such as two, three, four, five, six, seven or eight different metal chelates. Where the bolus contains a plurality of chelates, these may comprise the same amino acid moiety, or may comprise different amino acid moieties.
  • the metal is selected from cobalt, zinc, iron, magnesium and manganese.
  • the metal is selected from cobalt and zinc. More preferably the metal is zinc.
  • a copper-free intraruminal bolus is suitable for certain ruminant animals which cannot tolerate copper, such as some continental breeds of sheep. Thus, in some embodiments, the intraruminal bolus does not comprise copper.
  • the bolus contains a metal chelate and a metal in a non-chelated form, such as an oxide or carbonate. In some cases, the bolus contains both chelate and non-chelate forms of a metal, such as comprising both copper glycinate and copper oxide.
  • the amino acid chelate is thermally stable at the melting point of the erodible matrix.
  • the amino acid chelate does not denature or decompose at the melting point of the erodible matrix. This property is advantageous as it enables the intraruminal bolus to be
  • the amino acid chelate is copper glycinate or zinc glycinate. More preferably the intraruminal bolus comprises copper glycinate and zinc glycinate. Copper glycinate is preferably copper(ll) glycinate.
  • the amino acid chelate is refined, for example by being made through a dry solid-state process in which the oxygen is essentially entirely removed from a water-insoluble oxide starting material.
  • the amino acid chelate may be of the brand MAXCHELAT (Registered Trade Mark), produced by Provita Supplements.
  • the intraruminal bolus has an amino acid chelate content by mass of at least 1 .5%. More preferably the intraruminal bolus has an amino acid chelate content by mass of at least 2.0%. Most preferably the intraruminal bolus has an amino acid chelate content by mass of at least 2.5%.
  • the amino acid chelate content by mass is defined as the percentage of the total mass of the intraruminal bolus that is the mass of the amino acid chelate.
  • the total mass of the intraruminal bolus excludes the mass of a shell, if present, as described herein.
  • the intraruminal bolus further comprises a densifier dispersed in the erodible matrix.
  • a densifier increases the density of the intraruminal bolus. This is advantageous in order to ensure that the intraruminal bolus remains in the reticulum rumen cavity of a ruminant animal when in use.
  • the densifier is a component having a high density.
  • the densifier may be used as ballast.
  • the densifier has a density of at least 3.5 g/cm 3 . More preferably the densifier has a density of at least 4.0 g/cm 3 . Most preferably the densifier has a density of at least 4.5 g/cm 3 .
  • the densifier is barium sulfate or zinc oxide or a mixture thereof. In more preferred embodiments, the densifier is barium sulfate.
  • the density of the intraruminal bolus is at least 2.4 g/cm 3 . More preferably, the density of the intraruminal bolus is at least 2.5 g/cm 3 . Even more preferably, the density of the intraruminal bolus is at least 2.7 g/cm 3 . Most preferably, the density of the intraruminal bolus is at least 2.8 g/cm 3 .
  • the density of the intraruminal bolus is in a range of 2.4 g/cm 3 to 3.0 g/cm 3 . In more preferred embodiments, the density of the intraruminal bolus is in a range of 2.5 g/cm 3 to 3.0 g/cm 3 . In even more preferred embodiments, the density of the intraruminal bolus is approximately 2.8 g/cm 3 .
  • problems are encountered involving regurgitation of the intraruminal bolus by the ruminant animal. If the density of the intraruminal bolus is not sufficiently high, a densifier can be added in order to raise the density.
  • the erodible matrix erodes when in the rumen of a ruminant animal.
  • placement of the intraruminal bolus in the rumen of a ruminant animal causes erosion of the erodible matrix to commence.
  • the intraruminal bolus does not erode in normal storage conditions, such that the intraruminal bolus preferably has a shelf life of at least 1 year when stored between -10 °C and +25 °C. More preferably the intraruminal bolus has a shelf life of at least 2 years when stored between -10 °C and +25 °C. Most preferably the intraruminal bolus has a shelf life of at least 4 years when stored between -10 °C and +25 °C.
  • the erosion is effected by the conditions in the rumen, which are typically acidic and at an elevated temperature.
  • the rumen also comprises an aqueous variety of fermentation by-products, microflora and partially digested or undigested fibrous material.
  • the erosion of the erodible matrix results in gradual controlled release of the mineral nutrient.
  • the erodible matrix erodes, it gradually breaks down, resulting in the exposure and/or discharge of the mineral nutrient and, if present, any other constituent components. As the erodible matrix erodes, it becomes smaller in size until it is depleted.
  • the erodible matrix erodes in a process involving hydration of the surface of the erodible matrix, diffusion of acidic rumen fluid into a surface layer of the intraruminal bolus, dissolution of aqueous soluble components within the surface layer, and diffusion of the mineral components within the rumen fluid.
  • the erodible matrix comprises one or more components selected from a wax, a mixture of waxes, a resin or combination of resins, polylactic acid, polyglycolic acid, polycaprolactone, polyurethane, polyorthoester or soluble phosphate glass.
  • the wax may be selected from carnauba wax, glycerol monostearate and beeswax.
  • the wax is selected from carnauba wax, caranda wax, glycerol monostearate, beeswax, Chinese wax, sumac wax, candelilla wax, ouricury wax, rice bran wax, soy wax, castor wax, paraffin wax, microcrystalline wax, ceresin wax, montan wax, ozokerite, peat wax, polyethylene wax, poly(acrylic acid) and cetyl esters.
  • the wax is carnauba wax.
  • the mixture of waxes comprises carnauba wax.
  • the mixture of waxes comprises carnauba wax and glycerol monostearate.
  • the mixture of waxes comprises beeswax, cetyl esters and poly(acrylic acid).
  • Beeswax is preferably white beeswax.
  • Poly(acrylic acid) is preferably Carbopol 1342 or Carbopol 1382, or a mixture thereof.
  • the mixture of waxes is selected from two or more of carnauba wax, caranda wax, glycerol monostearate, beeswax, Chinese wax, sumac wax, candelilla wax, ouricury wax, rice bran wax, soy wax, castor wax, paraffin wax, microcrystalline wax, ceresin wax, montan wax, ozokerite, peat wax, polyethylene wax, poly(acrylic acid) and cetyl esters.
  • the bolus comprises 25% or less, 20% or less, 18% or less, 15% or less, 10% or less, or 5% or less total wax mixture content by mass.
  • the erodible matrix comprises a resin, such as rosin.
  • the erodible matrix may be formulated according to the desired nutrient release profile.
  • the erodible matrix may be formulated to provide a faster nutrient release rate or a slower nutrient release rate.
  • the size of the erodible matrix may be varied.
  • the material out of which the erodible matrix is made may be varied.
  • the concentration of the mineral nutrient dispersed in the erodible matrix may be varied.
  • the dispersion of the mineral nutrient in the erodible matrix may be varied.
  • the erodible matrix may be formulated by mixing waxes and/or polymers with other agents such as emulsifiers, stabilizers, solubilisers, anti-adherents, channelling agents, pH modifiers, surfactants or other additives in order to provide an erodible matrix with the appropriate properties of hardness or erodibility.
  • the surfactant may be, for example, a lignosulfonate such as sodium lignosulfonate.
  • the erodible matrix has poor solubility in water, so that it does not quickly dissolve in aqueous conditions in the rumen of a ruminant animal. It is also preferred that the erodible matrix is sufficiently hard, such that it erodes gradually and is not easily prematurely damaged, causing undesired accelerated release of the mineral nutrient.
  • the erodible matrix comprises a wax or a mixture of waxes.
  • a material that is a wax or a mixture of waxes provides several benefits.
  • the material is suitable for gradual erosion when in the rumen of a ruminant animal.
  • the material facilitates dispersion of a mineral nutrient in the erodible matrix, and enables the intraruminal bolus to be manufactured in a straightforward manner.
  • the intraruminal bolus may be manufactured by the methods disclosed herein.
  • the material is also low-cost and can be easily adapted according to the requirements of the intraruminal bolus.
  • the wax or the mixture of waxes is non-toxic in a ruminant animal. It is preferred that the wax or the mixture of waxes has a melting point which is not excessively high for ease of manufacture, but which is also not too low in order to avoid melting when in the rumen of a ruminant animal. Nevertheless, the wax may be or the mixture of waxes may comprise a high melting point wax such as carnauba wax. The melting point of carnauba wax is 81 to 86 °C, which is high amongst waxes but is not excessively high for ease of manufacture of the intraruminal bolus of the present invention.
  • the inventors have discovered through experimentation that the present intraruminal bolus comprising an amino acid chelate can be produced without denaturation of the amino acid component, even where the production involves the melting of a high melting point wax such as carnauba wax, at which temperature an amino acid would be expected to denature.
  • the wax or the mixture of waxes has poor solubility in water.
  • it is preferred that the wax or the mixture of waxes is sufficiently hard, such that it erodes gradually and is not easily prematurely damaged.
  • the wax has a melting point of at least 60 °C. In preferred embodiments, the wax has a melting point of at least 70 °C. In more preferred embodiments, the wax has a melting point of at least 75 °C. In most preferred embodiments, the wax has a melting point of at least 80 °C.
  • the wax has a melting point of at most 100 °C. In preferred embodiments, the wax has a melting point of at most 95 °C. In more preferred embodiments, the wax has a melting point of at least 90 °C. In most preferred embodiments, the wax has a melting point of at most 86 °C.
  • the mixture of waxes comprises a wax having a melting point of at least 60 °C. In preferred embodiments, the mixture of waxes comprises a wax having a melting point of at least 70 °C. In more preferred embodiments, the mixture of waxes comprises a wax having a melting point of at least 75 °C. In most preferred embodiments, the mixture of waxes comprises a wax having a melting point of at least 80 °C. In some embodiments, the mixture of waxes comprises a wax having a melting point of at most 100 °C. In preferred embodiments, the mixture of waxes comprises a wax having a melting point of at most 95 °C. In more preferred embodiments, the mixture of waxes comprises a wax having a melting point of at least 90 °C. In most preferred embodiments, the mixture of waxes comprises a wax having a melting point of at most 86 °C.
  • the intraruminal bolus has a total wax mixture content by mass of between 2% and 24%.
  • the total wax mixture content by mass is defined as the percentage of the total mass of the intraruminal bolus that is the mass of the wax or the mixture of waxes.
  • the total mass of the intraruminal bolus excludes the mass of a shell, if present, as described herein.
  • the intraruminal bolus has a total wax mixture content by mass of between 2% and 10%.
  • the intraruminal bolus has a total wax mixture content by mass of between 3% and 8%. More preferably the intraruminal bolus has a total wax mixture content by mass of between 4% and 6%. Most preferably the intraruminal bolus has a total wax mixture content by mass of approximately 5%.
  • the intraruminal bolus has a total wax mixture content by mass of between 14% and 24%.
  • the intraruminal bolus has a total wax mixture content by mass of between 15% and 22%. More preferably the intraruminal bolus has a total wax mixture content by mass of between 16% and 20%. Most preferably the intraruminal bolus has a total wax mixture content by mass of approximately 18%.
  • the total mass of the intraruminal bolus is between 10 grams and 150 grams.
  • the total mass of the intraruminal bolus is between 10 grams and 30 grams. In preferred embodiments, the total mass of the intraruminal bolus is between 15 grams and 25 grams. In more preferred embodiments, the total mass of the intraruminal bolus is between 18 grams and 22 grams.
  • the total mass of the intraruminal bolus is between 20 grams and 40 grams.
  • the total mass of the intraruminal bolus is between 25 grams and 35 grams. In more preferred embodiments, the total mass of the intraruminal bolus is between 29 grams and 33 grams.
  • the total mass of the intraruminal bolus is between 100 grams and 150 grams. In preferred embodiments, the total mass of the intraruminal bolus is between 1 10 grams and 130 grams. In more preferred embodiments, the total mass of the intraruminal bolus is between 1 15 grams and 125 grams.
  • the erodible matrix is comprised in a shell.
  • the shell may surround or enclose the erodible matrix either partly or entirely.
  • the shell may have the appearance of an outer wrapper.
  • the shell is made of a material that is resistant to acid.
  • the shell is made of a material that is degradable by UV radiation.
  • the shell is made of plastic.
  • the plastic is a heat shrink plastic.
  • the heat shrink plastic may be heat shrinkable tubing of the brand Shrink-Kon (Registered Trade Mark), such as VIT750-0-C or a product of another appropriate size.
  • the shell may be made of a fluid film, namely a liquid that solidifies on cooling to ambient temperature.
  • the shell comprises casein. In some embodiments, the shell consists of casein.
  • Inorganic components may be provided in the intraruminal bolus in addition to the amino acid chelate. Inorganic components may be added for the purpose of nutrition and/or health. The inorganic components may be selected in accordance with a deficiency or potential deficiency of a particular element in a ruminant animal.
  • the intraruminal bolus comprises a component comprising selenium.
  • the component comprising selenium is selenomethionine, a metal selenite or a metal selenate.
  • the metal selenite is sodium selenite.
  • the metal selenate is sodium selenate.
  • the intraruminal bolus comprises a component comprising iodine.
  • the component comprising iodine is a metal iodide or a metal iodate.
  • the metal iodide is sodium iodide or potassium iodide.
  • the metal iodate is calcium iodate or potassium iodate.
  • the intraruminal bolus comprises a component comprising selenium and further comprises a component comprising iodine.
  • the intraruminal bolus comprises one or more inorganic components
  • a metal sulfate independently selected from a metal sulfate, a metal oxide, a metal carbonate, a metal selenite, a metal selenate, a metal iodide, a metal iodate, a metal acetate and a metal propionate.
  • the intraruminal bolus comprises one or more inorganic components
  • the intraruminal bolus comprises an inorganic component comprising cobalt.
  • the intraruminal bolus comprises an inorganic component comprising zinc.
  • the intraruminal bolus comprises an inorganic component comprising copper. More preferably the intraruminal bolus comprises inorganic components independently comprising cobalt and zinc. More preferably the intraruminal bolus comprises inorganic components independently comprising cobalt and copper. More preferably the intraruminal bolus comprises inorganic components independently comprising copper and zinc. Most preferably the intraruminal bolus comprises inorganic components independently comprising cobalt, zinc and copper.
  • the intraruminal bolus comprises one or more inorganic components independently selected from copper sulfate, copper oxide, cobalt acetate, cobalt sulfate, cobalt carbonate, selenomethionine, selenocysteine, sodium selenite, sodium selenate, calcium iodate, calcium propionate, potassium iodide, sodium iodide, iron carbonate, iron sulfate, magnesium oxide, magnesium sulfate, manganese carbonate, manganese oxide, manganese sulfate, and zinc oxide.
  • the intraruminal bolus comprises inorganic components, wherein the inorganic components independently comprise copper, cobalt, zinc, selenium and iodine. In other preferred embodiments, the inorganic components independently comprise copper, cobalt and selenium.
  • the intraruminal bolus comprises inorganic components, wherein the inorganic components are copper sulfate, copper oxide, cobalt sulfate, cobalt carbonate,
  • the inorganic components are copper sulfate, copper oxide, cobalt sulfate, selenomethionine, sodium selenite, calcium iodate and zinc oxide.
  • the intraruminal bolus comprises one or more inorganic components independently selected from cobalt acetate, cobalt sulfate, cobalt carbonate,
  • a copper-free intraruminal bolus is suitable for certain ruminant animals which cannot tolerate copper, such as some continental breeds of sheep.
  • the intraruminal bolus comprises inorganic components, wherein the inorganic components independently comprise cobalt, zinc, selenium and iodine. In other preferred embodiments, the inorganic components independently comprise cobalt and selenium.
  • the intraruminal bolus comprises inorganic components, wherein the inorganic components are cobalt sulfate, cobalt carbonate, selenomethionine, sodium selenite, calcium iodate and zinc oxide. In other preferred embodiments, the inorganic components are cobalt sulfate, selenomethionine, sodium selenite, calcium iodate and zinc oxide.
  • the intraruminal bolus comprises selenomethionine and optionally one or more other inorganic components.
  • the intraruminal bolus has a selenomethionine content by mass of at least 0.05%.
  • the intraruminal bolus has a selenomethionine content by mass of between 0.05% and 1 %. More preferably the intraruminal bolus has a selenomethionine content by mass of between 0.05% and 0.5%.
  • the intraruminal bolus has a selenomethionine content by mass of between 0.1 % and 0.3%.
  • the selenomethionine content by mass is defined as the percentage of the total mass of the intraruminal bolus that is the mass of selenomethionine.
  • the total mass of the intraruminal bolus excludes the mass of a shell, if present, as described herein.
  • Copper oxide is preferably copper(ll) oxide.
  • Copper sulfate is preferably copper(ll) sulfate.
  • Copper sulfate is more preferably copper(ll) sulfate pentahydrate.
  • Cobalt carbonate is preferably cobalt(ll) carbonate.
  • Cobalt sulfate is preferably cobalt(ll) sulfate.
  • Cobalt sulfate is more preferably cobalt(ll) sulfate heptahydrate.
  • Calcium iodate is preferably calcium iodate anhydrous.
  • Selenomethionine may be provided raw or alternatively from selenium yeast, produced by fermenting Saccharomyces cerevisiae in a selenium-rich medium. Selenomethionine is preferably
  • Sodium selenite is preferably sodium selenite anhydrous.
  • the intraruminal bolus comprises copper glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate; an erodible matrix comprising carnauba wax and glycerol monostearate; barium sulfate as a densifier dispersed in the erodible matrix; and copper sulfate, copper oxide, cobalt sulfate, cobalt carbonate, selenomethionine, sodium selenite, calcium iodate and zinc oxide as inorganic components.
  • the intraruminal bolus comprises zinc glycinate as a mineral nutrient in the form of an amino acid chelate; an erodible matrix comprising carnauba wax and glycerol monostearate; barium sulfate as a densifier dispersed in the erodible matrix; and cobalt sulfate, cobalt carbonate, selenomethionine, sodium selenite, calcium iodate and zinc oxide as inorganic components.
  • the intraruminal bolus may further comprise magnesium salts. Magnesium salts are beneficial to help to prevent hypomagnesaemia.
  • the intraruminal bolus may further comprise monopropylene glycol.
  • Monopropylene glycol is beneficial to help to prevent ketosis.
  • the intraruminal bolus may further comprise one or more vitamins.
  • the intraruminal bolus comprises one or more vitamins selected from vitamin A, vitamin B1 , vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B12, vitamin C, vitamin D3, vitamin E, vitamin K, folic acid, calcifediol, D-calcium pantothenate, choline and b-carotene.
  • the intraruminal bolus is formulated, for example with regard to the erodible matrix, so that the mineral nutrient is released over an extended period of time of at least 91 days or at least 100 days, when the bolus is in the rumen of a ruminant animal.
  • the mineral nutrient when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 91 days. In some embodiments, when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 100 days. In some embodiments, when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 110 days. In some embodiments, when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 120 days. These periods of time are particularly suitable where the ruminant animal is a lamb. Preferably the lamb has a body weight of at least 20 kg.
  • the mineral nutrient when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 6 months. In some embodiments, when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 7 months. In some embodiments, when the intraruminal bolus is in the rumen of a ruminant animal, the mineral nutrient is released over a period of at least 8 months. These periods of time are particularly suitable where the ruminant animal is an adult sheep. Preferably the adult sheep has a body weight of at least 50 kg.
  • the mineral nutrient is released at an increasing release rate, when the intraruminal bolus is in the rumen of a ruminant animal. This property is particularly beneficial for a ruminant animal whose nutritional requirements increase over time; for example, a young, growing animal such as a lamb or a calf.
  • the mineral nutrient is released at a zero-order release rate.
  • the intraruminal bolus may be of any shape suitable for oral administration to a ruminant animal.
  • the intraruminal bolus is a shape selected from a cuboid, a cylinder, an elongate prism, a frustum, an ovoid and a sphere. More preferably the intraruminal bolus is of a cylinder shape. Where the shape is a cylinder or a cuboid, the shape is preferably elongate and/or is bullet-shaped, such that an end of the cylinder or cuboid is tapered.
  • the total volume of the intraruminal bolus is between 3 cm 3 and 60 cm 3 .
  • the total volume of the intraruminal bolus excludes a shell as described herein, if present.
  • the total volume of the intraruminal bolus is between 3 cm 3 and 12 cm 3 . In preferred embodiments, the total volume of the intraruminal bolus is between 5 cm 3 and 10 cm 3 . In more preferred embodiments, the total volume of the intraruminal bolus is between 6 cm 3 and 8 cm 3 .
  • the total volume of the intraruminal bolus is between 6 cm 3 and 16 cm 3 . In preferred embodiments, the total volume of the intraruminal bolus is between 8 cm 3 and 14 cm 3 . In more preferred embodiments, the total volume of the intraruminal bolus is between 10 cm 3 and 13 cm 3 .
  • the total volume of the intraruminal bolus is between 25 cm 3 and 60 cm 3 . In preferred embodiments, the total volume of the intraruminal bolus is between 35 cm 3 and 50 cm 3 . In more preferred embodiments, the total volume of the intraruminal bolus is between 38 cm 3 and 45 cm 3 .
  • the present invention provides the intraruminal bolus of the first aspect for use in a method of delivery of a mineral nutrient to a ruminant animal.
  • the intraruminal bolus is administered to the ruminant animal orally.
  • the bolus is administered to the rumen of the animal.
  • the erodible matrix of the intraruminal bolus erodes in the rumen of the ruminant mineral nutrient to release and deliver the mineral nutrient.
  • the present invention provides use of the intraruminal bolus of the first aspect in a method of delivery of a mineral nutrient to a ruminant animal.
  • the intraruminal bolus is administered to the ruminant animal orally.
  • the erodible matrix of the intraruminal bolus erodes in the rumen of the ruminant mineral nutrient to release and deliver the mineral nutrient.
  • the present invention provides a method of making an intraruminal bolus, the method comprising the steps of:
  • the bolus may be manufactured by any suitable method known in the art, such as injection moulding, tabletting, hot melt granulation or compression moulding. Compression may be applied by standard direct compression or roller compaction.
  • steps (A) and (B) are carried out in a mould.
  • step (A) is preceded by a step of preparing, in a mould, a mix of the wax or mixture of waxes and the mineral nutrient.
  • the wax or mixture of waxes and/or the mineral nutrient are in the form of finely ground powders.
  • a powder has a mean particle size of 100 microns or less. More preferably a powder has a mean particle size of 80 microns or less.
  • step (A) and/or step (B) pressure is applied.
  • the pressure is between 0.5 and 7.5 tonnes per square inch. More preferably the pressure is between 0.75 and 6.5 tonnes per square inch. In some embodiments, the pressure is between 0.8 and 2.0 tonnes per square inch, more preferably between 1 .0 and 1 .5 tonnes per square inch. In alternative embodiments, the pressure is between 3.5 and 6.0 tonnes per square inch, more preferably approximately 5.0 tonnes per square inch. High pressure facilitates infusion of the wax or mixture of waxes within the mineral nutrient, and increases the density of the composition.
  • the intraruminal bolus is an intraruminal bolus according to the first aspect.
  • the method further comprises the step of:
  • the shell may be applied manually.
  • the shell may be applied in liquid form which solidifies on cooling to ambient temperature, or the shell may be applied in solid form.
  • step (B) the composition is simultaneously agitated, such that segregation of the mineral nutrient and the wax or mixture of waxes is inhibited. This helps to ensure that the mineral nutrient is dispersed uniformly or according to design in the erodible matrix, which subsequently results in more predictable release of the mineral nutrient when in use.
  • the present invention provides an intraruminal bolus made according to the method of the fourth aspect.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided. Furthermore, any of the optional or preferred features of any one of the aspects may apply to any of the other aspects. In particular, optional features associated with a method or use may apply to an intraruminal bolus, and vice versa.
  • Mineral nutrients differ in their dissociation characteristics. Mineral nutrients therefore vary in the rate and extent to which they are absorbed, as well as the particular site at which they are absorbed, which may be the rumen, abomasum or intestine, for example.
  • chelates are known to deliver more of an element per unit mass of compound across the gut wall over a sustained period, and are thereafter better constructed to optimise biochemical function. Chelation protects a nutrient from digestion in the rumen, which allows the nutrient to be absorbed in the hind gut.
  • Amino acid chelates provide benefits originating from both the chelated nutrient and also the organic amino acid chelating agent, including improved biocompatibility and reduced harmful ecological effects compared with using a synthetic industrial chelating agent instead.
  • Amino acid moieties can be advantageously used in the body of a ruminant animal, including being incorporated in proteins.
  • cobalt(ll) sulfate heptahydrate delivers cobalt in ionic form within the rumen, so that rumen-residing microflora can utilise cobalt ions (Co 2+ ) to generate cyanocobalamin (vitamin B12). Meanwhile, cobalt(ll) carbonate is delivered to the abomasum.
  • copper(ll) sulfate pentahydrate delivers copper in ionic form within the rumen, so that copper ions (Cu 2+ ) become available to complex with thiomolybdate, which is a naturally occurring toxin created in the rumen by ingested sulfur and ingested molybdenum that impedes animal performance. It is therefore useful to include non-chelated sources of cobalt and copper in the bolus, so that a proportion of these metal ions are absorbed in the rumen, rather than being entirely protected by a chelating agent and subsequently absorbed elsewhere.
  • Sodium selenite and L-selenomethionine are sources of selenium in the exemplified boluses.
  • Selenium is an essential trace element in ruminants, which is required to avoid impaired growth, fertility and disorders such as nutritional muscular dystrophy (white muscle disease).
  • L-Selenomethionine is incorporated into general proteins and acts as a biological pool for selenium [Juniper et al., 2006] Through in vivo testing, the present inventors have found that the inclusion of sodium selenite is beneficial for delivering selenium to blood and tissue, evidenced by increased production of the selenium-containing enzyme, glutathione peroxidase (GSHPx).
  • Calcium iodate anhydrous is a source of iodine, which is important for the synthesis of thyroid hormones, triiodothyronine (T3) and thyroxine (T4). These hormones are vital for regulating energy metabolism in animals and a deficiency thereof can lead to goitre. Meanwhile, it is useful to include sources of zinc in the bolus, as a lack of zinc can lead to skin disorders, hindered growth and reduced fertility in animals [White, 1993]
  • intraruminal boluses of the examples comprise nutritional components (namely one or more amino acid chelates and several inorganic components) in specific quantities
  • an intraruminal bolus may alternatively be made comprising one or more of the nutritional components in greater quantities. This would enable more of a nutrient to be delivered, which may also be with a higher release rate.
  • an intraruminal bolus may be made in which one or more of the nutritional components are either absent or in smaller quantities. This would be a cheaper option where there is less concern regarding the deficiency of a particular element.
  • Examples of intraruminal boluses according to the present invention are described herein. Examples 1 to 6 are provided in Table 1 below, which shows the constituent components and properties of each intraruminal bolus.
  • Each of Examples 1 to 6 comprises a metal chelate dispersed in an erodible matrix made of a mixture of waxes.
  • the mixture of waxes is a mixture of carnauba wax and glycerol monostearate.
  • Each of Examples 1 to 6 has a total wax mixture content of 5%.
  • the melting point of carnauba wax is 81 to 86 °C, which is high amongst waxes but not excessively high for ease of manufacture of the intraruminal boluses.
  • Carnauba wax is a particularly hard natural wax which is practically insoluble in water, ensuring that it does not quickly dissolve in aqueous conditions in the rumen of a ruminant animal.
  • Glycerol monostearate acts an effective solidifier and emulsifying agent.
  • Each of Examples 1 to 6 comprises a barium sulfate densifier. Each of Examples 1 to 6 further comprises zinc oxide, which acts as an additional densifier and also as a source of zinc. Each of Examples 1 to 6 has a total bolus density of 2.80 g/cm 3 . This density is ideal to prevent regurgitation of the bolus by the ruminant animal, which is a problem at lower densities.
  • Each of Examples 1 to 6 comprises several inorganic components.
  • Each of Examples 1 to 6 is of a cylinder shape.
  • Each of Examples 1 to 6 is comprised in a heat shrink plastic tubing of type Shrink-Kon® VIT750-0-C or an alternative suitable size.
  • the heat shrink plastic tubing is not included in the calculations of mass, volume and density described herein.
  • the intraruminal bolus of Example 1 is particularly adapted for growing cattle.
  • This intraruminal bolus comprises copper(ll) glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate. It has dimensions of approximately 8.0 cm c 2.6 cm c 2.0 cm.
  • the intraruminal bolus of Example 2 is particularly adapted for lactating female dairy cows.
  • This intraruminal bolus comprises copper(ll) glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate. It has dimensions of approximately 8.0 cm c 2.6 cm c 2.0 cm. It contains higher quantities of copper(ll) oxide and calcium iodate, and lower quantities of the cobalt components than the intraruminal bolus of Example 1 .
  • the intraruminal bolus of Example 3 is adapted for copper-tolerant ewes, especially those of body weight of at least 50 kg.
  • This intraruminal bolus comprises copper(ll) glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate. It has dimensions of approximately 4.0 cm c 2.0 cm c 1 .4 cm.
  • the intraruminal bolus of Example 4 is adapted for copper-intolerant ewes, especially those of body weight of at least 50 kg.
  • This intraruminal bolus is free of copper. It comprises zinc glycinate as a mineral nutrient in the form of an amino acid chelate. It has dimensions of approximately 4.0 cm c 2.0 cm c 1 .4 cm.
  • the intraruminal boluses of Examples 3 and 4 are smaller in mass and volume than the intraruminal boluses of Examples 1 and 2 (adapted for cattle), reflecting the differences in body weight and size of the respective targeted ruminant animals.
  • the intraruminal bolus of Example 5 is adapted for copper-tolerant lambs, especially those of body weight of at least 20 kg.
  • This intraruminal bolus comprises copper(ll) glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate. It has dimensions of approximately 4.0 cm c 1 .5 cm c 1 .2 cm.
  • the intraruminal bolus of Example 6 is adapted for copper-intolerant lambs, especially those of body weight of at least 20 kg.
  • This intraruminal bolus is free of copper. It comprises zinc glycinate as a mineral nutrient in the form of an amino acid chelate. It has dimensions of approximately 4.0 cm c 1 .5 cm c 1 .2 cm.
  • the intraruminal boluses of Examples 5 and 6 are smaller in mass and volume than the intraruminal boluses of Examples 3 and 4 (adapted for ewes), reflecting the differences in body weight and size of the respective targeted ruminant animals.
  • Examples 3 and 4 also have a proportionally higher zinc content than Examples 5 and 6, which takes into account the greater nutritional requirement of zinc in breeding ewes.
  • the intraruminal boluses of Examples 1 to 6 were all made by the same general method. As finely ground powders (mean particle size of ⁇ 1 micron), carnauba wax and glycerol monostearate were mixed together with the amino acid chelate or chelates, the inorganic components (as appropriate) and the densifier, at ambient temperature. The resultant mixture was placed in a mould of suitable dimensions for the shape of the intraruminal bolus. The mould was then heated to a temperature of 82 to 86 °C, and a pressure of 5 tonnes per square inch was applied using a plunger. Under these conditions, the waxes infuse within the mixture of components. In this temperature range, the amino acid chelate or chelates are thermally stable.
  • Each of constituent components copper(ll) sulfate pentahydrate, copper(ll) oxide, copper(ll) glycinate, cobalt(ll) sulfate heptahydrate, cobalt(ll) carbonate, L-selenomethionine, sodium selenite anhydrous, calcium iodate anhydrous, zinc glycinate and zinc oxide is an approved additive on the European Union Register of Feed Additives, Edition 4/2019 (Regulation (EC) No 1831/2003).
  • the copper(ll) glycinate and zinc glycinate used in the intraruminal boluses of Examples 1 to 10 are of the brand MAXCHELAT (Registered Trade Mark), produced by Provita Supplements. These glycinates are refined to provide higher metal content than conventional glycinates, as they are made through a dry solid-state treatment process in which the oxygen is essentially entirely removed from a water-insoluble oxide starting material.
  • Table 2 shows the constituent components and properties of Examples 7 to 10, which are further intraruminal boluses of the present invention.
  • Each of Examples 7 to 10 comprises a metal chelate dispersed in an erodible matrix made of a mixture of waxes.
  • the mixture of waxes is a mixture of carnauba wax and glycerol monostearate.
  • Each of Examples 7 to 10 comprises copper(ll) glycinate and zinc glycinate as mineral nutrients in the form of an amino acid chelate.
  • Each of Examples 7 to 10 comprises a barium sulfate densifier.
  • Each of Examples 7 to 10 further comprises zinc oxide, which acts as an additional densifier and also as a source of zinc.
  • Each of Examples 7 to 10 has a total bolus mass of approximately 29.1 g.
  • Each of Examples 7 to 10 has a total bolus density in the range of 2.4 g/cm 3 to 2.9 g/cm 3 . This density range is ideal to prevent regurgitation of the bolus by the ruminant animal, which is a problem at lower densities.
  • Each of Examples 7 to 10 comprises several inorganic components.
  • Each of Examples 7 to 10 is of a cylinder shape. Each of Examples 7 to 10 is comprised in a heat shrink plastic tubing of type Shrink-Kon® VIT750-0-C or an alternative suitable size. The heat shrink plastic tubing is not included in the calculations of mass, volume or density described herein.
  • the intraruminal boluses of Examples 7 to 10 were all made by the same general method. As finely ground powders (mean particle size in the range of 45 to 80 micron), carnauba wax and glycerol monostearate were mixed together with the amino acid chelates, the inorganic components (as appropriate) and the densifier, at ambient temperature. The resultant mixture was placed into a mould of suitable dimensions for the shape of the intraruminal bolus. The mixture was then tamped down using a plunger to leave a flat surface on the top of the mould. The mould was then placed on a hot plate, and a thermocouple was placed very slightly above the level of the mixture within the mould.
  • the mould was then heated (together with the plunger to allow for any thermal expansion and to minimise leakage) to a temperature of 82 °C. Once at this temperature, the heat and thermocouple were removed, and the plunger was immediately inserted into the mould and a pressure of 1 .5 tonnes per square inch was applied. Under these conditions, the waxes infuse within the mixture of components, and the amino acid chelates are thermally stable. Once the mould had cooled after several minutes, the pressure was removed, and an erodible matrix was obtained in the solid state, having a rigid structure due to the infusion of the waxes. Finally, the erodible matrix was removed from the mould, and a shell of heat shrink plastic tubing of brand Shrink-Kon® was manually applied.
  • the procedure for release rate testing was as follows. The dry mass of the intraruminal bolus was measured, before the bolus was added to a container of artificial rumen solution (200 ml_) at 37.5 °C, and constant stirring was then applied. After 1 week, sample fluid was extracted and tested for the content of cobalt, copper and selenium. A fresh artificial rumen solution was then prepared, and the same bolus was then added to a container of the fresh solution (200 ml_) at 37.5 °C, and the process was repeated for a number of weeks.
  • the artificial rumen solution was prepared by weighing out and dissolving in 900 ml_ of deionised water: 9.8 g of NaHCOs, 0.57g of KCI, 0.04 g of CaCI 2 , 9.3 g of NaHP0 4 - 12H 2 0, 0.47 g of NaCI, and 0.12 g of MgSO hhO. The pH was then adjusted to 6.5 using HCI. The artificial rumen solution was stored at 37.5 °C.
  • sample fluid for testing 1000 pL of the extracted rumen solution was placed in a 10 mL volumetric flask.
  • 1000 pl_ of diluted yttrium solution 2000 mI_ yttrium certified reference material, Sigma Aldrich 01357, made up to 100 mL with dilute nitric acid, 0.3 mol dm 3 , 1 .34%, Fluka Analytical 02650) was added to act as an internal standard for the ICP-OES measurements.
  • the test solution was made up to 10 mL using dilute nitric acid.
  • a number of calibration solutions containing cobalt, copper and selenium certified reference samples (Sigma Aldrich 30329, 68921 , 50002) were made. Between each measurement, the ICP-OES system was cleansed using a“blank” solution (1000 pL of diluted yttrium solution and 1000 pl_ of matrix rumen solution, made up to 10 mL with dilute nitric acid). Also, before each measurement, the detector was checked using Agilent Wavelength calibration solution (1 mL, made up to 10 mL with ultrapure water).
  • the ICP-OES system was programmed to analyse three specific emission wavelengths for each element (Y, Co, Cu, Se), with emission wavelengths being chosen to ensure minimum interference with each other. Emission intensity was recorded at each chosen wavelength, and automatically plotted against the calculated concentration of each element to provide calibration curves. Emission from blank and test solutions was recorded and elemental concentration was derived from the calibration curves. Yttrium was used to verify consistency of measurements from each solution, acting as an internal standard for the system.
  • the release of copper and selenium in the initial weeks appears to be correlated to the content of the element within each bolus (and inversely correlated to the wax content), with the 5% wax bolus displaying a higher release rate than the 10% wax bolus, and the 10% wax bolus higher than the 15% wax bolus.
  • the 18% wax bolus displays a lower release in the initial and final weeks, but it has a much lower initial release and a more gradual decrease.
  • the boluses with a lower wax content have a much higher nutrient payload, incorporating more of each element.
  • the high initial burst may be due to exposed mineral nutrient at the end of the bolus dissolving rapidly.
  • the drop in release and levelling off of release rate week-to-week is presumably due to the initial exposed nutrient material having been depleted, and the release is more controlled by the necessity of either the rumen solution to ingress into the bolus, or for the wax to dissolve.
  • the release nevertheless appears to be linked to the amount of each element contained in a bolus (particularly for copper and selenium), rather than the amount of wax.
  • the wax content appears to be important to avoid an initial burst of nutrients, which in an extreme case could prove harmful to an animal.
  • the in vitro release rate analysis shows that the boluses continue to release nutrients over the testing period of eight weeks, and through extrapolation would be expected to do so over a significant further period of time beyond the testing period, providing nutrient release over a period of at least 91 days or at least 100 days in total. No nutrient release dropped to zero during the testing period.
  • DSC Differential scanning calorimetry
  • Instruments Q1000 DSC (LIMS 1796) machine. The sample was heated from 30 °C to 300 °C at a heating rate of 1 °C/min, using a pierced aluminium pan. A nitrogen purge gas was used throughout.
  • the first in vivo trial involved an analysis of blood and tissue of 3 groups of 10 lambs. After the lambs were weighed, the first group was given bolus C, the second group was given bolus D, and the third group was given placebo P. Blood and tissue samples were taken 7 and 14 days after administration, which were analysed and statistically interpreted. Two lambs from each group were culled, and their kidney, liver and rumen fluids were examined to study the mineral nutrient response.
  • the second in vivo trial involved an animal performance analysis of 3 matched groups of 50 hoggs (ewes in their first breeding season). The first group was given bolus C, the second group was given bolus D, and the third group was given bolus E (Essential Sheep, a commercially available bolus comprising inorganic mineral nutrients produced by Downland (Registered Trade Mark)). The hoggs were scanned for pregnancy and the results were collected (shown in Table 7).
  • Barren means that no lambs were detected.
  • the pregnancy results in Table 7 indicate that the intraruminal boluses of the invention are safe and efficacious. The results also encouragingly

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Abstract

La présente invention concerne un bolus intraruminal comprenant un nutriment minéral dispersé dans une matrice érodable, le nutriment minéral se présentant sous la forme d'un chélate d'acide aminé. Le bolus intraruminal est particulièrement utile pour l'administration d'un nutriment minéral à un ruminant. La présente invention concerne également un procédé de préparation du bolus intraruminal.
PCT/EP2020/065538 2019-06-04 2020-06-04 Bolus intraruminal et son procédé de préparation WO2020245303A1 (fr)

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