WO2024256811A1 - Additif biocompatible non toxique comprenant de l'éther d'alkyle cellulose et de la smectite - Google Patents

Additif biocompatible non toxique comprenant de l'éther d'alkyle cellulose et de la smectite Download PDF

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Publication number
WO2024256811A1
WO2024256811A1 PCT/GB2024/051495 GB2024051495W WO2024256811A1 WO 2024256811 A1 WO2024256811 A1 WO 2024256811A1 GB 2024051495 W GB2024051495 W GB 2024051495W WO 2024256811 A1 WO2024256811 A1 WO 2024256811A1
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WO
WIPO (PCT)
Prior art keywords
additive
core
smectite
alkyl cellulose
biocompatible
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2024/051495
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English (en)
Inventor
James BRINICOMBE
Keith Greig
Ian Hunter
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RUMBOL PRODUCTS Ltd
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RUMBOL PRODUCTS Ltd
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Publication of WO2024256811A1 publication Critical patent/WO2024256811A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A23K20/28—Silicates, e.g. perlites, zeolites or bentonites
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A23K40/35—Making capsules specially adapted for ruminants
    • A—HUMAN NECESSITIES
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0068—Rumen, e.g. rumen bolus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
    • Y02P60/20—Reduction of greenhouse gas [GHG] emissions in agriculture, e.g. CO2
    • Y02P60/22—Methane [CH4], e.g. from rice paddies

Definitions

  • the present invention relates to a biocompatible, non-toxic additive for a pellet (such as an animal feed pellet) or a bolus, and a method for producing the biocompatible, non-toxic additive.
  • the present invention also relates to a method for providing a pellet (such as an animal feed pellet) or bolus, comprising the biocompatible, non-toxic additive.
  • Trace element deficiency in grazing species of animals can lead to problems in reproduction, productivity in dairy herds, and other health issues such as disease.
  • These deficiencies are often linked to low levels of trace elements in the animal's feed, especially in foraging animals whose trace element intake is dependent on the presence of these elements in the soil.
  • These deficiencies can also move up the food chain into humans as a result of consuming both meat and milk.
  • a convenient way of supplying these animals with minerals, vitamins or other dietary needs is by means of administering a slow release bolus.
  • a bolus can also be used to administer therapeutic materials or other biologically active agents.
  • a bolus is effectively a large pill or pellet which is typically administered by mouth and fits in either of the first two stomach compartments of the animal. The contents of the bolus is released over a period of time, the length of which primarily depends on the construction of the bolus.
  • GB2122086A (The University Court of the University of Glasgow) describes a device, specifically a bolus, for introducing nutrients and other materials into ruminant animals in such a way that the release of the nutrients and/or therapeutic materials is continuous and controlled.
  • the application proposes a solution to these problems in the form of a bolus having a compressed core which is enclosed in a rigid skin which is sufficiently thin and brittle to require the support of the core to maintain its integrity, such that without the support of the core it disintegrates.
  • This is achieved by using a rigid skin, or coating, of polyester resin. Once the coating has disintegrated, it is expelled from the animal within its faeces.
  • resin coatings can contain styrene, which is undesirable from a regulatory and environmental perspective. There is therefore a need for an improved method for addressing trace element deficiency, and other such deficiencies or diseases/disorders in animals.
  • a biocompatible, non-toxic additive which is configured to provide for sustained supply of trace elements, or other materials into an animal.
  • an improved method for providing a biocompatible, non-toxic additive for a core, such as a bolus is provided.
  • a bolus which has excellent release characteristics while also being acceptable from a regulatory perspective, where its component parts, in particular a coating if present, are non-toxic and biocompatible.
  • a biocompatible, non-toxic additive for a core comprising, consisting essentially of or consisting of: alkyl cellulose ether; and smectite.
  • the additive is a coating for a core.
  • the core is a pellet such as an animal feed pellet, or a bolus.
  • a core having a coating wherein the coating comprises, consists essentially of or consists of an additive as described herein.
  • the core is a bolus.
  • the additive may for example be water insoluble or sparingly water soluble.
  • the additive is water insoluble, and in particular is insoluble in the rumen liquor of an animal.
  • the additive may be provided as a coating for applying to an outer surface of a core, for example of a pellet such as an animal feed pellet, or a bolus.
  • a pellet such as an animal feed pellet, or a bolus.
  • reference to animal “feed” and animal “feed” pellet is intended to encompass nutritional materials such as feed, minerals, vitamins or other dietary elements, but also therapeutic materials or other biologically active agents.
  • the additive may also be combined with components of a core, for example with components of an animal feed pellet, or a bolus, to provide an additive-containing core (for example additive-containing pellet (such as an animal feed pellet) or additive-containing bolus).
  • an additive-containing core for example additive-containing pellet (such as an animal feed pellet) or additive-containing bolus.
  • the additive is used solely as a coating on the core e.g. as a coating for a bolus.
  • a bolus it is desirable for a bolus to have a coating which allows the beneficial material within the core to be released in a consistent manner. This can be achieved by having a coating which breaks down in a consistent manner and does not obscure the remainder of the core material in the process of breaking down.
  • the bolus is an elongated shape such as a cylinder, as the coating breaks down and disintegrates, a consistent cross-section of the core is exposed to the rumen, leading to relatively constant erosion of the core and release of the material.
  • this is achieved by using a coating of synthetic resin such as a polyester, epoxy or acrylic resin coating.
  • a coating comprising an additive comprising alkyl cellulose ether and smectite has equivalent or similar physical properties to the prior art resin-based coatings (as shown in Example 4), while also being biocompatible and non-toxic. As such, when the coating is broken down and expelled from the animal it presents no regulatory or environmental concerns, unlike currently available bolus coatings based on resins.
  • the smectite is present to enhance rigidity and brittleness of the additive. The presence of smectite therefore helps to control the rate of degradation of the additive-containing core or additive coating, and therefore the rate of release of the core.
  • Smectite is a mineral mixture of various swelling sheet phyllosilicates, including montmorillonite and bentonite. Depending on the application, "smectite”, “montmorillonite” and “bentonite” are synonyms to indicate a class of swelling clays. In the context of the present invention, bentonite is defined as a swelling clay comprising mostly montmorillonite.
  • the smectite comprises bentonite. In one embodiment, the smectite consists essentially of, consists of, or is bentonite. Both calcium bentonite and sodium bentonite may be used.
  • Smectite and alkyl cellulose ether are approved for use with animal feeds and medicines by worldwide regulatory bodies such as US Food & Drug Administration (FDA).
  • FDA Food & Drug Administration
  • the alkyl cellulose ether may be any suitable alkyl cellulose ether.
  • alkyl cellulose ether may also be referred to herein as "alkyl cellulose”.
  • the alkyl cellulose ether has a molecular weight in the range of between 40,000 AMW to 1,300,000 AMW (average molecular weight).
  • the alkyl cellulose is ethyl cellulose
  • the molecular weight is preferably in the range of between 75KDa (75,000 AMW) and 400KDa (400,000 AMW), preferably between 150KDa (150,000 AMW) and 250KDa (250,000 AMW).
  • commercially available ethyl cellulose typically has ethoxyl content (w/w) of 47.5%-49.5%.
  • the alkyl group of the alkyl cellulose is a Ci-Cio alkyl group, preferably a C1-C5 alkyl group.
  • the alkyl group of the alkyl cellulose is preferably selected from one or more of: methyl; ethyl; or any combination thereof.
  • the alkyl cellulose is ethyl cellulose.
  • the alkyl group of the alkyl cellulose may be hydroxysubstituted.
  • the alkyl cellulose may comprise, consist essentially of or consist of one or more of: hydroxypropyl cellulose; hydroxypropylmethyl cellulose, or any combination thereof.
  • the alkyl cellulose comprises, consists essentially of or consists of hydroxypropyl cellulose.
  • the additive of the present invention may comprise a combination of alkyl cellulose ethers selected to provide the desired insolubility or sparing solubility of the additive in water.
  • the additive comprises, consists essentially of or consists of alkyl cellulose ether and smectite. In one embodiment, the additive comprises, consists essentially of or consists of alkyl cellulose ether and bentonite. In one embodiment, the additive comprises, consists essentially of or consists of ethyl cellulose and smectite. In one embodiment, the additive comprises, consists essentially of or consists of ethyl cellulose and bentonite.
  • the alkyl cellulose is present within the additive in an amount of at least 10% (w/w).
  • the alkyl cellulose is preferably present within the additive in an amount of no more than 90% (w/w).
  • the alkyl cellulose is present within the additive in an amount of between 30% and 70% (w/w).
  • the alkyl cellulose is present within the additive in an amount of approximately 60% (w/w).
  • the alkyl cellulose is present within the additive in an amount of between about 35% (w/w) and about 85% (w/w), such as between about 40% (w/w) and about 80% (w/w), between about 45% (w/w) and about 75% (w/w), between about 50% (w/w) and about 70% (w/w), or between about 55% (w/w) and about 65% (w/w).
  • smectite is present within the additive in an amount of at least 10% (w/w). Smectite is preferably present within the additive in an amount of no more than 90% (w/w). In one embodiment, smectite is present within the additive in an amount of between 20% and 80% (w/w). Preferably, smectite is present within the additive in an amount of approximately 40% (w/w).
  • smectite is present within the additive in an amount of between about 15% (w/w) and about 65% (w/w), such as between about 20% (w/w) and about 60% (w/w), between about 25% (w/w) and about 55% (w/w), between about 30% (w/w) and about 50% (w/w) or between about 35% (w/w) and about 45% (w/w).
  • the additive comprises, consists essentially of or consists of between about 55% w/w and about 65% w/w of alkyl cellulose (e.g. ethyl cellulose) and between about 35% w/w and about 45% w/w of smectite (e.g. bentonite).
  • alkyl cellulose e.g. ethyl cellulose
  • smectite e.g. bentonite
  • the additive may further comprise one or more active ingredients.
  • the additive may for example comprise one or more plant-based additives and/or heat sensitive additives.
  • the additive when applied to a core, for example a pellet such as an animal feed pellet or a bolus, containing a methane reducing additive, may reduce methane output from an animal, such as for example ruminant animals.
  • a core may comprise a methane reducing additive, such as for example bromoform.
  • the additive may be incorporated with the core or coated on the core, thereby reducing the rate of degradation of the core.
  • the additive of the invention may therefore reduce the rate of release of the methane reducing additive.
  • the additive may be provided within or on a core to provide for sustained release of the methane reducing additive.
  • the additive when in the form of a coating or incorporated within a core, is preferably free from nonbiocompatible components.
  • the additive in particular in the form of a coating, is free from resin e.g. vinyl ester resin, for example free from styrene.
  • the core is preferably a bolus.
  • a pellet or animal feed pellet is also a bolus.
  • a bolus is an object containing and releasing predetermined supplement or medicine and is configured to release these ingredients at a predetermined rate to improve or maintain the health of the animal.
  • a bolus is in a form suitable for oral administration to a ruminant animal, such as a bovine.
  • a bolus, in particular the core of a bolus may comprise predetermined trace elements.
  • a bolus in particular the core of a bolus, may comprise one or more of: vitamin A, vitamin D, vitamin E, cobalt carbonate, zinc sulphate, calcium iodate, copper oxide, zinc oxide, zinc sulphate, manganese sulphate, sodium selenite, biotin, or any combination thereof.
  • a bolus, in particular the core of a bolus comprises a methane reducing additive such as bromoform.
  • the bolus in particular the core of the bolus, may also contain a weighting agent or device to prevent early ejection of the device.
  • a weighting agent is typically a particulate substance of high specific gravity.
  • the core for example a bolus
  • the core may be configured to be administered directly into the rumen of an animal.
  • the core, for example a bolus, together with the coating are configured to slowly break down over a predetermined time period.
  • the coating (and optionally the core) is configured to break down, within for example the rumen of an animal, over a time period of at least 1 month, preferably at least 2 months, for example at least 4 months.
  • the coating (and optionally the core) is configured to break down, within for example the rumen of an animal, over a time period of no more than 1 year, preferably no more than 10 months, for example no more than 8 months.
  • the coating (and optionally the core) is configured to break down, within for example the rumen of an animal, over a time period of between 1 month and 1 year, preferably between 2 months and 10 months, for example between 4 months and 8 months.
  • the core of the bolus contains the desired material (such as supplement or medicine) and can also contain a non-active matrix material which controls the concentration of desired material release and/or can create release of the desired material at time intervals by being inserted at intervals between sections of the desired material. Suitable additional core materials are discussed below.
  • a smectite incorporated alkyl cellulose-solvent mixture comprising, consisting essentially of or consisting of: alkyl cellulose ether; smectite; and a solvent-system.
  • the solvent-system comprises, consists essentially of or consists of at least one alkyl ester and at least one alcohol.
  • the solvent-system comprises, consists essentially of or consists of one alkyl ester and one alcohol.
  • the at least one alkyl ester preferably comprises, consists essentially of, consists of at least one Ci-Cio alkyl ester, preferably at least one C2-C5 alkyl ester e.g. ethyl acetate, propyl acetate and/or butyl acetate.
  • the alkyl ester is butyl acetate.
  • the alkyl ester is selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate and mixtures thereof.
  • the at least one alcohol preferably comprises, consists essentially of or consists of at least one C1-C5 alcohol, preferably propanol.
  • the alcohol is propanol, in particular n-propanol.
  • the solvent-system comprises, consists essentially of or consists of at least C1-C10 alkyl ester and at least one C1-C5 alcohol.
  • the solvent-system comprises, consists essentially of or consists of at least C2-C6 alkyl ester and propanol, in particular n-propanol.
  • the ratio of the at least one alkyl ester to the at least one alcohol in the smectite incorporated alkyl cellulose-solvent mixture is preferably at least 2:1 (w/w).
  • the ratio of the at least one alkyl ester to the at least one alcohol in the smectite incorporated alkyl cellulose-solvent mixture is no more than 8:1 (w/w).
  • the ratio of the at least one alkyl ester to the at least one alcohol is in the range of from 3:1 to 6:1 (w/w).
  • the ratio of the at least one alkyl ester to the at least one alcohol is in the range of from 3:1 to 5:1 (w/w).
  • the smectite incorporated alkyl cellulose-solvent mixture may be applied to a core e.g. a bolus, for example animal feed, preferably an animal feed pellet.
  • a core e.g. a bolus, for example animal feed, preferably an animal feed pellet.
  • a composition for example an animal feed composition
  • a core for example a pellet such as an animal feed pellet or a bolus
  • a biocompatible, non-toxic additive as herein described.
  • the composition is in the form of a bolus, which is coated with the non-toxic additive as herein described.
  • the additive may be applied to an outer surface of the core.
  • the additive may be combined within the core.
  • the additive is applied to the outer surface of the core as a coating.
  • a core having a coating comprising, consisting essentially of or consisting of an additive as described herein.
  • the additive is provided as a coating which substantially or predominantly encapsulates the core.
  • the coating comprising (or consisting or consisting essentially of) the additive covers between about 60% and about 95% of the surface of the core, such as between about 65% and about 90%, between about 70% and about 90%, between about 75% and about 90%, between about 80% and about 90%, or between about 80% and about 87% of the surface of the core.
  • the core remains free from contact with the additive, to enable the additive free portion of the core to be contacted by digestive fluids within the rumen of an animal.
  • the additive requires the presence of the core to retain its integrity.
  • the core may have a coating free and hence additive free end.
  • the overlying portion of the coating breaks away from the core exposing further portions of the core.
  • the rumen fluid comes into contact with the further portions of the core causing the core to dissolve and to supply nutrients from the core to the animal at a consistent rate.
  • the core may comprise: a binder (for example magnesium stearate), a lubricant, and one or more trace elements e.g. selected from the group consisting of vitamin A, vitamin D, vitamin E, cobalt carbonate, zinc sulphate, calcium iodate, copper oxide, zinc oxide, zinc sulphate, manganese sulphate, sodium selenite, biotin, and bromoform and combinations thereof.
  • the binder, lubricant and trace elements are preferably mixed to form a homogenous mixture.
  • the choice of core components can be designed to control the release time and/or profile of the desired material.
  • the core may be compressed into a predetermined shape, for example under pressure.
  • the core may be cylindrical or spherical or disc shaped.
  • the core (coated or uncoated) may be of constant cross-sectional area throughout its length or it may vary in cross-section, which can result in the rate of release of the desired material being varied.
  • the core may comprise a weight formed of material having a high overall specific gravity, for example an iron weight, to prevent regurgitation of the core by an animal.
  • the core together with the additive may have any suitable dimensions.
  • the core together with the additive has a length of at least 50 mm, preferably at least 60 mm, for example 75 mm.
  • the core together with the additive has a length of no more than 100 mm, preferably no more than 80 mm.
  • the core together with the additive has a length of between 50 mm and 100 mm, such as between 60 mm and 95 mm or between 60 mm and 80 mm.
  • the additive may be applied as a coating having any suitable thickness.
  • the coating has a (total if more than one coating layer is applied) thickness of at least about 0.05 mm, preferably at least about 0.1 mm.
  • the coating has a thickness of no more than about 0.5 mm, preferably no more than about 0.3 mm.
  • the coating has a thickness of between about 0.1 mm and about 0.3 mm, such as between about 0.1 mm and about 0.2 mm, between about 0.12 mm and about 0.18 mm e.g. about 0.16 mm.
  • the thickness is the total thickness of two layers of the additive.
  • the duration of controlled release of the core may be controlled by one or more of: the composition of the additive, the amount of additive present, the thickness of the coating, the dimensions of the core, and/or the density of the core.
  • a method for the preparation of a biocompatible, non-toxic additive as herein described comprising: dissolving alkyl cellulose in a solvent-system to provide an alkyl cellulose-solvent mixture; introducing smectite into the alkyl cellulose-solvent mixture to provide a smectite incorporated alkyl cellulose-solvent mixture; and evaporating the solvent from the smectite incorporated alkyl cellulose-solvent mixture to provide an additive.
  • the additive is in the form of a water insoluble biocompatible coating.
  • alkyl cellulose, smectite and the solvent-system apply equally to this aspect of the invention.
  • the alkyl cellulose is dissolved in the solvent-system by high shear mixing.
  • the smectite is preferably incorporated into the alkyl cellulose-solvent mixture under high shear.
  • a method for incorporating a biocompatible, non-toxic additive with a core comprising: dissolving alkyl cellulose in a solvent-system to provide an alkyl cellulose-solvent mixture; introducing smectite into the alkyl cellulose-solvent mixture to provide a smectite incorporated alkyl cellulose-solvent mixture; treating a core with the smectite incorporated alkyl cellulose-solvent mixture to provide a smectite-incorporated alkyl cellulose-solvent containing core; and evaporating solvent from the smectite-incorporated alkyl cellulose-solvent containing core to provide a core comprising a biocompatible, non-toxic additive.
  • a core for example a pellet such as an animal pellet or a bolus
  • the smectite incorporated alkyl cellulose-solvent mixture may be applied as a coating to an outer surface of a core.
  • the smectite incorporated alkyl cellulose-solvent mixture may be incorporated by mixing together with components which form the core.
  • the core for example the pellet (e.g. animal feed pellet) or the bolus
  • the core may be coated with the smectite incorporated alkyl cellulose-solvent mixture, e.g. by dipping or spraying.
  • the core for example the pellet (e.g. animal feed pellet) or the bolus) is preferably coated with the smectite incorporated alkyl cellulose-solvent mixture by dipping.
  • the core may be dipped or sprayed for a predetermined time period, for example for at least 2 seconds, preferably at least 4 seconds.
  • the core may be repeatedly dipped or sprayed.
  • the composition may comprise a core and a plurality of layers of coatings of additive.
  • the layers of additive coating may be sequentially applied to the core.
  • the composition may comprise a plurality of additive coating layers, wherein at least one additive coating layer has a different composition to the other additive coating layers.
  • Dip coating enables the method to integrate easily into existing production lines.
  • the weight of the additive coating on a core may be at least 1 g, preferably at least 2 g.
  • the evaporation of the solvent may take place over a predetermined time period.
  • the solvent may be evaporated over a time period of at least 1 hour, preferably at least 2 hours.
  • the solvent may be evaporated over a time period of no more than 24 hours, for example no more than 12 hours.
  • the additive of the core is preferably sufficient such that the core is predominantly covered with the coating whilst providing an additive free portion of the core configured in use for exposure to digestive fluids within the rumen.
  • the method requires no additional steps to coat the core with the additive coating.
  • the core of the composition is predominantly coated with at least one coating layer of the additive.
  • at least one coating layer of the additive between about 60% and about 95% of the core is coated (with the additive of the invention), such as between about 65% and about 90%, between about 70% and about 90%, between about 75% and about 90%, between about 80% and about 90%, or between about 80% and about 87%.
  • the smectite incorporated alkyl cellulose-solvent mixture is applied to the core without requiring heating.
  • the additive may be applied to a core comprising heat sensitive components or additives without risk of degrading the components or additives during manufacture.
  • the additive of the present invention is applied to the core, for example a pellet such as an animal feed pellet or a bolus, and is configured to control release of active ingredients present within the core.
  • the additive of the present invention when applied to the core is able to provide for controlled and consistent release of active ingredients present within the core.
  • the additive of the present invention is biocompatible and non-toxic, and therefore can be used without producing any environmentally harmful byproducts.
  • the additive is preferably composed entirely of components of natural origin.
  • the composition comprising the core and the additive of the present invention is preferably introduced into the rumen of an animal.
  • the rumen juices (at a temperature of 37.5 °C to 40 °C) begin to breakdown an additive-free portion of the core.
  • an end (e.g. one end or two ends) of the core may be additive-free.
  • the core may be substantially cylindrical in shape and an end of the core may be additive-free.
  • the additive begins to separate/break away from the core, thereby exposing further portions of the core for sustained release the required material (for example trace elements) into the rumen juices.
  • an apparatus for incorporating a core with a biocompatible, non-toxic additive comprising: a carrier for receiving and retaining at least one core; a reservoir comprising a smectite incorporated alkyl cellulose-solvent mixture as herein described; in which the reservoir is in fluid communication with the carrier to provide smectite incorporated alkyl cellulose-solvent mixture for incorporation with the or each core(s) mounted (for example retained) on the carrier.
  • the reservoir is in fluid communication with the carrier to provide smectite incorporated alkyl cellulose-solvent mixture for coating an outer surface of the core(s) mounted (for example retained) on the carrier.
  • the reservoir may comprise a chamber configured to contain the smectite incorporated alkyl cellulose-solvent mixture, and at least one outlet in communication with the chamber.
  • the outlet may for example be a spray nozzle configured to supply the smectite incorporated alkyl cellulose-solvent mixture to outer surfaces of the core(s) retained on the carrier.
  • the outlet(s) may be configured to receive the carrier and/or the core(s) therethrough for dipping into the smectite incorporated alkyl cellulose-solvent mixture.
  • the outlet is configured to supply the smectite incorporated alkyl cellulose- solvent mixture for mixing with the core(s) on the carrier.
  • the apparatus may comprise a plurality of carriers enabling batchwise coating of a plurality of cores.
  • the present invention provides the use of a composition
  • a composition comprising: a core comprising trace elements, and an additive as herein described for the treatment of diseases associated with trace element deficiency (such as for example selenium, cobalt, vitamin E or copper deficiency) in grazing animals, such as for example cattle, sheep, goats or deer.
  • trace element deficiency can lead to poor coat condition, lack of live weight and decreased fertility of the animal.
  • Trace element deficiencies include for example parasitic gastroenteritis, pine, white muscle disease, nutritional muscular dystrophy, stiff lamb disease.
  • the present invention provides the use of a composition
  • a composition comprising: a core, and an additive as herein described to reduce methane output in grazing animals, such as for example cattle, sheep, goats or deer.
  • Figure 1 is a photograph of a bolus with two coating layers of an additive according to one embodiment of the present invention
  • Figures 2A-C are photographs of the bolus of Figure 1 after 24 hours in a saline solution (Figure 2A) and after 2 weeks in a saline solution ( Figures 2B-2C);
  • Figures 3A-B are photographs of the coating of the additive according to one embodiment of the present invention ( Figure 3A) and a conventional coating (vinyl resin; Figure 3B);
  • Figures 4A-D are photographs of boluses coated with an additive according to one embodiment of the present invention when exposed in ruminant fluid over time: Figure 4A (1 week); Figure 4B (2 week); Figure 4C (3 weeks); and Figure 4D (4 weeks).
  • Figure 5 shows the weight loss of a bolus in vivo (Example 4).
  • a smectite incorporated alkyl cellulose-solvent mixture comprising:
  • At least one alkyl cellulose ether in which the alkyl group of the alkyl cellulose is a Ci-Cio alkyl group, and in which the at least one alkyl cellulose ether has a molecular weight in the range of between 75KDa and 400KDa;
  • smectite 10% to 90% (w/w) smectite; and a solvent-system comprising at least one Ci-Cio alkyl ester, and at least one C1-C5 alcohol, in which the ratio of the at least one Ci-Cio alkyl ester to the at least one C1-C5 alcohol is between 2:1 and 8:1 (w/w).
  • Butyl acetate (210 g) and n-propanol (52.5 g) were poured into a 1 L vessel, before being stirred at 250 rpm using an overhead stirrer.
  • Ethyl cellulose (37.5 g) was then added to the stirring solvents, followed by Bentonite (24 g) portion-wise over a period of 15 minutes. The mixture was then allowed to stir for 15 minutes. The mixture was then covered and allowed to stand for 15 minutes to allow any air bubbles to escape.
  • Example 2 Method for producing a coated animal feed pellet (bolus)
  • the animal feed pellet (which can also be described a bolus) was formed by compression and composed of the following ingredients:
  • Cobalt Carbonate The mixture predominantly coated the outer surface of the animal feed pellet (between about 80% and about 87% coating coverage) whilst leaving a coating-free portion (between about 13% and about 20%) for exposure to rumen digestive fluids once administered to an animal.
  • the solvent was removed by evaporation to provide an additive coating comprising ethyl cellulose and bentonite.
  • a bolus of Example 2 is shown in Figure 1. It can be seen that the bolus has is substantially cylindrical in shape and has one end which is coating/additive free.
  • the additive coated bolus was placed in saline solution and monitored over time.
  • Figures 2A to 2C show that over time, the coating fragmented and broke away from the bolus when the underlying core dissolved in saline solution.
  • the fragmentation of the coating exposed further sections of the bolus to the saline solution which subsequently dissolved over time.
  • an end of the coating adjacent the coating/additive free end of the bolus began to split, fragment and pull away from the underlying bolus.
  • bolus adjacent the coating/additive free end had continued to dissolve resulting in larger sections of the coating breaking away and fragmenting, exposing further sections of the bolus to the saline solution.
  • the presence of the additive coating which was observed to be insoluble in water, therefore controlled exposure of the underlying core of the bolus to external saline, and therefore controlled the release or degradation of the underlying bolus over time.
  • the bolus is expected to show the same controlled exposure profile when exposed to rumen fluids, within an animal.
  • the additive of the present invention in the form of a coating, has been found to successfully provide for sustained release of ingredients within a bolus over a predetermined time period whilst having a substantially reduced thickness compared to conventional styrene-containing coatings.
  • the additive coating of the present invention has a total thickness of 0.16 mm (two coating layers) and provides for similar release properties as the conventional styrene containing coating shown in Figure 3B having a thickness of 0.34 mm. Therefore, the coating of the present invention provides for sustained release of ingredients within an underlying bolus whilst also being non-toxic and biocompatible.
  • the coating of the present invention requires the consumption of less materials during manufacture of the coated bolus, as the total thickness of the coating layer is typically less than coatings used in prior art boluses.
  • Figures 4A-D the degradation of the 2-layer additive coated bolus of Figure 1 within rumen fluids was monitored over a four week period after administration to an animal.
  • a first end of the substantially cylindrical bolus is free of additive coating. As shown in Figure 4A, the free end of the bolus begins to dissolve into the rumen fluids. However, the majority of the additive coating remains in tact surrounding the remaining portions of the bolus.
  • the free end of the bolus begins to dissolve into the rumen fluids and adjacent portions of the additive coating begin to detach and break away from the underlying bolus.
  • the detachment of the additive coating over time exposes further portions of the underlying bolus to rumen fluids, providing for sustained, controlled release of ingredients within the bolus into the rumen fluids.
  • Additive coating free portions of the bolus at or adjacent the end therefore continue to dissolve into the rumen fluids, thereby weakening the overlying coating layer, causing the additive coating to fragment, detach and break away from the bolus. Fragmentation and detachment of the additive coating thereby exposes still further portions of the bolus to the rumen fluids to provide further release of ingredients within the bolus.
  • a bolus was coated with ethyl cellulose and bentonite prepared according to General Method A.
  • the erosion rate of the finished device was tested in vivo by placing the bolus in the reticulum of a fistulated cow and removing it periodically, weighing and then returning the device to the animal.
  • the weight loss of the core with the passage of time is shown in the graph of Figure 5.
  • the study was carried out on two cows, hence the two plot lines. It can be seen that after a 5 day period (a typical "settling in" period for a bolus adapting to its new surroundings in the rumen fluid) the rate of loss of weight of the core material is substantially linear for both cows. It should be noted that the linear trend was observed from day 5 to day 180 of the study, although only days 0-30 are illustrated in Figure 5.

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Abstract

La présente invention concerne un additif biocompatible non toxique pour une pastille d'alimentation animale comprenant : de l'éther d'alkylcellulose; et de la smectite.
PCT/GB2024/051495 2023-06-13 2024-06-12 Additif biocompatible non toxique comprenant de l'éther d'alkyle cellulose et de la smectite Pending WO2024256811A1 (fr)

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GB2122086A (en) 1982-06-22 1984-01-11 Univ Glasgow Device for introducing nutrients and/or therapeutic materials into ruminant animals
US4670248A (en) * 1985-08-15 1987-06-02 International Minerals & Chemical Corp. Olivine bolus
WO2007131357A1 (fr) * 2006-05-12 2007-11-22 Isa Odidi Composition pharmaceutique à faible risque d'utilisation abusive
CN110771742A (zh) * 2019-10-21 2020-02-11 安徽农业大学 一种减少牛瘤胃甲烷排放的饲料添加剂及其制备方法
CN111296644A (zh) * 2020-03-24 2020-06-19 亚太星原农牧科技海安有限公司 一种保护饲料中油脂不被氧化的饲料制备方法与应用
KR20220105944A (ko) * 2021-01-21 2022-07-28 주식회사 코피텍 벤토나이트를 포함하는 필름 코팅용 조성물

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BR112012012248B1 (pt) * 2009-11-30 2020-10-20 Toray Industries, Inc agente de revestimento de filme para uma formulação sólida, e, formulação sólida

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GB2122086A (en) 1982-06-22 1984-01-11 Univ Glasgow Device for introducing nutrients and/or therapeutic materials into ruminant animals
US4670248A (en) * 1985-08-15 1987-06-02 International Minerals & Chemical Corp. Olivine bolus
WO2007131357A1 (fr) * 2006-05-12 2007-11-22 Isa Odidi Composition pharmaceutique à faible risque d'utilisation abusive
CN110771742A (zh) * 2019-10-21 2020-02-11 安徽农业大学 一种减少牛瘤胃甲烷排放的饲料添加剂及其制备方法
CN111296644A (zh) * 2020-03-24 2020-06-19 亚太星原农牧科技海安有限公司 一种保护饲料中油脂不被氧化的饲料制备方法与应用
KR20220105944A (ko) * 2021-01-21 2022-07-28 주식회사 코피텍 벤토나이트를 포함하는 필름 코팅용 조성물

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